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

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

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

Study Overview

• Status: Completed
• Conditions: Acquired Thrombotic Thrombocytopenic Purpura
• Intervention / Treatment: Biological: Caplacizumab; Biological: Placebo

• Study Type: Interventional
• Enrollment (Actual): 145
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Brisbane, Australia
    • Investigator Site
  • Melbourne, Australia
    • Investigator Site 1
  • Melbourne, Australia
    • Investigator Site 2
  • Melbourne, Australia
    • Investigator Site 3
  • Melbourne, Australia
    • Investigator Site 4
  • Melbourne, Australia
    • Investigator Site 5
  • Perth, Australia
    • Investigator Site
  • Sydney, Australia
    • Investigator Site 1
  • Sydney, Australia
    • Investigator Site 2
• Austria
  • Vienna, Austria
    • Investigator Site
• Belgium
  • Antwerp, Belgium
    • Investigator Site
  • Brussels, Belgium
    • Investigator Site
  • Haine-Saint-Paul, Belgium
    • Investigator Site
  • La Louviere, Belgium
    • Investigator Site
  • Leuven, Belgium
    • Investigator Site
• Canada
  • London, Canada
    • Investigator Site
  • Toronto, Canada
    • Investigator Site
  • Quebec
    • Montreal, Quebec, Canada
      • Invesigator Site
• Czechia
  • Brno, Czechia
    • Investigator Site
  • Hradec Kralove, Czechia
    • Investigator Site
  • Olomouc, Czechia
    • Investigator Site
  • Ostrava-Poruba, Czechia
    • Investigator Site
• France
  • Caen, France
    • Investigator Site
  • Lille, France
    • Investigator Site
  • Marseille, France
    • Investigator Site
  • Nantes, France
    • Investigator Site
  • Paris, France
    • Investigator Site 1
  • Paris, France
    • Investigator Site 2
  • Paris, France
    • Investigator Site 3
  • Paris, France
    • Investigator Site 4
  • Paris, France
    • Investigator Site 5
  • Rouen, France
    • Investigator Site
  • Salouel, France
    • Investigator Site
• Germany
  • Dresden, Germany
    • Investigator Site 1
  • Dresden, Germany
    • Investigator Site 2
  • Erlangen, Germany
    • Investigator Site
  • Goppingen, Germany
    • Investigator Site
  • Kiel, Germany
    • Investigator Site
  • Köln, Germany
    • Investigator Site
  • Leipzig, Germany
    • Investigator Site
  • Würzburg, Germany
    • Investigator Site
• Hungary
  • Budapest, Hungary
    • Investigator Site 1
  • Budapest, Hungary
    • Investigator Site 2
  • Debrecen, Hungary
    • Investigator Site
• Israel
  • Be'er Ya'aqov, Israel
    • Investigator Site 1
  • Be'er Ya'aqov, Israel
    • Investigator Site 2
  • Haifa, Israel
    • Investigator Site
  • Jerusalem, Israel
    • Investigator Site 1
  • Jerusalem, Israel
    • Investigator Site 2
  • Nahariya, Israel
    • Investigator Site
  • Petah Tiqva, Israel
    • Investigator Site
  • Tel Aviv, Israel
    • Investigator Site
• Italy
  • Catania, Italy
    • Investigator Site
  • Milan, Italy
    • Investigator Site 1
  • Milan, Italy
    • Investigator Site 2
  • Pesaro, Italy
    • Investigator Site
  • Rome, Italy
    • Investigator Site
  • Vicenza, Italy
    • Investigator Site
• Netherlands
  • Amersfoort, Netherlands
    • Investigator Site
  • Leiden, Netherlands
    • Investigator Site
  • Rotterdam, Netherlands
    • Investigator Site
  • Veldhoven, Netherlands
    • Investigator Site
• Spain
  • Barcelona, Spain
    • Investigator Site 1
  • Barcelona, Spain
    • Investigator Site 2
  • Madrid, Spain
    • Investigator Site
  • Sevilla, Spain
    • Investigator Site
  • Valencia, Spain
    • Investigator Site 1
  • Valencia, Spain
    • Investigator Site 2
  • Valencia, Spain
    • Investigator Site 3
• Switzerland
  • Bern, Switzerland
    • Investigator Site
  • Zurich, Switzerland
    • Investigator Site
• Turkey
  • Ankara, Turkey
    • Investigator Site
  • Denizli, Turkey
    • Investigator Site 1
  • Denizli, Turkey
    • Investigator Site 2
  • Denizli, Turkey
    • Investigator Site 3
  • Istanbul, Turkey
    • Investigator Site
  • Kayseri, Turkey
    • Investigator Site
  • Trabzon, Turkey
    • Investigator Site
• United Kingdom
  • Bristol, United Kingdom
    • Investigator Site
  • Liverpool, United Kingdom
    • Investigator Site
  • London, United Kingdom
    • Investigator Site 1
  • London, United Kingdom
    • Investigator Site 2
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • Investigator Site
  • California
    • Los Angeles, California, United States, 90033
      • Investigator Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Investigator Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Investigator Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Investigator Site
  • New York
    • Rochester, New York, United States, 14642
      • Investigator Site
    • Rochester, New York, United States, 55905
      • Investigator Site
    • Valhalla, New York, United States, 10595
      • Investigator Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Investigator Site
    • Durham, North Carolina, United States, 27710
      • Investigator Site
    • Winston-Salem, North Carolina, United States, 27157
      • Investigator Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Investigator Site
    • Columbus, Ohio, United States, 43210
      • Investigator Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Investigator Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Investigator Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Investigator Site
    • Greenville, South Carolina, United States, 27834
      • Investigator Site
  • Texas
    • Houston, Texas, United States, 77030
      • Investigator Site
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Investigator Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo once daily	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 Names: ALX-0081 Placebo
Experimental: Caplacizumab; Caplacizumab 10 mg once daily	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 Names: ALX-0081

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Days of Plasma Exchange	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).	Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Total Volume of Plasma Exchange	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).	Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Number of Days in Intensive Care Unit	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).	Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Number of Days in Hospital	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).	Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.

Collaborators and Investigators

• Sponsor: Ablynx, a Sanofi company
• Investigators: Study Director: Medical Monitor, Ablynx NV

Publications and helpful links

General 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.

Helpful Links

• Publication in New England Journal of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: September 14, 2015
• First Submitted That Met QC Criteria: September 16, 2015
• First Posted (Estimate): September 17, 2015

Study Record Updates

• Last Update Posted (Actual): April 5, 2023
• Last Update Submitted That Met QC Criteria: March 31, 2023
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Hematologic Diseases; Hemorrhage; Blood Coagulation Disorders; Skin Manifestations; Thrombocytopenia; Blood Platelet Disorders; Thrombophilia; Thrombotic Microangiopathies; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic
• Other Study ID Numbers: ALX0681-C301; 2015-001098-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes