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

Infertility Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03677336
• Other study ID #: DYDRA001
• Secondary ID: 2018-000105-23
• Status: Completed
• Phase: Phase 4
• Start date: May 1, 2019
• Est. completion date: August 24, 2020

Study information

• Verified date: December 2020
• Source: CRG UZ Brussel
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: August 24, 2020
• Est. primary completion date: August 24, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 35 Years

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

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
• Micronized progesterone
Capsule, vaginal, 200 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days
• Placebo Dydrogesterone oral tablet
Tablet, indistinguishable from dydrogesterone oral tablet
• Placebo Micronized progesterone
Capsule, indistinguishable from micronized vaginal progesterone capsules

Locations

Country	Name	City	State
Belgium	Centrum voor Reproductieve Geneeskunde	Jette	Brussel

Sponsors (4)

Lead Sponsor	Collaborator
CRG UZ Brussel	Abbott, KU Leuven, Universitätsklinikum Hamburg-Eppendorf

Country where clinical trial is conducted

Belgium, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Difference in pharmacokinetic profile: Progesterone: AUC0-t	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Difference in pharmacokinetic profile: Progesterone: ?z	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-dihydrodydrogesterone: AUC0-t	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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-dihydrodydrogesterone: ratios of AUC0-t 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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-dihydrodydrogesterone: Ctrough	using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)	On the eight day of LPS intake: 1 hour before morning dose.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-dihydrodydrogesterone: ?z	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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-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.
Secondary	Difference in pharmacokinetic profile: Dydrogesterone and 20a-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.
Secondary	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.
Secondary	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.