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Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura (HERCULES)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02553317
Recruitment Status : Completed
First Posted : September 17, 2015
Results First Posted : May 22, 2019
Last Update Posted : May 22, 2019
Sponsor:
Information provided by (Responsible Party):
Ablynx

Tracking Information
First Submitted Date  ICMJE September 14, 2015
First Posted Date  ICMJE September 17, 2015
Results First Submitted Date  ICMJE February 25, 2019
Results First Posted Date  ICMJE May 22, 2019
Last Update Posted Date May 22, 2019
Actual Study Start Date  ICMJE November 2015
Actual Primary Completion Date August 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 21, 2019)
Time to Platelet Count Response [ Time Frame: 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) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 16, 2015)
Time to Platelet Count Response [ Time Frame: For maximum 6 months ]
Initial platelet count ≥ 150×10E9/L with subsequent stop of daily plasma exchange within 5 days.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 21, 2019)
  • Number and Percentage of Subjects With TTP-Related Death, Recurrence of TTP, or a Major Thromboembolic Event During the Study Drug Treatment Period [ Time Frame: 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 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).
  • Number and Percentage of Subjects With a Recurrence of TTP in the Overall Study Period [ Time Frame: 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 a recurrence of TTP during the Overall Study Period (i.e., including follow-up [FU]) (i.e., second key secondary endpoint).
  • Number and Percentage of Subjects With Refractory Disease [ Time Frame: The study drug treatment period, a median (min, max) of 36 (2, 82) days. ]
    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).
  • Time to Normalization of Organ Damage Marker Levels [ Time Frame: 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. ]
    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).
Original Secondary Outcome Measures  ICMJE
 (submitted: September 16, 2015)
  • Proportion of subjects with an exacerbation and/or relapse of TTP as well as the number of such events [ Time Frame: From Day 1 until last follow-up visit (28 days after last dosing) ]
  • Proportion of subjects with treatment-emergent clinically significant TTP-related events as well as the number of such events [ Time Frame: From Day 1 until last follow-up visit (28 days after last dosing) ]
  • Area under the curve (AUC) of platelet count [ Time Frame: Day 5 ]
  • Time to lactate dehydrogenase (LDH) ≤ 2 x upper limit of normal (ULN) [ Time Frame: From Day 1 until last follow-up visit (28 days after last dosing) ]
  • Time to cardiac Troponin I (cTnI) ≤ 1 x ULN [ Time Frame: From Day 1 until last follow-up visit (28 days after last dosing) ]
  • Time to serum creatinine ≤ 1 x ULN [ Time Frame: From Day 1 until last follow-up visit (28 days after last dosing) ]
  • Mortality rate [ Time Frame: From Day 1 until last follow-up visit (28 days after last dosing) ]
  • (Serious) adverse events [ Time Frame: From Day 1 until last follow-up visit (28 days after last dosing) ]
Current Other Pre-specified Outcome Measures
 (submitted: May 21, 2019)
  • Number of Days of Plasma Exchange [ Time Frame: Overall study drug treatment period, a median (min, max) of 36 (2, 82) days. ]
    The number of days of PE during the overall study drug treatment period, including the number of days of PE during the open-label study drug treatment period. Data were analyzed according to the initial treatment allocation (both before and after switch to open-label caplacizumab).
  • Total Volume of Plasma Exchange [ Time Frame: Overall study drug treatment period, a median (min, max) of 36 (2, 82) days. ]
    The total volume of PE during the overall study drug treatment period, including the total volume of PE during the open-label study drug treatment period. Data were analyzed according to the initial treatment allocation (both before and after switch to open-label caplacizumab).
  • Number of Days in Intensive Care Unit [ Time Frame: Overall study drug treatment period, a median (min, max) of 36 (2, 82) days. ]
    The number of days in intensive care unit (ICU) during the overall study drug treatment period, including the number of days in ICU during the open-label study drug treatment period. Data were analyzed according to the initial treatment allocation (both before and after switch to open-label caplacizumab).
  • Number of Days in Hospital [ Time Frame: Overall study drug treatment period, a median (min, max) of 36 (2, 82) days. ]
    The number of days in hospital during the overall study drug treatment period, including the number of days in hospital during the open-label study drug treatment period. Data were analyzed according to the initial treatment allocation (both before and after switch to open-label caplacizumab).
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura
Official Title  ICMJE 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
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
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Acquired Thrombotic Thrombocytopenic Purpura
Intervention  ICMJE
  • Biological: 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.
    Other Name: ALX-0081
  • Biological: 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.
    Other Name: ALX-0081 Placebo
Study Arms  ICMJE
  • Experimental: Caplacizumab
    Caplacizumab 10 mg once daily
    Intervention: Biological: Caplacizumab
  • Placebo Comparator: Placebo
    Placebo once daily
    Intervention: Biological: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 22, 2017)
145
Original Estimated Enrollment  ICMJE
 (submitted: September 16, 2015)
92
Actual Study Completion Date  ICMJE August 2017
Actual Primary Completion Date August 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Canada,   Czechia,   France,   Germany,   Hungary,   Israel,   Italy,   Netherlands,   Spain,   Switzerland,   Turkey,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02553317
Other Study ID Numbers  ICMJE ALX0681-C301
2015-001098-42 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ablynx
Study Sponsor  ICMJE Ablynx
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Monitor Ablynx NV
PRS Account Ablynx
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP