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

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ClinicalTrials.gov Identifier: NCT03677336
Recruitment Status : Completed
First Posted : September 19, 2018
Last Update Posted : December 17, 2020
Sponsor:
Collaborators:
Universitätsklinikum Hamburg-Eppendorf
Abbott
KU Leuven
Information provided by (Responsible Party):
Mackens Shari, CRG UZ Brussel

Brief 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.

Condition or disease Intervention/treatment Phase
Infertility, Female Infertility Genital Diseases, Male Genital Diseases, Female Progesterone Dydrogesterone Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Progestins Drug: Dydrogesterone Oral Tablet Drug: Micronized progesterone Drug: Placebo Dydrogesterone oral tablet Drug: Placebo Micronized progesterone Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: A randomised, cross-over, double blind double dummy study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Blinded and packaged medication will be provided to the investigational site and dispensed to the participants. The participants, their treating physicians and the investigators will be blinded for the randomization of subjects to the treatment groups. Of both treatment medications, OD and MVP, a placebo version will be available and administered in both oocyte donation cycles. The medication will be given in a double blind double dummy fashion. All the tablets and capsules will be identical in appearance, shape, smell and taste, and packaged in the proper proportion to assure desired dosages and maintenance of the blinding.
Primary Purpose: Treatment
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.
Actual Study Start Date : May 1, 2019
Actual Primary Completion Date : August 24, 2020
Actual Study Completion Date : August 24, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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:
  • OD
  • Duphaston

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:
  • MVP
  • Utrogestan

Drug: Placebo Dydrogesterone oral tablet
Tablet, indistinguishable from dydrogesterone oral tablet
Other Name: Placebo OD

Drug: Placebo Micronized progesterone
Capsule, indistinguishable from micronized vaginal progesterone capsules
Other Name: Placebo MVP

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:
  • OD
  • Duphaston

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:
  • MVP
  • Utrogestan

Drug: Placebo Dydrogesterone oral tablet
Tablet, indistinguishable from dydrogesterone oral tablet
Other Name: Placebo OD

Drug: Placebo Micronized progesterone
Capsule, indistinguishable from micronized vaginal progesterone capsules
Other Name: Placebo MVP




Primary Outcome Measures :
  1. Molecular endometrial level using illumina RNA-seq [ Time Frame: On the eight day (at 8am) of LPS intake ]
    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

  2. Molecular endometrial level using immunohistochemistry [ Time Frame: On the eight day (at 8am) of LPS intake ]
    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

  3. Molecular endometrial level using flow cytometry [ Time Frame: On the eight day (at 8am) of LPS intake ]
    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


Secondary Outcome Measures :
  1. Difference in pharmacokinetic profile: Progesterone: AUC0-τ [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  2. Difference in pharmacokinetic profile: Progesterone: AUC0-t [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  3. Difference in pharmacokinetic profile: Progesterone: Cmax [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  4. Difference in pharmacokinetic profile: Progesterone: tmax [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  5. Difference in pharmacokinetic profile: Progesterone: Ctrough [ Time Frame: On the eight day of LPS intake: 1 hour before morning dose. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  6. Difference in pharmacokinetic profile: Progesterone: λz [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  7. Difference in pharmacokinetic profile: Progesterone: t1/2 [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  8. Difference in pharmacokinetic profile: Progesterone: CL/F [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  9. Difference in pharmacokinetic profile: Progesterone: Vz/F [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  10. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: AUC0-τ [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  11. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: ratios of AUC0-τ of dydrogesterone and DHD [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  12. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: AUC0-t [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  13. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: ratios of AUC0-t of dydrogesterone and DHD [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  14. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: Cmax [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  15. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: ratios of Cmax of dydrogesterone and DHD [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  16. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: tmax [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  17. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: Ctrough [ Time Frame: On the eight day of LPS intake: 1 hour before morning dose. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  18. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: λz [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  19. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: t1/2 [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  20. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: CL/F [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  21. Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: Vz/F [ Time Frame: 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. ]
    using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS)

  22. Difference in peripheral immunology [ Time Frame: On the first and eight day of LPS intake, 1hour before morning dose at 9 am. ]
    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)

  23. Difference in microbiota in the female genital tract [ Time Frame: On the first and eight day of LPS intake, 1 hour before morning dose at 9 am. ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03677336


Locations
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Belgium
Centrum voor Reproductieve Geneeskunde
Jette, Brussel, Belgium, 1090
Sponsors and Collaborators
CRG UZ Brussel
Universitätsklinikum Hamburg-Eppendorf
Abbott
KU Leuven
Investigators
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Principal Investigator: Herman Tournaye, PhD, MD Head of department CRG
Publications:
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Responsible Party: Mackens Shari, Principal investigator, CRG UZ Brussel
ClinicalTrials.gov Identifier: NCT03677336    
Other Study ID Numbers: DYDRA001
2018-000105-23 ( EudraCT Number )
First Posted: September 19, 2018    Key Record Dates
Last Update Posted: December 17, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Additional relevant MeSH terms:
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Infertility
Infertility, Female
Progesterone
Dydrogesterone
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs