Michele Sullivan

CHICAGO – An updated version of the drug methylene blue appears to slow cognitive decline significantly in patients with moderate Alzheimer's disease by dissolving tau tangles in the brain, according to the results of a phase II trial.

This is the first Alzheimer's agent to target tau, and the first time any purported disease-modifying agent has achieved its primary cognitive end point, Dr. Claude Wischik said at the International Conference on Alzheimer's Disease.

“Our data show that we are able to halt the progression of Alzheimer's disease by targeting the neurofibrillatory tangle with a tau aggregation inhibitor,” said Dr. Wischik, founder and director of TauRX Therapeutics Ltd, the Singapore company that funded and conducted the research.

In the wake of two failed phase III trials of anti-amyloid drugs, Dr. Wischik's study has drawn enormous media attention, with newspapers hailing the drug as a breakthrough and potential cure. But other researchers at the meeting took a more tempered view. Potential problems with blinding (the study drug turns the urine of some patients green), an apparent lack of efficacy in the overall analysis, and the folding-in of one of the active groups into the placebo group, all were red flags for Dr. Lon Schneider, professor of psychiatry and behavioral sciences at the University of Southern California, Los Angeles.

“If they had [shown] the overall results of the combined group, as they should have, instead of just focusing on the moderates, it would have looked much more clearly like what it really was: an unremarkable, underpowered study,” said Dr. Schneider, a respected expert on Alz-heimer's research, at the meeting sponsored by the Alzheimer's Association. “However, that's not all bad for a phase II trial, if you show general safety and no toxicity, which they did.”

The drug, trade-named Rember, is a purified version of methylene blue, a dye that has a weak antibacterial effect. Rember works two ways: by blocking the formation of tau oligomers and converting them to paired helical filaments, and by dissolving existing tau tangles, according to the company's Web site.

The phase II dose-finding study included 321 patients with mild-moderate Alzheimer's and was conducted in the United Kingdom and Singapore. Patients were randomized to placebo or one of three drug doses: 30 mg three times daily, 60 mg three times daily, or 100 mg three times daily. The compound was contained in a gelatin capsule.

The study was conducted in two parts: an initial 24-week blinded placebo-controlled study, followed by 60 weeks of blinded active treatment. At baseline and throughout the trial, subjects received cognitive testing; functional brain imaging was performed on some at baseline and at 25 weeks.

Although he said none of the patients was taking cholinesterase inhibitors, Dr. Wischik's presentation did not include data on any other baseline characteristics of the group, how many were randomized to each treatment arm, or the dropout rate.

At no time were the results of the 100-mg dose discussed. Dr. Wischik said the gelatin capsule containing this dose was defective, which delayed release of the drug until it was in the intestine. He said the defect rendered the 100-mg dose completely ineffective.

Instead of analyzing this group, Dr. Wischik folded all its data into the placebo arm analysis, an unusual practice, Dr. Schneider noted. “If they thought the 100-mg dose was badly put together, they should have eliminated it entirely and performed a conservative analysis on what they had.”

Describing the study's primary end point–cognitive decline at 24 weeks–Dr. Wischik did not give the overall results of the entire group. Instead, he presented separate results for the mild and moderate patients. The drug did not show any cognitive benefit among the mild patients at 24 weeks; neither the placebo group nor the active groups declined significantly from baseline. However, among the moderate patients, Rember appeared to have a positive effect.

The use of methylene blue predates the Food and Drug Administration. Dr. Wischik, who predicted that Rember would be available within 4 years, said he was counting on this grandfathered status to speed it through the approval process.

CHICAGO – An updated version of the drug methylene blue appears to slow cognitive decline significantly in patients with moderate Alzheimer's disease by dissolving tau tangles in the brain, according to the results of a phase II trial.

This is the first Alzheimer's agent to target tau, and the first time any purported disease-modifying agent has achieved its primary cognitive end point, Dr. Claude Wischik said at the International Conference on Alzheimer's Disease.

