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    Summary
    EudraCT Number:2019-000585-38
    Sponsor's Protocol Code Number:SQ411218
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-10-08
    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 ConcernedUK - MHRA
    A.2EudraCT number2019-000585-38
    A.3Full title of the trial
    Chronic Endometritis and Recurrent Miscarriage - The CERM trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Chronic Endometritis and Recurrent Miscarriage - The CERM trial
    A.3.2Name or abbreviated title of the trial where available
    The CERM Trial
    A.4.1Sponsor's protocol code numberSQ411218
    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 SponsorUniversity Hospitals Coventry and Warwickshire NHS Trust
    B.1.3.4CountryUnited Kingdom
    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 supportThe Efficacy and Mechanism Evaluation (EME) programme - National Institute for Health Research
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportUniversity Hospitals Coventry and Warwickshire NHS Trust
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportWarwick Clinical Trials Unit, The University of Warwick
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationWarwick Clinical Trials Unit
    B.5.2Functional name of contact pointCERM Trial Team
    B.5.3 Address:
    B.5.3.1Street AddressWarwick Clinical Trials Unit, University of Warwick, Gibbet Hill Campus
    B.5.3.2Town/ cityCoventry
    B.5.3.3Post codeCV4 7AL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02476150989
    B.5.5Fax number02476151136
    B.5.6E-mailcerm@warwick.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    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 Doxycycline Capsules 100mg
    D.2.1.1.2Name of the Marketing Authorisation holderActavis UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameDoxycycline Capsules 100mg
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDoxycycline
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100mg
    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 placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Endometritis and Recurrent Miscarriage
    E.1.1.1Medical condition in easily understood language
    In some women the lining of the womb (endometrium) is inflamed (endometritis) possible due to infection and researchers have found a link between this and miscarriage.
    E.1.1.2Therapeutic area Body processes [G] - Reproductive physiologi cal processes [G08]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Does doxycycline given prior to conception (conceiving a child) improve the number of on-going pregnancies and total live births in women with recurrent miscarriage associated with chronic endometritis (inflamed lining of the womb)?
    E.2.2Secondary objectives of the trial
    Does doxycycline improve chronic endometritis (inflamed lining of the womb) ?

    What are the effects of doxycycline on conception (conceiving a child), early miscarriage, and late miscarriage?

    Does doxycycline change Lactobacillus-deplete microbiota to a Lactobacillus-dominated microbiota? (Does doxycycline increase the numbers of friendly bacteria living in the community of microbes that live in the vagina, cervix and uterus?)

    Does doxycycline improve the differentiation potential and colony-forming activity of endometrial stromal cells? (Does doxycycline improved the ability for cells in the lining of the womb to change into specialised cells that can support a pregnancy?)

    Is chronic endometritis related to heightened senescence of endometrial stromal cells? (Is an inflamed lining of the womb related to more rapid aging cells in the lining of the womb?)

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria - screening
    • Age ≥18 to <42
    • Two or more consecutive first trimester intrauterine miscarriages (≤14 weeks gestation).
    • Women who agree to use barrier methods of contraception during the following cycles: biopsy preparation, screening-biopsy, waiting for the results and during the intervention.


    Inclusion criteria - RCT
    • Women with ≥5 CD138+ cells/10mm2.
    E.4Principal exclusion criteria
    Exclusion criteria – screening
    • Treatable cause(s) of RM for example:
    o antiphospholipid antibody syndrome
    o thyroid disease
    o parental karyotypical abnormalities.
    • Known sub-septate uterus.
    • Poorly controlled diabetes (HbA1c >48mmol/mol)
    • Allergy to doxycycline or its excipients.
    • Doxycycline contraindicated
    • Antibiotics in the current menstrual cycle
    • Taking a medication that may interact with doxycycline
    • Myasthenia Gravis.
    • Systemic lupus erythematosus (SLE).
    • Immunodeficiency disorder.
    • Alcohol dependency*
    • Long-term antibiotic(s) use.
    • Menstrual cycle ≤21 - ≥42 days.
    • Unable to give informed consent.
    • Participation in another clinical trial of an investigational medicinal product (CTIMP) within the last 90 days.
    • Women who are breast feeding.
    • Pregnancy

    Exclusion criteria – RCT
    • A course of antibiotics between screening registration and randomisation to RCT**
    • A delay of longer than three months between biopsy result and randomisation to RCT**
    • Known serious liver disease*1
    • Taking a medication that may interact with doxycycline
    • Any co-morbid disease or condition that would make the patient unsuitable for the trial*1
    • Pregnancy

    *As judged by a medically qualified doctor assessing trial eligibility informed by referral letter from GP and hospital records

    **If a woman has a course of antibiotics between screening registration and randomisation or was registered for screening over three months before randomisation to the RCT they will not be eligible for trial randomisation at the time. These women should be given the option to re-screen and have another biopsy to confirm eligibility for randomisation.

