Oral Dydrogesterone (OD) Versus Micronized Vaginal Progesterone (MVP) for Luteal Phase Support (LPS) in IVF/ICSI

Study Overview
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Brief Summary
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Female inability to conceive a child. The purpose of this prospective randomized, double-blinded, double dummy, two-arm cross-over study is to investigate the difference on histological, transcriptional and immunological level in endometrium between 3x10mg Dydrogesterone oral tablets and 3x200 mg Micronized progesterone intravaginal capsules for the luteal support in egg cell donors. Beside that, the pharmacokinetics, the impact on the peripheral immunology (by blood sampling) and the microbiota (by genital swabs) will be investigated.

Official Title
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Oral Dydrogesterone Versus Micronized Vaginal Progesterone for Luteal Phase Support in In Vitro Fertilisation (IVF)/ IntraCytoplasmic Sperm Injection (ICSI): Pharmacokinetics and the Impact on the Endometrium, the Microbiota of the Genital Tract and the Peripheral Immunology. Double Blind Crossover Study.

Conditions
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Progestins, Infertility, Female, Infertility, Genital Diseases, Male, Genital Diseases, Female, Progesterone, Dydrogesterone, Hormones, Hormones, Hormone Substitutes, and Hormone Antagonists, Physiological Effects of Drugs

Intervention / Treatment
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* Drug: Dydrogesterone Oral Tablet
* Drug: Micronized progesterone
* Drug: Placebo Dydrogesterone oral tablet
* Drug: Placebo Micronized progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Oocyte donor candidates Regularly cycling BMI ≥18 and ≤ 29 kg/m2 Signed informed consent Non-smokers. AMH <7,53 and >1,18 ng/mL (90th and 10th percentile for healthy women aged 25-29 according to the used Elecsys® AMH kit by Roche) PRL, T and TSH within the normal limits for the clinical laboratory, or considered not clinically significant by the investigator within 6 months prior or at screening Exclusion Criteria: Intra-uterine device Previous enrollment Evidence of cardiovascular, respiratory, urogenital, gastrointestinal/hepatic, hematologic/immunologic, HEENT (head, ears, eyes, nose, throat), dermatologic/connective tissue, musculoskeletal, metabolic/nutritional, endocrine, neurologic/psychiatric, allergy, recent major surgery (< 3 months), or other relevant diseases as revealed by history, physical examination and/or laboratory assessments which could limit participation in or completion of the study Acute urogenital disease during the course of the study Known allergic reactions to progesterone / dydrogesterone products (active substance or to any of the excipients) Intake of any experimental drug or any participation in any other clinical trial within 30 days prior to study start. Mental disability or any other lack of fitness, in the investigator's opinion, to preclude subjects in or to complete the study. Current or recent substance abuse, including alcohol and tobacco (patients who stopped tobacco usage at least 3 months prior to screening visit would be allowed) Refusal or inability to comply with the requirements of the study protocol for any reason, including scheduled clinic visits and laboratory tests. Known or suspected progestogen dependent neoplasms (e.g. meningioma) Serum progesterone level >1.5 ng/mL at ovulation triggering

