Investigational Contraceptive Patch Shows Promise

SAN DIEGO – Women who were randomized to an investigative low-dose ethinyl estradiol and levonorgestrel contraceptive patch had similar contraceptive efficacy, cycle control, and safety results, compared with those who were randomized to a standard oral contraceptive containing 20 mg ethinyl estradiol and 0.1 mg levonorgestrel, results from a phase III trial demonstrated.

In addition, efficacy of the once-weekly patch, developed by Princeton, N.J.–based Agile Therapeutics and known as AG200-15, was comparable among obese and nonobese women, a finding that surprised investigators, who were led by Dr. Andrew M. Kaunitz, professor of the department of obstetrics and gynecology at the University of Florida, Jacksonville.

"There has been controversy and concern over the past decade that obese women might experience higher failure rates with some hormonal contraceptive methods, particularly transdermal contraception," Dr. Kaunitz said in an interview in advance of a poster session at the annual meeting of the American College of Obstetricians and Gynecologists. "We found that efficacy was comparable regardless of body mass index. That was an unexpected, but welcome, finding."

Pharmacokinetic studies of AG200-15 have shown that it delivers ethinyl estradiol (EE) and levonorgestrel equivalent to that seen with a 30-mg dose of EE and a 120-mg dose of levonorgestrel oral contraceptives. This is in contrast to Ortho Evra (norelgestromin/ethinyl estradiol transdermal system, Ortho-McNeil–Janssen Pharmaceuticals), the first-generation contraceptive patch that gained popularity upon release, but was found to deliver a dose of EE substantially higher than conventional oral contraceptives.

"At the same time, some well-publicized cases of vascular events, including fatal pulmonary emboli, occurred in women using the Ortho Evra patch," Dr. Kaunitz said. "These cases generated a fair amount of medical-legal attention. Ortho Evra went through this boom/bust phenomenon, where it was wildly popular, and now I think I only have one patient who is using it. I think it points out that if there were a lower-[dose] estrogen patch that provided effective contraception, but did not expose women to more estrogen than with current low-dose birth control pills, it could occupy an important contraceptive niche for U.S. women."

For the current study, which was conducted at 96 centers, 1,128 women were treated for 1 year (13 cycles) with AG200-15, and 375 were treated for six cycles with oral contraceptives followed by seven cycles of AG200-15. Blood draws were performed at cycles 2, 6, and 13, and complete physical and gynecologic exams were performed at baseline, cycle 7, and the final visit, which was 14 days after the removal of the last patch or intake of the last oral contraceptive.

The mean age of the study participants was 26 years, 55% were white/non-Hispanic, and their mean body mass index was 27.5 kg/m². More than half (60%) were new users of hormonal contraceptives; 14% switched from another contraceptive prior to the study.

Dr. Kaunitz reported that there were no clinically meaningful differences in contraceptive efficacy among the intent-to-treat population between the oral contraceptive group and the AG200-15 group (a Pearl Index [PI] of 4.02 vs. 4.92). When the PI was stratified by BMI for the intent-to-treat population in the AG200-15 group, the PI for obese patients (defined as a BMI of 32 kg/m² or greater) was similar to that of the nonobese patients (PI of 2.85 vs. 3.17).

When the researchers stratified the study participants by race/ethnicity, the PI for the AG200-15 and oral contraceptive groups was lowest in the white subgroup, followed by the Hispanic and the black subgroups. This likely reflects that women of lower socioeconomic status take oral contraceptives less consistently than other women, Dr. Kaunitz said, a phenomenon that has been observed by other investigators (Contraception 2012;85:465-9).

Cycle control was similar between the two treatment groups. In cycle 3, for example, the incidence of breakthrough bleeding and/or spotting episodes was 24.8% in the AG200-15 group, compared with 23.2% in the oral contraceptive group. In cycle 5, the incidence of these events was 22.3% and 21.9.

Nearly half of women (48%) chose to apply AG200-15 to their buttocks, while 40% chose the abdomen, and 12% chose the upper torso. "We found that there was good adhesiveness, as fewer than 3% of women experienced patch detachment," Dr. Kaunitz said. "Also, there was no suggestion that patches would come off with a lot of sweating or vigorous physical activity."

