E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10016401 |
E.1.2 | Term | Female infertility of other specified origin |
E.1.2 | System Organ Class | 100000004872 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025511 |
E.1.2 | Term | Male infertility, unspecified |
E.1.2 | System Organ Class | 100000004872 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10016403 |
E.1.2 | Term | Female infertility of tubal origin |
E.1.2 | System Organ Class | 100000004872 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. Do specific autocrine, paracrine and endocrine factors act as gate keepers to cyclic follicle recruitment?
2. Does ovarian stimulation disrupt cyclic follicle recruitment by altering these factors and can this effect be modulated by suppressing the associated supra-physiological rise in sex steroids using co-treatment with aromatase inhibitors?
3. Does suppression of supra-physiological estradiol with AI alter the intrafollicular endocrine milieu, reduce uterine contractility and the disruption of cytokine markers of endometrial receptivity caused by ovarian stimulation with exogenous gonadotropin?
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E.2.2 | Secondary objectives of the trial |
Oocyte fertilization, embryo quality, implantation, pregnancy rate |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The current trial also provides data for EudraCT number 2015-005682-24
"Reducing the Impact of Ovarian Stimulation - STUDY RIOT A: The role of Aromatase Inhibitor in reducing the detrimental effects of ovarian stimulation to optimize outcomes infresh embryo transfer cycles"
PRIMARY ENDPOINTS
1. Serum progesterone level on day of hCG
2. Area under the curve from day 4 to day 14 post hCG administration for E2, P and 17-hydroxyprogesterone (17-HP).
SECONDARY ENDPOINTS
1. Serum E2, and testosterone (Tst) levels on Stimulation day 5, day of hCG administration (or the day before) and day 7 after hCG administration.
2. Follicular fluid E2, Tst, inhibin B and AMH levels
3. Total IU of FSH used per cycle.
4. Number of follicles > 12 mm on day of hCG (or the day before) and oocytes obtained.
5. Proportion of oocytes resulting in top quality day 2 (or day 3) embryos according to validated morphological criteria.
6. Oocyte fertilization rate
7. Number and quality of embryos obtained, including rate of blastocyst formation.
8. Endometrial thickness on day of hCG (or the day before) and day of embryo transfer.
9. Implantation rate, biochemical and ongoing pregnancy rate.
10. Reported side effects
11. Morphokinetic parameters of embryo quality as measured using a Time Lapse analysis in centers employing this technology.
12. If additional funding is available, the impact of Letrozole exposure on gene expression in cumulus cells will be studied.
13. Clinical pregnancy rate
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E.3 | Principal inclusion criteria |
INCLUSION CRITERIA
Indication for IVF/ICSI treatment
Eligible for IVF/ICSI treatment according to local criteria
IVF/ICSI treatment with single embryo transfer
Regular cycles 21-35 days (both included)
Age < 40 years
AMH 8-32 (both included)
Written consent
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E.4 | Principal exclusion criteria |
EXCLUSION CRITERIA
Any contraindication for IVF/ICSI treatment according to local criteria
Previous stimulation for IVF/ICSI with < 4 oocytes obtained
PCOS
Undergoing IVF/ICSI for the purpose of fertility preservation
Allergy towards study drug
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E.5 End points |
E.5.1 | Primary end point(s) |
KEY ENDPOINTS
1. Size of follicle cohort in relation to serum endocrine and paracrine markers including
AMH, E2, FSH, LH, Tst, Androstenedione, P, 17-HP
PAPP-A and A2
Inhibin A and B
BMPs
2. Size of the cyclically recruited follicle cohort (AFC) after ovarian stimulation with and without co-treatment with AI.
3. Expression of cytokine and growth factors in endometrial secretions, uterine contractility and follicular fluid endocrine and paracrine markers following co-treatment with AI compared with placebo control.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
DURATION
Patient recruitment: March 2016 – March 2018
Data analysis: March 2018 – September 2018
Publication of results: September 2018 – March 2019
The duration for each patient will not exceed 3 months from inclusion to last visit.
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E.5.2 | Secondary end point(s) |
1.Area under the curve from day 4 to day 10 post hCG administration for, P and 17-hydroxyprogesterone (17-HP).
2.Serum E2, P T and androstenedione levels on Stimulation day 5, day of hCG administration (or the day before), day of oocyte pick up, day 7 and 10 after hCG administration.
3. Total IU of FSH used per cycle.
4. Number of follicles > 12 mm on day of hCG (or the day before) and oocytes obtained.
5. Proportion of oocytes resulting in top quality day 2 (or day 3) embryos according to validated morphological criteria.
6. Oocyte fertilization rate
7. Number and quality of embryos obtained.
8. Endometrial thickness on day of hCG (or the day before) and day of embryo transfer.
9. Uterine contraction rate (contractions/minute) day 3 or 4 or 5 after ovulation (determined by urine LH test) in natural cycle and just prior to embryo transfer in stimulated cycle
10. Implantation rate, biochemical and ongoing pregnancy rate (viable intra-uterine pregnancy recorded at week 7-8 ultrasound).
11. Reported side effects
12. Morphometric/kinetic markers of embryo quality
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
DURATION
Patient recruitment: August 2016 – March 2018
Data analysis: March 2018 – September 2018
Publication of results: September 2018 – March 2019
The duration for each patient will not exceed 3 months from inclusion to last visit.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |