Caplacizumab and Immunosuppressive Therapy Without Firstline Therapeutic Plasma Exchange in Adults With Immune-mediated Thrombotic Thrombocytopenic Purpura

Study Overview
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Brief Summary
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This is a single group, treatment, Phase 3, open-label, single-arm study to evaluate the efficacy and safety of caplacizumab and immunosuppressive therapy (IST) without firstline therapeutic plasma exchange (TPE) with primary endpoint of remission in male and female participants aged 18 to 80 years with immune-mediated thrombotic thrombocytopenic purpura (iTTP). The anticipated study duration per participant without a recurrence while on therapy is maximum 24 weeks (ie, approximately 1 day for screening + maximum 12 weeks of treatment for the presenting episode + 12 weeks of follow-up). Participants will have daily assessments during hospitalization and weekly visits for assessments during ongoing treatment with caplacizumab and IST. There will be 3 outpatient visits for assessments during the follow-up period. There will be two additional follow-up visits for participants who do not have ADAMTS13 activity levels of ≥50% at the time of caplacizumab discontinuation.

Detailed Description
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The anticipated study duration per participant with the presenting episode therefore is a maximum of about 24 weeks (ie, 1 day of screening + maximum 12 weeks of treatment for the presenting episode + 12 weeks of follow-up).

Official Title
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An Open-label, Single-arm, Multicenter Study to Evaluate the Efficacy and Safety of Caplacizumab and Immunosuppressive Therapy Without Firstline Therapeutic Plasma Exchange in Adults With Immune-mediated Thrombotic Thrombocytopenic Purpura

Conditions
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Thrombotic Thrombocytopenic Purpura