“Our data show that we are able to halt the progression of Alzheimer's disease by targeting the neurofibrillatory tangle with a tau aggregation inhibitor,” said Dr. Wischik, founder and director of TauRX Therapeutics Ltd, the Singapore company that funded and conducted the research.

In the wake of two failed phase III trials of anti-amyloid drugs, Dr. Wischik's study has drawn enormous media attention, with newspapers hailing the drug as a breakthrough and potential cure. But other researchers at the meeting took a more tempered view. Potential problems with blinding (the study drug turns the urine of some patients green), an apparent lack of efficacy in the overall analysis, and the folding-in of one of the active groups into the placebo group, all were red flags for Dr. Lon Schneider, professor of psychiatry and behavioral sciences at the University of Southern California, Los Angeles.

“If they had [shown] the overall results of the combined group, as they should have, instead of just focusing on the moderates, it would have looked much more clearly like what it really was: an unremarkable, underpowered study,” said Dr. Schneider, a respected expert on Alz-heimer's research, at the meeting sponsored by the Alzheimer's Association. “However, that's not all bad for a phase II trial, if you show general safety and no toxicity, which they did.”

The drug, trade-named Rember, is a purified version of methylene blue, a dye that has a weak antibacterial effect. Rember works two ways: by blocking the formation of tau oligomers and converting them to paired helical filaments, and by dissolving existing tau tangles, according to the company's Web site.

The phase II dose-finding study included 321 patients with mild-moderate Alzheimer's and was conducted in the United Kingdom and Singapore. Patients were randomized to placebo or one of three drug doses: 30 mg three times daily, 60 mg three times daily, or 100 mg three times daily. The compound was contained in a gelatin capsule.

The study was conducted in two parts: an initial 24-week blinded placebo-controlled study, followed by 60 weeks of blinded active treatment. At baseline and throughout the trial, subjects received cognitive testing; functional brain imaging was performed on some at baseline and at 25 weeks.

Although he said none of the patients was taking cholinesterase inhibitors, Dr. Wischik's presentation did not include data on any other baseline characteristics of the group, how many were randomized to each treatment arm, or the dropout rate.

At no time were the results of the 100-mg dose discussed. Dr. Wischik said the gelatin capsule containing this dose was defective, which delayed release of the drug until it was in the intestine. He said the defect rendered the 100-mg dose completely ineffective.

Instead of analyzing this group, Dr. Wischik folded all its data into the placebo arm analysis, an unusual practice, Dr. Schneider noted. “If they thought the 100-mg dose was badly put together, they should have eliminated it entirely and performed a conservative analysis on what they had.”

Describing the study's primary end point–cognitive decline at 24 weeks–Dr. Wischik did not give the overall results of the entire group. Instead, he presented separate results for the mild and moderate patients. The drug did not show any cognitive benefit among the mild patients at 24 weeks; neither the placebo group nor the active groups declined significantly from baseline. However, among the moderate patients, Rember appeared to have a positive effect.

The use of methylene blue predates the Food and Drug Administration. Dr. Wischik, who predicted that Rember would be available within 4 years, said he was counting on this grandfathered status to speed it through the approval process.

CHICAGO – An updated version of the drug methylene blue appears to slow cognitive decline significantly in patients with moderate Alzheimer's disease by dissolving tau tangles in the brain, according to the results of a phase II trial.

This is the first Alzheimer's agent to target tau, and the first time any purported disease-modifying agent has achieved its primary cognitive end point, Dr. Claude Wischik said at the International Conference on Alzheimer's Disease.

“Our data show that we are able to halt the progression of Alzheimer's disease by targeting the neurofibrillatory tangle with a tau aggregation inhibitor,” said Dr. Wischik, founder and director of TauRX Therapeutics Ltd, the Singapore company that funded and conducted the research.

In the wake of two failed phase III trials of anti-amyloid drugs, Dr. Wischik's study has drawn enormous media attention, with newspapers hailing the drug as a breakthrough and potential cure. But other researchers at the meeting took a more tempered view. Potential problems with blinding (the study drug turns the urine of some patients green), an apparent lack of efficacy in the overall analysis, and the folding-in of one of the active groups into the placebo group, all were red flags for Dr. Lon Schneider, professor of psychiatry and behavioral sciences at the University of Southern California, Los Angeles.

“If they had [shown] the overall results of the combined group, as they should have, instead of just focusing on the moderates, it would have looked much more clearly like what it really was: an unremarkable, underpowered study,” said Dr. Schneider, a respected expert on Alz-heimer's research, at the meeting sponsored by the Alzheimer's Association. “However, that's not all bad for a phase II trial, if you show general safety and no toxicity, which they did.”

The drug, trade-named Rember, is a purified version of methylene blue, a dye that has a weak antibacterial effect. Rember works two ways: by blocking the formation of tau oligomers and converting them to paired helical filaments, and by dissolving existing tau tangles, according to the company's Web site.

The phase II dose-finding study included 321 patients with mild-moderate Alzheimer's and was conducted in the United Kingdom and Singapore. Patients were randomized to placebo or one of three drug doses: 30 mg three times daily, 60 mg three times daily, or 100 mg three times daily. The compound was contained in a gelatin capsule.

The study was conducted in two parts: an initial 24-week blinded placebo-controlled study, followed by 60 weeks of blinded active treatment. At baseline and throughout the trial, subjects received cognitive testing; functional brain imaging was performed on some at baseline and at 25 weeks.

Although he said none of the patients was taking cholinesterase inhibitors, Dr. Wischik's presentation did not include data on any other baseline characteristics of the group, how many were randomized to each treatment arm, or the dropout rate.

At no time were the results of the 100-mg dose discussed. Dr. Wischik said the gelatin capsule containing this dose was defective, which delayed release of the drug until it was in the intestine. He said the defect rendered the 100-mg dose completely ineffective.

Instead of analyzing this group, Dr. Wischik folded all its data into the placebo arm analysis, an unusual practice, Dr. Schneider noted. “If they thought the 100-mg dose was badly put together, they should have eliminated it entirely and performed a conservative analysis on what they had.”

Describing the study's primary end point–cognitive decline at 24 weeks–Dr. Wischik did not give the overall results of the entire group. Instead, he presented separate results for the mild and moderate patients. The drug did not show any cognitive benefit among the mild patients at 24 weeks; neither the placebo group nor the active groups declined significantly from baseline. However, among the moderate patients, Rember appeared to have a positive effect.

The use of methylene blue predates the Food and Drug Administration. Dr. Wischik, who predicted that Rember would be available within 4 years, said he was counting on this grandfathered status to speed it through the approval process.

PHILADELPHIA – A central venous line hub access protocol using 2% chlorhexidine was linked to an almost 50% decline in overall line infections in an urban neonatal intensive care unit.

It's unclear whether the decrease in line sepsis was related to the choice of antiseptic agent, adherence to a specific protocol, staff education, or a combination of all these factors, Dr. Sulaiman Sannoh said at the annual meeting of the Eastern Society for Pediatric Research.

“I think it was the combination of the new line care technique and the specific disinfectant,” said Dr. Sannoh, a neonatology fellow at the Maria Fareri Children's Hospital in Valhalla, N.Y. “There are no universal protocols for central venous line care, and the infection rates vary tremendously between hospitals. Studies have shown that adhering to a specific protocol is one way of decreasing line sepsis.”

His prospective trial compared central venous line (CVL) infections over two 9-month periods. In the first period, 163 neonatal intensive care unit (NICU) infants' lines were accessed using an alcohol solution.

In the second period, 158 NICU infants' CVL hubs were accessed using a semisterile protocol and disinfected with 2% chlorhexidine. Staff applied the chlorhexidine solution 10 times in a circular motion and allowed 30 seconds of air-dry time. All supplies for line access were kept in a sterile field. Staff members learned the new protocol in group sessions using an audiovisual presentation; the presentation was subsequently available online for future reference and reinforcement.

