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.

Potential biomarkers to predict return to fertility after discontinuation of female contraceptives-looking to the future.

Nowadays there are multiple types of contraceptive methods, from reversible to permanent, for those choosing to delay pregnancy. Misconceptions about contraception and infertility are a key factor for discontinuation or the uptake of family planning methods. Regaining fertility (the ability to conceive) after contraceptive discontinuation is therefore pivotal. Technical studies to date have evaluated return to fertility by assessing pregnancy as an outcome, with variable results, or return to ovulation as a surrogate measure by assessing hormone levels (such as progesterone, LH, FSH) with or without transvaginal ultrasound. In general, relying on time to pregnancy as an indicator of return to fertility following contraceptive method discontinuation can be problematic due to variable factors independent of contraceptive effects on fertility, hormone clearance, and fertility recovery. Since the ability to conceive after contraceptive method discontinuation is a critical factor influencing product uptake, it is important to have robust biomarkers that easily and accurately predict the timing of fertility return following contraception and isolate that recovery from extrinsic and circumstantial factors. The main aim of this review is to summarize the current approaches, existing knowledge, and gaps in methods of evaluating return-to-fertility as well as to provide insights into the potential of new biomarkers to more accurately predict fertility restoration after contraceptive discontinuation. Biomarker candidates proposed in this document include those associated with folliculogenesis, cumulus cell expansion, follicular rupture and ovulation, and endometrial transport and receptivity which have been selected and scored on predefined criteria meant to evaluate their probable viability for advancement. The review also describes limitations, regulatory requirements, and a potential path to clinically testing these selected biomarkers. It is important to understand fertility restoration after contraceptive method discontinuation to provide users and health providers with accurate evidence-based information. Predictive biomarkers, if easy and low-cost, have the potential to enable robust evaluation of RTF, and provide potential users the information they desire when selecting a contraceptive method. This could lead to expanded uptake and continuation of modern contraception and inform the development of new contraceptive methods to widen user's family planning choices.

What Have We Learned? Implementation of a Shared Learning Agenda and Access Strategy for the Hormonal Intrauterine Device.

In 2015, a global learning agenda for the hormonal intrauterine device (IUD) was developed with priority research questions regarding use of the method in low- and middle-income countries. In addition, members of the Hormonal IUD Access Group aligned on a strategy to expand access in the context of volunteerism and contraceptive method choice. This article synthesizes evidence generated since then and describes steps taken to address demand- and supply-side barriers to access. Findings demonstrated high continuation rates and satisfaction among hormonal IUD users that are comparable to other long-acting reversible contraceptives (LARCs). Across studies, a sizable number of users reported they would have chosen a short-acting method or no method at all if the hormonal IUD were not an option, which suggests that women did not see the hormonal IUD as interchangeable with other LARC options and thus it may fill an important niche in the market. With several countries now poised to scale up the method, resource mobilization will be key. On the demand side, investments in implementation research will be critical to understanding how best to launch and scale the method, while ensuring the sustainability of multiple quality-assured suppliers with affordable public-sector pricing will be necessary on the supply side.

Return to ovulation after Sayana Press is injected every 4 months for one year: Empirical and pharmacokinetic/pharmacodynamic modeling results.