Overall, 80% of women reported no skin irritation. Only 0.1% of women reported severe irritation; 17%, mild skin irritation; and 2%-3%, moderate skin irritation.

The incidence of hormone-related adverse events was similar between the two groups: 1.3% in the AG200-15 group vs. 1.2% in the oral contraceptive group. Breast tenderness was uncommon, reported by fewer than 2% of women in both groups. "That was a reassuring safety signal," Dr. Kaunitz said.

The investigators reported one serious adverse event in the oral contraceptive group (one case with an unspecified liver problem) and three adverse events in the AG200-15 group (one case with a blood clot in the left subclavian vein, one case of uncontrollable nausea and vomiting, and one case of drug overdose with Benadryl) to be possibly or probably related to the study drug.

Going forward, Dr. Kaunitz said that he would like to see clinical trials of AG200-15 that involve shorter hormone intervals than the classic schedule of 21 active tablets followed by 7 hormone-free days as followed in this study. "Newer contraceptives tend to have shorter hormone-free intervals or be continuous," he said. "Going forward, I’d be interested in clinical trials of this patch using hormone-free intervals shorter than 7 days or cycles longer than 1 month."

Agile Therapeutics has submitted a New Drug Application for AG200-15 with the Food and Drug Administration.

The study was funded by Agile Therapeutics. Dr. Kaunitz disclosed that he is a consultant for the company.

SAN DIEGO – Women who were randomized to an investigative low-dose ethinyl estradiol and levonorgestrel contraceptive patch had similar contraceptive efficacy, cycle control, and safety results, compared with those who were randomized to a standard oral contraceptive containing 20 mg ethinyl estradiol and 0.1 mg levonorgestrel, results from a phase III trial demonstrated.

In addition, efficacy of the once-weekly patch, developed by Princeton, N.J.–based Agile Therapeutics and known as AG200-15, was comparable among obese and nonobese women, a finding that surprised investigators, who were led by Dr. Andrew M. Kaunitz, professor of the department of obstetrics and gynecology at the University of Florida, Jacksonville.

"There has been controversy and concern over the past decade that obese women might experience higher failure rates with some hormonal contraceptive methods, particularly transdermal contraception," Dr. Kaunitz said in an interview in advance of a poster session at the annual meeting of the American College of Obstetricians and Gynecologists. "We found that efficacy was comparable regardless of body mass index. That was an unexpected, but welcome, finding."

Pharmacokinetic studies of AG200-15 have shown that it delivers ethinyl estradiol (EE) and levonorgestrel equivalent to that seen with a 30-mg dose of EE and a 120-mg dose of levonorgestrel oral contraceptives. This is in contrast to Ortho Evra (norelgestromin/ethinyl estradiol transdermal system, Ortho-McNeil–Janssen Pharmaceuticals), the first-generation contraceptive patch that gained popularity upon release, but was found to deliver a dose of EE substantially higher than conventional oral contraceptives.

"At the same time, some well-publicized cases of vascular events, including fatal pulmonary emboli, occurred in women using the Ortho Evra patch," Dr. Kaunitz said. "These cases generated a fair amount of medical-legal attention. Ortho Evra went through this boom/bust phenomenon, where it was wildly popular, and now I think I only have one patient who is using it. I think it points out that if there were a lower-[dose] estrogen patch that provided effective contraception, but did not expose women to more estrogen than with current low-dose birth control pills, it could occupy an important contraceptive niche for U.S. women."

For the current study, which was conducted at 96 centers, 1,128 women were treated for 1 year (13 cycles) with AG200-15, and 375 were treated for six cycles with oral contraceptives followed by seven cycles of AG200-15. Blood draws were performed at cycles 2, 6, and 13, and complete physical and gynecologic exams were performed at baseline, cycle 7, and the final visit, which was 14 days after the removal of the last patch or intake of the last oral contraceptive.

The mean age of the study participants was 26 years, 55% were white/non-Hispanic, and their mean body mass index was 27.5 kg/m². More than half (60%) were new users of hormonal contraceptives; 14% switched from another contraceptive prior to the study.

