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

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.

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.

Study Overview

• Status: Completed
• Conditions: Infertility; Infertility, Female; Dydrogesterone; Genital Diseases, Female; Progesterone; Hormones; Physiological Effects of Drugs; Genital Diseases, Male; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins
• Intervention / Treatment: Drug: Dydrogesterone Oral Tablet; Drug: Micronized progesterone; Drug: Placebo Dydrogesterone oral tablet; Drug: Placebo Micronized progesterone

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Brussel
    • Jette, Brussel, Belgium, 1090
      • Centrum voor Reproductieve Geneeskunde

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Group l: 1st cycle MVP/placebo OD; 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; Tablet, oral, 10 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days; Other Names: Duphaston; OD; Drug: Micronized progesterone; Capsule, vaginal, 200 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days; Other Names: Utrogestan; MVP; Drug: Placebo Dydrogesterone oral tablet; Tablet, indistinguishable from dydrogesterone oral tablet; Other Names: Placebo OD; Drug: Placebo Micronized progesterone; Capsule, indistinguishable from micronized vaginal progesterone capsules; Other Names: Placebo MVP
Other: Group ll: 1st cycle placebo MVP/OD; 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; Tablet, oral, 10 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days; Other Names: Duphaston; OD; Drug: Micronized progesterone; Capsule, vaginal, 200 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days; Other Names: Utrogestan; MVP; Drug: Placebo Dydrogesterone oral tablet; Tablet, indistinguishable from dydrogesterone oral tablet; Other Names: Placebo OD; Drug: Placebo Micronized progesterone; Capsule, indistinguishable from micronized vaginal progesterone capsules; Other Names: Placebo MVP

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: CRG UZ Brussel
• Collaborators: KU Leuven; Abbott; Universitätsklinikum Hamburg-Eppendorf
• Investigators: Principal Investigator: Herman Tournaye, PhD, MD, Head of department CRG

Publications and helpful links

General Publications

• Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod. 2017 May 1;32(5):1019-1027. doi: 10.1093/humrep/dex023. Erratum In: Hum Reprod. 2017 Oct 1;32(10):2152.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2019
• Primary Completion (Actual): August 24, 2020
• Study Completion (Actual): August 24, 2020

Study Registration Dates

• First Submitted: September 4, 2018
• First Submitted That Met QC Criteria: September 18, 2018
• First Posted (Actual): September 19, 2018

Study Record Updates

• Last Update Posted (Actual): December 17, 2020
• Last Update Submitted That Met QC Criteria: December 14, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility; Infertility, Female; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone; Dydrogesterone
• Other Study ID Numbers: DYDRA001; 2018-000105-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No