Intervention / Treatment
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* Drug: Caplacizumab
* Drug: Corticosteroids
* Biological: anti-CD20 antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with a clinical diagnosis of iTTP (initial or recurrent), which includes thrombocytopenia, microangiopathic hemolytic anemia (eg, presence of schistocytes in peripheral blood smear) and relatively preserved renal function. The iTTP diagnosis should be confirmed by ADAMTS13 testing within 48 hours (2 days). Participants with a clinical diagnosis of iTTP and a French TMA score of 1 or 2. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: Is a woman of nonchildbearing potential (WONCBP), OR Is a woman of childbearing potential (WOCBP) and agrees to use an acceptable contraceptive method during the overall treatment period and for at least 2 months after the last study drug administration. Male participants with female partners of childbearing potential must agree to follow the contraceptive guidance as per protocol during the overall treatment period and for at least 2 months after last study drug administration. Exclusion Criteria: Platelet count ≥100 x 10^9/L. Serum creatinine level >2.26 mg/dL (200 µmol/L) in case platelet count is >30 x 10^9/L (to exclude possible cases of atypical HUS). Known other causes of thrombocytopenia including but not limited to: Clinical evidence of enteric infection with E. coli 0157 or related organism. Atypical HUS. Hematopoietic stem cell, bone marrow or solid organ transplantation-associated thrombotic microangiopathy. Known or suspected sepsis. Diagnosis of disseminated intravascular coagulation. Congenital TTP (known at the time of study entry). Clinically significant active bleeding or known co-morbidities associated with high risk of bleeding (excluding thrombocytopenia). Inherited or acquired coagulation disorders. Malignant arterial hypertension. Participants requiring or expected to require invasive procedures immediately (eg, stroke requiring thrombolytic therapy, those who need mechanical ventilation, etc.). Those presenting with severe neurological or cardiac disease. Clinical condition other than that associated with TTP, with life expectancy <6 months, such as end-stage malignancy. Known chronic treatment with anticoagulants and anti-platelet drugs that cannot be stopped (interrupted) safely, including but not limited to: vitamin K antagonists. direct-acting oral anticoagulants. heparin or low molecular weight heparin (LMWH). non-steroidal anti-inflammatory molecules other than acetyl salicylic acid. Participants who were previously enrolled in this clinical study (study EFC16521). Participants who received an investigational drug, or device, other than caplacizumab, within 30 days of anticipated IMP administration or 5 half-lives of the previous investigational drug, whichever is longer. Positive result on COVID test. The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Caplacizumab & immunosuppressive therapy without 1st-line TPE<br>All participants will receive open label caplacizumab daily and immunosuppressive therapy (corticosteroid +/-anti-CD20 therapy antibody [rituximab or biosimilar]) without first line TPE | Drug: Caplacizumab<br>* Lyophilized powder for solution for injection.<br>* Other names: Cablivi®;Drug: Corticosteroids<br>* Solution for injection or Tablet<br>* Other names: Prednisone® /Prednisolone®;Biological: anti-CD20 antibody<br>* Solution for injection<br>* Other names: rituximab or biosimilar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving Remission without requiring therapeutic plasma exchange (TPE). | Remission is defined as sustained Clinical Response (sustained platelet count ≥150 x 10^9/L and lactate dehydrogenase [LDH] <1.5 x upper limit of normal [ULN] and no clinical evidence of new or progressive ischemic organ injury for at least 2 consecutive visits) with either (a) no TPE and no anti- von Willebrand factor (anti-vWF) therapy for ≥ 30 days (Clinical Remission), or (b) with attainment of a disintegrin and metalloproteinase with a thrombospondin type 1 motif13 (ADAMTS13) ≥ 50% (Complete ADAMTS13 remission), whichever occurs first | Overall study period from day 1 to day 168 (treatment period + 12 weeks of follow-up) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving Remission |  | Overall study period from day 1 to day 168 | 
| Proportion of participants who require TPE |  | On-treatment period from day 1 to day 84 | 
| The occurrence of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) |  | Treatment-emergent (TE) period from day 1 to day 112 | 
| Proportion of participants achieving Clinical Response | Clinical Response is defined as sustained platelet count ≥150 x 10^9/L and LDH <1.5 x ULN and no clinical evidence of new or progressive ischemic organ injury for at least 2 consecutive visits. | On-treatment period from day 1 to day 84 | 
| Proportion of participants achieving Clinical Response |  | Overall study period from day 1 to day 168 | 
| Time to platelet count response | Platelet count response defined as time from start of treatment to initial platelet count ≥150 x 10^9/L that is sustained for ≥2 days | From day 1 to day 168 | 
| Proportion of participants refractory to therapy | Refractory to therapy defined as lack of sustained platelet count increment (over 2 consecutive days) or platelet counts <50 x10^9/L and persistently elevated LDH (>1.5 x ULN) despite 5 days of treatment | On-treatment period from day 1 to day 84 | 
| Proportion of participants with TTP-related death |  | On-treatment period from day 1 to day 84 | 
| Proportion of participants with TTP-related death |  | Overall study period from day 1 to day 168 | 
| Proportion of participants with a clinical exacerbation of iTTP | Clinical Exacerbation is defined as after a Clinical Response and before a Clinical Remission, platelet count decreases to <150 x 10^9/L (with other causes of thrombocytopenia excluded), with or without clinical evidence of new or progressive ischemic organ injury, within 30 days of stopping TPE or anti vWF therapy. | On-treatment period from day 1 to day 84 | 
| Proportion of participants with a clinical exacerbation of iTTP |  | Overall study period from day 1 to day 168 | 
| Proportion of participants with a clinical relapse of iTTP | Clinical Relapse is defined as after a Clinical Remission, platelet count decreases to <150 x 10^9/L (with other causes of thrombocytopenia ruled out), with or without clinical evidence of new ischemic organ injury. A Clinical Relapse must be confirmed by documentation of severe ADAMTS13 deficiency (<10%). | On-treatment period from day 1 to day 84 | 
| Proportion of participants with a clinical relapse of iTTP |  | Overall study period from day 1 to day 168 |