Dr. Kaunitz reported that there were no clinically meaningful differences in contraceptive efficacy among the intent-to-treat population between the oral contraceptive group and the AG200-15 group (a Pearl Index [PI] of 4.02 vs. 4.92). When the PI was stratified by BMI for the intent-to-treat population in the AG200-15 group, the PI for obese patients (defined as a BMI of 32 kg/m² or greater) was similar to that of the nonobese patients (PI of 2.85 vs. 3.17).

When the researchers stratified the study participants by race/ethnicity, the PI for the AG200-15 and oral contraceptive groups was lowest in the white subgroup, followed by the Hispanic and the black subgroups. This likely reflects that women of lower socioeconomic status take oral contraceptives less consistently than other women, Dr. Kaunitz said, a phenomenon that has been observed by other investigators (Contraception 2012;85:465-9).

Cycle control was similar between the two treatment groups. In cycle 3, for example, the incidence of breakthrough bleeding and/or spotting episodes was 24.8% in the AG200-15 group, compared with 23.2% in the oral contraceptive group. In cycle 5, the incidence of these events was 22.3% and 21.9.

Nearly half of women (48%) chose to apply AG200-15 to their buttocks, while 40% chose the abdomen, and 12% chose the upper torso. "We found that there was good adhesiveness, as fewer than 3% of women experienced patch detachment," Dr. Kaunitz said. "Also, there was no suggestion that patches would come off with a lot of sweating or vigorous physical activity."

Overall, 80% of women reported no skin irritation. Only 0.1% of women reported severe irritation; 17%, mild skin irritation; and 2%-3%, moderate skin irritation.

The incidence of hormone-related adverse events was similar between the two groups: 1.3% in the AG200-15 group vs. 1.2% in the oral contraceptive group. Breast tenderness was uncommon, reported by fewer than 2% of women in both groups. "That was a reassuring safety signal," Dr. Kaunitz said.

The investigators reported one serious adverse event in the oral contraceptive group (one case with an unspecified liver problem) and three adverse events in the AG200-15 group (one case with a blood clot in the left subclavian vein, one case of uncontrollable nausea and vomiting, and one case of drug overdose with Benadryl) to be possibly or probably related to the study drug.

Going forward, Dr. Kaunitz said that he would like to see clinical trials of AG200-15 that involve shorter hormone intervals than the classic schedule of 21 active tablets followed by 7 hormone-free days as followed in this study. "Newer contraceptives tend to have shorter hormone-free intervals or be continuous," he said. "Going forward, I’d be interested in clinical trials of this patch using hormone-free intervals shorter than 7 days or cycles longer than 1 month."

Agile Therapeutics has submitted a New Drug Application for AG200-15 with the Food and Drug Administration.

The study was funded by Agile Therapeutics. Dr. Kaunitz disclosed that he is a consultant for the company.

SAN DIEGO – Women who were randomized to an investigative low-dose ethinyl estradiol and levonorgestrel contraceptive patch had similar contraceptive efficacy, cycle control, and safety results, compared with those who were randomized to a standard oral contraceptive containing 20 mg ethinyl estradiol and 0.1 mg levonorgestrel, results from a phase III trial demonstrated.

In addition, efficacy of the once-weekly patch, developed by Princeton, N.J.–based Agile Therapeutics and known as AG200-15, was comparable among obese and nonobese women, a finding that surprised investigators, who were led by Dr. Andrew M. Kaunitz, professor of the department of obstetrics and gynecology at the University of Florida, Jacksonville.

"There has been controversy and concern over the past decade that obese women might experience higher failure rates with some hormonal contraceptive methods, particularly transdermal contraception," Dr. Kaunitz said in an interview in advance of a poster session at the annual meeting of the American College of Obstetricians and Gynecologists. "We found that efficacy was comparable regardless of body mass index. That was an unexpected, but welcome, finding."

Pharmacokinetic studies of AG200-15 have shown that it delivers ethinyl estradiol (EE) and levonorgestrel equivalent to that seen with a 30-mg dose of EE and a 120-mg dose of levonorgestrel oral contraceptives. This is in contrast to Ortho Evra (norelgestromin/ethinyl estradiol transdermal system, Ortho-McNeil–Janssen Pharmaceuticals), the first-generation contraceptive patch that gained popularity upon release, but was found to deliver a dose of EE substantially higher than conventional oral contraceptives.