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 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
Interventional Model Description: A randomised, cross-over, double blind double dummy study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group l: 1st cycle MVP/placebo OD<br>2 cycles of controlled ovarian stimulation, dual triggering, oocyte retrieval (OR) and LPS, with an interval period of 2 to 12 months. The only difference of the second cycle being the other LPS study medication as compared to the first cycle. 1st cycle: Start on day of oocyte retrieval (OR) (=d1): Dydrogesterone Oral Tablet 10 mg 3 times daily + Placebo micronized vaginal progesterone 200 mg capsules 3 times daily, for 8 days. 2nd cycle: Start on day of oocyte retrieval (OR) (=day 1): 'Micronized Progesterone 200 mg intravaginal capsules 3 times daily + placebo 'Dydrogesterone Oral Tablet 10 mg 3 times daily, for 8 days. | Drug: Dydrogesterone Oral Tablet<br>* Tablet, oral, 10 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days<br>* Other names: Duphaston;Drug: Micronized progesterone<br>* Capsule, vaginal, 200 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days<br>* Other names: Utrogestan;Drug: Placebo Dydrogesterone oral tablet<br>* Tablet, indistinguishable from dydrogesterone oral tablet<br>* Other names: Placebo OD;Drug: Placebo Micronized progesterone<br>* Capsule, indistinguishable from micronized vaginal progesterone capsules<br>* Other names: Placebo MVP;|
| Other: Group ll: 1st cycle placebo MVP/OD<br>2 cycles of controlled ovarian stimulation, dual triggering, oocyte retrieval (OR) and LPS, with an interval period of 2 to 12 months. The only difference of the second cycle being the other LPS study medication as compared to the first cycle. 1st cycle: Start on day of oocyte retrieval (OR) (=day 1): Micronized Progesterone 200 mg intravaginal capsules 3 times daily + placebo Dydrogesterone Oral Tablet 10 mg 3 times daily, for 8 days. 2nd cycle: Start on day of oocyte retrieval (OR) (=day 1): Dydrogesterone Oral Tablet 10 mg 3 times daily + Placebo micronized progesterone 200 mg intravaginal capsules 3 times daily, for 8 days. | Drug: Dydrogesterone Oral Tablet<br>* Tablet, oral, 10 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days<br>* Other names: Duphaston;Drug: Micronized progesterone<br>* Capsule, vaginal, 200 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days<br>* Other names: Utrogestan;Drug: Placebo Dydrogesterone oral tablet<br>* Tablet, indistinguishable from dydrogesterone oral tablet<br>* Other names: Placebo OD;Drug: Placebo Micronized progesterone<br>* Capsule, indistinguishable from micronized vaginal progesterone capsules<br>* Other names: Placebo MVP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular endometrial level using illumina RNA-seq | To study the difference of OD versus MVP as LPS after controlled ovarian stimulation (COS) on the molecular endometrial level using Illumina RNA-seq on endometrial derived single cell suspensions | On the eight day (at 8am) of LPS intake | 
| Molecular endometrial level using immunohistochemistry | To study the difference of OD versus MVP as LPS after controlled ovarian stimulation (COS) on the molecular endometrial level using immunohistochemistry on endometrial derived single cell suspensions | On the eight day (at 8am) of LPS intake | 
| Molecular endometrial level using flow cytometry | To study the difference of OD versus MVP as LPS after controlled ovarian stimulation (COS) on the molecular endometrial level using flow cytometry on endometrial derived single cell suspensions | On the eight day (at 8am) of LPS intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in pharmacokinetic profile: Progesterone: AUC0-τ | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first and eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Progesterone: AUC0-t | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. | 
| Difference in pharmacokinetic profile: Progesterone: Cmax | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first and eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Progesterone: tmax | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first and eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Progesterone: Ctrough | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the eight day of LPS intake: 1 hour before morning dose. | 
| Difference in pharmacokinetic profile: Progesterone: λz | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Progesterone: t1/2 | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Progesterone: CL/F | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Progesterone: Vz/F | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: AUC0-τ | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first and eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: ratios of AUC0-τ of dydrogesterone and DHD | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first and eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: AUC0-t | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: ratios of AUC0-t of dydrogesterone and DHD | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: Cmax | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first and eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: ratios of Cmax of dydrogesterone and DHD | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first and eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: tmax | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the first and eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: Ctrough | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the eight day of LPS intake: 1 hour before morning dose. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: λz | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: t1/2 | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: CL/F | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: Vz/F | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) | On the eight day of LPS intake: 1 hour before morning dose, 0.5 hour, 1 hour, 1 hour 30, 2 hours, 2 hours 30, 3 hours, 4 hours, 5 hours post-dose. One blood sample on the 9th, 10th and 11th day. | 
| Difference in peripheral immunology | To study the effects of OD versus MVP on the peripheral immunology (using flow cytometry to investigate T regulatory and T effector cells derived from peripheral blood) | On the first and eight day of LPS intake, 1hour before morning dose at 9 am. | 
| Difference in microbiota in the female genital tract | by cervical swab, a vaginal swab (posterior fornix) and an intra-uterine sample using an empty embryo catheter. Evaluation using 16S rRNA amplicon sequencing - Illumina miSeq | On the first and eight day of LPS intake, 1 hour before morning dose at 9 am. |