Objective: To characterize return to ovulation after injecting Sayana Press (104 mg/0.65 mL medroxyprogesterone acetate [MPA] in the Uniject device) every 4 months for 1 year of treatment. Study design: We followed a subset of women for return to ovulation in a trial that demonstrated Sayana Press remains highly effective when the subcutaneous reinjection interval is extended from 3 to 4 months. We measured serum progesterone in weeks 38 to 42 and 46 to 50 after a final (third) injection and used a concentration ≥4.7 ng/mL as a surrogate for ovulation. We also performed pharmacokinetic and pharmacodynamic modeling to predict differences in MPA accumulation and return to ovulation had - contrary to fact - injections been given every 3 months. Results: Ten of 19 women (53%; 95% confidence interval: 29-76) ovulated within 50 weeks of their last injection. We predicted that typical 12-month trough MPA concentrations are 34% lower (0.46 vs 0.69 ng/mL) and the median time from last dose to ovulation is 1.1 months shorter (13.1 vs 14.2 months) when injections are given every four months for 1 year. Conclusion: Extending the Sayana Press reinjection interval from 3 to 4 months leads to less drug accumulation, without a noticeable loss in efficacy. Although the Sayana Press patient leaflet specifies that over 80% of women desiring pregnancy will conceive within a year of stopping the method (independent of treatment duration), our empirical and modeling results indicate women should anticipate waiting a year or more for fertility to return after repeat dosing, with a somewhat shorter delay were the reinjection interval extended to four months. Implications: Providers should counsel women regarding the distinct possibility that return to fertility will take a year or longer following repeat use of Sayana Press. Extending the dosing interval from 3 to 4 months would result in approximately a 1-month shorter delay, without any appreciable reduction in contraceptive efficacy.

Global research and learning agenda for building evidence on contraceptive-induced menstrual changes for research, product development, policies, and programs.

Background: Contraceptive-induced menstrual changes (CIMCs) can affect family planning (FP) users' lives in both positive and negative ways, resulting in both opportunities and consequences. Despite this, and despite the important links between FP and menstrual health (MH), neither field adequately addresses CIMCs, including in research, product development, policies, and programs globally. Methods: In November 2020, a convening of both MH and FP experts reviewed the existing evidence on CIMCs and identified significant gaps in key areas. Results: These gaps led to the establishment of a CIMC Task Force in April 2021 and the development of the Global Research and Learning Agenda: Building Evidence on Contraceptive-Induced Menstrual Changes in Research, Product Development, Policies, and Programs Globally (the CIMC RLA) , which includes four research agendas for (1) measurement, (2) contraceptive research and development (R&D) and biomedical research, (3) social-behavioral and user preferences research, and (4) programmatic research. Conclusions: Guided by the CIMC RLA, researchers, product developers, health care providers, program implementers, advocates, policymakers, and funders are urged to conduct research and implement strategies to address the beneficial and negative effects of CIMCs and support the integration of FP and MH. CIMCs need to be addressed to improve the health and well-being of women, girls, and other people who menstruate and use contraceptives globally. Disclaimer : The views expressed in this article are those of the authors. Publication in Gates Open Research does not imply endorsement by the Gates Foundation.

Ovulation suppression following subcutaneous administration of depot medroxyprogesterone acetate.

Objectives: To characterize the relationship between serum medroxyprogesterone acetate (MPA) concentrations and ovulation suppression, and to estimate the risk of ovulation for investigational subcutaneous regimens of Depo-Provera CI (Depo-Provera) and Depo-subQ Provera 104 (Depo-subQ). Study Design: We performed a secondary analysis of 2 studies that assessed the pharmacokinetics and pharmacodynamics of MPA when Depo-Provera is administered subcutaneously rather than by the labeled intramuscular route. Each woman received a single 45 mg to 300 mg subcutaneous injection of Depo-Provera, a single 104 mg subcutaneous injection of Depo-subQ, or 2 injections of Depo-subQ at 3-month intervals. We used an elevation of serum progesterone ≥4.7 ng/mL as a surrogate for ovulation and non-parametric statistical methods to assess pharmacokinetic and pharmacodynamic relationships. Results: This analysis included 101 women with body mass index (BMI) 18 to 34 kg/m2. Return of ovulation occurred at a median MPA concentration of 0.07 ng/mL (95% CI: 0.06-0.08) and the 90th percentile was 0.10 ng/mL (95% CI: 0.09-0.14). Neither age, race, nor BMI significantly influenced this relationship. The estimated probabilities of ovulation within 4 months of a 104 mg subcutaneous injection and within 7 months of a 150 mg subcutaneous injection (6 plus a 1-month grace) were each below 2.2%. Conclusions: The typical MPA concentration associated with loss of ovulation suppression is substantially less than the commonly cited threshold of 0.2 ng/mL. Based on our results, MPA levels would rarely be low enough to permit ovulation if the Depo-subQ reinjection interval were extended to four months or if 150 mg Depo-Provera were injected subcutaneously every 6 months. Implications: Extending the three-month Depo-subQ reinjection interval by one month would result in a 25% reduction in yearly MPA exposure, with little risk of pregnancy. Off-label subcutaneous administration of 150 mg Depo-Provera every 6 months would be a highly effective repurposing of an excellent product, with a similar reduction in cumulative exposure.

