PKB171 Against Placebo in Couples With Mild Male Factor Infertility

Phase II/III multicenter, randomized, double‐blind, placebo‐controlled trial to assessthe efficacy and safety of a post‐coital intravaginal gel of PKB171 in couples with mildmale factor infertility.The purpose of this study is to assess the safety and efficacy of the gel PKB171 comparedto a placebo gel in couples with mild male factor infertility, unable to conceive in thelast 6 and 24 months. Gel PKB171 contains pentoxifylline, which is used in assistedreproduction to treat sperm samples because of its ability to improve progressive spermmobility and has reported to increase the pregnancy rate in couples with oligospermiaand/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 atdelivery (preterm, full‐term, post‐term delivery), fetal anomalies, incidence ofobstetric complications (gestational hypertension, gestational diabetes, post‐partumhemorrhage, NICU admission, maternal admission to ICU), mode of delivery, and livebirth rate.Screening period At the first visit (V1), inclusion criteria will be assessed to checkeligibility. 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., themean value over the last six cycles). The length of the menstrual cycle is defined as thenumber of days from the first day of menstrual bleeding to the first day of the nextperiod.The next visit (V2) will be performed between Day 2 and Day 5 of the female subject'smenstrual cycle and after 2 to 5 days of abstinence for the male subject. In this visitthe antral follicle count, spermiogram and biochemical tests will be performed.Randomization visit: Double‐blind treatment period‐ First treatment cycle The couple willbe randomized to Gel PKB171 200 mg or placebo (randomization ratio 1:1). Trial staff willdispense four units (one reserve) of investigational medicinal product (IMP), ovulationtest strips and subject diary and will explain their use to the couple. Trial staff willschedule visit 4 (V4) within 9‐17 days of the menstrual cycle, depending on the menstrualcycle 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 hoursuntil the follicle reaches the desired size (mean diameter of the dominant folliclebetween 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 beinstructed to perform two ovulation tests (LH dipstick) each day, preferably at the sametime 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 atmaximum.Within 72 hours after positive ovulation test, the couple shall have three timesintercourse, at intervals of approximately 24 hours. The minimum interval will be 24hours. IMP will be applied after each intercourse.Within 24 hours after third IMP use, the couple will attend visit V5 for safetyassessments.Post‐treatment period‐ Early follow up The next visit (V6) will be performed 14 daysafter the last intercourse to perform blood pregnancy test.If the pregnancy test is positive, the next visit (V7) will take place 6‐8 weeks afterLMP (2‐4 weeks after V6), to confirm clinical pregnancy and fetal heart activity bytransvaginal ultrasound (TVUS). If heartbeat is not yet visible at this visit, afollow‐up ultrasound will be scheduled one week later to confirm clinical pregnancy andpositive 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 repeateduntil V6 ‐ Cycle 2 (V6.2). If pregnancy test is positive at V6.2, patients will performV7. If pregnancy test is negative at V6.2, patients will repeat the protocol treatmentone more time (cycle 3).It could happen that female menstruation starts before V6, during the next 14 days afterthe 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 telephoneappointments at 14‐16 weeks of pregnancy, 22‐24 weeks of pregnancy and 4 weeks after theestimated delivery date. The following information will be collected: result of thecombined first trimester screening (CFTS) if available, information on pregnancy outcomeand fetal examinations, delivery information (gestational age, delivery mode and/ordelivery complications), infant information (such as sex, birthweight, birth defects).Double‐blind Treatment Period‐ Second treatment cycle If the female subject is notpregnant at V6, trial staff will dispense IMP, ovulation test strips and subject diaryfor the second treatment cycle. Ovulation testing and sexual intercourse, including IMPuse, 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 notpregnant at V6, trial staff will dispense IMP, ovulation test strips and subject diaryfor the second treatment cycle. Ovulation testing and sexual intercourse, including IMPuse, 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 lasttrial visit.