E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Warm autoimmune hemolytic anemia |
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E.1.1.1 | Medical condition in easily understood language |
Blood and lymphatic diseases |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10047822 |
E.1.2 | Term | Warm type haemolytic anaemia |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
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 |
• Part A: To evaluate the safety and tolerability of subcutaneous injections of isatuximab in adults
with wAIHA
• Part B: To evaluate the efficacy of the selected dose in adults with wAIHA |
|
E.2.2 | Secondary objectives of the trial |
Part A (Cohorts 2 and 3 only)
-To evaluate the efficacy of isatuximab in adults with wAIHA
-To evaluate the durability of response to isatuximab and time to response
-To evaluate the impact of isatuximab treatment on fatigue
• Part B
-To evaluate the safety and tolerability of isatuximab in adults with wAIHA
-To evaluate the durability of response to isatuximab and time to response
-To evaluate the impact of isatuximab treatment on fatigue
• Parts A (all Cohorts) and B
-To evaluate the effect of isatuximab on markers of hemolysis
-To characterize the pharmacokinetic profile of isatuximab in adults with wAIHA
-To evaluate the immunogenicity of isatuximab |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Participant must be ≥18 to years of age, inclusive, at the time of signing the informed consent.
- Males and females with a confirmed diagnosis of primary w AIHA or systemic lupus erythematosus (SLE)-associated w AIHA (without other SLE-related manifestations apart from cutaneous and musculoskeletal manifestations) who meet the following criteria:
a) Hemoglobin level <10 g/dL at screening.
b) Hemolysis (haptoglobin ≤40 mg/dL and total bilirubin above the upper limit of normal).
c) Positive direct antiglobulin test (DAT) (IgG or IgG + complement C3d pattern or IgM warm autoantibodies (positive dual DAT)).
- Participants who have previously failed to maintain a sustained response after treatment with corticosteroids (corticosteroid-refractory or corticosteroid-dependent primary wAIHA).
- Part A only: Participants who have previously failed to maintain a sustained response after treatment with rituximab (or other anti-CD20 monoclonal antibodies). The last dose of the anti-CD20 antibody must have been administered at least 12 weeks before enrollment.
- Part B: Participants who have had an insufficient response to at least 1 prior therapy in addition to corticosteroids (splenectomy is regarded as a prior therapy).
- Contraceptive use by men and women |
|
E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
- Clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the participant or compromise the quality of the data derived from his or her participation in the study as determined by the Investigator.
- Serious infection that required hospitalization within 3 months prior to enrollment.
- Secondary wAIHA from any cause including drugs, lymphoproliferative disorders, infectious or autoimmune disease (SLE without other SLE-related manifestations apart from cutaneous and musculoskeletal manifestations is allowed), or active hematologic malignancies. Participants with positive antinuclear antibodies but without a definitive diagnosis of an autoimmune disease are allowed.
- History of coagulation or bleeding disorders (Evans Syndrome is allowed).
- Uncontrolled or active HBV or HCV infection
- HIV infection.
- Serum gammaglobulin levels <3 g/L.
- Females who are pregnant, lactating, or considered unreliable with respect to contraceptive practice.
- Concurrent treatment with corticosteroids, unless the participant has been on a stable daily dose for ≥ 30 days prior to enrollment.
- Treatment with cyclophosphamide within 4 weeks prior to enrollment.
- Treatment with cytotoxic drugs (other than cyclophosphamide) within 12 weeks prior to enrollment. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Part A: To assess safety and tolerability
Standard clinical and laboratory parameters and adverse events
Part B : To evaluate overall response rate (R) or complete response (CR) at Day 85
R is defined as an increase in hemoglobin by ≥2 g/dL from baseline and an absence of transfusion in the last 7 days and absence of rescue medications in the past 4 weeks. Biochemical evidence of hemolysis may still be present.
CR is defined as hemoglobin ≥11 g/dL (women) or ≥12 g/dL (men), no evidence of hemolysis (normal bilirubin, LDH, haptoglobin, and reticulocytes), absence of transfusion in the last 7 days and absence of rescue medication in the past 4 weeks
|
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: Through Day 169
Part B: Through Day 85 |
|
E.5.2 | Secondary end point(s) |
1 - Part A (Cohorts 2 and 3 Only) : To evaluate overall response rate (R) or complete response (CR) at Day 85 ; R is defined as an increase in hemoglobin by ≥2 g/dL from baseline and an absence of transfusion in the last 7 days and absence of rescue medications in the past 4 weeks. Biochemical evidence of hemolysis may still be present.
CR is defined as hemoglobin ≥11 g/dL (women) or ≥12 g/dL(men), no evidence of hemolysis (normal bilirubin, LDH, haptoglobin, and reticulocytes), and absence of transfusion in the last 7 days and absence of rescue medication in the past 4 weeks.
2 - Part A (Cohorts 2 and 3 Only) and Part B : Proportion of participants with durable hemoglobin response by Day 169 ; Durable response is defined as Hb level ≥10 g/dL with an increase from baseline of ≥2 g/dL on three consecutive evaluable visits during the study period; with absence of transfusion and no rescue medication during the period of 3 consecutive visits and for at least 7 days (transfusions) and 4 weeks (rescue medication) prior to the first consecutive visit.
3 - Part A (Cohorts 2 and 3 Only) and Part B : Overall response rate at Day 169, median time to R or CR, median time to loss of R or CR, proportion of participants requiring rescue therapy (any wAIHA-directed therapy other than prednisone or transfusion) or splenectomy ; Overall response rate at Day 169, median time to R or CR, median time to loss of R or CR (loss of R defined as hemoglobin <10 g/dL at two consecutive visits at least 7 days apart and initiation of new treatment for anemia or increase in steroid dose; loss of CR is defined as hemoglobin <11 g/dL (women) or <12 g/dL (men) at two consecutive visits at least 7 days apart), proportion of participants requiring rescue therapy (any wAIHAdirected therapy other than prednisone or transfusion) or splenectomy
4 - Part A (Cohorts 2 and 3 Only) and Part B : FACIT-fatigue scale score
5 - Part B : To assess safety and tolerability ; Standard clinical and laboratory parameters and adverse events.
6 - Part A (All Cohorts) and B : Change from baseline in LDH
7 - Part A (All Cohorts) and B: Change from baseline in haptoglobin,
8 - Part A (All Cohorts) and B : Change from baseline in reticulocytes
9 - Part A (All Cohorts) and B : Change from baseline in total bilirubin
10 - Part A (All Cohorts) and B : PK parameters after subcutaneous administrations (Cmax) ; Maximum concentration received after injection (Cmax) and area under the plasma concentration versus time curve calculated over the dosing interval T (336 h) (AUC0-2week)
11 - Part A (All Cohorts) and B : PK parameters after subcutaneous administrations (AUC0-2week) ; Area under the plasma concentration versus time curve calculated over the dosing interval T (336 h) (AUC0-2week)
12 - Part A (All Cohorts) and B : Incidence of anti-isatuximab antibodies
13 - Part A (All Cohorts) and B : Titer (if relevant) of anti-isatuximab antibodies |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 : Through Day 85
2 to 13 : Through Day 169 |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
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 | 4 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Belgium |
France |
Germany |
Hungary |
Italy |
Netherlands |
United Kingdom |
|
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
|
|
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 | 3 |
E.8.9.1 | In the Member State concerned days | 28 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 28 |