A Real-world study to evaluate the Reproductive outcomes and Safety Profile in patients treated with Dydrogesterone for Luteal Phase Support in ART: A Prospective Observational Study

Study Title A Real-world study to evaluate the Reproductive outcomes and Safety Profile in patients treated with Dydrogesterone for Luteal Phase Support in ART: A Prospective Observational Study

Background Patients with threatening or recurrent miscarriages are given progestogens in the first trimester to help the pregnancy progress, although this treatment is controversial. Micronized Progesterone (P4) supplementation is safe and effective; however, most patients find the vaginal or subcutaneous injection unreliable. [1] Dydrogesterone (DG) is a retroprogesterone, it has replaced micronized P4 in clinical practice with high patient compliance. Similarly, for Luteal phase support during the Assisted Reproductive Techniques (ART) the usual treatment provided is Progesterone supplementation or human chorionic gonadotropin (hCG). However, these are associated with risk of ovarian hyperstimulation syndrome. Dydrogesterone is an established oral retro progesterone is being used for treatment of threatened and recurrent miscarriage (associated with proven progesterone deficiency), and infertility due to luteal phase insufficiency since 1960. Recent clinical trials have supported the use of Dydrogesterone which is proven to be as effective as Micronized Vaginal Progesterone (P4), hence the doctors are using it routinely for Luteal Phase Support during the Assisted reproductive techniques (ART) [2] Dydrogesterone, is a powerful oral progesterone receptor agonist discovered in the 1950s, has been widely used since the 1960s for menstrual problems like premenstrual syndrome, menstrual cycle irregularity, endometriosis, threatening and recurrent miscarriages, and postmenopausal hormone therapy. Unlike other progestins, dydrogesterone and its principal active metabolite, 20α hydroxy-dydrogesterone, have no clinically meaningful agonistic or antagonistic activity on the androgen, oestrogen, and glucocorticoid receptors and only moderate anti mineralocorticoid characteristics [3]

Due to Dydrogesterone’s excellent selectivity for the progesterone receptor, it can be administered at levels 10–20 times lower than micronized progesterone. In addition, unlike other forms of progesterone, the primary metabolite of dydrogesterone, 20-dihydro-dydrogesterone, has the same progestogenic selectivity as the parent molecule, hence decreasing side effects. Dydrogesterone has been shown to have a good safety profile with a low incidence of maternal complications. It also seems to be as well tolerated as vaginal progesterone in safety analyses from studies assessing Dydrogesterone use in luteal phase support (LPS) during in vitro fertilization (IVF) as well as those investigating Dydrogesterone use in threatened and recurrent miscarriage. An RCT comparing Dydrogesterone versus vaginal progesterone gel in luteal phase support confirmed that patients receiving progesterone gel experienced a higher incidence of vaginal irritation and discharge, vaginal bleeding, and interference with sexual activity compared with patients receiving Dydrogesterone [4] There are no sufficient data of larger real-world evidence-based studies conducted in the Indian setting. Hence this real-world, multicenter, prospective, observational study has been planned to evaluate the effectiveness of Dydrogesterone and patient outcomes in Luteal Phase Support treatment.

Study Objective

Primary objective:

To evaluate the Reproductive outcomes in patients treated with Dydrogesterone for Luteal Phase Support.

Secondary Objective:

To evaluate the safety in IVF patients treated with Dydrogesterone.

Study Design

A Prospective, Multicentric, Observational, Real-world Evidence Study

Study Phase

Real-world, Observational Study

Study Sites

The study is planned to be conducted at 50 sites and 9 locations across India

Sample size

The required sample size for recruitment for the study would be 431 patients. However, we plan to enrol 1000 female patients undergoing LPS treatment from up to 50 clinical study sites in India to meet the required sample size number.

Study Patients

Inclusion Criteria:

Patients meeting with following criteria to be included in the study:

Female patients of age ≥ 21 years.

