A randomized crossover study to evaluate local tolerability following subcutaneous administration of a new depot medroxyprogesterone acetate contraceptive formulation.

Objectives: This study aimed to evaluate and compare local tolerability of investigational drug TV-46046 and reference drug Depo-subQ Provera 104, both containing medroxyprogesterone acetate (MPA) as an active ingredient. Study design: We conducted a randomized, crossover, single-center study. Twenty-seven healthy women aged 25 to 47 years at low risk of pregnancy received a subcutaneous injection of each of the four study drugs (120 mg/0.3 mL of TV-46046, 60 mg/0.3 mL of diluted TV-46046, 0.3 mL of TV-46046 placebo, and 104 mg/0.65 mL of Depo-subQ 104) in different quadrants of the abdomen. We assessed local tolerability by occurrence of injection site reactions (ISRs), as well as injection site pain and overall safety for at least 9 months postinjections. Results: Of a total of 108 study injections, three injections were partial due to needle blockage. We observed a total of 30 ISRs following 105 full-dose injections, including hypopigmentation (n = 24), bruising (n = 4), and atrophy/dimple (n = 2). Eleven cases of hypopigmentation occurred following 25 full-dose injections of undiluted TV-46046 (44.0%), six following 27 full-dose injections of diluted TV-46046 (22.2%), and seven following 26 full-dose injections of Depo-subQ 104 (26.9%). Hypopigmentations occurred on average 8 months postinjection. Injection pain was minimal and dissipated quickly after all four injections. Conclusions: Subcutaneous administration of MPA in a suspension formulation is associated with the delayed onset of hypopigmentation at the site of injection. Although not statistically significant, the rate of ISRs was over 60% higher for undiluted TV-46046 compared to Depo-subQ 104. This difference bears careful monitoring in future studies of TV-46046. Implications: From a safety standpoint, investigational drug TV-46046 is appropriate for further clinical testing as a 6-month contraceptive injectable. The previously underreported hypopigmentation associated with subcutaneous administration of MPA warrants further investigation and acceptability assessment among users of existing Depo-subQ 104 as well as careful monitoring of local tolerability of TV-46046 in future clinical trials. Trial registration: Registered at clinicaltrials.gov no: NCT02817464.

Suppression of ovulation and pharmacokinetics following subcutaneous administration of various doses of Depo-Provera®: a randomized trial.

OBJECTIVES: To identify the lowest dose of Depo-Provera that, when administered off-label subcutaneously, suppressed ovulation and had a pharmacokinetic profile consistent with a 4-month contraceptive effect. STUDY DESIGN: We conducted a randomized, multicenter, parallel-group study to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of medroxyprogesterone acetate (MPA) after subcutaneous injection of three different doses of Depo-Provera. We randomized sixty women between 18 and 40 years of age at low risk of pregnancy with confirmed ovulation and body mass index of 18 to 35 kg/m2 to receive a single injection of 45, 75 or 105 mg of Depo-Provera, or a single injection of Depo-subQ provera 104 as a reference drug (15 women per group) and followed them for 7.5 months. We evaluated suppression of ovulation as the primary outcome, and MPA concentrations, pharmacokinetic parameters, safety, and local tolerability as secondary outcomes. RESULTS: Five women ovulated within four months of treatment initiation (three in the 45 mg group and two in the 75 mg group). MPA levels associated with ovulation were in general low, largely ≤ 0.2 ng/mL (the presumed contraceptive threshold). No women in either the 105 mg group or the Depo-subQ provera 104 group ovulated within four months. The PK parameters including Cmax, C119, and AUC0-119 for these 2 groups were similar but not equivalent. CONCLUSION: A dose of 105 mg of Depo-Provera injected subcutaneously was the lowest tested dose that consistently suppressed ovulation and maintained serum MPA levels consistent with contraceptive effect for at least 4 months. The PK and PD results for the 105 mg dose were similar to Depo-subQ provera 104 over this period.

