Noriko Satake, MD

Photo courtesy of the

University of California Davis

Researchers say they have developed a targeted conjugate therapy that harnesses a monoclonal antibody to deliver antisense DNA to acute lymphoblastic leukemia (ALL) cells.

Once delivered, the therapeutic DNA reduces levels of MXD3, a protein that helps cancer cells survive.

This conjugate therapy proved cytotoxic in ALL cell lines and showed promise in animal models, destroying ALL cells while limiting other damage.

“We’ve shown, for the first time, that anti-CD22 antibody-antisense conjugates are a potential therapeutic agent for ALL,” said Noriko Satake, MD, of the University of California Davis in Sacramento.

“This could be a new type of treatment that kills leukemia cells with few side effects.”

Dr Satake and her colleagues described the treatment in Molecular Medicine.

To create the therapy, the researchers attached antisense DNA that inhibits the MXD3 protein to an antibody that binds to CD22, a protein receptor expressed almost exclusively on ALL cells and normal B cells.

Once the antibody binds to CD22, the conjugate is drawn inside the cell, allowing the antisense molecule to prevent MXD3 production. Without this anti-apoptotic protein, cells are more prone to death.

The conjugate therapy was effective against ALL cell lines and primary ALL cells in a xenograft mouse model. Animals that received the therapy survived significantly longer than those in the control group.

While the conjugate therapy does target healthy B cells along with ALL cells, it is expected to leave hematopoietic stem cells and other tissues unharmed.

“Our novel conjugate is designed so that it does not harm hair, eyes, heart, kidneys, or other types of cells,” Dr Satake said.

She and her colleagues noted that, although this study shows the conjugate therapy can knock down MXD3, it is not clear exactly how this is accomplished. So the researchers plan to investigate the mechanism.

The team also plans to look into combining the conjugate therapy with other treatments. Because it hastens cell death, the conjugate could make traditional chemotherapy drugs more effective, and it might work against other cancers.

“You can see this as proof of principle,” Dr Satake said. “You could switch the target and substitute the antibody, which could be used to treat other cancers or even other diseases.”

This study was not industry-funded, but 4 study authors are employees and stockholders of Isis Pharmaceuticals.

Noriko Satake, MD

Photo courtesy of the

University of California Davis

Researchers say they have developed a targeted conjugate therapy that harnesses a monoclonal antibody to deliver antisense DNA to acute lymphoblastic leukemia (ALL) cells.

Once delivered, the therapeutic DNA reduces levels of MXD3, a protein that helps cancer cells survive.

This conjugate therapy proved cytotoxic in ALL cell lines and showed promise in animal models, destroying ALL cells while limiting other damage.

“We’ve shown, for the first time, that anti-CD22 antibody-antisense conjugates are a potential therapeutic agent for ALL,” said Noriko Satake, MD, of the University of California Davis in Sacramento.

“This could be a new type of treatment that kills leukemia cells with few side effects.”

Dr Satake and her colleagues described the treatment in Molecular Medicine.

To create the therapy, the researchers attached antisense DNA that inhibits the MXD3 protein to an antibody that binds to CD22, a protein receptor expressed almost exclusively on ALL cells and normal B cells.

Once the antibody binds to CD22, the conjugate is drawn inside the cell, allowing the antisense molecule to prevent MXD3 production. Without this anti-apoptotic protein, cells are more prone to death.

The conjugate therapy was effective against ALL cell lines and primary ALL cells in a xenograft mouse model. Animals that received the therapy survived significantly longer than those in the control group.

While the conjugate therapy does target healthy B cells along with ALL cells, it is expected to leave hematopoietic stem cells and other tissues unharmed.

“Our novel conjugate is designed so that it does not harm hair, eyes, heart, kidneys, or other types of cells,” Dr Satake said.

She and her colleagues noted that, although this study shows the conjugate therapy can knock down MXD3, it is not clear exactly how this is accomplished. So the researchers plan to investigate the mechanism.

The team also plans to look into combining the conjugate therapy with other treatments. Because it hastens cell death, the conjugate could make traditional chemotherapy drugs more effective, and it might work against other cancers.

“You can see this as proof of principle,” Dr Satake said. “You could switch the target and substitute the antibody, which could be used to treat other cancers or even other diseases.”

This study was not industry-funded, but 4 study authors are employees and stockholders of Isis Pharmaceuticals.

Noriko Satake, MD

Photo courtesy of the

University of California Davis

Researchers say they have developed a targeted conjugate therapy that harnesses a monoclonal antibody to deliver antisense DNA to acute lymphoblastic leukemia (ALL) cells.

Once delivered, the therapeutic DNA reduces levels of MXD3, a protein that helps cancer cells survive.

This conjugate therapy proved cytotoxic in ALL cell lines and showed promise in animal models, destroying ALL cells while limiting other damage.

“We’ve shown, for the first time, that anti-CD22 antibody-antisense conjugates are a potential therapeutic agent for ALL,” said Noriko Satake, MD, of the University of California Davis in Sacramento.

“This could be a new type of treatment that kills leukemia cells with few side effects.”

Dr Satake and her colleagues described the treatment in Molecular Medicine.

To create the therapy, the researchers attached antisense DNA that inhibits the MXD3 protein to an antibody that binds to CD22, a protein receptor expressed almost exclusively on ALL cells and normal B cells.

Once the antibody binds to CD22, the conjugate is drawn inside the cell, allowing the antisense molecule to prevent MXD3 production. Without this anti-apoptotic protein, cells are more prone to death.

The conjugate therapy was effective against ALL cell lines and primary ALL cells in a xenograft mouse model. Animals that received the therapy survived significantly longer than those in the control group.

While the conjugate therapy does target healthy B cells along with ALL cells, it is expected to leave hematopoietic stem cells and other tissues unharmed.

“Our novel conjugate is designed so that it does not harm hair, eyes, heart, kidneys, or other types of cells,” Dr Satake said.

She and her colleagues noted that, although this study shows the conjugate therapy can knock down MXD3, it is not clear exactly how this is accomplished. So the researchers plan to investigate the mechanism.

The team also plans to look into combining the conjugate therapy with other treatments. Because it hastens cell death, the conjugate could make traditional chemotherapy drugs more effective, and it might work against other cancers.

“You can see this as proof of principle,” Dr Satake said. “You could switch the target and substitute the antibody, which could be used to treat other cancers or even other diseases.”

This study was not industry-funded, but 4 study authors are employees and stockholders of Isis Pharmaceuticals.

Administering 5 mg of zoledronic acid at the start of antiretroviral therapy to HIV-infected patients who have never previously undergone ART can significantly decrease the risk of bone density loss.

Those are the findings reported in a study of 63 viremic HIV patients, all of whom were aged 30 to 50 and had never undergone ART before. The participants were randomized into cohorts receiving either a single dose of 5 mg zoledronic acid or a placebo. ART consisted of atazanavir / ritonavir in combination with tenofovir / emtricitabine. “The skeletal effects of ART, though varied in magnitude, appear to be universal to all ART types including tenofovir alafenamide (TAF) containing and tenofovir disoproxil fumarate (TDF) sparing regimens,” according to the study, led by Ighovwerha Ofotokun, MD, of Emory University in Atlanta, and colleagues.

“We hypothesized that the preponderance of bone loss in this setting would occur during early period of therapy when T-cell recovery is most pronounced, providing an exploitable window for preemptive intervention to mitigate ART-induced bone resorption and preserve natural bone in this population,” the authors added.

Investigators performed plasma bone turnover markers and bone mineral density analyses at 0, 12, 24, and 48 weeks. Significant reductions in bone resorption was noted as early as 12 weeks after commencement, with a 73% reduction (P < .001); resorption reductions did not stay as robust but were similarly strong through 48 weeks (57%, P < .001).

C-terminal telopeptide of collagen (CTx) levels, the primary outcome, was not significantly different between the two cohorts at baseline: 0.154 nanograms per milliliter (ng/ml) for zoledronic acid vs. 0.190 ng/ml for placebo (P = 0.22). However, zoledronic acid was significantly lower than placebo at 12-, 24-, and 48-week follow-ups: 0.083 ng/ml vs. 0.305 ng/ml (P < .001) at 12 weeks, 0.117 ng/ml vs. 0.338 ng/ml (P < 0.001) at 24 weeks, and 0.116 ng/ml vs. 0.269 ng/ml, (P < 0.001) at 48 weeks. Additionally, higher improvements in lumbar spine, hip, and femoral BMD were noted in the zoledronic acid group at 12, 24, and 48 weeks, compared with the placebo group.

“[Zoledronic acid] at a single dose was safe and well tolerated, and resulted in comparable rate of virologic suppression and similar magnitude of CD4 T-cell reconstitution,” the authors concluded, adding that “these data define an optimal window for a pre-emptive intervention to forestall ART-induced bone loss and provide robust information needed to guide the design and implementation of larger confirmatory phase III, multicenter randomized clinical trials.”

The study was funded by the National Institute on Aging, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Ofotokun and other colleagues did not report relevant financial disclosures.

[email protected]

Administering 5 mg of zoledronic acid at the start of antiretroviral therapy to HIV-infected patients who have never previously undergone ART can significantly decrease the risk of bone density loss.

Those are the findings reported in a study of 63 viremic HIV patients, all of whom were aged 30 to 50 and had never undergone ART before. The participants were randomized into cohorts receiving either a single dose of 5 mg zoledronic acid or a placebo. ART consisted of atazanavir / ritonavir in combination with tenofovir / emtricitabine. “The skeletal effects of ART, though varied in magnitude, appear to be universal to all ART types including tenofovir alafenamide (TAF) containing and tenofovir disoproxil fumarate (TDF) sparing regimens,” according to the study, led by Ighovwerha Ofotokun, MD, of Emory University in Atlanta, and colleagues.

“We hypothesized that the preponderance of bone loss in this setting would occur during early period of therapy when T-cell recovery is most pronounced, providing an exploitable window for preemptive intervention to mitigate ART-induced bone resorption and preserve natural bone in this population,” the authors added.

Investigators performed plasma bone turnover markers and bone mineral density analyses at 0, 12, 24, and 48 weeks. Significant reductions in bone resorption was noted as early as 12 weeks after commencement, with a 73% reduction (P < .001); resorption reductions did not stay as robust but were similarly strong through 48 weeks (57%, P < .001).

C-terminal telopeptide of collagen (CTx) levels, the primary outcome, was not significantly different between the two cohorts at baseline: 0.154 nanograms per milliliter (ng/ml) for zoledronic acid vs. 0.190 ng/ml for placebo (P = 0.22). However, zoledronic acid was significantly lower than placebo at 12-, 24-, and 48-week follow-ups: 0.083 ng/ml vs. 0.305 ng/ml (P < .001) at 12 weeks, 0.117 ng/ml vs. 0.338 ng/ml (P < 0.001) at 24 weeks, and 0.116 ng/ml vs. 0.269 ng/ml, (P < 0.001) at 48 weeks. Additionally, higher improvements in lumbar spine, hip, and femoral BMD were noted in the zoledronic acid group at 12, 24, and 48 weeks, compared with the placebo group.

“[Zoledronic acid] at a single dose was safe and well tolerated, and resulted in comparable rate of virologic suppression and similar magnitude of CD4 T-cell reconstitution,” the authors concluded, adding that “these data define an optimal window for a pre-emptive intervention to forestall ART-induced bone loss and provide robust information needed to guide the design and implementation of larger confirmatory phase III, multicenter randomized clinical trials.”

The study was funded by the National Institute on Aging, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Ofotokun and other colleagues did not report relevant financial disclosures.

[email protected]

Administering 5 mg of zoledronic acid at the start of antiretroviral therapy to HIV-infected patients who have never previously undergone ART can significantly decrease the risk of bone density loss.

Those are the findings reported in a study of 63 viremic HIV patients, all of whom were aged 30 to 50 and had never undergone ART before. The participants were randomized into cohorts receiving either a single dose of 5 mg zoledronic acid or a placebo. ART consisted of atazanavir / ritonavir in combination with tenofovir / emtricitabine. “The skeletal effects of ART, though varied in magnitude, appear to be universal to all ART types including tenofovir alafenamide (TAF) containing and tenofovir disoproxil fumarate (TDF) sparing regimens,” according to the study, led by Ighovwerha Ofotokun, MD, of Emory University in Atlanta, and colleagues.

“We hypothesized that the preponderance of bone loss in this setting would occur during early period of therapy when T-cell recovery is most pronounced, providing an exploitable window for preemptive intervention to mitigate ART-induced bone resorption and preserve natural bone in this population,” the authors added.

Investigators performed plasma bone turnover markers and bone mineral density analyses at 0, 12, 24, and 48 weeks. Significant reductions in bone resorption was noted as early as 12 weeks after commencement, with a 73% reduction (P < .001); resorption reductions did not stay as robust but were similarly strong through 48 weeks (57%, P < .001).

C-terminal telopeptide of collagen (CTx) levels, the primary outcome, was not significantly different between the two cohorts at baseline: 0.154 nanograms per milliliter (ng/ml) for zoledronic acid vs. 0.190 ng/ml for placebo (P = 0.22). However, zoledronic acid was significantly lower than placebo at 12-, 24-, and 48-week follow-ups: 0.083 ng/ml vs. 0.305 ng/ml (P < .001) at 12 weeks, 0.117 ng/ml vs. 0.338 ng/ml (P < 0.001) at 24 weeks, and 0.116 ng/ml vs. 0.269 ng/ml, (P < 0.001) at 48 weeks. Additionally, higher improvements in lumbar spine, hip, and femoral BMD were noted in the zoledronic acid group at 12, 24, and 48 weeks, compared with the placebo group.

“[Zoledronic acid] at a single dose was safe and well tolerated, and resulted in comparable rate of virologic suppression and similar magnitude of CD4 T-cell reconstitution,” the authors concluded, adding that “these data define an optimal window for a pre-emptive intervention to forestall ART-induced bone loss and provide robust information needed to guide the design and implementation of larger confirmatory phase III, multicenter randomized clinical trials.”

The study was funded by the National Institute on Aging, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Ofotokun and other colleagues did not report relevant financial disclosures.

[email protected]

The cost of new medicines for patients infected with hepatitis C virus vary widely around the globe, especially when adjusted for national wealth, results from an economic analysis led by World Health Organization officials suggest.

“These prices threaten the sustainability of health systems in many countries and prevent large-scale provision of treatment,” Suzanne Hill, PhD, of the World Health Organization, Geneva, and her associates wrote (PLoS Med. 2016 May 31;[5]:e1002032. doi:10.1371/journal.pmed.1002032).

“Stakeholders should implement a fairer pricing framework to deliver lower prices that take account of affordability. Without lower prices, countries are unlikely to be able to increase investment to minimize the burden of hepatitis C.”

In an effort to calculate the potential total cost of sofosbuvir and ledipasvir/sofosbuvir for different national health systems and individual patients in 30 countries, the researchers obtained 2015 prices for a 12-week course of treatment with the medications for as many countries as possible. Sources of reference were the Pharma Price Information service of the Austrian public health institute Gesundheit Österreich GmbH, national government and drug reimbursement authority website, and press releases.

Using data compiled between July 17, 2015, and Jan. 25, 2016, medication prices in Organisation for Economic Co-operation and Development (OECD) member countries and certain low- and middle-income countries were converted to U.S. dollars using period average exchange rates and were adjusted for purchasing power parity (PPP). “We analyzed prices compared to national economic performance and estimated market size and the cost of these drugs in terms of countries’ annual total pharmaceutical expenditure (TPE) and in terms of the duration of time an individual would need to work to pay for treatment out of pocket,” the researchers explained. “Patient affordability was calculated using 2014 OECD average annual wages, supplemented International Labour Organization median wages where necessary.”

Dr. Sullivan and her associates found that HCV medication prices varied significantly across countries, especially when adjusted for national wealth. For example, the median price of a 12-week course of sofosbuvir across 26 OECD countries was $42,017 in U.S. dollars, ranging from $37,729 in Japan to $64,680 in the United States. At the same time, countries in central and eastern Europe had higher PPP-adjusted prices, compared with other countries. For example, the PPP-adjusted prices of sofosbuvir in Poland and Turkey were $101,063 and $70,331, respectively, compared with a price of $64,680 in the Unite States. At the same time, the PPP-adjusted price of ledipasvir/sofosbuvir in Poland was $118,754, compared with a price of $72,765 in the United States.

The researchers also found that the PPP-adjusted price of a full course of sofosbuvir alone would be equivalent to at least 1 year of the PPP-adjusted average earnings for individuals in 12 of the 30 countries analyzed. In Poland, Slovakia, Portugal, and Turkey, a course of sofosbuvir alone would cost at least 2 years’ of average annual wages. “This analysis is conservative because prices were ex-factory prices with an assumed 23% price reduction, and did not include supply chain mark-ups and other costs such as the cost of diagnosis, daclatasvir, ribavirin, and health service costs,” they wrote.

They characterized the costs of sofosbuvir and ledipasvir/sofosbuvir as “not ‘affordable’ for most OECD countries at the nominal and PPP-adjusted prices, with Central and Eastern European countries being the most affected. While determining what is affordable or not is a value judgment, funding these treatments in these national health systems would consume large proportions of their TPE and increase pressure on existing budgets.”

They acknowledged certain limitations of the analysis, including the accuracy of the estimates of the numbers of people infected and of the price information that was accessible. “We have also not included all likely costs, such as the costs of combination treatment with ribavirin, other health care services, and increases in the duration of treatment in patients with cirrhosis; thus, our budget impact estimates are underestimates of the cost of treatment. We are also aware that in some countries, the prices are probably lower than the publicly accessible prices because of confidential discounts or rebates negotiated with the manufacturer.”

Dr. Hill disclosed that she is a member of the PLoS Medicine editorial board.

[email protected]

The cost of new medicines for patients infected with hepatitis C virus vary widely around the globe, especially when adjusted for national wealth, results from an economic analysis led by World Health Organization officials suggest.

“These prices threaten the sustainability of health systems in many countries and prevent large-scale provision of treatment,” Suzanne Hill, PhD, of the World Health Organization, Geneva, and her associates wrote (PLoS Med. 2016 May 31;[5]:e1002032. doi:10.1371/journal.pmed.1002032).

“Stakeholders should implement a fairer pricing framework to deliver lower prices that take account of affordability. Without lower prices, countries are unlikely to be able to increase investment to minimize the burden of hepatitis C.”

In an effort to calculate the potential total cost of sofosbuvir and ledipasvir/sofosbuvir for different national health systems and individual patients in 30 countries, the researchers obtained 2015 prices for a 12-week course of treatment with the medications for as many countries as possible. Sources of reference were the Pharma Price Information service of the Austrian public health institute Gesundheit Österreich GmbH, national government and drug reimbursement authority website, and press releases.

Using data compiled between July 17, 2015, and Jan. 25, 2016, medication prices in Organisation for Economic Co-operation and Development (OECD) member countries and certain low- and middle-income countries were converted to U.S. dollars using period average exchange rates and were adjusted for purchasing power parity (PPP). “We analyzed prices compared to national economic performance and estimated market size and the cost of these drugs in terms of countries’ annual total pharmaceutical expenditure (TPE) and in terms of the duration of time an individual would need to work to pay for treatment out of pocket,” the researchers explained. “Patient affordability was calculated using 2014 OECD average annual wages, supplemented International Labour Organization median wages where necessary.”

Dr. Sullivan and her associates found that HCV medication prices varied significantly across countries, especially when adjusted for national wealth. For example, the median price of a 12-week course of sofosbuvir across 26 OECD countries was $42,017 in U.S. dollars, ranging from $37,729 in Japan to $64,680 in the United States. At the same time, countries in central and eastern Europe had higher PPP-adjusted prices, compared with other countries. For example, the PPP-adjusted prices of sofosbuvir in Poland and Turkey were $101,063 and $70,331, respectively, compared with a price of $64,680 in the Unite States. At the same time, the PPP-adjusted price of ledipasvir/sofosbuvir in Poland was $118,754, compared with a price of $72,765 in the United States.

The researchers also found that the PPP-adjusted price of a full course of sofosbuvir alone would be equivalent to at least 1 year of the PPP-adjusted average earnings for individuals in 12 of the 30 countries analyzed. In Poland, Slovakia, Portugal, and Turkey, a course of sofosbuvir alone would cost at least 2 years’ of average annual wages. “This analysis is conservative because prices were ex-factory prices with an assumed 23% price reduction, and did not include supply chain mark-ups and other costs such as the cost of diagnosis, daclatasvir, ribavirin, and health service costs,” they wrote.

They characterized the costs of sofosbuvir and ledipasvir/sofosbuvir as “not ‘affordable’ for most OECD countries at the nominal and PPP-adjusted prices, with Central and Eastern European countries being the most affected. While determining what is affordable or not is a value judgment, funding these treatments in these national health systems would consume large proportions of their TPE and increase pressure on existing budgets.”

They acknowledged certain limitations of the analysis, including the accuracy of the estimates of the numbers of people infected and of the price information that was accessible. “We have also not included all likely costs, such as the costs of combination treatment with ribavirin, other health care services, and increases in the duration of treatment in patients with cirrhosis; thus, our budget impact estimates are underestimates of the cost of treatment. We are also aware that in some countries, the prices are probably lower than the publicly accessible prices because of confidential discounts or rebates negotiated with the manufacturer.”

Dr. Hill disclosed that she is a member of the PLoS Medicine editorial board.

[email protected]

The cost of new medicines for patients infected with hepatitis C virus vary widely around the globe, especially when adjusted for national wealth, results from an economic analysis led by World Health Organization officials suggest.

“These prices threaten the sustainability of health systems in many countries and prevent large-scale provision of treatment,” Suzanne Hill, PhD, of the World Health Organization, Geneva, and her associates wrote (PLoS Med. 2016 May 31;[5]:e1002032. doi:10.1371/journal.pmed.1002032).

“Stakeholders should implement a fairer pricing framework to deliver lower prices that take account of affordability. Without lower prices, countries are unlikely to be able to increase investment to minimize the burden of hepatitis C.”

In an effort to calculate the potential total cost of sofosbuvir and ledipasvir/sofosbuvir for different national health systems and individual patients in 30 countries, the researchers obtained 2015 prices for a 12-week course of treatment with the medications for as many countries as possible. Sources of reference were the Pharma Price Information service of the Austrian public health institute Gesundheit Österreich GmbH, national government and drug reimbursement authority website, and press releases.

Using data compiled between July 17, 2015, and Jan. 25, 2016, medication prices in Organisation for Economic Co-operation and Development (OECD) member countries and certain low- and middle-income countries were converted to U.S. dollars using period average exchange rates and were adjusted for purchasing power parity (PPP). “We analyzed prices compared to national economic performance and estimated market size and the cost of these drugs in terms of countries’ annual total pharmaceutical expenditure (TPE) and in terms of the duration of time an individual would need to work to pay for treatment out of pocket,” the researchers explained. “Patient affordability was calculated using 2014 OECD average annual wages, supplemented International Labour Organization median wages where necessary.”

Dr. Sullivan and her associates found that HCV medication prices varied significantly across countries, especially when adjusted for national wealth. For example, the median price of a 12-week course of sofosbuvir across 26 OECD countries was $42,017 in U.S. dollars, ranging from $37,729 in Japan to $64,680 in the United States. At the same time, countries in central and eastern Europe had higher PPP-adjusted prices, compared with other countries. For example, the PPP-adjusted prices of sofosbuvir in Poland and Turkey were $101,063 and $70,331, respectively, compared with a price of $64,680 in the Unite States. At the same time, the PPP-adjusted price of ledipasvir/sofosbuvir in Poland was $118,754, compared with a price of $72,765 in the United States.

The researchers also found that the PPP-adjusted price of a full course of sofosbuvir alone would be equivalent to at least 1 year of the PPP-adjusted average earnings for individuals in 12 of the 30 countries analyzed. In Poland, Slovakia, Portugal, and Turkey, a course of sofosbuvir alone would cost at least 2 years’ of average annual wages. “This analysis is conservative because prices were ex-factory prices with an assumed 23% price reduction, and did not include supply chain mark-ups and other costs such as the cost of diagnosis, daclatasvir, ribavirin, and health service costs,” they wrote.

They characterized the costs of sofosbuvir and ledipasvir/sofosbuvir as “not ‘affordable’ for most OECD countries at the nominal and PPP-adjusted prices, with Central and Eastern European countries being the most affected. While determining what is affordable or not is a value judgment, funding these treatments in these national health systems would consume large proportions of their TPE and increase pressure on existing budgets.”

They acknowledged certain limitations of the analysis, including the accuracy of the estimates of the numbers of people infected and of the price information that was accessible. “We have also not included all likely costs, such as the costs of combination treatment with ribavirin, other health care services, and increases in the duration of treatment in patients with cirrhosis; thus, our budget impact estimates are underestimates of the cost of treatment. We are also aware that in some countries, the prices are probably lower than the publicly accessible prices because of confidential discounts or rebates negotiated with the manufacturer.”

Dr. Hill disclosed that she is a member of the PLoS Medicine editorial board.

[email protected]

SCOTTSDALE, ARIZ. – A sublingual formulation of cyclobenzaprine taken at bedtime was significantly better than placebo at reducing symptoms of military-related posttraumatic stress disorder, and study participants taking cyclobenzaprine also reported better sleep, a study showed.

After 12 weeks of nightly use at bedtime, 5.6 mg of sublingual cyclobenzaprine (CBP) resulted in a significant reduction on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), compared with placebo. Under several different analytic and data imputation methods, CAPS-5 values improved by 20.2 to 22.6 points from baseline for the 5.6-mg group, compared with reductions of 17.4 to 20.6 for the placebo group (P value range, 0.038-0.016). Improvement in the CAPS-5 was the study’s primary efficacy outcome measure.

Patients also saw significantly improved global symptoms, as assessed by the Clinician Global Impression – Improvement scale (CGI-I; 63.3% responders cyclobenzaprine versus 44.6% placebo, P = 0.041).

Significant reductions in hyperarousal (P less than 0.05) and exaggerated startle (P =0.015) symptoms also were seen in the 5.6-mg cyclobenzaprine group, and those participants also had significantly less symptom-related disruption in work/school, and in social/leisure activities, as measured by those domains on the Sheehan Disability Scale (for both, P less than 0.050).

Gregory M. Sullivan, MD, chief medical officer of Tonix Pharmaceuticals, presented these findings from AtEase, a randomized, placebo-controlled, double-blind study of sublingual cyclobenzaprine for military PTSD, at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Drug Clinical Evaluation Unit meeting.

The phase II safety, efficacy, and dose-ranging study of 245 patients (231 in the modified intent-to-treat population, and 237 in the safety population) also compared 2.8- and 5.6-mg sublingual doses. At the end of the 12-week study period, those on the lower dose did not experience significantly improved sleep or PTSD symptoms.

The AtEase participants were current or former servicemembers with PTSD. Ninety-three percent of the patients were male and had been deployed an average of 2.3 times. The index trauma occurred a mean of 7 years ago. Demographic distribution was representative of the U.S. military, according to Dr. Sullivan. The mean CAPS-5 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were similar across treatment arms. The mean CAPS-5 score for participants in the study was 39.5 representing “severe” PTSD. “These people are quite ill,” said Seth Lederman, MD, Tonix CEO, in an interview.

Oral symptoms were the most frequent side effects reported in the safety analysis. Of those taking the 2.8-mg cyclobenzaprine dose, 38.7% (36/93) experienced oral hypoesthesia, as did 36% (18/50) of the 5.6-mg dosing group. This compared with 2.1% (2/94) of the placebo group. Somnolence was noted by 11.8% (11/93) of the lower dose group, by 16% (8/50) of the higher dose group, and by 6.4% (6/94) of the placebo group. No participants discontinued the study because of adverse events.

Military traumatic brain injury may be different from most civilian TBI, said Dr. Lederman, because of both the intensity and duration of the events that precipitated the condition. Most military-related trauma stems from combat, and most patients with military-related trauma are men; in the civilian population, PTSD patients are predominantly women. “Especially in today’s military, servicemembers are deploying multiple times,” he noted. “Everyone has their breaking point.”

Effective medical treatments for military PTSD are lacking, said Dr. Sullivan. One multicenter trial found that sertraline not effective for PTSD in military veterans (J Clin Psychiatry. 2007 May;68[5]:711-20), and selective serotonin reuptake inhibitors are associated with sexual dysfunction and insomnia for some patients.

Cyclobenzaprine is thought to interact with several receptors thought to be important for sleep, including 5-HT2A, alpha-1 adrenergic, and H1 histamine receptors.

Problems with sleep for individuals with PTSD may include nightmares, as well as sleep disturbances associated with the hyperarousal that characterizes the disorder. Sleep disruption may contribute to “attenuated extinction consolidation, or a delay in the processing of emotionally charged memories,” Dr. Sullivan said. Sleep disturbances in those with PTSD also are associated with depression, substance use disorders, and suicidal behavior.

“Processing memories is an essential part of learning and extinction,” Dr. Lederman said. “We saw startle improve” in the clinical trial of sublingual cyclobenzaprine, an indication of diminished hyperarousal, he said.

The sublingual formulation, said Dr. Lederman, avoids first-pass metabolism of cyclobenzaprine, which converts large amounts of the dose to norcyclobenzaprine. This metabolite has a much longer half-life than cyclobenzaprine and is responsible, in large part, for the persistent grogginess many patients report when taking the oral formulation of the medication. Previous work showed that the exposure ratio for cyclobenzaprine/norcyclobenzaprine for oral immediate-release cyclobenzaprine was 1.2, compared with 1.9 for sublingual cyclobenzaprine

“With the sublingual formulation, we hope to achieve a true ‘on-off’ effect, really helping sleep quality and improving sleep architecture,” Dr. Lederman said.

“Early effects on sleep and hyperarousal are consistent with the mechanistic hypothesis that TNX-102 SL’s primary actions on sleep architecture and autonomic balance underlie the observed PTSD treatment effect,” wrote Dr. Sullivan. The later reduction in exaggerated startle is consistent with the memory consolidation hypothesis, he said.

Sublingual cyclobenzaprine also is being trialed for fibromyalgia, another condition where significant sleep disruption can be a prominent symptom. Next steps for military PTSD include a larger clinical trial that plans to enroll 450 patients, said Dr. Lederman.

Dr. Lederman and Dr. Sullivan are both employed by Tonix Pharmaceuticals, which was the sponsor of the AtEase study.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – A sublingual formulation of cyclobenzaprine taken at bedtime was significantly better than placebo at reducing symptoms of military-related posttraumatic stress disorder, and study participants taking cyclobenzaprine also reported better sleep, a study showed.

After 12 weeks of nightly use at bedtime, 5.6 mg of sublingual cyclobenzaprine (CBP) resulted in a significant reduction on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), compared with placebo. Under several different analytic and data imputation methods, CAPS-5 values improved by 20.2 to 22.6 points from baseline for the 5.6-mg group, compared with reductions of 17.4 to 20.6 for the placebo group (P value range, 0.038-0.016). Improvement in the CAPS-5 was the study’s primary efficacy outcome measure.

Patients also saw significantly improved global symptoms, as assessed by the Clinician Global Impression – Improvement scale (CGI-I; 63.3% responders cyclobenzaprine versus 44.6% placebo, P = 0.041).

Significant reductions in hyperarousal (P less than 0.05) and exaggerated startle (P =0.015) symptoms also were seen in the 5.6-mg cyclobenzaprine group, and those participants also had significantly less symptom-related disruption in work/school, and in social/leisure activities, as measured by those domains on the Sheehan Disability Scale (for both, P less than 0.050).

Gregory M. Sullivan, MD, chief medical officer of Tonix Pharmaceuticals, presented these findings from AtEase, a randomized, placebo-controlled, double-blind study of sublingual cyclobenzaprine for military PTSD, at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Drug Clinical Evaluation Unit meeting.

The phase II safety, efficacy, and dose-ranging study of 245 patients (231 in the modified intent-to-treat population, and 237 in the safety population) also compared 2.8- and 5.6-mg sublingual doses. At the end of the 12-week study period, those on the lower dose did not experience significantly improved sleep or PTSD symptoms.

The AtEase participants were current or former servicemembers with PTSD. Ninety-three percent of the patients were male and had been deployed an average of 2.3 times. The index trauma occurred a mean of 7 years ago. Demographic distribution was representative of the U.S. military, according to Dr. Sullivan. The mean CAPS-5 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were similar across treatment arms. The mean CAPS-5 score for participants in the study was 39.5 representing “severe” PTSD. “These people are quite ill,” said Seth Lederman, MD, Tonix CEO, in an interview.

Oral symptoms were the most frequent side effects reported in the safety analysis. Of those taking the 2.8-mg cyclobenzaprine dose, 38.7% (36/93) experienced oral hypoesthesia, as did 36% (18/50) of the 5.6-mg dosing group. This compared with 2.1% (2/94) of the placebo group. Somnolence was noted by 11.8% (11/93) of the lower dose group, by 16% (8/50) of the higher dose group, and by 6.4% (6/94) of the placebo group. No participants discontinued the study because of adverse events.

Military traumatic brain injury may be different from most civilian TBI, said Dr. Lederman, because of both the intensity and duration of the events that precipitated the condition. Most military-related trauma stems from combat, and most patients with military-related trauma are men; in the civilian population, PTSD patients are predominantly women. “Especially in today’s military, servicemembers are deploying multiple times,” he noted. “Everyone has their breaking point.”

Effective medical treatments for military PTSD are lacking, said Dr. Sullivan. One multicenter trial found that sertraline not effective for PTSD in military veterans (J Clin Psychiatry. 2007 May;68[5]:711-20), and selective serotonin reuptake inhibitors are associated with sexual dysfunction and insomnia for some patients.

Cyclobenzaprine is thought to interact with several receptors thought to be important for sleep, including 5-HT2A, alpha-1 adrenergic, and H1 histamine receptors.

Problems with sleep for individuals with PTSD may include nightmares, as well as sleep disturbances associated with the hyperarousal that characterizes the disorder. Sleep disruption may contribute to “attenuated extinction consolidation, or a delay in the processing of emotionally charged memories,” Dr. Sullivan said. Sleep disturbances in those with PTSD also are associated with depression, substance use disorders, and suicidal behavior.

“Processing memories is an essential part of learning and extinction,” Dr. Lederman said. “We saw startle improve” in the clinical trial of sublingual cyclobenzaprine, an indication of diminished hyperarousal, he said.

The sublingual formulation, said Dr. Lederman, avoids first-pass metabolism of cyclobenzaprine, which converts large amounts of the dose to norcyclobenzaprine. This metabolite has a much longer half-life than cyclobenzaprine and is responsible, in large part, for the persistent grogginess many patients report when taking the oral formulation of the medication. Previous work showed that the exposure ratio for cyclobenzaprine/norcyclobenzaprine for oral immediate-release cyclobenzaprine was 1.2, compared with 1.9 for sublingual cyclobenzaprine

“With the sublingual formulation, we hope to achieve a true ‘on-off’ effect, really helping sleep quality and improving sleep architecture,” Dr. Lederman said.

“Early effects on sleep and hyperarousal are consistent with the mechanistic hypothesis that TNX-102 SL’s primary actions on sleep architecture and autonomic balance underlie the observed PTSD treatment effect,” wrote Dr. Sullivan. The later reduction in exaggerated startle is consistent with the memory consolidation hypothesis, he said.

Sublingual cyclobenzaprine also is being trialed for fibromyalgia, another condition where significant sleep disruption can be a prominent symptom. Next steps for military PTSD include a larger clinical trial that plans to enroll 450 patients, said Dr. Lederman.

Dr. Lederman and Dr. Sullivan are both employed by Tonix Pharmaceuticals, which was the sponsor of the AtEase study.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – A sublingual formulation of cyclobenzaprine taken at bedtime was significantly better than placebo at reducing symptoms of military-related posttraumatic stress disorder, and study participants taking cyclobenzaprine also reported better sleep, a study showed.

After 12 weeks of nightly use at bedtime, 5.6 mg of sublingual cyclobenzaprine (CBP) resulted in a significant reduction on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), compared with placebo. Under several different analytic and data imputation methods, CAPS-5 values improved by 20.2 to 22.6 points from baseline for the 5.6-mg group, compared with reductions of 17.4 to 20.6 for the placebo group (P value range, 0.038-0.016). Improvement in the CAPS-5 was the study’s primary efficacy outcome measure.

Patients also saw significantly improved global symptoms, as assessed by the Clinician Global Impression – Improvement scale (CGI-I; 63.3% responders cyclobenzaprine versus 44.6% placebo, P = 0.041).

Significant reductions in hyperarousal (P less than 0.05) and exaggerated startle (P =0.015) symptoms also were seen in the 5.6-mg cyclobenzaprine group, and those participants also had significantly less symptom-related disruption in work/school, and in social/leisure activities, as measured by those domains on the Sheehan Disability Scale (for both, P less than 0.050).

Gregory M. Sullivan, MD, chief medical officer of Tonix Pharmaceuticals, presented these findings from AtEase, a randomized, placebo-controlled, double-blind study of sublingual cyclobenzaprine for military PTSD, at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Drug Clinical Evaluation Unit meeting.

The phase II safety, efficacy, and dose-ranging study of 245 patients (231 in the modified intent-to-treat population, and 237 in the safety population) also compared 2.8- and 5.6-mg sublingual doses. At the end of the 12-week study period, those on the lower dose did not experience significantly improved sleep or PTSD symptoms.

The AtEase participants were current or former servicemembers with PTSD. Ninety-three percent of the patients were male and had been deployed an average of 2.3 times. The index trauma occurred a mean of 7 years ago. Demographic distribution was representative of the U.S. military, according to Dr. Sullivan. The mean CAPS-5 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were similar across treatment arms. The mean CAPS-5 score for participants in the study was 39.5 representing “severe” PTSD. “These people are quite ill,” said Seth Lederman, MD, Tonix CEO, in an interview.

Oral symptoms were the most frequent side effects reported in the safety analysis. Of those taking the 2.8-mg cyclobenzaprine dose, 38.7% (36/93) experienced oral hypoesthesia, as did 36% (18/50) of the 5.6-mg dosing group. This compared with 2.1% (2/94) of the placebo group. Somnolence was noted by 11.8% (11/93) of the lower dose group, by 16% (8/50) of the higher dose group, and by 6.4% (6/94) of the placebo group. No participants discontinued the study because of adverse events.

Military traumatic brain injury may be different from most civilian TBI, said Dr. Lederman, because of both the intensity and duration of the events that precipitated the condition. Most military-related trauma stems from combat, and most patients with military-related trauma are men; in the civilian population, PTSD patients are predominantly women. “Especially in today’s military, servicemembers are deploying multiple times,” he noted. “Everyone has their breaking point.”

Effective medical treatments for military PTSD are lacking, said Dr. Sullivan. One multicenter trial found that sertraline not effective for PTSD in military veterans (J Clin Psychiatry. 2007 May;68[5]:711-20), and selective serotonin reuptake inhibitors are associated with sexual dysfunction and insomnia for some patients.

Cyclobenzaprine is thought to interact with several receptors thought to be important for sleep, including 5-HT2A, alpha-1 adrenergic, and H1 histamine receptors.

Problems with sleep for individuals with PTSD may include nightmares, as well as sleep disturbances associated with the hyperarousal that characterizes the disorder. Sleep disruption may contribute to “attenuated extinction consolidation, or a delay in the processing of emotionally charged memories,” Dr. Sullivan said. Sleep disturbances in those with PTSD also are associated with depression, substance use disorders, and suicidal behavior.

“Processing memories is an essential part of learning and extinction,” Dr. Lederman said. “We saw startle improve” in the clinical trial of sublingual cyclobenzaprine, an indication of diminished hyperarousal, he said.

The sublingual formulation, said Dr. Lederman, avoids first-pass metabolism of cyclobenzaprine, which converts large amounts of the dose to norcyclobenzaprine. This metabolite has a much longer half-life than cyclobenzaprine and is responsible, in large part, for the persistent grogginess many patients report when taking the oral formulation of the medication. Previous work showed that the exposure ratio for cyclobenzaprine/norcyclobenzaprine for oral immediate-release cyclobenzaprine was 1.2, compared with 1.9 for sublingual cyclobenzaprine

“With the sublingual formulation, we hope to achieve a true ‘on-off’ effect, really helping sleep quality and improving sleep architecture,” Dr. Lederman said.

“Early effects on sleep and hyperarousal are consistent with the mechanistic hypothesis that TNX-102 SL’s primary actions on sleep architecture and autonomic balance underlie the observed PTSD treatment effect,” wrote Dr. Sullivan. The later reduction in exaggerated startle is consistent with the memory consolidation hypothesis, he said.

Sublingual cyclobenzaprine also is being trialed for fibromyalgia, another condition where significant sleep disruption can be a prominent symptom. Next steps for military PTSD include a larger clinical trial that plans to enroll 450 patients, said Dr. Lederman.

Dr. Lederman and Dr. Sullivan are both employed by Tonix Pharmaceuticals, which was the sponsor of the AtEase study.

[email protected]

On Twitter @karioakes

LAKE BUENA VISTA, FLA. – Mortality related to prescription opioids is still climbing nationwide but not in centers or regions where there has been widespread implementation of guidelines for appropriate use, according to an expert involved in implementing guidelines in Washington state.

“If you follow guidelines for use of opioids, you can do what we did in Washington state and change the direction of those mortality curves,” reported David J. Tauben, MD, chief of pain medicine at the University of Washington, Seattle.

In data presented at the meeting, Dr. Tauben showed that the steep increase in opioid-related deaths and hospitalizations dating back to 1997 plateaued in Washington soon after the guidelines were implemented in 2007 and have followed a steep downward trajectory through the last year of follow-up in 2014.

Those data contrast starkly with nationwide figures updated June 21, 2016, on the Centers for Disease Control and Prevention website. In those figures, which also track data through 2014, the rates of deaths tied to drug overdose overall and to related to prescription opioids specifically have continued to climb. On the CDC website, which states that deaths related to prescription opioids have quadrupled since 1999, it was noted that more patients died from drug overdoses in 2014 than in any previous year. Prescriptions opioids were characterized as the “driving force” of this ongoing epidemic.

Washington state’s guidelines were created by the State Agency Medical Directors’ Group. But Dr. Tauben said that the principles of appropriate use of prescription opioids are well established and most recently were described in the CDC’s March 15, 2016, Morbidity and Mortality Weekly Report (MMWR). He suggested that adherence to these recommendations, which guide who to treat, how to treat, and how to assess for those most at risk for complications from opioids, can be expected to produce the same result.

Not least important, clinicians can keep the risk of overdose low by keeping doses low. Collating data from several studies, Dr. Tauben showed that the risk of overdose remains modest at opioid equivalent doses of 20 mg to about 50 mg per day. Graphically, the daily 50-mg equivalent was characterized as “the point of deflection where patients get in trouble.” In three of four published studies, the rise of rates in overdose was precipitous at about this point.

Keeping patients at a daily dose of 50 mg or below is further supported by the fact that “there is no evidence that a higher dose provides any additional benefit,” Dr. Tauben said. He also cited a study showing that patients at higher doses are more likely to have psychiatric comorbidity that complicates the pain complaint and may be better treated by alternative strategies.

At the University of Washington, chronic pain now is addressed routinely with a collaborative team approach that not only includes pain specialists but nursing care coordinators, pharmacists, physical therapists, and others, Dr. Tauben said. He considers increased physical activity, one of the goals in a collaborative multidisciplinary approach to chronic pain, a “miracle cure,” but acknowledged that designing comprehensive treatment that includes such strategies takes time and, at least initially, increases costs. However, he believes there is a clear return on investment.

“The evidence shows that effective control of chronic pain ultimately reduces costs,” Dr. Tauben said. Citing several studies, Dr. Tauben explained that chronic pain patients are major consumers of health care services and that consumption diminishes markedly when pain is controlled. He believes that most institutions would adopt and fund multidisciplinary pain care if fully informed of the cost benefits.

Although he acknowledged that many clinicians consider chronic pain patients challenging, Dr. Tauben said comprehensive pain management strategies are effective in most patients. After many years in general practice, Dr. Tauben switched to a focus on chronic pain because of the large unmet need and the success that can be achieved when a multidisciplinary treatment approach is applied.

“I became a pain specialist because it was the most satisfying part of my career,” Dr. Tauben reported.

To see the June 21 CDC data on opioid overdose, visit http//www.cdc.gov/drugoverdose/date/overdose.html. The March 15 MMWR report on the CDC guideline for prescribing opioids for chronic pain can be found at www.cdc.gov/mmwr/volumes/65/rr/6501e1.htm.

The meeting was held by the American Pain Society and Global Academy for Medical Education. Global Academy and this news organization are owned by the same company. Dr. Tauben reported no potential financial conflicts of interest.

LAKE BUENA VISTA, FLA. – Mortality related to prescription opioids is still climbing nationwide but not in centers or regions where there has been widespread implementation of guidelines for appropriate use, according to an expert involved in implementing guidelines in Washington state.

“If you follow guidelines for use of opioids, you can do what we did in Washington state and change the direction of those mortality curves,” reported David J. Tauben, MD, chief of pain medicine at the University of Washington, Seattle.

In data presented at the meeting, Dr. Tauben showed that the steep increase in opioid-related deaths and hospitalizations dating back to 1997 plateaued in Washington soon after the guidelines were implemented in 2007 and have followed a steep downward trajectory through the last year of follow-up in 2014.

Those data contrast starkly with nationwide figures updated June 21, 2016, on the Centers for Disease Control and Prevention website. In those figures, which also track data through 2014, the rates of deaths tied to drug overdose overall and to related to prescription opioids specifically have continued to climb. On the CDC website, which states that deaths related to prescription opioids have quadrupled since 1999, it was noted that more patients died from drug overdoses in 2014 than in any previous year. Prescriptions opioids were characterized as the “driving force” of this ongoing epidemic.

Washington state’s guidelines were created by the State Agency Medical Directors’ Group. But Dr. Tauben said that the principles of appropriate use of prescription opioids are well established and most recently were described in the CDC’s March 15, 2016, Morbidity and Mortality Weekly Report (MMWR). He suggested that adherence to these recommendations, which guide who to treat, how to treat, and how to assess for those most at risk for complications from opioids, can be expected to produce the same result.

Not least important, clinicians can keep the risk of overdose low by keeping doses low. Collating data from several studies, Dr. Tauben showed that the risk of overdose remains modest at opioid equivalent doses of 20 mg to about 50 mg per day. Graphically, the daily 50-mg equivalent was characterized as “the point of deflection where patients get in trouble.” In three of four published studies, the rise of rates in overdose was precipitous at about this point.

Keeping patients at a daily dose of 50 mg or below is further supported by the fact that “there is no evidence that a higher dose provides any additional benefit,” Dr. Tauben said. He also cited a study showing that patients at higher doses are more likely to have psychiatric comorbidity that complicates the pain complaint and may be better treated by alternative strategies.

At the University of Washington, chronic pain now is addressed routinely with a collaborative team approach that not only includes pain specialists but nursing care coordinators, pharmacists, physical therapists, and others, Dr. Tauben said. He considers increased physical activity, one of the goals in a collaborative multidisciplinary approach to chronic pain, a “miracle cure,” but acknowledged that designing comprehensive treatment that includes such strategies takes time and, at least initially, increases costs. However, he believes there is a clear return on investment.

“The evidence shows that effective control of chronic pain ultimately reduces costs,” Dr. Tauben said. Citing several studies, Dr. Tauben explained that chronic pain patients are major consumers of health care services and that consumption diminishes markedly when pain is controlled. He believes that most institutions would adopt and fund multidisciplinary pain care if fully informed of the cost benefits.

Although he acknowledged that many clinicians consider chronic pain patients challenging, Dr. Tauben said comprehensive pain management strategies are effective in most patients. After many years in general practice, Dr. Tauben switched to a focus on chronic pain because of the large unmet need and the success that can be achieved when a multidisciplinary treatment approach is applied.

“I became a pain specialist because it was the most satisfying part of my career,” Dr. Tauben reported.

To see the June 21 CDC data on opioid overdose, visit http//www.cdc.gov/drugoverdose/date/overdose.html. The March 15 MMWR report on the CDC guideline for prescribing opioids for chronic pain can be found at www.cdc.gov/mmwr/volumes/65/rr/6501e1.htm.

The meeting was held by the American Pain Society and Global Academy for Medical Education. Global Academy and this news organization are owned by the same company. Dr. Tauben reported no potential financial conflicts of interest.

LAKE BUENA VISTA, FLA. – Mortality related to prescription opioids is still climbing nationwide but not in centers or regions where there has been widespread implementation of guidelines for appropriate use, according to an expert involved in implementing guidelines in Washington state.

“If you follow guidelines for use of opioids, you can do what we did in Washington state and change the direction of those mortality curves,” reported David J. Tauben, MD, chief of pain medicine at the University of Washington, Seattle.

In data presented at the meeting, Dr. Tauben showed that the steep increase in opioid-related deaths and hospitalizations dating back to 1997 plateaued in Washington soon after the guidelines were implemented in 2007 and have followed a steep downward trajectory through the last year of follow-up in 2014.

Those data contrast starkly with nationwide figures updated June 21, 2016, on the Centers for Disease Control and Prevention website. In those figures, which also track data through 2014, the rates of deaths tied to drug overdose overall and to related to prescription opioids specifically have continued to climb. On the CDC website, which states that deaths related to prescription opioids have quadrupled since 1999, it was noted that more patients died from drug overdoses in 2014 than in any previous year. Prescriptions opioids were characterized as the “driving force” of this ongoing epidemic.

Washington state’s guidelines were created by the State Agency Medical Directors’ Group. But Dr. Tauben said that the principles of appropriate use of prescription opioids are well established and most recently were described in the CDC’s March 15, 2016, Morbidity and Mortality Weekly Report (MMWR). He suggested that adherence to these recommendations, which guide who to treat, how to treat, and how to assess for those most at risk for complications from opioids, can be expected to produce the same result.

Not least important, clinicians can keep the risk of overdose low by keeping doses low. Collating data from several studies, Dr. Tauben showed that the risk of overdose remains modest at opioid equivalent doses of 20 mg to about 50 mg per day. Graphically, the daily 50-mg equivalent was characterized as “the point of deflection where patients get in trouble.” In three of four published studies, the rise of rates in overdose was precipitous at about this point.

Keeping patients at a daily dose of 50 mg or below is further supported by the fact that “there is no evidence that a higher dose provides any additional benefit,” Dr. Tauben said. He also cited a study showing that patients at higher doses are more likely to have psychiatric comorbidity that complicates the pain complaint and may be better treated by alternative strategies.

At the University of Washington, chronic pain now is addressed routinely with a collaborative team approach that not only includes pain specialists but nursing care coordinators, pharmacists, physical therapists, and others, Dr. Tauben said. He considers increased physical activity, one of the goals in a collaborative multidisciplinary approach to chronic pain, a “miracle cure,” but acknowledged that designing comprehensive treatment that includes such strategies takes time and, at least initially, increases costs. However, he believes there is a clear return on investment.

“The evidence shows that effective control of chronic pain ultimately reduces costs,” Dr. Tauben said. Citing several studies, Dr. Tauben explained that chronic pain patients are major consumers of health care services and that consumption diminishes markedly when pain is controlled. He believes that most institutions would adopt and fund multidisciplinary pain care if fully informed of the cost benefits.

Although he acknowledged that many clinicians consider chronic pain patients challenging, Dr. Tauben said comprehensive pain management strategies are effective in most patients. After many years in general practice, Dr. Tauben switched to a focus on chronic pain because of the large unmet need and the success that can be achieved when a multidisciplinary treatment approach is applied.

“I became a pain specialist because it was the most satisfying part of my career,” Dr. Tauben reported.

To see the June 21 CDC data on opioid overdose, visit http//www.cdc.gov/drugoverdose/date/overdose.html. The March 15 MMWR report on the CDC guideline for prescribing opioids for chronic pain can be found at www.cdc.gov/mmwr/volumes/65/rr/6501e1.htm.

The meeting was held by the American Pain Society and Global Academy for Medical Education. Global Academy and this news organization are owned by the same company. Dr. Tauben reported no potential financial conflicts of interest.

BOSTON – Surgery is the standard of care for most skin cancers, but nonsurgical and adjuvant treatments can be good options for certain skin cancers when surgery would be neither curative nor feasible, according to Anthony Rossi, MD.

“Whether you’re treating a superficial basal cell or superficial squamous cell carcinoma, I think first and foremost, if you’re going to use nonsurgical treatment options, it’s important to have a good biopsy diagnosis,” Dr. Rossi said at the American Academy of Dermatology summer meeting. He also advised that the biopsy capture the entire lesion or a good portion of it to get a good representation. “You don’t want to be surprised by any hiding, high-risk subtypes,” said Dr. Rossi, of the Memorial Sloan Kettering Cancer Center in New York.

Deciding on a nonsurgical treatment option should be based on knowing the patient. For example, know the patient’s concerns about cosmetic deformities, willingness to undergo surgery or not, and ability and willingness to do follow-up self-care.

For superficial basal cell or squamous cell carcinomas in situ and even lentigo maligna in situ not amenable to surgery, imiquimod may be an appropriate treatment. Dr. Rossi said his practice is to use it in an incremental fashion, starting with application five times per week, going to every day if there is no response after 1 to 2 weeks. If the response remains inadequate, he recommended adding a topical retinoid, such as tazarotene, in an effort to increase penetration.

For basal cell carcinomas and squamous cell carcinoma in situ, he uses imiquimod for a total of 6 to 8 weeks, starting from the time of the first reaction. For melanoma in situ, he uses it for more than 60 applications (12 weeks).

To show patients where they should be applying any topical treatment, Dr. Rossi marks the skin, photographs it, and prints out a picture for the patient. Sometimes he uses the patient’s phone to take the picture. For a basal cell or squamous cell carcinoma in situ, he indicates an area at least 5 to 10 mm beyond the margin of the tumor. The area is even larger for melanomas.

Dr. Rossi studies confocal microscopy to detect skin cancers. He uses it before treating a lesion to define the clinical boundaries of the lesion and the boundaries for the nonsurgical treatments, and then he uses it on follow up to look for any recurrences.

New anti-tumor agents

Two oral inhibitors of the sonic hedgehog pathway have been approved within the past 5 years for locally advanced or metastatic basal cell carcinomas. “In the right person, they can be quite beneficial if surgery would leave them with a very large cosmetic deformity or if surgery would be not curative,” Dr. Rossi said. “We’re seeing good results” with acceptable adverse events, specifically taste disturbances, muscle cramps, and hair loss. The first such drug, vismodegib (Erivedge), was approved in 2012, and sonidegib (Odomzo) came on the market about 1 year ago.

Besides oral agents, photodynamic therapy (PDT) with photosensitizers are another option for certain skin tumors. Dr. Rossi said his practice is to keep the treatment room fairly warm to assure good blood flow to the skin and thus good penetration of the drug. Because PDT acts by generating singlet oxygen to kill tumors, good blood flow to the tumor is necessary. To minimize discomfort, he uses pretreatment acetaminophen if patients can take it. After a skin reaction occurs, cool compresses are used, along with dilute acetic acid soaks on crusted or scaling lesions in an effort to prevent infection.

And while these treatments can produce quite angry-looking lesions in the short term, very good healing usually occurs if patients are diligent about wound care. However, Dr. Rossi cautioned that they may need “more hand holding with these nonsurgical treatments, because it is a longer duration of treatment.”

In general for counseling patients on nonsurgical treatments, Dr. Rossi said it is advisable to have good pretreatment and post-treatment plans. “They have to know that they will need to be following up to make sure that there is no recurrence,” he said. “We don’t have clear surgical margins if we’re using these topical treatments, so we have to make sure that they have good, constant follow-up.”

Dr. Rossi reported consulting relationships with Merz, DynaMed, and Novartis.

BOSTON – Surgery is the standard of care for most skin cancers, but nonsurgical and adjuvant treatments can be good options for certain skin cancers when surgery would be neither curative nor feasible, according to Anthony Rossi, MD.

“Whether you’re treating a superficial basal cell or superficial squamous cell carcinoma, I think first and foremost, if you’re going to use nonsurgical treatment options, it’s important to have a good biopsy diagnosis,” Dr. Rossi said at the American Academy of Dermatology summer meeting. He also advised that the biopsy capture the entire lesion or a good portion of it to get a good representation. “You don’t want to be surprised by any hiding, high-risk subtypes,” said Dr. Rossi, of the Memorial Sloan Kettering Cancer Center in New York.

Deciding on a nonsurgical treatment option should be based on knowing the patient. For example, know the patient’s concerns about cosmetic deformities, willingness to undergo surgery or not, and ability and willingness to do follow-up self-care.

For superficial basal cell or squamous cell carcinomas in situ and even lentigo maligna in situ not amenable to surgery, imiquimod may be an appropriate treatment. Dr. Rossi said his practice is to use it in an incremental fashion, starting with application five times per week, going to every day if there is no response after 1 to 2 weeks. If the response remains inadequate, he recommended adding a topical retinoid, such as tazarotene, in an effort to increase penetration.

For basal cell carcinomas and squamous cell carcinoma in situ, he uses imiquimod for a total of 6 to 8 weeks, starting from the time of the first reaction. For melanoma in situ, he uses it for more than 60 applications (12 weeks).

To show patients where they should be applying any topical treatment, Dr. Rossi marks the skin, photographs it, and prints out a picture for the patient. Sometimes he uses the patient’s phone to take the picture. For a basal cell or squamous cell carcinoma in situ, he indicates an area at least 5 to 10 mm beyond the margin of the tumor. The area is even larger for melanomas.

Dr. Rossi studies confocal microscopy to detect skin cancers. He uses it before treating a lesion to define the clinical boundaries of the lesion and the boundaries for the nonsurgical treatments, and then he uses it on follow up to look for any recurrences.

New anti-tumor agents

Two oral inhibitors of the sonic hedgehog pathway have been approved within the past 5 years for locally advanced or metastatic basal cell carcinomas. “In the right person, they can be quite beneficial if surgery would leave them with a very large cosmetic deformity or if surgery would be not curative,” Dr. Rossi said. “We’re seeing good results” with acceptable adverse events, specifically taste disturbances, muscle cramps, and hair loss. The first such drug, vismodegib (Erivedge), was approved in 2012, and sonidegib (Odomzo) came on the market about 1 year ago.

Besides oral agents, photodynamic therapy (PDT) with photosensitizers are another option for certain skin tumors. Dr. Rossi said his practice is to keep the treatment room fairly warm to assure good blood flow to the skin and thus good penetration of the drug. Because PDT acts by generating singlet oxygen to kill tumors, good blood flow to the tumor is necessary. To minimize discomfort, he uses pretreatment acetaminophen if patients can take it. After a skin reaction occurs, cool compresses are used, along with dilute acetic acid soaks on crusted or scaling lesions in an effort to prevent infection.

And while these treatments can produce quite angry-looking lesions in the short term, very good healing usually occurs if patients are diligent about wound care. However, Dr. Rossi cautioned that they may need “more hand holding with these nonsurgical treatments, because it is a longer duration of treatment.”

In general for counseling patients on nonsurgical treatments, Dr. Rossi said it is advisable to have good pretreatment and post-treatment plans. “They have to know that they will need to be following up to make sure that there is no recurrence,” he said. “We don’t have clear surgical margins if we’re using these topical treatments, so we have to make sure that they have good, constant follow-up.”

Dr. Rossi reported consulting relationships with Merz, DynaMed, and Novartis.

BOSTON – Surgery is the standard of care for most skin cancers, but nonsurgical and adjuvant treatments can be good options for certain skin cancers when surgery would be neither curative nor feasible, according to Anthony Rossi, MD.

“Whether you’re treating a superficial basal cell or superficial squamous cell carcinoma, I think first and foremost, if you’re going to use nonsurgical treatment options, it’s important to have a good biopsy diagnosis,” Dr. Rossi said at the American Academy of Dermatology summer meeting. He also advised that the biopsy capture the entire lesion or a good portion of it to get a good representation. “You don’t want to be surprised by any hiding, high-risk subtypes,” said Dr. Rossi, of the Memorial Sloan Kettering Cancer Center in New York.

Deciding on a nonsurgical treatment option should be based on knowing the patient. For example, know the patient’s concerns about cosmetic deformities, willingness to undergo surgery or not, and ability and willingness to do follow-up self-care.

For superficial basal cell or squamous cell carcinomas in situ and even lentigo maligna in situ not amenable to surgery, imiquimod may be an appropriate treatment. Dr. Rossi said his practice is to use it in an incremental fashion, starting with application five times per week, going to every day if there is no response after 1 to 2 weeks. If the response remains inadequate, he recommended adding a topical retinoid, such as tazarotene, in an effort to increase penetration.

For basal cell carcinomas and squamous cell carcinoma in situ, he uses imiquimod for a total of 6 to 8 weeks, starting from the time of the first reaction. For melanoma in situ, he uses it for more than 60 applications (12 weeks).

To show patients where they should be applying any topical treatment, Dr. Rossi marks the skin, photographs it, and prints out a picture for the patient. Sometimes he uses the patient’s phone to take the picture. For a basal cell or squamous cell carcinoma in situ, he indicates an area at least 5 to 10 mm beyond the margin of the tumor. The area is even larger for melanomas.

Dr. Rossi studies confocal microscopy to detect skin cancers. He uses it before treating a lesion to define the clinical boundaries of the lesion and the boundaries for the nonsurgical treatments, and then he uses it on follow up to look for any recurrences.

New anti-tumor agents

Two oral inhibitors of the sonic hedgehog pathway have been approved within the past 5 years for locally advanced or metastatic basal cell carcinomas. “In the right person, they can be quite beneficial if surgery would leave them with a very large cosmetic deformity or if surgery would be not curative,” Dr. Rossi said. “We’re seeing good results” with acceptable adverse events, specifically taste disturbances, muscle cramps, and hair loss. The first such drug, vismodegib (Erivedge), was approved in 2012, and sonidegib (Odomzo) came on the market about 1 year ago.

Besides oral agents, photodynamic therapy (PDT) with photosensitizers are another option for certain skin tumors. Dr. Rossi said his practice is to keep the treatment room fairly warm to assure good blood flow to the skin and thus good penetration of the drug. Because PDT acts by generating singlet oxygen to kill tumors, good blood flow to the tumor is necessary. To minimize discomfort, he uses pretreatment acetaminophen if patients can take it. After a skin reaction occurs, cool compresses are used, along with dilute acetic acid soaks on crusted or scaling lesions in an effort to prevent infection.

And while these treatments can produce quite angry-looking lesions in the short term, very good healing usually occurs if patients are diligent about wound care. However, Dr. Rossi cautioned that they may need “more hand holding with these nonsurgical treatments, because it is a longer duration of treatment.”

In general for counseling patients on nonsurgical treatments, Dr. Rossi said it is advisable to have good pretreatment and post-treatment plans. “They have to know that they will need to be following up to make sure that there is no recurrence,” he said. “We don’t have clear surgical margins if we’re using these topical treatments, so we have to make sure that they have good, constant follow-up.”

Dr. Rossi reported consulting relationships with Merz, DynaMed, and Novartis.

BOSTON – Most ulcers seen in the clinic setting are venous, arterial, or neuropathic, but about 10% are tied to “more unusual causes” and require biopsy, according to Tania J. Phillips, MD.

A particular concern is malignancy, Dr. Phillips, professor of dermatology at Boston University, said at the American Academy of Dermatology summer meeting.

“We do need to have a low threshold for biopsying wounds – particularly if they are wounds of long duration and are not healing,”

A rule of thumb for performing biopsy is 3 months of non-healing, she said.

“If you have a non-healing wound and you’re doing good wound care, you have to re-evaluate. Do you have the right diagnosis? You may need several biopsies on several different occasions to get the right diagnosis,” she said.

Other reasons to biopsy include suspected infection – whether bacterial, fungal, or mycobacterial; atypical appearance; suspected vasculitis; and recent travel history.

Ideally, the biopsy will include a deep wedge containing wound margin and the wound bed.

“Failing that, [take] multiple punch biopsies from the wound bed and the margins,” she said.

While many people are nervous about biopsying an ulcer, most biopsy sites heal very well with no complications, she noted.

As for what to do with the tissue, it can be sent in formalin.

“But if you’re going to do immunofluorescence, you will need Michel’s medium. And if you want to culture, just check with your microbiology lab, because often they will take your piece of tissue and they’ll mix it up, and they’ll divide it and will send it out for bacterial, fungal, mycobacterial culture and you won’t have to do that yourself,” she said.

Dr. Phillips noted that she doesn’t usually suture an ulcer biopsy site.

“The skin around ulcers is usually very friable, the sutures often pull out, and you can usually just pack the biopsy site with gel foam or with an alginate, and then just apply firm compression like a wrap over the biopsy site and you’ll do just fine,” she said.

Dr. Phillips reported a financial relationship with Hygeia.

[email protected]

BOSTON – Most ulcers seen in the clinic setting are venous, arterial, or neuropathic, but about 10% are tied to “more unusual causes” and require biopsy, according to Tania J. Phillips, MD.

A particular concern is malignancy, Dr. Phillips, professor of dermatology at Boston University, said at the American Academy of Dermatology summer meeting.

“We do need to have a low threshold for biopsying wounds – particularly if they are wounds of long duration and are not healing,”

A rule of thumb for performing biopsy is 3 months of non-healing, she said.

“If you have a non-healing wound and you’re doing good wound care, you have to re-evaluate. Do you have the right diagnosis? You may need several biopsies on several different occasions to get the right diagnosis,” she said.

Other reasons to biopsy include suspected infection – whether bacterial, fungal, or mycobacterial; atypical appearance; suspected vasculitis; and recent travel history.

Ideally, the biopsy will include a deep wedge containing wound margin and the wound bed.

“Failing that, [take] multiple punch biopsies from the wound bed and the margins,” she said.

While many people are nervous about biopsying an ulcer, most biopsy sites heal very well with no complications, she noted.

As for what to do with the tissue, it can be sent in formalin.

“But if you’re going to do immunofluorescence, you will need Michel’s medium. And if you want to culture, just check with your microbiology lab, because often they will take your piece of tissue and they’ll mix it up, and they’ll divide it and will send it out for bacterial, fungal, mycobacterial culture and you won’t have to do that yourself,” she said.

Dr. Phillips noted that she doesn’t usually suture an ulcer biopsy site.

“The skin around ulcers is usually very friable, the sutures often pull out, and you can usually just pack the biopsy site with gel foam or with an alginate, and then just apply firm compression like a wrap over the biopsy site and you’ll do just fine,” she said.

Dr. Phillips reported a financial relationship with Hygeia.

[email protected]

BOSTON – Most ulcers seen in the clinic setting are venous, arterial, or neuropathic, but about 10% are tied to “more unusual causes” and require biopsy, according to Tania J. Phillips, MD.

A particular concern is malignancy, Dr. Phillips, professor of dermatology at Boston University, said at the American Academy of Dermatology summer meeting.

“We do need to have a low threshold for biopsying wounds – particularly if they are wounds of long duration and are not healing,”

A rule of thumb for performing biopsy is 3 months of non-healing, she said.

“If you have a non-healing wound and you’re doing good wound care, you have to re-evaluate. Do you have the right diagnosis? You may need several biopsies on several different occasions to get the right diagnosis,” she said.

Other reasons to biopsy include suspected infection – whether bacterial, fungal, or mycobacterial; atypical appearance; suspected vasculitis; and recent travel history.

Ideally, the biopsy will include a deep wedge containing wound margin and the wound bed.

“Failing that, [take] multiple punch biopsies from the wound bed and the margins,” she said.

While many people are nervous about biopsying an ulcer, most biopsy sites heal very well with no complications, she noted.

As for what to do with the tissue, it can be sent in formalin.

“But if you’re going to do immunofluorescence, you will need Michel’s medium. And if you want to culture, just check with your microbiology lab, because often they will take your piece of tissue and they’ll mix it up, and they’ll divide it and will send it out for bacterial, fungal, mycobacterial culture and you won’t have to do that yourself,” she said.

Dr. Phillips noted that she doesn’t usually suture an ulcer biopsy site.

“The skin around ulcers is usually very friable, the sutures often pull out, and you can usually just pack the biopsy site with gel foam or with an alginate, and then just apply firm compression like a wrap over the biopsy site and you’ll do just fine,” she said.

Dr. Phillips reported a financial relationship with Hygeia.

[email protected]

Very little evidence exists for how to avoid using seclusion and restraints when de-escalating aggression in psychiatric patients in acute care settings, a recent report from the Agency for Healthcare Research and Quality shows.

Historically, aggression in patients has been met with either involuntary placement of the patient in a secured area, or with the involuntary administration of some form of restraint, which might be mechanical, pharmacologic.

Since the late 1990s, however, the Centers for Medicare & Medicaid Services and the Joint Commission have required using seclusion and restraints only after less restrictive measures have failed. Nearly two decades since, those requirements have been universally in force. “Despite practice guidelines advocating limitations of the use of seclusion or restraints as much as possible,” the interventions are used for 10%-30% of patients admitted to acute psychiatric units in the United States and Europe, the authors wrote.

Yet, when reviewing strategies such as creating a calm environment, medication modifications, staffing changes, training programs, and peer-based interventions, only risk assessment had “any reasonable evidence” that it is an effective method for avoiding aggression in psychiatric patients in nonpsychiatric hospital settings compared with usual care, the investigators found.

“The current evidence base leaves clinicians, administrators, policymakers, and patients without clear guidance,” they wrote, noting that even the strength of the favorable evidence is “at best, low.”

The findings suggest that policymakers are at a disadvantage for measuring performance improvement of these kinds of facilities seeking to reduce their use of seclusion and restraint. The authors asked, “What is the role of quality measures, designed to create incentives to improve the quality of care, when the evidence base for those measures is unclear?”

For the review, patient aggression was defined as making specific imminent verbal threats, or using actual violence toward self, others, or property. The review spanned the literature published between January 1991 and February 2016, and focused on studies with adults having a diagnosed psychiatric disorder, including delirium, who received interventions targeting aggressive behavior in acute care settings. Studies of psychiatric hospitals were excluded, since such facilities often use multimodal strategies that are not suitable for acute care settings that do not care for long-term patients with chronic psychiatric diagnoses.

The studies reviewed had as their primary outcomes either or both data on decreased aggression in terms of frequency, severity, or duration; and a reduction in the use of seclusion and restraints. Ultimately, out of 1,921 potentially relevant citations, the investigators found a combined total of 11 randomized, controlled trials and cluster randomized trials that qualified for their evidence review, the authors wrote in the report’s executive summary.

Finding strong evidence for any one method of de-escalation was complicated by studies that did not adhere to strict use of cluster randomized trial protocols, or did not report precise correlations between specific, targeted interventions for patients actively exhibiting aggression. In addition, the interventions themselves often were described inexactly, or as a matrix of interventions, making them difficult to classify. The reviewers also complained in their report about the absence of data on treatment effect modifiers.

The current evidence base leaves clinicians, administrators, policymakers, and patients without clear guidance,” they wrote, noting that even the strength of the favorable evidence is “at best, low.” Evidence for how to de-escalate active aggression was “even more limited” according to the authors.

Until more evidence is gathered and reviewed, policymakers could find themselves wondering whether “implementation decisions [should] be delayed until more evidence becomes available,” they wrote.

The AHRQ’s Effective Health Care Program produced the report, titled “Strategies to de-escalate aggressive behavior in psychiatric patients.”

[email protected]

On Twitter @whitneymcknight

Very little evidence exists for how to avoid using seclusion and restraints when de-escalating aggression in psychiatric patients in acute care settings, a recent report from the Agency for Healthcare Research and Quality shows.

Historically, aggression in patients has been met with either involuntary placement of the patient in a secured area, or with the involuntary administration of some form of restraint, which might be mechanical, pharmacologic.

Since the late 1990s, however, the Centers for Medicare & Medicaid Services and the Joint Commission have required using seclusion and restraints only after less restrictive measures have failed. Nearly two decades since, those requirements have been universally in force. “Despite practice guidelines advocating limitations of the use of seclusion or restraints as much as possible,” the interventions are used for 10%-30% of patients admitted to acute psychiatric units in the United States and Europe, the authors wrote.

Yet, when reviewing strategies such as creating a calm environment, medication modifications, staffing changes, training programs, and peer-based interventions, only risk assessment had “any reasonable evidence” that it is an effective method for avoiding aggression in psychiatric patients in nonpsychiatric hospital settings compared with usual care, the investigators found.

“The current evidence base leaves clinicians, administrators, policymakers, and patients without clear guidance,” they wrote, noting that even the strength of the favorable evidence is “at best, low.”

The findings suggest that policymakers are at a disadvantage for measuring performance improvement of these kinds of facilities seeking to reduce their use of seclusion and restraint. The authors asked, “What is the role of quality measures, designed to create incentives to improve the quality of care, when the evidence base for those measures is unclear?”

For the review, patient aggression was defined as making specific imminent verbal threats, or using actual violence toward self, others, or property. The review spanned the literature published between January 1991 and February 2016, and focused on studies with adults having a diagnosed psychiatric disorder, including delirium, who received interventions targeting aggressive behavior in acute care settings. Studies of psychiatric hospitals were excluded, since such facilities often use multimodal strategies that are not suitable for acute care settings that do not care for long-term patients with chronic psychiatric diagnoses.

The studies reviewed had as their primary outcomes either or both data on decreased aggression in terms of frequency, severity, or duration; and a reduction in the use of seclusion and restraints. Ultimately, out of 1,921 potentially relevant citations, the investigators found a combined total of 11 randomized, controlled trials and cluster randomized trials that qualified for their evidence review, the authors wrote in the report’s executive summary.

Finding strong evidence for any one method of de-escalation was complicated by studies that did not adhere to strict use of cluster randomized trial protocols, or did not report precise correlations between specific, targeted interventions for patients actively exhibiting aggression. In addition, the interventions themselves often were described inexactly, or as a matrix of interventions, making them difficult to classify. The reviewers also complained in their report about the absence of data on treatment effect modifiers.

The current evidence base leaves clinicians, administrators, policymakers, and patients without clear guidance,” they wrote, noting that even the strength of the favorable evidence is “at best, low.” Evidence for how to de-escalate active aggression was “even more limited” according to the authors.

Until more evidence is gathered and reviewed, policymakers could find themselves wondering whether “implementation decisions [should] be delayed until more evidence becomes available,” they wrote.

The AHRQ’s Effective Health Care Program produced the report, titled “Strategies to de-escalate aggressive behavior in psychiatric patients.”

[email protected]

On Twitter @whitneymcknight

Very little evidence exists for how to avoid using seclusion and restraints when de-escalating aggression in psychiatric patients in acute care settings, a recent report from the Agency for Healthcare Research and Quality shows.

Historically, aggression in patients has been met with either involuntary placement of the patient in a secured area, or with the involuntary administration of some form of restraint, which might be mechanical, pharmacologic.

Since the late 1990s, however, the Centers for Medicare & Medicaid Services and the Joint Commission have required using seclusion and restraints only after less restrictive measures have failed. Nearly two decades since, those requirements have been universally in force. “Despite practice guidelines advocating limitations of the use of seclusion or restraints as much as possible,” the interventions are used for 10%-30% of patients admitted to acute psychiatric units in the United States and Europe, the authors wrote.

Yet, when reviewing strategies such as creating a calm environment, medication modifications, staffing changes, training programs, and peer-based interventions, only risk assessment had “any reasonable evidence” that it is an effective method for avoiding aggression in psychiatric patients in nonpsychiatric hospital settings compared with usual care, the investigators found.

“The current evidence base leaves clinicians, administrators, policymakers, and patients without clear guidance,” they wrote, noting that even the strength of the favorable evidence is “at best, low.”

The findings suggest that policymakers are at a disadvantage for measuring performance improvement of these kinds of facilities seeking to reduce their use of seclusion and restraint. The authors asked, “What is the role of quality measures, designed to create incentives to improve the quality of care, when the evidence base for those measures is unclear?”

For the review, patient aggression was defined as making specific imminent verbal threats, or using actual violence toward self, others, or property. The review spanned the literature published between January 1991 and February 2016, and focused on studies with adults having a diagnosed psychiatric disorder, including delirium, who received interventions targeting aggressive behavior in acute care settings. Studies of psychiatric hospitals were excluded, since such facilities often use multimodal strategies that are not suitable for acute care settings that do not care for long-term patients with chronic psychiatric diagnoses.

The studies reviewed had as their primary outcomes either or both data on decreased aggression in terms of frequency, severity, or duration; and a reduction in the use of seclusion and restraints. Ultimately, out of 1,921 potentially relevant citations, the investigators found a combined total of 11 randomized, controlled trials and cluster randomized trials that qualified for their evidence review, the authors wrote in the report’s executive summary.

Finding strong evidence for any one method of de-escalation was complicated by studies that did not adhere to strict use of cluster randomized trial protocols, or did not report precise correlations between specific, targeted interventions for patients actively exhibiting aggression. In addition, the interventions themselves often were described inexactly, or as a matrix of interventions, making them difficult to classify. The reviewers also complained in their report about the absence of data on treatment effect modifiers.

The current evidence base leaves clinicians, administrators, policymakers, and patients without clear guidance,” they wrote, noting that even the strength of the favorable evidence is “at best, low.” Evidence for how to de-escalate active aggression was “even more limited” according to the authors.

Until more evidence is gathered and reviewed, policymakers could find themselves wondering whether “implementation decisions [should] be delayed until more evidence becomes available,” they wrote.

The AHRQ’s Effective Health Care Program produced the report, titled “Strategies to de-escalate aggressive behavior in psychiatric patients.”

[email protected]

On Twitter @whitneymcknight

Aedes aegypti mosquito

Photo courtesy of

Muhammad Mahdi Karim

Officials have announced what is likely the first known occurrence of local mosquito-borne Zika virus transmission in the continental US.*

Fourteen cases of Zika virus in 2 Florida counties are believed to have been caused by bites of local Aedes aegypti mosquitoes.

The Florida Department of Health (DOH) believes that active transmission of the Zika virus is only occurring in a small area in Miami-Dade County.

The US Centers for Disease Control and Prevention (CDC) has recommended that women who are pregnant or thinking of becoming pregnant avoid unnecessary travel to the impacted area. The agency has also issued a guidance for people living in or traveling to the area.

“All the evidence we have seen indicates that this is mosquito-borne transmission that occurred several weeks ago in several blocks in Miami,” said Tom Frieden, MD, director of the CDC.

The exact location is within the boundaries of the following area: NW 5th Avenue to the west, US 1 to the east, NW/NE 38th Street to the north and NW/NE 20th Street to the south. This is about one square mile.

Protecting the blood supply

The US Food and Drug Administration (FDA) has requested that all blood centers in Miami-Dade and Broward counties stop collecting blood immediately.

Blood centers in these counties can resume blood collection once they begin testing each unit of blood with an available investigational donor screening test for Zika virus RNA or once they implement the use of an approved or investigational pathogen inactivation technology.

The FDA also recommended that blood centers in nearby counties implement the same precautions as soon as possible to help maintain the safety of the blood supply. The agency has encouraged screening of the blood supply in regions of the US at risk of local mosquito-borne Zika transmission.

The FDA said it is working with companies that are making blood screening tests available under an Investigational New Drug (IND) application to ensure these companies are ready to expand testing as needed. Blood collection centers may choose to participate in testing under an IND even in the absence of local mosquito-borne transmission of Zika virus.

Florida/CDC response

Florida state officials have implemented mosquito control measures and a community-wide search for additional Zika cases. Thus far, Florida’s DOH has conducted testing for the Zika virus in more than 2300 people statewide.

The DOH has activated the Joint Information Center within the State Emergency Operations Center to ensure the area impacted by local transmission of the Zika virus has coordinated access to information and resources.

The DOH has also begun the process of contracting with commercial pest control companies to enhance and expand mosquito mitigation and abatement, including increased spraying, in the impacted area.

Earlier this year, Florida’s governor, Rick Scott, directed the State Surgeon General to activate a Zika Virus Information Hotline for Florida residents and visitors. The number for this hotline is 1-855-622-6735.

The CDC said it is coordinating with Florida officials leading the ongoing investigation into local transmission of the Zika virus. At the state’s request, the CDC sent a medical epidemiologist to provide additional assistance.

Governor Scott has also asked the CDC to activate a CDC Emergency Response Team to assist the DOH and other partners in their investigation, sample collection, and mosquito control efforts.

To date, the CDC has provided Florida with more than $8 million in Zika-specific funding and about $27 million in emergency preparedness funding that can be used for Zika response efforts.

“We have been working with state and local governments to prepare for the likelihood of local mosquito-borne Zika virus transmission in the continental United States and Hawaii,” said Lyle Petersen, MD, incident manager for CDC’s Zika virus response.

“We anticipate that there may be additional cases of ‘homegrown’ Zika in the coming weeks. Our top priority is to protect pregnant women from the potentially devastating harm caused by Zika.”

For more information about the Zika virus, visit http://www.cdc.gov/zika/.

*This story was updated on August 1.

Aedes aegypti mosquito

Photo courtesy of

Muhammad Mahdi Karim

Officials have announced what is likely the first known occurrence of local mosquito-borne Zika virus transmission in the continental US.*

Fourteen cases of Zika virus in 2 Florida counties are believed to have been caused by bites of local Aedes aegypti mosquitoes.

The Florida Department of Health (DOH) believes that active transmission of the Zika virus is only occurring in a small area in Miami-Dade County.

The US Centers for Disease Control and Prevention (CDC) has recommended that women who are pregnant or thinking of becoming pregnant avoid unnecessary travel to the impacted area. The agency has also issued a guidance for people living in or traveling to the area.

“All the evidence we have seen indicates that this is mosquito-borne transmission that occurred several weeks ago in several blocks in Miami,” said Tom Frieden, MD, director of the CDC.

The exact location is within the boundaries of the following area: NW 5th Avenue to the west, US 1 to the east, NW/NE 38th Street to the north and NW/NE 20th Street to the south. This is about one square mile.

Protecting the blood supply

The US Food and Drug Administration (FDA) has requested that all blood centers in Miami-Dade and Broward counties stop collecting blood immediately.

Blood centers in these counties can resume blood collection once they begin testing each unit of blood with an available investigational donor screening test for Zika virus RNA or once they implement the use of an approved or investigational pathogen inactivation technology.

The FDA also recommended that blood centers in nearby counties implement the same precautions as soon as possible to help maintain the safety of the blood supply. The agency has encouraged screening of the blood supply in regions of the US at risk of local mosquito-borne Zika transmission.

The FDA said it is working with companies that are making blood screening tests available under an Investigational New Drug (IND) application to ensure these companies are ready to expand testing as needed. Blood collection centers may choose to participate in testing under an IND even in the absence of local mosquito-borne transmission of Zika virus.

Florida/CDC response

Florida state officials have implemented mosquito control measures and a community-wide search for additional Zika cases. Thus far, Florida’s DOH has conducted testing for the Zika virus in more than 2300 people statewide.

The DOH has activated the Joint Information Center within the State Emergency Operations Center to ensure the area impacted by local transmission of the Zika virus has coordinated access to information and resources.

The DOH has also begun the process of contracting with commercial pest control companies to enhance and expand mosquito mitigation and abatement, including increased spraying, in the impacted area.

Earlier this year, Florida’s governor, Rick Scott, directed the State Surgeon General to activate a Zika Virus Information Hotline for Florida residents and visitors. The number for this hotline is 1-855-622-6735.

The CDC said it is coordinating with Florida officials leading the ongoing investigation into local transmission of the Zika virus. At the state’s request, the CDC sent a medical epidemiologist to provide additional assistance.

Governor Scott has also asked the CDC to activate a CDC Emergency Response Team to assist the DOH and other partners in their investigation, sample collection, and mosquito control efforts.

To date, the CDC has provided Florida with more than $8 million in Zika-specific funding and about $27 million in emergency preparedness funding that can be used for Zika response efforts.

“We have been working with state and local governments to prepare for the likelihood of local mosquito-borne Zika virus transmission in the continental United States and Hawaii,” said Lyle Petersen, MD, incident manager for CDC’s Zika virus response.

“We anticipate that there may be additional cases of ‘homegrown’ Zika in the coming weeks. Our top priority is to protect pregnant women from the potentially devastating harm caused by Zika.”

For more information about the Zika virus, visit http://www.cdc.gov/zika/.

*This story was updated on August 1.

Aedes aegypti mosquito

Photo courtesy of

Muhammad Mahdi Karim

Officials have announced what is likely the first known occurrence of local mosquito-borne Zika virus transmission in the continental US.*

Fourteen cases of Zika virus in 2 Florida counties are believed to have been caused by bites of local Aedes aegypti mosquitoes.

The Florida Department of Health (DOH) believes that active transmission of the Zika virus is only occurring in a small area in Miami-Dade County.

The US Centers for Disease Control and Prevention (CDC) has recommended that women who are pregnant or thinking of becoming pregnant avoid unnecessary travel to the impacted area. The agency has also issued a guidance for people living in or traveling to the area.

“All the evidence we have seen indicates that this is mosquito-borne transmission that occurred several weeks ago in several blocks in Miami,” said Tom Frieden, MD, director of the CDC.

The exact location is within the boundaries of the following area: NW 5th Avenue to the west, US 1 to the east, NW/NE 38th Street to the north and NW/NE 20th Street to the south. This is about one square mile.

Protecting the blood supply

The US Food and Drug Administration (FDA) has requested that all blood centers in Miami-Dade and Broward counties stop collecting blood immediately.

Blood centers in these counties can resume blood collection once they begin testing each unit of blood with an available investigational donor screening test for Zika virus RNA or once they implement the use of an approved or investigational pathogen inactivation technology.

The FDA also recommended that blood centers in nearby counties implement the same precautions as soon as possible to help maintain the safety of the blood supply. The agency has encouraged screening of the blood supply in regions of the US at risk of local mosquito-borne Zika transmission.

The FDA said it is working with companies that are making blood screening tests available under an Investigational New Drug (IND) application to ensure these companies are ready to expand testing as needed. Blood collection centers may choose to participate in testing under an IND even in the absence of local mosquito-borne transmission of Zika virus.

Florida/CDC response

Florida state officials have implemented mosquito control measures and a community-wide search for additional Zika cases. Thus far, Florida’s DOH has conducted testing for the Zika virus in more than 2300 people statewide.

The DOH has activated the Joint Information Center within the State Emergency Operations Center to ensure the area impacted by local transmission of the Zika virus has coordinated access to information and resources.

The DOH has also begun the process of contracting with commercial pest control companies to enhance and expand mosquito mitigation and abatement, including increased spraying, in the impacted area.

Earlier this year, Florida’s governor, Rick Scott, directed the State Surgeon General to activate a Zika Virus Information Hotline for Florida residents and visitors. The number for this hotline is 1-855-622-6735.

The CDC said it is coordinating with Florida officials leading the ongoing investigation into local transmission of the Zika virus. At the state’s request, the CDC sent a medical epidemiologist to provide additional assistance.

Governor Scott has also asked the CDC to activate a CDC Emergency Response Team to assist the DOH and other partners in their investigation, sample collection, and mosquito control efforts.

To date, the CDC has provided Florida with more than $8 million in Zika-specific funding and about $27 million in emergency preparedness funding that can be used for Zika response efforts.

“We have been working with state and local governments to prepare for the likelihood of local mosquito-borne Zika virus transmission in the continental United States and Hawaii,” said Lyle Petersen, MD, incident manager for CDC’s Zika virus response.

“We anticipate that there may be additional cases of ‘homegrown’ Zika in the coming weeks. Our top priority is to protect pregnant women from the potentially devastating harm caused by Zika.”

For more information about the Zika virus, visit http://www.cdc.gov/zika/.

*This story was updated on August 1.

VANCOUVER—MD1003, a pharmaceutical-grade formulation of biotin, reverses disease progression in a significant proportion of patients with progressive multiple sclerosis (MS), according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug is safe and remains effective throughout two years of treatment. Delayed treatment with MD1003 is beneficial, but the delay results in higher levels of disability, compared with immediate treatment.

The drug, however, does not significantly improve visual acuity, compared with placebo, in patients with relapsing-remitting or progressive MS and chronic optic neuropathy, said Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France.

MD1003 and Disease Progression

To investigate MD1003’s effect on disease progression in patients with progressive MS, Dr. Tourbah and colleagues conducted a placebo-controlled, double-blind study. Eligible patients had primary or secondary progressive MS and an Expanded Disability Status Scale (EDSS) score between 4.5 and 7. In addition, participants had to have had disease progression in the previous two years without evidence of clinical or MRI inflammatory activity within the previous year.

In the first phase of the trial, which lasted for 12 months, patients were randomized 2:1 to MD1003 or placebo. A 12-month extension phase followed, in which all patients received MD1003. Patients and clinicians remained blinded to the treatment assignments of the double-blind phase. The trial’s primary end point was the proportion of patients that improved at month nine and had confirmed improvement at month 12 on EDSS or the Timed 25-Foot Walk, compared with the best baseline measures.

In all, 103 patients were randomized to MD1003, and 51 patients were randomized to placebo. Ninety-one patients from the MD1003 group entered the extension phase, along with 42 patients from the placebo group. In the extension phase, 17 patients originally assigned to MD1003 and four patients originally assigned to placebo discontinued treatment. The main reason for discontinuation in both arms was consent withdrawal.

At baseline, the researchers observed no major differences between treatment arms with regard to sex ratio, mean age, mean disease duration, and mean EDSS score. Slightly more patients in the MD1003 arm had primary progressive MS than in the placebo arm. Approximately 40% of patients were taking concomitant disease-modifying therapies.

In the double-blind phase, 12.6% of patients receiving MD1003 had improvement at month nine and confirmed improvement at month 12. No patient receiving placebo had these outcomes, and the difference between groups was statistically significant. In the extension phase, treatment efficacy was maintained among patients randomized to MD1003 and became apparent in patients who were switched from placebo to MD1003. The level of disability remained higher in the latter group, however.

The rate of adverse events was consistent from the trial’s double-blind phase through its extension phase. The most frequent side effects were infections and infestations and disorders involving the nervous, gastrointestinal, musculoskeletal, and connective tissue systems. Patients originally randomized to placebo did not have more adverse events after switching to MD1003. A few cases of apparent hyperthyroidism were encountered. These are known to be related to interferences between high doses of biotin and biotin-based laboratory tests. Two cases of neoplasm were reported in the extension phase and were not reported as related to the treatment.

“This is the first time that a drug has reversed the progression of the disease in a statistically significant proportion of patients,” said Dr. Tourbah. “Almost no progression was observed in patients treated with MD1003 for 24 months, and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6,000 patients overall, this is clearly the best effect size ever observed.”

MD1003 and Visual Acuity

In a separate study, Dr. Tourbah and colleagues analyzed the efficacy of MD1003, compared with placebo, in patients with relapsing-remitting or progressive MS and visual loss related to chronic optic neuropathy. Eligible participants had at least one eye with confirmed visual acuity of 20/40 or less on a standard chart, and worsening of visual acuity within the previous three years. The investigators categorized patients as having progressive optic neuropathy (ie, progressive visual loss observed at two separate ophthalmologic examinations within the three years preceding inclusion) or nonprogressive optic neuropathy (ie, a fixed visual loss for six months or more following an episode of acute optic neuritis).

Patients were randomized 2:1 to MD1003 or placebo for six months. In a subsequent six-month extension phase, patients on placebo were switched to MD1003. Patients and clinicians remained blinded to the treatments that had been given in the double-blind phase. The primary end point was the mean change in visual acuity between month zero and month six in the eye with worse visual acuity at baseline and visual worsening within the previous three years. Dr. Tourbah and colleagues used the Early Treatment Diabetic Retinopathy Study chart at 100% to evaluate visual acuity.

