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    Summary
    EudraCT Number:2021-003613-19
    Sponsor's Protocol Code Number:APHP210303
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-07-30
    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 ConcernedFrance - ANSM
    A.2EudraCT number2021-003613-19
    A.3Full title of the trial
    AbataCept for the treatment of immune-cHeckpoint inhibitors induced mYocarditiS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    AbataCept for the treatment of immune-cHeckpoint inhibitors induced mYocarditiS
    A.3.2Name or abbreviated title of the trial where available
    ACHLYS
    ACHLYS
    A.4.1Sponsor's protocol code numberAPHP210303
    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 SponsorASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    B.1.3.4CountryFrance
    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 supportFédération Francaise de Cardiologie
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportBristol-Myers Squibb International Corporation
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE - HOPITAUX DE PARIS
    B.5.2Functional name of contact pointSophie COURTIAL-DESTEMBERT
    B.5.3 Address:
    B.5.3.1Street AddressDRCI Hôpital St Louis, 1 av. Claude Vellefaux
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number+33140275591
    B.5.5Fax number+33144841771
    B.5.6E-mailsophie.courtial-destembert@aphp.fr
    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 ORENCIA 250 mg powder for concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderBRISTOL MYERS SQUIBB PHARMA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNABATACEPT
    D.3.9.1CAS number 332348-12-6
    D.3.9.4EV Substance CodeSUB20635
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    All adult patients with cancer (all cancer types) treated by immune checkpoint inhibitors (anti-PD1, anti-PDL1, anti-CTLA4 monotherapies or combination) and presenting drug-induced myocarditis. There will be no limitation based on gender and upper limit age.
    E.1.1.1Medical condition in easily understood language
    Adult patients with all cancer types treated by immune checkpoint inhibitors and presenting drug-induced myocarditis
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    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
    to find the lowest dose required to achieve a circulating monocytes CD86RO≥80% within the first week of treatment and sustainably over three weeks
    E.2.2Secondary objectives of the trial
    - To evaluate the immunological, myocardial and muscular pharmacodynamic effects of 3 different doses of abatacept in the initial phase (first 21 days) of ICI-myocarditis treatment.
    - To assess the pharmacokinetic properties of abatacept used in ICI-myocarditis
    - Pharmacokinetic / pharmacodynamic (PK-PD) modeling of abatacept in ICI-myocarditis
    - To assess the safety of these different doses (pro-tumorigenicity, infections).
    - To evaluate long-term effects of abatacept treatment in ICI-myocarditis over months, up to one year
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years old
    2. Patients treated with ICI immunotherapy (monotherapy or combination), including anti-PD1, anti-PDL1, anti-CTLA4; and including any type of cancer
    3. Definite, probable or possible ICI-induced myocarditis according to the diagnostic criteria of the most recent expert consensus recommendations
    4. Severe or corticosteroid-resistant ICI-myocarditis:
    - Severe ICI-myocarditis is defined either 1/ by the appearance of an alteration of the LVEF<50% or a wall motion kinetics abnormality, or 2/ by the appearance of ventricular tachycardias or high-grade conductive disorders (atrioventricular block grade 2 or 3) or 3/ by the association with myasthenia gravis-like-syndrome (diplopia, ptosis, diaphragmatic dysfunction, dysarthria, dysphonia, dysphagia).
    - Corticosteroid-resistant ICI-myocarditis is defined by the absence of decrease in troponin levels or the appearance/persistence of severity criteria despite receiving prednisone dose ≥1 mg/kg/day for ≥2 days.
    5. Signature of informed consent before any trial procedure from the patient or legal representative or the close relative
    6. Patients covered by social security regimen (excepting AME)
    E.4Principal exclusion criteria
    1. Untreated bacterial, fungal, or viral infection
    2. Pregnancy, breast-feeding or planning to become pregnant during the study period
    3. For women of childbearing age, lack of effective contraception throughout the duration of participation in the study
    4. Being treated with abatacept or belatacept within 3 months prior to inclusion
    5. Known hypersensitivity to abatacept or belatacept
    6. Being treated with anti-thymoglobulin, or alemtuzumab within 6 weeks of the first scheduled dose of abatacept
    7. Patient participating to another interventional study (RIPH1 only)
    8. People under legal protection measure (tutorship, curatorship or safeguard measures)
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients with CD86RO saturation ≥80% within the first week of treatment and sustainably over three weeks after randomization. CD86RO will be assessed versus baseline levels (one hour before abatacept administration) at the following timepoints: once 1 to 3 hours after, and once 24 to 72 hours after the first, 2nd and 3rd abatacept dose and a last one at Day 21 after the first administration of abatacept. A patient will be considered with a CD86RO saturation ≥80% within the first week of treatment if at least three CD86RO assessments are over 80% until Day 21 after the first administration of abatacept.