Clinical trial to evaluate pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after subcutaneous administration of Depo-Provera.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after a single subcutaneous injection in the abdomen of 150 or 300 mg Depo-Provera and compare results to two injections of Depo-SubQ Provera 104 given 3 months apart. DESIGN: Partially randomized, multicenter, parallel-group study. SETTING: Research unit. PATIENT(S): Forty-two women of reproductive age with confirmed ovulatory cycle and body mass index of 18-35 kg/m2. INTERVENTION(S): Women received a single subcutaneous injection of 150 mg (n = 24) or 300 mg (n = 9) of Depo-Provera or two injections of Depo-SubQ Provera 104 (n = 9). MAIN OUTCOME MEASURE(S): Suppression of ovulation as measured by progesterone, serum medroxyprogesterone acetate concentrations, and estimated pharmacokinetics parameters. RESULT(S): No ovulations were observed during 7 months after a single injection of 150 or 300 mg Depo-Provera. The 150 mg group had a similar Cmax as observed over two injection cycles of Depo-SubQ Provera 104 and a similar 6-month trough concentration as the 3-month trough of Depo-SubQ Provera 104. CONCLUSION(S): Our pharmacodynamics and pharmacokinetics data provide proof of concept that Depo-Provera (150 mg) may be an effective contraceptive method when injected subcutaneously every 6 months, with up to a 4-week grace period for reinjections. CLINICAL TRIAL REGISTRATION NUMBER: NCT02456584.

Towards the development of a longer-acting injectable contraceptive: past research and current trends.

OBJECTIVES: A longer-acting injectable contraceptive that lasts for 6 months would be a valuable addition to the contraceptive method mix and ideal for women who are interested in spacing births and/or uncertain about their future reproductive plans. Here we review past applications of drug delivery technologies to injectable contraceptives as well as recent advancements in sustained drug delivery technologies that hold promise for the development of a new longer-acting injectable contraceptive product. STUDY DESIGN: A global landscape analysis was conducted, promising sustained drug delivery technologies, and research opportunities and partnerships were established with experts in the fields of contraception and drug delivery to identify new approaches in developing a longer-acting injectable contraceptive product. RESULTS: The landscape analysis confirmed that a number of existing polymer systems, such as poly-lactic-co-glycolic acid and poly(epsilon-caprolactone), remain promising candidates for application to a longer-acting injectable product. Novel polymers and materials also hold promise for achieving longer release profiles and/or having other advantages over existing polymer systems, but products using these materials could potentially have longer roads to regulatory approval. Additionally, recent advancements in the manufacturing process of microspheres may benefit the development of a longer-acting injectable contraceptive. CONCLUSION: The design of any new injectable product must take into account the limitations of current injectable contraceptives and address concerns that women may have for a longer-acting product. FHI 360 is supporting several research collaborations for proof of concept of various drug delivery approaches for achieving longer-acting product that fits an established target product profile.

Continuous compared with cyclic use of oral contraceptive pills in the Dominican Republic: a randomized controlled trial.

OBJECTIVE: To estimate whether continuous combined oral contraceptive pill (OCP) use leads to higher continuation and lower pregnancy rates over 12 months than cyclic use in a developing country setting. METHODS: We enrolled healthy women aged 18 to 30 years, in Santo Domingo, Dominican Republic. We randomly assigned women to cyclic or continuous use of OCPs. Participants made quarterly clinic visits for 12 months. During follow-up, we reviewed OCP adherence and continuation, side effects, and bleeding, and we tested for pregnancy. RESULTS: We enrolled 358 women (mean age, 22.7 years) and 335 (93.6%) completed the study. In intent-to-treat analyses, 77.6% of the continuous use group and 71.7% of the cyclic group continued OCPs at 12 months (P=.21). The main reason for OCP discontinuation in both groups was running out of OCPs or forgetting. Across all visits, 26.1% of women in the continuous use group and 22.3% of women in the cyclic group ever reported missing three or more OCPs in the past month (P=.43). In multivariable analyses, regimen was not associated with discontinuation, but both previous birth and perceived ease of use of OCPs decreased risk of discontinuation, whereas desire for reduced menstruation increased risk of discontinuation. Although more women reported amenorrhea or infrequent bleeding in the continuous use group, more women in the cyclic group found their bleeding patterns acceptable. Bleeding was not associated with discontinuation in multivariable analyses. Pregnancy rates at 12 months were similar (16.2% continuous and 17.4% cyclic). CONCLUSIONS: Continuous and cyclic OCP regimens were associated with similar 12-month continuation and pregnancy rates. Few factors predicted OCP discontinuation or pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00570440. LEVEL OF EVIDENCE: I.

