PKB171 Against Placebo in Couples With Mild Male Factor Infertility

Phase II/III multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of a post-coital intravaginal gel of PKB171 in couples with mild male factor infertility.

The purpose of this study is to assess the safety and efficacy of the gel PKB171 compared to a placebo gel in couples with mild male factor infertility, unable to conceive in the last 6 and 24 months. Gel PKB171 contains pentoxifylline, which is used in assisted reproduction to treat sperm samples because of its ability to improve progressive sperm mobility and has reported to increase the pregnancy rate in couples with oligospermia and/or asthenozoospermia previous in vitro fertilization (IVF) failures.

The trial consisted of:

• A screening period
• Up to three double-blind treatment cycles.
• Follow-up of up to 6-8 weeks of gestation to check for clinical pregnancy (detectable fetal heartbeat).
• Long-term follow-up period until 4 weeks after delivery to assess gestational age at delivery (preterm, full-term, post-term delivery), fetal anomalies, incidence of obstetric complications (gestational hypertension, gestational diabetes, post-partum hemorrhage, NICU admission, maternal admission to ICU), mode of delivery, and live birth rate.

Screening period At the first visit (V1), inclusion criteria will be assessed to check eligibility. Trial staff will interview the couple and explain the study protocol. Consent form will be signed at that appointment.

The female subject will be asked about the usual length of her menstrual cycle (i.e., the mean value over the last six cycles). The length of the menstrual cycle is defined as the number of days from the first day of menstrual bleeding to the first day of the next period.

The next visit (V2) will be performed between Day 2 and Day 5 of the female subject's menstrual cycle and after 2 to 5 days of abstinence for the male subject. In this visit the antral follicle count, spermiogram and biochemical tests will be performed.

Randomization visit: Double-blind treatment period- First treatment cycle The couple will be randomized to Gel PKB171 200 mg or placebo (randomization ratio 1:1). Trial staff will dispense four units (one reserve) of investigational medicinal product (IMP), ovulation test strips and subject diary and will explain their use to the couple. Trial staff will schedule visit 4 (V4) within 9-17 days of the menstrual cycle, depending on the menstrual cycle length*, to confirm the presence of a dominant follicle by intravaginal ultrasound (defined as follicle ≥ 14mm). Subsequent follow-ups will be scheduled every 48-72 hours until the follicle reaches the desired size (mean diameter of the dominant follicle between 16 and 18mm).

Once the presence of a 16-18mm follicle has been confirmed, ovulation testing will start (luteinizing hormone (LH) ovulation tests (urine dipstick)). The female subject will be instructed to perform two ovulation tests (LH dipstick) each day, preferably at the same time of day. The tests should be separated by approximately 12 hours (±3 hours). Ovulation testing will be continued until positive result for up to 7 consecutive days at maximum.

Within 72 hours after positive ovulation test, the couple shall have three times intercourse, at intervals of approximately 24 hours. The minimum interval will be 24 hours. IMP will be applied after each intercourse.

Within 24 hours after third IMP use, the couple will attend visit V5 for safety assessments.

Post-treatment period- Early follow up The next visit (V6) will be performed 14 days after the last intercourse to perform blood pregnancy test.

If the pregnancy test is positive, the next visit (V7) will take place 6-8 weeks after LMP (2-4 weeks after V6), to confirm clinical pregnancy and fetal heart activity by transvaginal ultrasound (TVUS). If heartbeat is not yet visible at this visit, a follow-up ultrasound will be scheduled one week later to confirm clinical pregnancy and positive fetal heart activity.

If the pregnancy test is negative, the trial protocol will be repeated in the next cycle. Couples will attend to V3 - Cycle 2 (V3.2) and the study procedures will be repeated until V6 - Cycle 2 (V6.2). If pregnancy test is positive at V6.2, patients will perform V7. If pregnancy test is negative at V6.2, patients will repeat the protocol treatment one more time (cycle 3).

It could happen that female menstruation starts before V6, during the next 14 days after the last intercourse. In this case V6 wouldn't perform and a new cycle would start.

Observation period- Long term follow-up Visits 8, 9 and 10 will be performed as telephone appointments at 14-16 weeks of pregnancy, 22-24 weeks of pregnancy and 4 weeks after the estimated delivery date. The following information will be collected: result of the combined first trimester screening (CFTS) if available, information on pregnancy outcome and fetal examinations, delivery information (gestational age, delivery mode and/or delivery complications), infant information (such as sex, birthweight, birth defects).

Double-blind Treatment Period- Second treatment cycle If the female subject is not pregnant at V6, trial staff will dispense IMP, ovulation test strips and subject diary for the second treatment cycle. Ovulation testing and sexual intercourse, including IMP use, after positive ovulation test will be repeated as in the first treatment cycle.

Double-blind Treatment Period- Third treatment cycle If the female subject is not pregnant at V6, trial staff will dispense IMP, ovulation test strips and subject diary for the second treatment cycle. Ovulation testing and sexual intercourse, including IMP use, after positive ovulation test will be repeated as in the first treatment cycle.

If the female subject is not pregnant at V6 of the third cycle, this will be the last trial visit.