In all, 65 patients were randomized to MD1003, and 28 patients to placebo. One patient did not enter the extension phase of the trial. Demographic characteristics were similar in the two treatment arms, but the majority of patients had nonprogressive chronic optic neuropathy, especially in the placebo arm. Slightly more patients randomized to MD1003 were taking disease-modifying therapies, compared with the placebo arm.

At six months, visual acuity improved in all patients. Improvement was more pronounced in patients receiving MD1003, but the difference between groups was not statistically significant. When the investigators examined only patients with nonprogressive chronic optic neuropathy, they found no difference between treatment groups at six months. When they examined participants with progressive chronic optic neuropathy, however, patients randomized to MD1003 had improved visual acuity at six months, while patients randomized to placebo had worsened visual acuity.

In the extension phase, patients who had improved on placebo continued to improve after switching to MD1003, and patients who had improved on MD1003 continued to improve. The researchers saw no differences in visual acuity between groups at 12 months. Among participants with nonprogressive chronic optic neuropathy, visual acuity improved in both treatment arms, and the researchers saw little difference between them at 12 months. Among patients with progressive chronic optic neuropathy, disease progression stopped in participants who switched from placebo to MD1003.

These results suggest that the treatment has no indication in patients with relapsing-remitting MS and show a trend toward efficacy in patients with progressive chronic optic neuropathy, which is consistent with the results of the MS-SPI study.

In addition, Dr. Tourbah and colleagues observed no major differences between treatment arms regarding the most frequent adverse events (ie, infections and infestations, nervous system disorders, and intestinal disorders). They noted, however, that more patients receiving MD1003 had relapses, compared with patients receiving placebo. “Whether MD1003 may trigger exacerbations in patients with relapsing-remitting MS deserves further investigation,” Dr. Tourbah concluded.

—Erik Greb

VANCOUVER—MD1003, a pharmaceutical-grade formulation of biotin, reverses disease progression in a significant proportion of patients with progressive multiple sclerosis (MS), according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug is safe and remains effective throughout two years of treatment. Delayed treatment with MD1003 is beneficial, but the delay results in higher levels of disability, compared with immediate treatment.

The drug, however, does not significantly improve visual acuity, compared with placebo, in patients with relapsing-remitting or progressive MS and chronic optic neuropathy, said Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France.

MD1003 and Disease Progression

To investigate MD1003’s effect on disease progression in patients with progressive MS, Dr. Tourbah and colleagues conducted a placebo-controlled, double-blind study. Eligible patients had primary or secondary progressive MS and an Expanded Disability Status Scale (EDSS) score between 4.5 and 7. In addition, participants had to have had disease progression in the previous two years without evidence of clinical or MRI inflammatory activity within the previous year.

In the first phase of the trial, which lasted for 12 months, patients were randomized 2:1 to MD1003 or placebo. A 12-month extension phase followed, in which all patients received MD1003. Patients and clinicians remained blinded to the treatment assignments of the double-blind phase. The trial’s primary end point was the proportion of patients that improved at month nine and had confirmed improvement at month 12 on EDSS or the Timed 25-Foot Walk, compared with the best baseline measures.

In all, 103 patients were randomized to MD1003, and 51 patients were randomized to placebo. Ninety-one patients from the MD1003 group entered the extension phase, along with 42 patients from the placebo group. In the extension phase, 17 patients originally assigned to MD1003 and four patients originally assigned to placebo discontinued treatment. The main reason for discontinuation in both arms was consent withdrawal.

At baseline, the researchers observed no major differences between treatment arms with regard to sex ratio, mean age, mean disease duration, and mean EDSS score. Slightly more patients in the MD1003 arm had primary progressive MS than in the placebo arm. Approximately 40% of patients were taking concomitant disease-modifying therapies.

In the double-blind phase, 12.6% of patients receiving MD1003 had improvement at month nine and confirmed improvement at month 12. No patient receiving placebo had these outcomes, and the difference between groups was statistically significant. In the extension phase, treatment efficacy was maintained among patients randomized to MD1003 and became apparent in patients who were switched from placebo to MD1003. The level of disability remained higher in the latter group, however.

The rate of adverse events was consistent from the trial’s double-blind phase through its extension phase. The most frequent side effects were infections and infestations and disorders involving the nervous, gastrointestinal, musculoskeletal, and connective tissue systems. Patients originally randomized to placebo did not have more adverse events after switching to MD1003. A few cases of apparent hyperthyroidism were encountered. These are known to be related to interferences between high doses of biotin and biotin-based laboratory tests. Two cases of neoplasm were reported in the extension phase and were not reported as related to the treatment.

“This is the first time that a drug has reversed the progression of the disease in a statistically significant proportion of patients,” said Dr. Tourbah. “Almost no progression was observed in patients treated with MD1003 for 24 months, and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6,000 patients overall, this is clearly the best effect size ever observed.”

MD1003 and Visual Acuity

In a separate study, Dr. Tourbah and colleagues analyzed the efficacy of MD1003, compared with placebo, in patients with relapsing-remitting or progressive MS and visual loss related to chronic optic neuropathy. Eligible participants had at least one eye with confirmed visual acuity of 20/40 or less on a standard chart, and worsening of visual acuity within the previous three years. The investigators categorized patients as having progressive optic neuropathy (ie, progressive visual loss observed at two separate ophthalmologic examinations within the three years preceding inclusion) or nonprogressive optic neuropathy (ie, a fixed visual loss for six months or more following an episode of acute optic neuritis).

Patients were randomized 2:1 to MD1003 or placebo for six months. In a subsequent six-month extension phase, patients on placebo were switched to MD1003. Patients and clinicians remained blinded to the treatments that had been given in the double-blind phase. The primary end point was the mean change in visual acuity between month zero and month six in the eye with worse visual acuity at baseline and visual worsening within the previous three years. Dr. Tourbah and colleagues used the Early Treatment Diabetic Retinopathy Study chart at 100% to evaluate visual acuity.

In all, 65 patients were randomized to MD1003, and 28 patients to placebo. One patient did not enter the extension phase of the trial. Demographic characteristics were similar in the two treatment arms, but the majority of patients had nonprogressive chronic optic neuropathy, especially in the placebo arm. Slightly more patients randomized to MD1003 were taking disease-modifying therapies, compared with the placebo arm.

At six months, visual acuity improved in all patients. Improvement was more pronounced in patients receiving MD1003, but the difference between groups was not statistically significant. When the investigators examined only patients with nonprogressive chronic optic neuropathy, they found no difference between treatment groups at six months. When they examined participants with progressive chronic optic neuropathy, however, patients randomized to MD1003 had improved visual acuity at six months, while patients randomized to placebo had worsened visual acuity.

In the extension phase, patients who had improved on placebo continued to improve after switching to MD1003, and patients who had improved on MD1003 continued to improve. The researchers saw no differences in visual acuity between groups at 12 months. Among participants with nonprogressive chronic optic neuropathy, visual acuity improved in both treatment arms, and the researchers saw little difference between them at 12 months. Among patients with progressive chronic optic neuropathy, disease progression stopped in participants who switched from placebo to MD1003.

These results suggest that the treatment has no indication in patients with relapsing-remitting MS and show a trend toward efficacy in patients with progressive chronic optic neuropathy, which is consistent with the results of the MS-SPI study.

In addition, Dr. Tourbah and colleagues observed no major differences between treatment arms regarding the most frequent adverse events (ie, infections and infestations, nervous system disorders, and intestinal disorders). They noted, however, that more patients receiving MD1003 had relapses, compared with patients receiving placebo. “Whether MD1003 may trigger exacerbations in patients with relapsing-remitting MS deserves further investigation,” Dr. Tourbah concluded.

—Erik Greb

VANCOUVER—MD1003, a pharmaceutical-grade formulation of biotin, reverses disease progression in a significant proportion of patients with progressive multiple sclerosis (MS), according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug is safe and remains effective throughout two years of treatment. Delayed treatment with MD1003 is beneficial, but the delay results in higher levels of disability, compared with immediate treatment.

The drug, however, does not significantly improve visual acuity, compared with placebo, in patients with relapsing-remitting or progressive MS and chronic optic neuropathy, said Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France.

MD1003 and Disease Progression

To investigate MD1003’s effect on disease progression in patients with progressive MS, Dr. Tourbah and colleagues conducted a placebo-controlled, double-blind study. Eligible patients had primary or secondary progressive MS and an Expanded Disability Status Scale (EDSS) score between 4.5 and 7. In addition, participants had to have had disease progression in the previous two years without evidence of clinical or MRI inflammatory activity within the previous year.

In the first phase of the trial, which lasted for 12 months, patients were randomized 2:1 to MD1003 or placebo. A 12-month extension phase followed, in which all patients received MD1003. Patients and clinicians remained blinded to the treatment assignments of the double-blind phase. The trial’s primary end point was the proportion of patients that improved at month nine and had confirmed improvement at month 12 on EDSS or the Timed 25-Foot Walk, compared with the best baseline measures.

In all, 103 patients were randomized to MD1003, and 51 patients were randomized to placebo. Ninety-one patients from the MD1003 group entered the extension phase, along with 42 patients from the placebo group. In the extension phase, 17 patients originally assigned to MD1003 and four patients originally assigned to placebo discontinued treatment. The main reason for discontinuation in both arms was consent withdrawal.

At baseline, the researchers observed no major differences between treatment arms with regard to sex ratio, mean age, mean disease duration, and mean EDSS score. Slightly more patients in the MD1003 arm had primary progressive MS than in the placebo arm. Approximately 40% of patients were taking concomitant disease-modifying therapies.

In the double-blind phase, 12.6% of patients receiving MD1003 had improvement at month nine and confirmed improvement at month 12. No patient receiving placebo had these outcomes, and the difference between groups was statistically significant. In the extension phase, treatment efficacy was maintained among patients randomized to MD1003 and became apparent in patients who were switched from placebo to MD1003. The level of disability remained higher in the latter group, however.

The rate of adverse events was consistent from the trial’s double-blind phase through its extension phase. The most frequent side effects were infections and infestations and disorders involving the nervous, gastrointestinal, musculoskeletal, and connective tissue systems. Patients originally randomized to placebo did not have more adverse events after switching to MD1003. A few cases of apparent hyperthyroidism were encountered. These are known to be related to interferences between high doses of biotin and biotin-based laboratory tests. Two cases of neoplasm were reported in the extension phase and were not reported as related to the treatment.

“This is the first time that a drug has reversed the progression of the disease in a statistically significant proportion of patients,” said Dr. Tourbah. “Almost no progression was observed in patients treated with MD1003 for 24 months, and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6,000 patients overall, this is clearly the best effect size ever observed.”

MD1003 and Visual Acuity

In a separate study, Dr. Tourbah and colleagues analyzed the efficacy of MD1003, compared with placebo, in patients with relapsing-remitting or progressive MS and visual loss related to chronic optic neuropathy. Eligible participants had at least one eye with confirmed visual acuity of 20/40 or less on a standard chart, and worsening of visual acuity within the previous three years. The investigators categorized patients as having progressive optic neuropathy (ie, progressive visual loss observed at two separate ophthalmologic examinations within the three years preceding inclusion) or nonprogressive optic neuropathy (ie, a fixed visual loss for six months or more following an episode of acute optic neuritis).

Patients were randomized 2:1 to MD1003 or placebo for six months. In a subsequent six-month extension phase, patients on placebo were switched to MD1003. Patients and clinicians remained blinded to the treatments that had been given in the double-blind phase. The primary end point was the mean change in visual acuity between month zero and month six in the eye with worse visual acuity at baseline and visual worsening within the previous three years. Dr. Tourbah and colleagues used the Early Treatment Diabetic Retinopathy Study chart at 100% to evaluate visual acuity.

In all, 65 patients were randomized to MD1003, and 28 patients to placebo. One patient did not enter the extension phase of the trial. Demographic characteristics were similar in the two treatment arms, but the majority of patients had nonprogressive chronic optic neuropathy, especially in the placebo arm. Slightly more patients randomized to MD1003 were taking disease-modifying therapies, compared with the placebo arm.

At six months, visual acuity improved in all patients. Improvement was more pronounced in patients receiving MD1003, but the difference between groups was not statistically significant. When the investigators examined only patients with nonprogressive chronic optic neuropathy, they found no difference between treatment groups at six months. When they examined participants with progressive chronic optic neuropathy, however, patients randomized to MD1003 had improved visual acuity at six months, while patients randomized to placebo had worsened visual acuity.

In the extension phase, patients who had improved on placebo continued to improve after switching to MD1003, and patients who had improved on MD1003 continued to improve. The researchers saw no differences in visual acuity between groups at 12 months. Among participants with nonprogressive chronic optic neuropathy, visual acuity improved in both treatment arms, and the researchers saw little difference between them at 12 months. Among patients with progressive chronic optic neuropathy, disease progression stopped in participants who switched from placebo to MD1003.

These results suggest that the treatment has no indication in patients with relapsing-remitting MS and show a trend toward efficacy in patients with progressive chronic optic neuropathy, which is consistent with the results of the MS-SPI study.

In addition, Dr. Tourbah and colleagues observed no major differences between treatment arms regarding the most frequent adverse events (ie, infections and infestations, nervous system disorders, and intestinal disorders). They noted, however, that more patients receiving MD1003 had relapses, compared with patients receiving placebo. “Whether MD1003 may trigger exacerbations in patients with relapsing-remitting MS deserves further investigation,” Dr. Tourbah concluded.

—Erik Greb