A single-arm study to evaluate the efficacy, safety and acceptability of pericoital oral contraception with levonorgestrel.

BACKGROUND: An oral dose of 0.75 mg levonorgestrel (LNG) taken shortly after sex was marketed as a routine, nonemergency contraceptive method until the 1990s. Because a hormonal method used only at the time of intercourse may be desirable for women who have infrequent sex, we conducted a study to reevaluate the potential of pericoital LNG as a primary means of contraception. METHODS: We enrolled women aged 18-45 years in Brazil and the USA who expected to have sex 1-4 days per month for 6.5 months. Participants were instructed to take one tablet 0.75 mg LNG within 24 h before or after sex, with no more than one dose in any 24-h period. The primary efficacy measure was the Pearl Index among women aged 18-35 years. RESULTS: The study was stopped after 72 of the planned 300 participants were enrolled due to slow recruitment and related feasibility considerations. In the primary analysis, three pregnancies occurred during 13.4 woman-years of follow-up, resulting in a Pearl Index of 22.4 (95% confidence interval, 4.6-65.4). No serious adverse events were reported, and vaginal bleeding patterns were generally acceptable. CONCLUSIONS: Our estimated Pearl Index was noticeably higher than expected from previous research of LNG for pericoital contraception. Although the regimen was safe and generally acceptable, the study was challenged by slow enrollment and curtailed person-years of follow-up, resulting in poor precision for the estimated treatment effect. Future research may inform whether our results are symptomatic of the regimen, study design or characteristics of the populations from which we recruited. IMPLICATIONS: Our study failed to confirm prior data suggesting that 0.75 mg LNG for pericoital contraception could be more effective than typical use of barrier methods among women having infrequent sex. Characterizing populations most likely to adhere to, and benefit from, pericoital regimens is essential to future research on these methods.

Preferences for a potential longer-acting injectable contraceptive: perspectives from women, providers, and policy makers in Kenya and Rwanda.

BACKGROUND: Between 1995 and 2005, injectable use doubled worldwide. However, discontinuation rates remain high, partly because of side effects but also because of missed appointments for reinjection. A longer-acting injectable (LAI) may improve compliance by reducing the required number of reinjection visits, thereby reducing unintentional discontinuation. This study examined acceptability of LAI characteristics comprising the target product profile (TPP). METHODS: In 2012, we conducted qualitative case studies in Kenya and Rwanda, consisting of 19 focus group discussions (FGDs) with 177 current, previous, or never users of injectables and 46 in-depth interviews (IDIs) with providers, program implementers, and policy makers. FGDs and IDIs assessed current injectable experiences; attitudes toward potential LAI products; and perceptions of TPP attributes, including ranking preferences for the most and least important characteristics. In addition, we obtained completed electronic surveys from 28 international family planning opinion leaders about the perceived need for an LAI, important product characteristics, and challenges to LAI development or introduction. RESULTS: Many FGD participants and interviewees spontaneously expressed strong interest in an LAI, but there was some variation in TPP preferences. The majority of participants ranked effectiveness as the most important TPP attribute. Providers were generally more concerned about side effects than potential users; some potential users suggested that side effects were related less to the product than to their own body chemistry and that side effects were acceptable as long as they did not last a long time or disrupt daily activities. Women and providers, especially in Kenya, preferred a method with a predictable return to fertility. Some participants associated amenorrhea with delayed or reduced fertility. Most women and providers preferred delivery of the LAI in a single, prepackaged, disposable injection system to facilitate injections by providers and to reduce the risk of pain or discomfort for women. While providers and policy makers ranked cost as one of the most important issues, it was among the least important issues for most potential users. Many Kenyan, but few Rwandan, participants appeared willing to pay for an LAI, with some presuming cost savings from reduced menstruation and fewer clinic visits. CONCLUSIONS: Some TPP preferences for an LAI have implications for product development decisions about formulation, delivery mechanism, or presentation, while others point to the need for tailored communication and counseling approaches to ensure acceptability and adherence within clinical trials and beyond.

