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] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011475 |
E.1.2 | Term | Cryoglobulinemia |
E.1.2 | System Organ Class | 100000004866 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the complete clinical response rate of Isatuximab in type I IgG cryoglobulinemia |
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E.2.2 | Secondary objectives of the trial |
• Safety and tolerability of treatment as assessed by frequency and severity of adverse clinical events
• Early complete response rate at W12
• Complete, partial (improvement in some but not all organs involved at baseline) and non clinical (no clinical improvement) response rate at W12 and W20
• Rate of cryoglobulinemia clearance
• Rate of negativation of rheumatoid factor activity
• Rate of normalization of C4 complement level
• Early failure rate at W4 (non clinical response at W4)
• Clinical relapse rate and the time to relapse,
• Course of plasma cell associated disorder
• Evolution of gammaglobulin and of CD19+ B cells levels
• Quality of life scores (SF-36) (Appendix 1),
• Rate of infections (severe or not) and other complications
• Birmingham Vasculitis Activity Score (BVAS) (Appendix 2)
• Immunomonitoring (deep immunophenotyping, cytokines production, spectrometry, Fish analysis, single plasma cell repertoire)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age > 18 years
• Written informed consent
• Indolent Multiple myeloma or monoclonal gammopathy of unknown significance (MGUS) with monoclonal IgG component
• Active cryoglobulinemia vasculitis defined by positive type I IgG cryoglobulinemia and a clinically active cryoglobulinemia with skin, joint, renal, and/or peripheral involvement,
• Treated naïve or relapsers type I cryoglobulinemia patients
• Affiliated to National French social security system
• Contraception :
a) Male participants : A male participant must agree to use a highly effective method of contraception during the participation period and for at least 5 months after the last dose of study treatment and refrain from donating sperm during this period.
b) Female participants : A female participant is eligible to participate if she is not pregnant, not breastfeeding, and with at least one of the following conditions:
Not a female of childbearing potential (FCBP), OR
A FCBP who must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 24 hours of starting study medication and must apply a highly effective method of contraception during the participation period and for at least 7 months after the last dose of study treatment and refrain from donating oocyte during this period
• HIV negative serology; negative HBs Ag test; HCV negative serology and/or negative HCV RNA if positive HCV serology |
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E.4 | Principal exclusion criteria |
• Patient with a vasculitis unrelated to cryoglobulinemia
• Patient with non-active cryoglobulinemia vasculitis,
• Patient with diagnosis of multiple myeloma
• Patient treated with immunosuppressant (e.g alkylating agent, Rituximab, chemotherapy for plasma-cell neoplasms) introduced or increased in the month prior to the inclusion,
• Live vaccines within 30 days prior to baseline or concurrently with Isatuximab
• Infection requiring hospitalization and/or use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 60 days of Day 0.
• Active tuberculosis
• HIV positive, positive Ag HbS, positive HCV RNA
• Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose excessive risk to the patient or may interfere with compliance or interpretation of the study results.
• Hypersensitivity or history of intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study therapy that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
• Hypersensitivity to the active substances (isatuximab and premedication) or to any of their excipients
• Received any investigational drug within 14 days prior to inclusion or within 5 half-lives of the investigational drug, whichever is longer.
• Participation in another interventional study or being in the exclusion period at the end of a previous study.
• Vulnerable populations (e.g. pregnant or breastfeeding women)
• Neutrophils < 1000/mm3
• Platelets < 75000/mm3 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Complete clinical response rate of cryoglobulinemia vasculitis symptoms at week (W) 20 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Safety and tolerability of treatment as assessed by frequency and severity of adverse clinical events at W20
• Complete, partial and non-clinical response rate at W12, and at W20.
• Rate of cryoglobulinemia clearance, of negativation of rheumatoid factor activity and of normalization of C4 complement level at W12, and at W20.
• Rate of early failures (non-clinical response at W4),
• Rate of renal complete remission defined as proteinuria <0.5g/24h or proteinuria/creatininuria <50 mg/mmol, disappearance of hematuria, and glomerular filtration rate ≥60ml/min/1.73m² at W12, and at W20.
• Clinical relapse rate defined by de novo appearance or reappearance of a manifestation attributable to cryoglobulinemia vasculitis during 48 weeks of follow-up,
• Rate and time to relapse from baseline to W48
• Course of plasma cell associated disorder W12, and at W20.
• Mean change of gammaglobulin and CD19+ B cells levels from baseline to W20
• Quality of life score SF-36 at baseline, and W20,
• Rate of infections (severe or not) and other complications during the 48 weeks of follow-up
• BVAS activity score at baseline, W12, and W20.
• Immunomonitoring (deep immunophenotyping, cytokines production, spectrometry, Fish analysis, single plasma cell repertoire) at baseline, week 12, and week 20
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
baseline, week 12, and week 20 |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
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 | 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
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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 | |
E.8.9.1 | In the Member State concerned months | 24 |
E.8.9.1 | In the Member State concerned days | |