Contraceptive effectiveness, pharmacokinetics, and safety of Sayana® Press when injected every four months: a multicenter phase 3 trial.

BACKGROUND: Sayana Press® is a 3-monthly contraceptive injection approved by regulatory agencies in more than 40 countries worldwide. Existing effectiveness and pharmacokinetics (PK) data suggest that high contraceptive efficacy may be maintained if the reinjection interval of Sayana Press is extended from 3 to 4 months. METHODS: We conducted a phase 3 trial at three sites in the Dominican Republic, Brazil, and Chile from September 2017 through April 2020. We enrolled 750 women at risk of pregnancy who agreed to use Sayana Press off-label every 4 months (3 treatment cycles) for 12 months. The effectiveness cohort included 710 participants randomized equally to receive injections in the abdomen or thigh. Forty additional participants received injections in the back of the upper arm for comparative PK analyses. The primary outcome was pregnancy, defined by a positive urine pregnancy test confirmed by ultrasound and/or serum human chorionic gonadotropin. Secondary outcomes included PK, safety, and acceptability. Laboratory and trial Sponsor staff were blind to injection site. This study is registered with ClinicalTrials.gov, number NCT03154125. FINDINGS: There were no pregnancies during follow-up; the Pearl Index during 629.3 woman-years (WY) of follow-up in the primary effectiveness analysis was 0.00 (95% CI 0.00, 0.59). Pharmacokinetic profiles differed by injection site, with higher geometric mean (GM) medroxyprogesterone acetate concentrations for the abdomen than the thigh and arm. At month 8, significantly higher GM concentrations were observed in the abdomen and the thigh as compared to the arm, as well as at month 12 in the abdomen as compared to the arm. Injection site reactions were reported by 10.7% of participants. INTERPRETATION: Both pregnancy and PK results confirm that Sayana Press is a highly effective contraceptive method when administered every 4 months. These findings may inform modification of the dosing schedule, or duration of the grace period for reinjection, or both, to reduce overall drug exposure while maintaining contraceptive efficacy. FUNDING: This work is made possible by the generous support of the American people through the U.S. Agency for International Development (USAID), provided to FHI 360 through Cooperative Agreement AID-OAA-A-15-00,045, and a grant from the Gates Foundation. The contents are the responsibility of FHI 360 and do not necessarily reflect the views of USAID, the United States Government, or the Gates Foundation, nor does any mention of trade names, commercial products, or organizations imply endorsement by FHI 360, USAID, the United States Government, or the Gates Foundation.

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.

Levonorgestrel release rates measured through analysis of two-rod contraceptive explants.

OBJECTIVE: The objective was to characterize and compare in vivo rates of levonorgestrel (LNG) release from Sino-implant (II) and Jadelle® contraceptive implants. STUDY DESIGN: We sampled 48 Sino-implant (II) and 49 Jadelle® explant sets for residual LNG content from participants treated for up to 51 months in a randomized contraceptive efficacy trial in the Dominican Republic (DR). Additional Sino-implant (II) explants were obtained from 8 women who became pregnant in the DR trial and 10 who contributed 3 to 5 years of use in a cohort study in China. Baseline LNG loads were estimated from five unused implant sets per device type. Release profiles were estimated using mixture models that captured initial burst fractions and compared with efficacy and pharmacokinetics data from the DR trial. RESULTS: Estimated baseline LNG loads for Sino-implant (II) and Jadelle® were 142.8 mg and 150.5 mg, respectively (vs. the labeled 150 mg). There was an initial burst release of drug (5.6% and 7.9%, respectively) followed by an exponential decrease in LNG content evident for each device. Release rates were significantly lower for Sino-implant (II) throughout the treatment period, with estimated rates after 3 years of 24.2 mcg/day and 29.0 mcg/day for Sino-implant (II) and Jadelle®, respectively. The estimated Sino-implant (II) rate after 3 years was similar to the predicted rate after 5 years (23.6 mcg/day) for Jadelle® (rate ratio: 1.03; 95% confidence interval: 0.92-1.13). CONCLUSIONS: Sino-implant (II) LNG release rates were significantly lower than Jadelle® with Sino-implant (II) rates through year 3 comparable to Jadelle® rates through year 5. These results reinforce the 3-year duration of action for which Sino-implant (II) was prequalified by the World Health Organization. IMPLICATIONS: This analysis confirms the WHO prequalification of Sino-implant (II) for 3 years of use and supports different durations of action for Jadelle® and Sino-implant (II). It provides additional evidence that this approach can complement efficacy trials in determining duration of action of hormonal contraceptives in general.

Planning for Outcomes (P4O) Modeling Tool: Estimating the Impact of Changing the Proportion of Injectable Progestins in the Contraceptive Method Mix.

BACKGROUND: Observational studies raise concern about a potential link between injectable progestin contraceptive use and HIV acquisition risk. This possible link is particularly relevant in sub-Saharan Africa where HIV risk is high and the method mix is skewed toward injectables. We developed the Planning for Outcomes (P4O) model (https://planning4outcomes.ctiexchange.org/) to predict changes in maternal and child health (MCH) and HIV outcomes that could occur if the proportion of injectables in the method mix is changed. METHODS: P4O incorporates evidence-based assumptions to predict yearly changes in unintended pregnancies, morbidity/mortality, HIV infections (women and infants), and anticipated health care costs associated with changing the proportions of injectable users in 22 selected countries. Users of this model designate all countries or a subset and adjust inputs including percentage of injectable users who discontinue, percentage of discontinuers who begin use of an alternative method, hazard ratio for HIV infection with injectable use, method mix used by injectable discontinuers, annual probabilities of method-specific pregnancy and mother-to-child transmission of HIV, condom effectiveness against HIV, risk of HIV during pregnancy, and HIV incidence among women of reproductive age. RESULTS: Illustrative results from all sub-Saharan African countries combined and from selected countries demonstrate the potential of P4O to inform program planning and procurement decisions. In countries with high use of long-acting reversible contraception, the removal of injectables from the method mix is associated with improvement in MCH and HIV indicators if most injectable users switch to more effective methods (e.g., implants). In countries with high use of short-acting methods (e.g., condoms), the model predicts mostly negative MCH outcomes. CONCLUSIONS: Policy makers and program planners may use P4O to inform programming and policy decisions. In all scenarios, programmatic preparation to accommodate changes to the contraceptive method mix, considerations of how the individual desires of women will be addressed, and potential burden of anticipated MCH-related costs warrant advanced consideration.

Pharmacokinetic, biologic and epidemiologic differences in MPA- and NET-based progestin-only injectable contraceptives relative to the potential impact on HIV acquisition in women.

Access to safe and effective contraceptive choices is a reproductive right and contributes tremendously to improvements in maternal and child health. Progestin-only injectables, particularly intramuscularly injected depot medroxyprogesterone acetate (DMPA-IM), have received increased attention given findings suggesting a potential association with increased HIV risk. For women at high risk of HIV, the World Health Organization's Medical eligibility criteria for contraceptive use currently aggregate recommendations for all progestin-only injectables, including DMPA-IM, subcutaneously injected DMPA (DMPA-SC) and intramuscularly injected norethindrone/ norethisterone enanthate (NET-EN), except in the case of some drug interactions. We considered whether published data indicate differences or similarities between these injectables relevant to risk of acquiring HIV. In vitro data confirm different biological activities of these distinct progestins, including that MPA, and not NET, binds and activates the glucocorticoid receptor resulting in different biological effects relevant to immune function. Limited clinical data suggest changes in immunologic activity following DMPA-IM and NET-EN initiation, but interstudy variation and study design differences diminish ability to determine clinical relevance and the degree to which DMPA-IM and NET-EN could act differentially. The highest-quality epidemiologic studies suggest a potential 40% increase in HIV incidence in users of DMPA-IM relative to women not using hormonal contraception but no significant increase in risk in users of NET-EN. In our opinion, most of the available biologic activity and epidemiologic data indicate that DMPA and NET-EN are likely to act differently, and data remain too limited to evaluate differences between DMPA-IM and DMPA-SC.

Injectable contraception: updates and innovation.

PURPOSE OF REVIEW: Injectable contraception is a highly effective form of birth control that is globally popular. Recent research has focused on ways to make injectables such as depot medroxyprogesterone acetate (DMPA) more accessible and to improve the side-effect profile of injectables. This review will focus on new directions and approaches to the use of injectable contraception. RECENT FINDINGS: Research in the area of injectable contraception has focused on improving access for women through home or self-injection, and also task-shifting and community-based distribution in low-resource areas. Specific to DMPA, studies have focused on lowering the overall dose of medication while maintaining efficacy, and improving drug-delivery systems. More research into the association between DMPA and HIV is needed, and also the effects of administration of DMPA at the time of medication abortion. SUMMARY: Injectable contraceptives are an important part of the global method mix of highly effective birth control. Improving the accessibility and side effect profile of commodities such as DMPA will make injectables even more valuable for women seeking effective contraception.

Medroxyprogesterone acetate levels among Kenyan women using depot medroxyprogesterone acetate in the FEM-PrEP trial.

OBJECTIVE: To describe medroxyprogesterone acetate (MPA) levels among Kenyan depot medroxyprogesterone acetate (DMPA) users in the FEM-PrEP HIV prevention trial, and to compare MPA levels between ARV for HIV prevention (treatment) and placebo groups. STUDY DESIGN: We measured MPA in previously collected plasma samples from 63 Kenyan trial participants who used DMPA for one or two complete intervals. We separately assessed MPA levels among the nine DMPA users who became pregnant at this site. RESULTS: Mean MPA levels at the end of each 12week injection interval were 0.37ng/ml (95% CI: 0.25, 1.99) and 0.28ng/ml (95% CI: 0.19, 1.22) among participants assigned TDF/FTC and 0.49 (95% CI: 0.40, 1.27) and 0.39 (95% CI: 0.31, 1.17) among those assigned placebo. The difference between groups was not statistically significant overall, or in an analysis which adjusted for the observed low adherence to TDF/FTC. Unanticipated findings of this analysis were low 12-week MPA levels among DMPA users in both study arms. Of 61 women who contributed data for the first DMPA injection interval, 26.2% had MPA levels<0.1ng/ml and 9.8% had levels below the detection level (0.02ng/ml) at 12weeks post-injection. Levels were similar at the end of the second injection interval. Five of nine women who became pregnant had levels below 0.15ng/mL at the time of their last negative pregnancy test. CONCLUSIONS: Use of TDF/FTC did not appear to affect serum MPA levels, however we found lower than expected MPA concentrations at the end of the dosing interval among DMPA users in the FEM-PrEP trial, the cause of which are unknown. IMPLICATIONS: This study presents some of the few available data on MPA levels among DMPA users in Africa. The low levels among users described here, together with a number of pregnancies among DMPA users, are potentially concerning and require further investigation.

Addressing gaps in the contraceptive method mix: methods in development.

Despite the availability of a variety of contraceptive methods, millions of women still have an unmet need for contraceptive choices. Short-acting methods are plagued by issues with adherence, leading to imperfect or inconsistent use and subsequent unintended pregnancy. Long-acting contraceptive methods such as intrauterine devices and contraceptive implants, while providing highly effective and safe contraception, do not meet the needs of all women, often due to cost, access or acceptability issues. Several new methods are in various stages of development and are designed to address the shortcomings of current methods. Providers should be aware of these future options and how they might better meet women's needs.