Effectiveness, safety and acceptability of Sino-implant (II) during the first year of use: results from Kenya and Pakistan.

BACKGROUND: Sino-implant (II) is a two-rod subcutaneous contraceptive implant used up to 4 years, containing 150 mg of levonorgestrel. We conducted two observational studies of Sino-implant (II) to evaluate its performance in routine service delivery settings. METHODS: We enrolled 1326 women age 18-44 who had Sino-implant (II) inserted at clinics in Pakistan and Kenya. Women were followed-up using either an active or passive follow-up scheme in each study. Study outcomes were: one-year cumulative pregnancy and discontinuation rates; rates of insertion and removal complications; adverse event and side effect rates; reasons for discontinuation; and implant acceptability and satisfaction with clinic services. RESULTS: A total of 754 women returned for at least one follow-up visit. The overall Pearl pregnancy rate was 0.4 per 100 woman-years [95% confidence interval (CI) 0.1, 0.9] resulting from 1 confirmed post-insertion pregnancy in Kenya and 4 in Pakistan. Country-specific Pearl rates were 0.2 (95% CI 0.0, 0.9) in Kenya and 0.6 (95% CI 0.2, 1.6) in Pakistan. The total cumulative 12-month probability of removal was 7.6% (95% CI 6.1, 9.1), with country-specific removal probabilities of 3.7% in Kenya (95% CI 2.1, 5.3) and 10.8% in Pakistan (95% CI 8.5, 13.2). Four serious adverse events occurred in Kenya and none occurred in Pakistan; one SAE (an ectopic pregnancy) was possibly related to Sino-implant (II). Most women in both countries said they would recommend the implant to others. CONCLUSION: The results from these studies reveal high effectiveness and favorable safety and acceptability during the first year of use of Sino-implant. IMPLICATION: The favorable Sino-implant (II) findings from Kenya and Pakistan provide further evidence from disparate regions that Sino-implant (II) is safe, effective and acceptable during routine service delivery.

Rationale, design, and cohort enrolment of a prospective observational study of the clinical performance of the new contraceptive implant (Femplant) in Pakistan.

INTRODUCTION: The use of hormonal implants has gained positive traction in family planning programs in recent times. Compared to other popular methods, such as long-term reversible intrauterine devices, the use of hormonal implants as a family planning method has distinct advantages in terms of long-term efficiency and better user compliance and availability. This paper presents a study protocol to document and evaluate the efficacy, safety, and acceptability of Femplant (contraceptive implant) in Pakistan during the first year of its use among married women of reproductive age (18-44 years) at clinics in two provinces of Pakistan (Sindh and Punjab). MATERIALS AND METHODS: A total of 724 married women were enrolled in a noncomparative prospective observational study. The study involved six government clinics from the Population Welfare Department in Sindh Province and 13 clinics run by the Marie Stopes Society (a local nongovernmental organization) in both provinces. The participation of women was subject to voluntary acceptance and medical eligibility. All respondents were interviewed at baseline and subsequently at each scheduled visit during the study period. Side effects, complications and adverse events, if any, were recorded for every participant at each visit to the facility. DISCUSSION: Over the next 5-year period (2013-2018), 27 million hormonal implants will be made available in lower- to middle-income countries by international donors and agencies. The evidence generated from this study will identify factors affecting the acceptability and satisfaction of end users with Femplant (Sino-implant II). This will help to guide policies to enhance access to and the use of long-acting contraceptive implants in Pakistan and similar developing countries.

Nevirapine-based antiretroviral therapy does not reduce oral contraceptive effectiveness.

