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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02553317
Registration number
NCT02553317
Ethics application status
Date submitted
14/09/2015
Date registered
17/09/2015
Titles & IDs
Public title
Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura
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Scientific title
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
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Secondary ID [1]
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2015-001098-42
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Secondary ID [2]
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ALX0681-C301
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Universal Trial Number (UTN)
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Trial acronym
HERCULES
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acquired Thrombotic Thrombocytopenic Purpura
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Condition category
Condition code
Inflammatory and Immune System
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Autoimmune diseases
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Blood
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Other blood disorders
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Blood
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Haematological diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Other - Caplacizumab
Treatment: Other - Placebo
Experimental: Caplacizumab - Caplacizumab 10 mg once daily
Placebo comparator: Placebo - Placebo once daily
Treatment: Other: Caplacizumab
* 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.
Treatment: Other: Placebo
* 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.
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Intervention code [1]
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Treatment: Other
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Time to Platelet Count Response
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Assessment method [1]
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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.
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Timepoint [1]
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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)
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Secondary outcome [1]
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Number and Percentage of Subjects With TTP-Related Death, Recurrence of TTP, or a Major Thromboembolic Event During the Study Drug Treatment Period
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Assessment method [1]
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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).
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Timepoint [1]
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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.
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Secondary outcome [2]
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Number and Percentage of Subjects With a Recurrence of TTP in the Overall Study Period
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Assessment method [2]
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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).
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Timepoint [2]
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The overall study period (covers both the overall treatment period and the follow-up period), a median (min, max) of 65 (2, 110) days.
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Secondary outcome [3]
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Number and Percentage of Subjects With Refractory Disease
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Assessment method [3]
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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).
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Timepoint [3]
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The study drug treatment period, a median (min, max) of 36 (2, 82) days.
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Secondary outcome [4]
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Time to Normalization of Organ Damage Marker Levels
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Assessment method [4]
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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).
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Timepoint [4]
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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.
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Eligibility
Key inclusion criteria
1. Adult male or female = 18 years of age at the time of signing the informed consent form (ICF).
2. 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).
3. Required initiation of daily PE treatment and had received 1 PE treatment prior to randomization
4. Others as defined in the protocol
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Platelet count =100×10E9/L.
2. Serum creatinine level >200 µmol/L in case platelet count is > 30×10E9/L
3. Known other causes of thrombocytopenia
4. Congenital TTP (known at the time of study entry).
5. Pregnancy or breast-feeding.
6. Subjects who were previously enrolled in a clinical study with caplacizumab and received caplacizumab or for whom the assigned treatment arm is unknown
7. Others as defined in the protocol
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/11/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/08/2017
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Sample size
Target
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Accrual to date
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Final
145
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Recruitment in Australia
Recruitment state(s)
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Investigator Site - Brisbane
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Investigator Site 1 - Melbourne
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- Brisbane
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- Melbourne
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- Perth
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- Sydney
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Recruitment outside Australia
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Alabama
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Ablynx, a Sanofi company
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Address
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Ethics approval
Ethics application status
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Summary
Brief summary
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
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Trial website
https://clinicaltrials.gov/study/NCT02553317
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Trial related presentations / publications
Peyvandi F, Cataland S, Scully M, Coppo P, Knoebl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Minkue Mi Edou J, De Winter H, Callewaert F. Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis. Blood Adv. 2021 Apr 27;5(8):2137-2141. doi: 10.1182/bloodadvances.2020001834. Knoebl P, Cataland S, Peyvandi F, Coppo P, Scully M, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Minkue Mi Edou J, De Winter H, Callewaert F. Efficacy and safety of open-label caplacizumab in patients with exacerbations of acquired thrombotic thrombocytopenic purpura in the HERCULES study. J Thromb Haemost. 2020 Feb;18(2):479-484. doi: 10.1111/jth.14679. Epub 2019 Dec 9. Scully M, Cataland SR, Peyvandi F, Coppo P, Knobl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Callewaert F, Biswas D, De Winter H, Zeldin RK; HERCULES Investigators. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019 Jan 24;380(4):335-346. doi: 10.1056/NEJMoa1806311. Epub 2019 Jan 9.
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Public notes
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Contacts
Principal investigator
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Medical Monitor
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Address
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Ablynx NV
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
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When will data be available (start and end dates)?
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Available to whom?
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Available for what types of analyses?
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How or where can data be obtained?
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What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/17/NCT02553317/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/17/NCT02553317/SAP_001.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT02553317