There were no significant differences at baseline between the two groups. A total of 40% had a birth weight below 1,000 g. The rates of necrotizing enterocolitis, ventilator days, length of stay, and mortality were also similar.

There was a significant decline in line-related sepsis after the chlorhexidine protocol was instituted. The incidence of peripherally inserted central catheter (PICC) sepsis decreased from 23 in 1,000 catheter-days to 11 in 1,000 catheter-days. There was also a significant decrease in the combined rates of sepsis associated with umbilical artery and vein catheters (14 in 1,000 catheter-days to 3 in 1,000 catheter-days).

The overall percentage of infected catheters dropped significantly, from 17% to 9%. The biggest decrease occurred in the percentage of infected Broviac catheters (60% to 31%). The decline in line sepsis occurred despite high CVL device utilization rates. There were nonsignificant decreases in the percentage of infections in PICC lines and umbilical artery and vein catheters.

Gram-negative sepsis also decreased significantly after the protocol was introduced, Dr. Sannoh said, but the rates of line sepsis caused by gram-positive bacteria and fungus were unchanged.

The audiovisual presentations were an effective tool in changing practice, and the protocol adherence appeared good throughout the study, Dr. Sannoh added. The cumulative infection rate increased very slightly in the first month of protocol institution, and then began a decline that continued its downward trajectory throughout the implementation period.

Dr. Sannoh acknowledged that protocol compliance rates tend to decrease over time, but said the online audiovisual reinforcement program may positively influence that tendency. “The staff found it very helpful and consulted it frequently,” he said.

Dr. Boriana Parvez, Barbara Clones, R.N., and Dr. Jose Munoz were coinvestigators in the study.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA – A central venous line hub access protocol using 2% chlorhexidine was linked to an almost 50% decline in overall line infections in an urban neonatal intensive care unit.

It's unclear whether the decrease in line sepsis was related to the choice of antiseptic agent, adherence to a specific protocol, staff education, or a combination of all these factors, Dr. Sulaiman Sannoh said at the annual meeting of the Eastern Society for Pediatric Research.

“I think it was the combination of the new line care technique and the specific disinfectant,” said Dr. Sannoh, a neonatology fellow at the Maria Fareri Children's Hospital in Valhalla, N.Y. “There are no universal protocols for central venous line care, and the infection rates vary tremendously between hospitals. Studies have shown that adhering to a specific protocol is one way of decreasing line sepsis.”

His prospective trial compared central venous line (CVL) infections over two 9-month periods. In the first period, 163 neonatal intensive care unit (NICU) infants' lines were accessed using an alcohol solution.

In the second period, 158 NICU infants' CVL hubs were accessed using a semisterile protocol and disinfected with 2% chlorhexidine. Staff applied the chlorhexidine solution 10 times in a circular motion and allowed 30 seconds of air-dry time. All supplies for line access were kept in a sterile field. Staff members learned the new protocol in group sessions using an audiovisual presentation; the presentation was subsequently available online for future reference and reinforcement.

There were no significant differences at baseline between the two groups. A total of 40% had a birth weight below 1,000 g. The rates of necrotizing enterocolitis, ventilator days, length of stay, and mortality were also similar.

There was a significant decline in line-related sepsis after the chlorhexidine protocol was instituted. The incidence of peripherally inserted central catheter (PICC) sepsis decreased from 23 in 1,000 catheter-days to 11 in 1,000 catheter-days. There was also a significant decrease in the combined rates of sepsis associated with umbilical artery and vein catheters (14 in 1,000 catheter-days to 3 in 1,000 catheter-days).

The overall percentage of infected catheters dropped significantly, from 17% to 9%. The biggest decrease occurred in the percentage of infected Broviac catheters (60% to 31%). The decline in line sepsis occurred despite high CVL device utilization rates. There were nonsignificant decreases in the percentage of infections in PICC lines and umbilical artery and vein catheters.

