Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura

Study Overview
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Brief Summary
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The study was a Phase III, double-blind, placebo-controlled, randomized study to evaluate the efficacy of caplacizumab in more rapidly restoring normal platelet counts as measure of prevention of further microvascular thrombosis

Official Title
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A Phase III Double-blind, Randomized, Parallel Group, Multicenter Placebo-controlled Trial to Study the Efficacy and Safety of Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura

Conditions
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Acquired Thrombotic Thrombocytopenic Purpura

Intervention / Treatment
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* Biological: Caplacizumab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female ≥ 18 years of age at the time of signing the informed consent form (ICF). Clinical diagnosis of acquired thrombotic thrombocytopenic purpura (aTTP) (initial or recurrent), which included thrombocytopenia and microscopic evidence of red blood cell fragmentation (e.g., schistocytes). Required initiation of daily PE treatment and had received 1 PE treatment prior to randomization Others as defined in the protocol Exclusion Criteria: Platelet count ≥100×10E9/L. Serum creatinine level >200 µmol/L in case platelet count is > 30×10E9/L Known other causes of thrombocytopenia Congenital TTP (known at the time of study entry). Pregnancy or breast-feeding. Subjects who were previously enrolled in a clinical study with caplacizumab and received caplacizumab or for whom the assigned treatment arm is unknown Others as defined in the protocol

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Caplacizumab<br>Caplacizumab 10 mg once daily | Biological: Caplacizumab<br>* First day of treatment: 10 mg intravenous (i.v.) injection prior to plasma exchange (PE) followed by a 10 mg subcutaneous (s.c.) injection (in the abdominal region) after completion of PE on that day. Subsequent days of treatment during PE: daily 10 mg s.c. injection (in the abdominal region) following PE. Treatment after PE period: daily 10 mg s.c. injections for 30 days. If the underlying immunological disease was not resolved, treatment could be extended for a maximum of 4 additional 1-week periods (i.e., 28 days) and was to be accompanied by optimization of immunosuppression.<br>* Other names: ALX-0081;|
| Placebo Comparator: Placebo<br>Placebo once daily | Biological: Placebo<br>* First day of treatment: i.v. injection prior to PE followed by a s.c. injection (in the abdominal region) after completion of PE on that day. Subsequent days of treatment during PE: daily s.c. injection (in the abdominal region) following PE. Treatment after PE period: daily s.c. injections for 30 days. If the underlying immunological disease was not resolved, treatment could be extended for a maximum of 4 additional 1-week periods (i.e., 28 days) and was to be accompanied by optimization of immunosuppression.<br>* Other names: ALX-0081 Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Platelet Count Response | Platelet count response was defined as initial platelet count ≥ 150,000/μL with subsequent stop of daily PE within 5 days. It refers to the first time both conditions, platelet count ≥ 150,000/μL and the stop of daily PE within 5 days, were met. | Only data from the DB daily PE period (median = 5 days) up to the cut-off were used. The cut-off point was defined by whichever occured first: 1) 45 days of daily PE after start of study drug, 2) stop of daily PE, 3) stop of study drug (median = 34 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects With TTP-Related Death, Recurrence of TTP, or a Major Thromboembolic Event During the Study Drug Treatment Period | Number and percentage of subjects with TTP-related death, a recurrence of TTP, or at least one treatment-emergent major thromboembolic event during the study drug treatment period (i.e., first key secondary endpoint). | The study drug treatment period, a median (min, max) of 36 (2, 82) days. For both treatment groups, only events that occurred prior to a switch to open-label caplacizumab were evaluated for this analysis. | 
| Number and Percentage of Subjects With a Recurrence of TTP in the Overall Study Period | Number and percentage of subjects with a recurrence of TTP during the Overall Study Period (i.e., including follow-up [FU]) (i.e., second key secondary endpoint). | The overall study period (covers both the overall treatment period and the follow-up period), a median (min, max) of 65 (2, 110) days. | 
| Number and Percentage of Subjects With Refractory Disease | Number and percentage of subjects with refractory TTP, defined as absence of platelet count doubling after 4 days of standard treatment, and lactate dehydrogenase (LDH) > upper limit of normal (ULN) (i.e., third key secondary endpoint). | The study drug treatment period, a median (min, max) of 36 (2, 82) days. | 
| Time to Normalization of Organ Damage Marker Levels | Time to first normalization of LDH, cardiac troponin I (cTnI) and serum creatinine was defined as: first time of LDH ≤ ULN and cTnI ≤ ULN and serum creatinine ≤ ULN - time of first i.v. loading dose of study drug after randomization + 1 minute. Subjects in either initial treatment group who switched to open-label caplacizumab before having reached the endpoint were censored at time of switch. Of note, the key secondary endpoints were hierarchically ordered to allow statistical testing for these endpoints at the same nominal significance level of 5% without adjustment, as long as the tests occurred in the pre-defined sequential order, and given that all null hypotheses tested for endpoints with a higher rank (including the primary endpoint) were rejected. No confirmatory testing was done for this fourth key secondary endpoint, as the statistical test was not significant for the proportion of subjects with refractory disease (i.e., the third key secondary endpoint). | Overall study period, a median (min, max) of 65 (2, 110) days. For both treatment groups, normalizations occurring during the open-label period were not evaluated in this analysis. |