OBJECTIVE: To evaluate the effect of nevirapine-containing antiretroviral therapy (ART) on combined oral contraceptive (COC) effectiveness. DESIGN: Nonrandomized prospective clinical trial. METHODS: We enrolled HIV-infected women aged 18-35 years in South Africa and Uganda who had regular menses, were sexually active, and had no medical contraindications to COC use. We enrolled 196 women taking nevirapine-containing ART and 206 women not yet eligible for ART as a control group. We treated all participants with low-dose COCs. Our main outcomes were ovulation and pregnancy rates. We estimated ovulation in the first two cycles using weekly serum progesterone and tested for pregnancy monthly for 24 weeks. RESULTS: The median age of participants was 29 and their median CD4 cell count was 486. In the ART group, 43 of 168 (26%) ovulated in cycle 1, 30 of 163 (18%) in cycle 2, and 18 of 163 (11%) in both cycles. In the non-ART group, 26 of 168 (16%) ovulated in cycle 1, 31 of 165 (19%) in cycle 2, and 20 of 165 (12%) in both cycles. We found no significant difference in ovulation rates between groups: unadjusted odds ratio 1.36 (95% confidence interval 0.85-2.18). Pregnancy rates also did not differ: 10.0 per 100-women-years in the ART group and 10.1 per 100-women-years in the non-ART group. Self-reported COC adherence, condom use, vaginal bleeding, and adverse events were similar. Five serious adverse events were reported, all in the non-ART group. CONCLUSION: ART use did not affect risk of ovulation or pregnancy in women taking COCs, suggesting that nevirapine-containing ART does not interfere with COC contraceptive effectiveness.

Exploration of a new procedure for sterilization by intrauterine instillation of a methylcellulose gel.

BACKGROUND: Our goal was to evaluate a new gel and procedure for non-surgical sterilization. STUDY DESIGN: We injected a methylcellulose-based gel containing a radiographic contrast agent into the uteri of 15 women, varying the gel viscosity, volume injected, injection speed and continuity and duration of cervical blockage. We monitored gel distribution with fluoroscopy and spot imaging, and subjects' condition by interview and examination. RESULTS: The gel and procedure were safe and acceptable. The low-viscosity gel reached at least the ampullae of all tubes, but retention in the isthmuses was shorter than 5 min in more than 25% of tubes studied. The high-viscosity gel did not consistently pass into and through the fallopian tubes. CONCLUSIONS: This study did not identify a gel and insertion procedure that would reliably provide exposure of both fallopian tubes to a sclerosing agent for more than a brief period of time.

SAVVY vaginal gel (C31G) for prevention of HIV infection: a randomized controlled trial in Nigeria.

BACKGROUND: The objective of this trial was to determine the effectiveness of 1.0% C31G (SAVVY) in preventing male-to-female vaginal transmission of HIV infection among women at high risk. METHODOLOGY/PRINCIPAL FINDINGS: This was a Phase 3, double-blind, randomized, placebo-controlled trial. Participants made up to 12 monthly follow-up visits for HIV testing, adverse event reporting, and study product supply. The study was conducted between September 2004 and December 2006 in Lagos and Ibadan, Nigeria, where we enrolled 2153 HIV-negative women at high risk of HIV infection. Participants were randomized 1 ratio 1 to SAVVY or placebo. The effectiveness endpoint was incidence of HIV infection as indicated by detection of HIV antibodies in oral mucosal transudate (rapid test) or blood (ELISA), and confirmed by Western blot or PCR testing. We observed 33 seroconversions (21 in the SAVVY group, 12 in the placebo group). The Kaplan-Meier estimates of the cumulative probability of HIV infection at 12 months were 0.028 in the SAVVY group and 0.015 in the placebo group (2-sided p-value for the log-rank test of treatment effect 0.121). The point estimate of the hazard ratio was 1.7 for SAVVY versus placebo (95% confidence interval 0.9, 3.5). Because of lower-than-expected HIV incidence, we did not observe the required number of HIV infections (66) for adequate power to detect an effect of SAVVY. Follow-up frequencies of adverse events, reproductive tract adverse events, abnormal pelvic examination findings, chlamydial infections and vaginal infections were similar in the study arms. No serious adverse event was attributable to SAVVY use. CONCLUSIONS/SIGNIFICANCE: SAVVY did not reduce the incidence of HIV infection. Although the hazard ratio was higher in the SAVVY than the placebo group, we cannot conclude that there was a harmful treatment effect of SAVVY.