Gram-negative sepsis also decreased significantly after the protocol was introduced, Dr. Sannoh said, but the rates of line sepsis caused by gram-positive bacteria and fungus were unchanged.

The audiovisual presentations were an effective tool in changing practice, and the protocol adherence appeared good throughout the study, Dr. Sannoh added. The cumulative infection rate increased very slightly in the first month of protocol institution, and then began a decline that continued its downward trajectory throughout the implementation period.

Dr. Sannoh acknowledged that protocol compliance rates tend to decrease over time, but said the online audiovisual reinforcement program may positively influence that tendency. “The staff found it very helpful and consulted it frequently,” he said.

Dr. Boriana Parvez, Barbara Clones, R.N., and Dr. Jose Munoz were coinvestigators in the study.

ELSEVIER GLOBAL MEDICAL NEWS

PHILADELPHIA – A central venous line hub access protocol using 2% chlorhexidine was linked to an almost 50% decline in overall line infections in an urban neonatal intensive care unit.

It's unclear whether the decrease in line sepsis was related to the choice of antiseptic agent, adherence to a specific protocol, staff education, or a combination of all these factors, Dr. Sulaiman Sannoh said at the annual meeting of the Eastern Society for Pediatric Research.

“I think it was the combination of the new line care technique and the specific disinfectant,” said Dr. Sannoh, a neonatology fellow at the Maria Fareri Children's Hospital in Valhalla, N.Y. “There are no universal protocols for central venous line care, and the infection rates vary tremendously between hospitals. Studies have shown that adhering to a specific protocol is one way of decreasing line sepsis.”

His prospective trial compared central venous line (CVL) infections over two 9-month periods. In the first period, 163 neonatal intensive care unit (NICU) infants' lines were accessed using an alcohol solution.

In the second period, 158 NICU infants' CVL hubs were accessed using a semisterile protocol and disinfected with 2% chlorhexidine. Staff applied the chlorhexidine solution 10 times in a circular motion and allowed 30 seconds of air-dry time. All supplies for line access were kept in a sterile field. Staff members learned the new protocol in group sessions using an audiovisual presentation; the presentation was subsequently available online for future reference and reinforcement.

There were no significant differences at baseline between the two groups. A total of 40% had a birth weight below 1,000 g. The rates of necrotizing enterocolitis, ventilator days, length of stay, and mortality were also similar.

There was a significant decline in line-related sepsis after the chlorhexidine protocol was instituted. The incidence of peripherally inserted central catheter (PICC) sepsis decreased from 23 in 1,000 catheter-days to 11 in 1,000 catheter-days. There was also a significant decrease in the combined rates of sepsis associated with umbilical artery and vein catheters (14 in 1,000 catheter-days to 3 in 1,000 catheter-days).

The overall percentage of infected catheters dropped significantly, from 17% to 9%. The biggest decrease occurred in the percentage of infected Broviac catheters (60% to 31%). The decline in line sepsis occurred despite high CVL device utilization rates. There were nonsignificant decreases in the percentage of infections in PICC lines and umbilical artery and vein catheters.

Gram-negative sepsis also decreased significantly after the protocol was introduced, Dr. Sannoh said, but the rates of line sepsis caused by gram-positive bacteria and fungus were unchanged.

The audiovisual presentations were an effective tool in changing practice, and the protocol adherence appeared good throughout the study, Dr. Sannoh added. The cumulative infection rate increased very slightly in the first month of protocol institution, and then began a decline that continued its downward trajectory throughout the implementation period.

Dr. Sannoh acknowledged that protocol compliance rates tend to decrease over time, but said the online audiovisual reinforcement program may positively influence that tendency. “The staff found it very helpful and consulted it frequently,” he said.

Dr. Boriana Parvez, Barbara Clones, R.N., and Dr. Jose Munoz were coinvestigators in the study.

ELSEVIER GLOBAL MEDICAL NEWS