    E.5.1.1Timepoint(s) of evaluation of this end point
    D21
    E.5.2Secondary end point(s)
    - Quantification of proxies reflecting the resolution of systemic immune activation: % of regulator T-cells CTLA4+, levels of pro and anti-inflammatory cytokines, C-reactive protein levels, % of circulating monocytes expressing PDL1, % of circulating T-cells expressing PD1. There will be assessed versus baseline levels (one hour before abatacept treatment) and at the following timepoints: once 1 to 3 hours after, and once 24 to 72 hours after the first, 2nd and 3rd abatacept dose, then every ten days up to day 90, and then every three months up to a year of follow-up. In case of additional doses of abatacept, these proxies will also be additionally measured one hour before and one to three hours after each dose of abatacept.
    - Quantification of the corticosteroid decrease kinetics (total cumulative dose) and the proportion of patients for whom it was necessary to add other immunosuppressants in addition to glucocorticoids to control the disease during the first 21 days and then 90days of the disease : Area under the curve of troponin-T levels; incidence of heart failure (defined as left-ventricular drop below 50%); and incidence of life-threatening cardiac arrhythmias (defined a sustained ≥30 seconds ventricular tachycardia episode, ventricular fibrillation, cardiac arrest, sinus arrest >4 seconds and complete atrio-ventricular block).
    - Quantification of proxies reflecting the resolution of myocarditis: troponin-T and -I, CK, NT-proBNP, left ventricular ejection fraction by echocardiography, cardiac inflammation and myocardial edema quantification evaluated by cardiac MRI, arrhythmias and ventricular conductive disorders quantified on electrocardiographic Holter acquisitions; and humoral autoimmunity against the myocardium or the muscles (anti-troponin I and T, anti-myosin, anti-musK, anti-acetylcholine receptor antibodies). The imaging modalities (MRI, echocardiography) will be assessed at least once as soon as possible after admission, 3 months and one year after abatacept start. The holter ECG (48 hours duration) will be assessed at least once as soon as possible after admission, at day 7, day 14, day 21, and at 3 months and one year after abatacept start. The biological parameters will be assessed at admission, then at least every 3 to 4 days during the 21 first days, then every ten days up to day 90 and then every three months up to a year of follow-up
    - Quantification of proxies reflecting the involvement and resolution of any associated myositis: muscles MRI, electromyogram, capnography, functional respiratory exploration, diaphragmatic MRI and echography. These modalities will be assessed at least once as soon as possible after admission, 3 months and one year after abatacept start.
    - Pharmacokinetic / pharmacodynamic (PK-PD) modeling of abatacept in ICI-myocarditis with determination of the volume of distribution, terminal half-life, clearance, maximum (Cmax) and residual (Cmin) concentration of circulating abatacept and time to Cmax / Cmin (Tmax/Tmin). Modeling of the 50% median effective concentration of abatacept to saturate CD86 receptor on circulating monocytes and to normalize troponin levels. Abatacept circulating levels, ICI circulating levels, troponin-T blood levels and CD86RO on circulating monocytes will be assessed at baseline (one hour before abatacept treatment) and at the following timepoints: once 1 to 3 hours after, and once 24 to 72 hours after the first, 2nd and 3rd abatacept dose, then every ten days up to day 90, and then every three months up to a year of follow-up. In case of additional doses of abatacept, these proxies will also be additionally measured one hour before and one to three hours after each dose of abatacept.
    - Quantification of tumor progression by appropriate examination depending on the tumor type (e.g. CT-scan for lung or renal cancer) using the best monitoring work-up used in standard of care. The imaging modalities will be assessed at least once as soon as possible after admission, after 3 months and one year after abatacept start.
    E.5.2.1Timepoint(s) of evaluation of this end point
    D21, M3 and M12
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 Yes
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    other doses of same IMP
    E.8.2.4Number of treatment arms in the trial3
    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 concerned9
    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 years
    E.8.9.1In the Member State concerned months36
    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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 11
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    If the patient is not able to consent, the investigator will obtain written consent from the family or the trusted person. Consent for prosecution will be obtained from the patient, as soon as the latter has recovered the capacity to consent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state21
    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)
    expected normal treatment of that condition
    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 Decision2021-09-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2025-01-28
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