    1If a clinician has doubts about a participants’ suitability for the trial because of a long-term medical condition they should undertake a Full Blood Count (FBC) and Liver function tests (LFTs); in order for a woman to be included in the trial the following should apply:
    • WBC >3x10^9/L,
    • Neutrophils >1.5x10^9/L,
    • Platelets >75x10^9/L, Hb>100g/L
    • Bilirubin <1.5XULN*
    • AST/ALT <3xULN*
    • Albumin >30g/dL).
    * ULN = Upper Limit of Normal
    All required additional checks must be documented in the patients’ medical notes
    E.5 End points
    E.5.1Primary end point(s)
    Primary outcome measures
    This trial will use an adaptive design methodology so that we can stop the trial early in the case of better than expected efficacy or futility. Therefore we need two primary outcome measures. One that is reached earlier than the whole 40 weeks of pregnancy. Hence, one explanatory, primary outcome measure will be ongoing pregnancy.

    Primary Outcome 1
    The first pragmatic primary outcome measure will be on-going pregnancy at 12 weeks. Ongoing pregnancy is defined as the number of viable pregnancies, with a crown rump length >54 mm, reaching 12+6 weeks of gestation as a percentage of the total number of first pregnancies after the intervention. As 98% of miscarriages occur before 12 weeks, the number of ongoing pregnancies will be very similar to number of live births.

    Primary Outcome 2
    The second pragmatic primary outcome measure will be the total live births defined as total live births plus ongoing pregnancies at the end of study. Defined as: On-going pregnancy at 12+6 weeks gestation the presence of a fetal heart beat when the Crown Rump Length >54mm / total number of women randomised

    • Total live births = Projected live births >24 weeks in first or subsequent pregnancy analysed at the end of the study as proportion of women (whilst some babies born at 22 and 23 of weeks of gestation survive, they are at risk of long term disability and hence will not be included in this outcome measure).

    • The maximum denominator for both of these analyses will be the 1,500 women randomised. This change does not affect any of our simulations for likelihood of early stopping.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary Outcome 1
    • On-going pregnancy at 12 weeks.

    Primary Outcome 2
    • Total live births.

    The trial is using an adaptive trial approach with the on-going pregnancy rate for efficient trial design Instead of a fixed trial design. The trial will stop early if, based on data at any interim analysis, it is either very unlikely that a positive result would be obtained, or efficacy or harm has already been convincingly demonstrated.
    E.5.2Secondary end point(s)
    Secondary outcome 1
    • To find out if doxycycline treatment improves CE?

    Secondary outcome 2
    To examine the separate effects of doxycycline on conception, early miscarriage, and late miscarriage. In addition assess the mediation effect of each of these, on the primary outcome, with treatment effect as a covariate.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary outcome 1
    • Density of CD138+ cells in the endometrium before and after treatment with doxycycline/placebo.

    Secondary outcome 2
    • Time to first conception
    • Anticipated time to first live birth
    • The proportion of women with a live birth after 24 weeks of gestation in their first pregnancy after randomisation.
    • Pregnancy complications
    • Early pregnancy complications
    • Type of miscarriage
    • On-going pregnancy and live births per patient in women excluded from randomisation by having low CD138+ cell scores and those randomised to placebo.
    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 Yes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    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 Yes
    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
    The trial is an adaptive design that allows frequent statistical review; leading to either continuation, stopping or adapting the trial. The trial will end once 1500 women have been randomised and any pregnant women have been followed up at 6 - 8 weeks post-delivery or pregnancy demise, or before this dependent upon efficacy and futility.

    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1500
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    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 state3062
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 3062
    F.4.2.2In the whole clinical trial 0
    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)
    Not applicable.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation The University of Warwick
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-08-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-08-20
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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