This is a randomized clinical trial designed to evaluate the effectiveness, safety and acceptability of Sayana® Press when injected every 4 months (17-18 weeks) for 3 treatment cycles (12 months) of use.

This is a randomized, partially-blinded, multi-center, parallel-group study to evaluate the effectiveness, PK, safety, and acceptability of Sayana® Press when injected every 4 months (17-18 weeks) rather than the currently prescribed 3-month (12-14 weeks) regimen.

A total of 750 healthy, sexually active women aged 18 to 35 years with regular menstrual cycles and no DMPA use in the previous 12 months will be enrolled and followed for pregnancy. Among all enrolled, 710 will be randomized to receive injections in the abdomen or upper thigh in accordance with the PATH Sayana® injection instructions, which are consistent with prescribing information, for the primary effectiveness analysis. An additional 40 women will be randomized to receive injections subcutaneously in the back of the upper arm to assess whether differences in PK may exist which could impact the grace period for reinjections for that injection site.

A single MPA serum sample will be collected from all participants at baseline. All participants will receive re-injections at month 4 and month 8, and complete their scheduled follow-up at month 12. There will be a plus 7-day grace period for re-injections, but women who are up to 28 days late may continue treatment if they have a negative urine pregnancy test. Urine pregnancy testing will be performed at month 4, at study exit and at any other time during the study if clinically indicated. Participants will be evaluated for injection site reactions and asked to provide information on adverse events, prohibited concomitant medication and other contraceptive use, vaginal bleeding, and method acceptability at all regular follow-up visits (i.e., not including the PK visits at Months 2 and 3). Serious adverse events and adverse events leading to product withdrawal, will be recorded throughout the study.

Inclusion Criteria:

• not pregnant and no desire to become pregnant in the next 18 months
• regular menstrual cycles (25 to 35 days in length when not using hormonal contraception, pregnant, or lactating)
• at risk of pregnancy (no diagnosis of infertility, no history of tubal ligation or hysterectomy, and an average of 1 or more unprotected acts of vaginal intercourse per month)
• in good general health as determined by a medical history
• 18 to 35 years of age, inclusive
• willing to provide informed consent, follow all study requirements, and rely on Sayana® Press injected every 4 months as the only means of contraception for 12 months
• has only one sexual partner and expects to have that same sexual partner for the next 12 months

Exclusion Criteria:

• has a primary partner who has received a vasectomy or is otherwise sterile
• medical contraindications to depot medroxyprogesterone acetate (DMPA) per World Health Organization medical eligibility criteria for contraceptive use
• known HIV-infection (for her or her partner)
• diagnosis or treatment for a sexually transmitted infection in the past month (for her or a partner), excluding recurrent herpes or condyloma
• received an injection of a progestin-only containing contraceptive (DMPA or norethisterone enanthate) in the past 12 months
• received an injection of a combined injectable contraceptive in the past 6 months
• known or suspected allergic reaction to DMPA
• used a levonorgestrel-releasing intrauterine system, NuvaRing, contraceptive patch, oral contraceptives or a contraceptive implant in the 7 days prior to enrollment (PK cohort only)
• previous (within 1 month prior to enrollment), current or planned (in the next 12 months) use of an investigational drug, prohibited drug per protocol or other drug which in the opinion of the site investigator could complicate study findings
• has been pregnant in the past month
• is lactating
• plans to move to another location in the next 12 months
• has a social or medical condition which in the opinion of the site investigator would make study participation unsafe, or interfere with adherence to protocol requirements.

Study sites will collect baseline and longitudinal data among 750 women in Brazil, Chile and the Dominican Republic relevant to the protocol objectives including demographics; sexual, reproductive and medical history; acceptability; serious adverse events; concomitant medication use and laboratory data (including serum blood medroxyprogesterone acetate concentrations in a subset of women).

• FHI 360 will submit the study dataset using the platform-independent and non-proprietary comma separated values (also known as [CSV]) format. The study dataset will be posted to a third-party data repository, then the link will be submitted to USAID's Data Development Library within 30 calendar days after the dataset is first used to produce an Intellectual Work.

A code book defining all variables, a data dictionary describing the relationships among the files within the dataset, and a document describing the methodology used to collect the data will be shared with the study dataset.

Within 30 calendar days after the dataset is first used to produce an Intellectual Work

12 months

Neither participants nor site staff will be blinded to SC injection sites. However, laboratory staff analyzing serum MPA specimens and staff at FHI 360 responsible for adjudicating pregnancy outcomes and coding adverse events will be blinded to individual participant injection site assignments for the duration of each participant's follow up.