Patients who are legally married

Patients who require Luteal Phase Support during the Assisted reproductive techniques (ART)

Patients who are prescribed Dydrogesterone as part of routine clinical practice as determined by the Investigator.

Patients or their legally representatives who are willing provide written informed consent to participate in the study and are willing to adhere to the study procedures as per the protocol.

Exclusion Criteria:

Patients meeting with following criteria to be excluded from the study:

Patients with known severe liver or severe kidney or liver dysfunction at the time of initiation of trial

Patients who are allergic to Dydrogesterone

Presence of any other clinically significant disease or laboratory findings that in the Investigator’s opinion may affect the study outcome parameter data.

Participation in another study concurrently or within 4 weeks before initiation of trial.

Study Medications

Dydrogesterone

Study Duration

Enrolment : 2 Months, Follow-up : 3 Months

Study Follow-up Duration/Visits

Once enrolled into the study the patient will be instructed to return for follow-up after +12 ±5 days, 30 ±10 days, & at 70 ±10 days post embryo transfer, clinical pregnancy and at on-going pregnancy of embryo transfer. In between follow-up of the patients as and when necessary, will be performed by the Investigators at their discretion as part of routine clinical practice.

Primary Outcomes

Proportion of patients with presence of Foetal Heartbeat at approximately 7 weeks of pregnancy.

Proportion of patients with presence of Foetal Heartbeat at 12 weeks of pregnancy.

Physician’s global assessment of safety and tolerability of the treatment with Dydrogesterone using a 5-point Likert Scale.

Patient’s global assessment of acceptability, satisfaction, and tolerability of the treatment with Dydrogesterone using a 5-point Likert Scale.

Secondary Outcomes

Proportion of patients with positive pregnancy test at +12 ±5 days, 30 ±10 days, & at 70 ±10 days after embryo transfer (Biochemical Evaluation through Beta-HCG).

Assessment of Per vaginal Bleeding

Adverse events and serious adverse events reported by patient or identified by the investigator will be recorded and reported.

Safety Outcomes

Adverse events (AE) or serious adverse events (SAE), either spontaneously reported by the patient, or noticed by the investigator will be recorded during the study.

Study Methodology

This is a prospective, multicentre, observational, real-world, investigator-initiated clinical study.

Infertility patients who are treated with Dydrogesterone by the Investigator as part of routine clinical practice will be considered for enrolment into the study. Written informed consent will be obtained from the patients prior to their enrolment into the study.

We plan to enrol 1,000 female patients undergoing LPS treatment from up to 50 clinical study sites in India. After enrolment the Investigator would request the patient to come for follow-up once after +12 ±5 days, 30 ±10 days, & at 70 ±10 days post embryo transfer, then at 6 weeks post embryo transfer and at 12 weeks post embryo transfer. During the follow-up visits patient’s pregnancy status and study outcomes will be assessed.

The patient’s acceptability, satisfaction, tolerability of treatment with Dydrogesterone using a 5-point Likert scale will be reviewed by the investigator at the clinic after 12 weeks. As well as Physician’s global assessment of safety and tolerability of the treatment with Dydrogesterone will be captured using a 5-point Likert scale after 12 weeks of treatment with Dydrogesterone. The duration of study for each study patient would be 12 weeks. The study will be completed after 12 weeks.

Statistical Methodology

Demographic Characteristics:

Continuous data like Age, Height, Weight etc., will be summarized with n, mean, SD, and range. Categorical data will be depicted with count (%)

Study Outcome Analysis:

For continuous variables n, mean, SD, range and mean change from baseline will be derived and paired t-test will be applied to assess the statistical significance.

For categorical variables such the results will be summarized with count (%). If applicable chi-square test will be performed to assess the statistical significance.

A p-value of <0.05 will be considered as statistically significant.

Safety Analysis:

Incidence of adverse events will be summarized with count (%). Other safety measures such as physical examination and vital signs will be summarized using descriptive statistics and change from baseline, if applicable.

All the statistical analysis will be performed using STATA software.