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    Summary
    EudraCT Number:2015-005683-41
    Sponsor's Protocol Code Number:RIOTB2015
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-01-07
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2015-005683-41
    A.3Full title of the trial
    REDUCING THE IMPACT OF OVARIAN STIMULATION - THE RIOT PROJECT

    RIOT STUDY B: MAPPING THE ENDOCRINE DETERMINANTS OF OVARIAN STIMULATION TO OPTIMIZE OUTCOMES IN FRESH EMBRYO TRANSFER CYCLES
    RIOT STUDIE B : KORTLÆGGELSE AF DE ENDOKRINE DETERMINANTER FOR AT OPTIMERE OUTCOME I FRISKE IN VITRO FERTILISATIONS CYKLI
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    RIOT STUDY B: MAPPING OF SPECIFIC FACTORS THAT DETERMINE STIMULATION OF THE OVARIES UNDER FERTILITY TREATMENT IN ORDER TO IMPROVE PREGNANCY CHANCE
    RIOT STUDIE B : KORTLÆGGELSE AF SPECIFIKKE FAKTORER SOM BESTEMMER STIMULATION AF ÆGGESTOKKENE UNDER FERTILITETSBEHANDLING FOR AT ØGE GRAVIDITETSCHANCERNE
    A.4.1Sponsor's protocol code numberRIOTB2015
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02939898
    A.5.4Other Identifiers
    Name:Danish Data Protection AgencyNumber:HGH-2016-033, I-Suite: 04482
    Name:Regional Scientific Ethics CommitteeNumber:H-15021852
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSven O. Skouby, Professor, MD, DMSc. Unit of reproductive Medicine, Herlev/Gentofte Hospital
    B.1.3.4CountryDenmark
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportReproUnion
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSven O. Skouby, Professor, MD, DMSc. Unit of reproductive Medicine, Herlev Hospital
    B.5.2Functional name of contact pointUnit of Reproductive Medicine
    B.5.3 Address:
    B.5.3.1Street AddressHerlev Ringvej 75
    B.5.3.2Town/ cityHerlev
    B.5.3.3Post code2730
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4538683796
    B.5.6E-mailsven.olaf.skouby@regionh.dk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Letrozole "Accord"
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Research Limited Sage House, 319 Pinner Road, North Harrow, Middlesex, HA1 4HF, UK
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLetrozole
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPGastroenteral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLETROZOLE
    D.3.9.1CAS number 112809-51-5
    D.3.9.4EV Substance CodeSUB08444MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboGastroenteral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Infertility
    Infertilitet
    E.1.1.1Medical condition in easily understood language
    Infertlity
    Barnløshed
    E.1.1.2Therapeutic 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.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10016401
    E.1.2Term Female infertility of other specified origin
    E.1.2System Organ Class 100000004872
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10025511
    E.1.2Term Male infertility, unspecified
    E.1.2System Organ Class 100000004872
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10016403
    E.1.2Term Female infertility of tubal origin
    E.1.2System Organ Class 100000004872
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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?
    E.2.2Secondary objectives of the trial
    Oocyte fertilization, embryo quality, implantation, pregnancy rate
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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
    E.3Principal 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
    E.4Principal 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
    E.5 End points
    E.5.1Primary 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.


    E.5.1.1Timepoint(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.
    E.5.2Secondary 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

    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 32
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state32
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-02-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-01-09
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