Luteal Phase Ovarian Stimulation With Follitropin Delta and Dydrogesterone

Study Overview
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Brief Summary
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The last decade has shown a progressive scientific interest for new strategies to improve the outcomes of controlled ovarian stimulation (COS). Given the fact that interovulatory period has been described to have multiple waves of follicular recruitment, luteal phase ovarian stimulation (LPOS) has been proposed as new protocol for COS, with satisfactory ovarian response and pregnancy outcomes. On the other hand progestin-primed ovarian stimulation (PPOS) is today considered an innovative protocol aiming to achieve multi-follicle recruitment and block the luteinizing hormone (LH) surge through progesterone administration in place of the traditional down regulating or gonadotropin-releasing hormone (GnRH) antagonist. This protocol has been shown to be equally effective as LH suppression with GnRH antagonist reporting equivalent oocyte retrieval rates, endocrine profiles, viable embryo numbers, and pregnancy outcomes. Due to the feasibility and patients-friendly characteristics of PPOS in oocytes donors, the current study aims to investigate the impact on the number of cumulus-oocyte complexes (COCs) when a PPOS protocol is associated to both conventional follicular phase stimulation and LPOS for vitrification of oocytes in oocyte donors. Moreover, it aims to determine whether LPOS using PPOS protocol has comparable outcomes to conventional follicular phase stimulation with PPOS protocol, in oocyte donor patients.

Detailed Description
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The current study is a single centre randomized, crossover, open label, pilot trial. The study will be conducted on 50 patients who wish to donate their oocytes. All participants will be informed about the nature of the study and informed consent will be taken from all of them. Patients will randomly undergo two treatment sequences, treatment sequence 1 and treatment sequence 2. Treatment sequence 1 consists of treatment A followed by treatment B; treat-ment sequence 2 consists of treatment B followed by treatment A. The time-interval between the two treatments (washout period) will be minimum two months after trigger and maximum twelve months. All patients will undergo PPOS: one cycle with follicular phase ovarian stimulation and one cycle with LPOS. Work up: Complete history, hormonal investigations (FSH, LH, E2, Progesterone, Prolactine, AMH, TSH), Basal transvaginal ultrasound Treatment A: Ovarian stimulation is started on day 2 of the follicular phase with daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily from day 2 of the follicular phase onwards. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 6 until the day of trigger. Patients response will be monitored by: Serum E2, P, FSH, LH and human chorionic gonadotropin (HCG) levels on day 2 of the follicular phase. Patients will be reevaluated on stimulation day 8 every 2 days with ultrasound scan to assess follicular growth and endocrine monitoring with E2, P, FSH and LH levels until the criteria for oocyte trigger are achieved. Treatment B: From day 20 of the menstrual cycle onwards, daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily will be administered. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 6 or when serum LH > 10 IU/L until day of trigger. Patients response will be monitored by: Serum estradiol E2, P, FSH, LH and HCG levels on day 20 of the follicular phase In case of absence of luteal phase values (progesterone > 1.5 ng/ml) at the blood sample of day 20, stimulation will not be started. In this case, hormonal serum assessment with evaluation of E2, P, FSH and LH levels will be repeated every 2 days until luteal phase values will be achieved, and the stimulation will be started. Patient will be reevaluated on stimulation day 8 every 2 days with ultrasound scan to assess follicular growth and endocrine monitoring with E2, P, FSH and LH levels until the criteria for oocyte trigger are achieved. Both treatments: Oocyte maturation trigger will be planned when transvaginal ultrasound shows at least 3 follicles >20mm in diameter with a single subcutaneous injection of GnRH agonist (0.2 mg Gonapeptyl). Oocyte retrieval will be performed 36 hours after trigger. The retrieved cumulus oocyte complexes will be counted, denuded and the number of mature oocytes evaluated Statistical Considerations and Sample size Justification Fifty - patients (25 for each sequence) need to be included. Considering a dropout rate of about 15%, 66 patients will probably be required to reach an adequate sample size.This is a pilot study, and 50 subjects is considered both practically feasible and sufficient to get reliable results in order to guide further trials in this research area. The primary endpoint, the total number of cumulus-oocyte complexes, will be compared between the two treatments using an analysis of variance model with subject, period, and treatment as factors. The mean difference between the two treatments and its 95% confidence interval will be estimated from the model.

Official Title
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Luteal Phase Ovarian Stimulation With Follitropin Delta and Dydrogesterone: a Randomized Cross Over Pilot Trial

Conditions
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Oocyte Donors, Oocyte Donation

Intervention / Treatment
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* Drug: Follitropin delta (Rekovelle)
* Drug: Duphaston
* Drug: GnRH agonist (Gonapeptyl)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass Index (BMI) ≥18 to < 28 Signed informed consent Regular menstrual cycle length i.e. 24-35 days Exclusion Criteria: Contraindications to the use of gonadotropins Endometriosis grade 3-4 Patients with Anti-mullerian hormone (AMH) <1.1 ng/ml and/or antral follicular count (AFC)<7 Patients with Follicle Number Per Ovary (FNPO) ≥ 19 and/or AMH >5ng/ml Patients under contraception with hormonal intrauterine device (IUD) Any untreated endocrine abnormality

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 36 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Follitropin delta and dydrogesterone (treatment A followed by treatment B)<br>Treatment A: Ovarian stimulation is started with daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily from day 2 of the follicular phase onwards. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 until the criteria for oocyte trigger are achieved. Treatment B: From day 20 of the menstrual cycle onwards, daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily will be administered. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 or when serum LH > 10 IU/L until day of trigger. For both treatment (A and B) oocyte maturation trigger will be planned when transvaginal ultrasound shows at least 3 follicles >20mm in diameter with a single subcutaneous injection of GnRH agonist (Gonapeptyl 0.2 mg). Oocyte retrieval will be performed 36 hours after trigger. The retrieved cumulus oocyte complexes will be counted, denuded and the number of mature oocytes evaluated. | Drug: Follitropin delta (Rekovelle)<br>* 12 mcg/day will be used for ovarian stimulation in both arms<br>Drug: Duphaston<br>* 20 mg/day will be used for pituitary suppression in both arms<br>Drug: GnRH agonist (Gonapeptyl)<br>* (2 ampules:0.2 mg) will be used for ovulation triggering in both arms<br>|
| Other: Follitropin delta and dydrogesterone (treatment B followed by treatment A)<br>Treatment B: From day 20 of the menstrual cycle onwards, daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily will be administered. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 or when serum LH > 10 IU/L until day of trigger. Treatment A: Ovarian stimulation is started with daily subcutaneous injections of Follitropin delta12 mcg/daily (Rekovelle) from day 2 of the follicular phase onwards. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 until the criteria for oocyte trigger are achieved. For both treatment (B and A) oocyte maturation trigger will be planned when transvaginal ultrasound shows at least 3 follicles >20mm in diameter with a single subcutaneous injection of GnRH agonist (Gonapeptyl 0.2 mg). Oocyte retrieval will be performed 36 hours after trigger. The retrieved cumulus oocyte complexes will be counted, denuded and the number of mature oocytes evaluated. | Drug: Follitropin delta (Rekovelle)<br>* 12 mcg/day will be used for ovarian stimulation in both arms<br>Drug: Duphaston<br>* 20 mg/day will be used for pituitary suppression in both arms<br>Drug: GnRH agonist (Gonapeptyl)<br>* (2 ampules:0.2 mg) will be used for ovulation triggering in both arms<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of retrieved COCs in both treatment groups | number of retrieved cumulus-oocyte complexes | 10-20 minutes after oocyte retrieval | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endocrine profile in both treatment groups | evaluation of serum E2, FSH, LH, Progesterone | through study completion, an average of 1 year | 
| Consumption of gonadotrophins in both treatment groups | (mcg) of gonadotrophins used during ovarian stimulation | through study completion, an average of 1 year | 
| Duration of ovarian stimulation in both treatment groups | days of ovarian stimulation | through study completion, an average of 1 year | 
| Days of progestin use in both treatment groups | days of progestin use during ovarian stimulation | through study completion, an average of 1 year | 
| Total number of MII oocytes in both treatment groups | the number of MII oocytes retrieved that will be assessed after denudation | 1-2 hours after oocyte retrieval | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cumulus-oocyte complexes, progestin primed ovarian stimulation, controlled ovarian stimulation, luteal phase ovarian stimulation, follicular phase ovarian stimulation, follitropin delta, dydrogesterone