"At the same time, some well-publicized cases of vascular events, including fatal pulmonary emboli, occurred in women using the Ortho Evra patch," Dr. Kaunitz said. "These cases generated a fair amount of medical-legal attention. Ortho Evra went through this boom/bust phenomenon, where it was wildly popular, and now I think I only have one patient who is using it. I think it points out that if there were a lower-[dose] estrogen patch that provided effective contraception, but did not expose women to more estrogen than with current low-dose birth control pills, it could occupy an important contraceptive niche for U.S. women."

For the current study, which was conducted at 96 centers, 1,128 women were treated for 1 year (13 cycles) with AG200-15, and 375 were treated for six cycles with oral contraceptives followed by seven cycles of AG200-15. Blood draws were performed at cycles 2, 6, and 13, and complete physical and gynecologic exams were performed at baseline, cycle 7, and the final visit, which was 14 days after the removal of the last patch or intake of the last oral contraceptive.

The mean age of the study participants was 26 years, 55% were white/non-Hispanic, and their mean body mass index was 27.5 kg/m². More than half (60%) were new users of hormonal contraceptives; 14% switched from another contraceptive prior to the study.

Dr. Kaunitz reported that there were no clinically meaningful differences in contraceptive efficacy among the intent-to-treat population between the oral contraceptive group and the AG200-15 group (a Pearl Index [PI] of 4.02 vs. 4.92). When the PI was stratified by BMI for the intent-to-treat population in the AG200-15 group, the PI for obese patients (defined as a BMI of 32 kg/m² or greater) was similar to that of the nonobese patients (PI of 2.85 vs. 3.17).

When the researchers stratified the study participants by race/ethnicity, the PI for the AG200-15 and oral contraceptive groups was lowest in the white subgroup, followed by the Hispanic and the black subgroups. This likely reflects that women of lower socioeconomic status take oral contraceptives less consistently than other women, Dr. Kaunitz said, a phenomenon that has been observed by other investigators (Contraception 2012;85:465-9).

Cycle control was similar between the two treatment groups. In cycle 3, for example, the incidence of breakthrough bleeding and/or spotting episodes was 24.8% in the AG200-15 group, compared with 23.2% in the oral contraceptive group. In cycle 5, the incidence of these events was 22.3% and 21.9.

Nearly half of women (48%) chose to apply AG200-15 to their buttocks, while 40% chose the abdomen, and 12% chose the upper torso. "We found that there was good adhesiveness, as fewer than 3% of women experienced patch detachment," Dr. Kaunitz said. "Also, there was no suggestion that patches would come off with a lot of sweating or vigorous physical activity."

Overall, 80% of women reported no skin irritation. Only 0.1% of women reported severe irritation; 17%, mild skin irritation; and 2%-3%, moderate skin irritation.

The incidence of hormone-related adverse events was similar between the two groups: 1.3% in the AG200-15 group vs. 1.2% in the oral contraceptive group. Breast tenderness was uncommon, reported by fewer than 2% of women in both groups. "That was a reassuring safety signal," Dr. Kaunitz said.

The investigators reported one serious adverse event in the oral contraceptive group (one case with an unspecified liver problem) and three adverse events in the AG200-15 group (one case with a blood clot in the left subclavian vein, one case of uncontrollable nausea and vomiting, and one case of drug overdose with Benadryl) to be possibly or probably related to the study drug.

Going forward, Dr. Kaunitz said that he would like to see clinical trials of AG200-15 that involve shorter hormone intervals than the classic schedule of 21 active tablets followed by 7 hormone-free days as followed in this study. "Newer contraceptives tend to have shorter hormone-free intervals or be continuous," he said. "Going forward, I’d be interested in clinical trials of this patch using hormone-free intervals shorter than 7 days or cycles longer than 1 month."

Agile Therapeutics has submitted a New Drug Application for AG200-15 with the Food and Drug Administration.

The study was funded by Agile Therapeutics. Dr. Kaunitz disclosed that he is a consultant for the company.