Dydrogesterone, Genital Diseases, Female, Genital Diseases, Male, Hormones, Hormones, Hormone Substitutes, and Hormone Antagonists, Infertility, Infertility, Female, Physiological Effects of Drugs, Progesterone, Progestins
Conditions
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.
Interventions
Tablet, oral, 10 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days
DRUGMicronized progesterone
Capsule, vaginal, 200 mg, 3 times daily, starting on the day of oocyte retrieval in the morning and during 8 days
DRUGPlacebo Dydrogesterone oral tablet
Tablet, indistinguishable from dydrogesterone oral tablet
DRUGPlacebo Micronized progesterone
Capsule, indistinguishable from micronized vaginal progesterone capsules
Sponsors
Universitätsklinikum Hamburg-Eppendorf
Abbott
KU Leuven
CRG UZ Brussel
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
Intervention model description
A randomised, cross-over, double blind double dummy study
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Molecular endometrial level using illumina RNA-seq | 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 |
| Molecular endometrial level using immunohistochemistry | 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 |
| Molecular endometrial level using flow cytometry | 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
| Measure | Time frame | Description |
|---|---|---|
| Difference in pharmacokinetic profile: Progesterone: tmax | 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) |
| Difference in pharmacokinetic profile: Progesterone: Ctrough | On the eight day of LPS intake: 1 hour before morning dose. | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) |
| Difference in pharmacokinetic profile: Progesterone: λz | 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) |
| Difference in pharmacokinetic profile: Progesterone: t1/2 | 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) |
| Difference in pharmacokinetic profile: Progesterone: CL/F | 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) |
| Difference in pharmacokinetic profile: Progesterone: Vz/F | 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) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: AUC0-τ | 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) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: ratios of AUC0-τ of dydrogesterone and DHD | 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) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: AUC0-t | 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) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: ratios of AUC0-t of dydrogesterone and DHD | 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) |
| Difference in pharmacokinetic profile: Progesterone: AUC0-τ | 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) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: ratios of Cmax of dydrogesterone and DHD | 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) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: tmax | 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) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: Ctrough | On the eight day of LPS intake: 1 hour before morning dose. | using Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: λz | 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) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: t1/2 | 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) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: CL/F | 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) |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: Vz/F | 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) |
| Difference in peripheral immunology | 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) |
| Difference in microbiota in the female genital tract | 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 |
| Difference in pharmacokinetic profile: Dydrogesterone and 20α-dihydrodydrogesterone: Cmax | 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) |
| Difference in pharmacokinetic profile: Progesterone: AUC0-t | 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) |
| Difference in pharmacokinetic profile: Progesterone: Cmax | 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) |
Countries
Belgium
Outcome results
None listed