Follow-up Study for Patients Who Completed Study ALX0681-C301 (Post-HERCULES)

Prospective Follow-up Study for Patients Who Completed Study ALX0681-C301 (HERCULES) to Evaluate Long-term Safety and Efficacy of Caplacizumab (Post-HERCULES)

The objectives of this study were to evaluate long-term safety and efficacy of caplacizumab, to evaluate safety and efficacy of repeated use of caplacizumab and to characterize long-term impact of acquired thrombotic thrombocytopenic purpura (aTTP).

Study Overview

• Status: Completed
• Conditions: Acquired Thrombotic Thrombocytopenic Purpura
• Intervention / Treatment: Biological: Caplacizumab; Other: Standard of Care

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria
    • Investigator site
• Belgium
  • Antwerp, Belgium
    • Investigator site
  • Bruxelles, Belgium
    • Investigator site
  • La Louviere, Belgium
    • Investigator site
  • Leuven, Belgium
    • Investigator site
• Canada
  • Halifax, Canada
    • Investigator site
  • Quebec, Canada
    • Investigator site
  • Toronto, Canada
    • Investigator site
• Czechia
  • Brno, Czechia
    • Investigator site
  • Olomouc, Czechia
    • Investigator site
• France
  • Caen, France
    • Investigator site
  • Lille, France
    • Investigator site
  • Marseille, France
    • Investigator site
  • Paris, France
    • Investigator Site 1
  • Paris, France
    • Investigator Site 2
• Hungary
  • Budapest, Hungary
    • Investigator site
  • Debrecen, Hungary
    • Investigator site
• Israel
  • Haifa, Israel
    • Investigator site
  • Jerusalem Region, Israel
    • Investigator site
  • Nahariya, Israel
    • Investigator site
• Italy
  • Catania, Italy
    • Investigator site
  • Milan, Italy
    • Investigator site
  • Pesaro, Italy
    • Investigator site
  • Rome, Italy
    • Investigator site
  • Vicenza, Italy
    • Investigator site
• Spain
  • Barcelona, Spain
    • Investigator Site 1
  • Barcelona, Spain
    • Investigator Site 2
  • Sevilla, Spain
    • Investigator site
  • Valencia, Spain
    • Investigator Site 2
  • Valencia, Spain
    • Investyigator Site 1
• Switzerland
  • Bern, Switzerland
    • Investigator site
• Turkey
  • Ankara, Turkey
    • Investigator site
  • Istanbul, Turkey
    • Investigator site
  • Kayseri, Turkey
    • Investigator site
• United Kingdom
  • Bristol, United Kingdom
    • Investigator site
  • Liverpool, United Kingdom
    • Investigator site
  • London, United Kingdom
    • Investigator site
• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Investigator site
  • New York
    • Valhalla, New York, United States, 10595
      • Investigator site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Investigator site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Investigator site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Investigator site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Investigator site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Investigator site
    • Greenville, South Carolina, United States, 27834
      • Investigator site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Completed the Final (28 day) follow-up visit in Study ALX0681-C301.
2. >= 18 years of age at the time of signing the informed consent form.
3. Provided informed consent prior to initiation of any study specific activity/procedure.

Exclusion Criteria:

1. Not being able/willing to comply with the study protocol procedures.
2. Currently enrolled in a clinical study with another investigational drug or device.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: caplacizumab; Participants who completed study ALX0681-C301 (NCT02553317) with standard of care (plasma exchange [PE], corticosteroid and other immunosuppressive agents) or caplacizumab with PE and immunosuppressive agents were enrolled in study LTS16371. Participants upon each recurrence of aTTP in LTS16371 and not meeting any criteria (namely: pregnancy, history of severe and/or serious hypersensitivity reaction to investigational medicinal product [IMP], withdrawal before receiving IMP, received more than 1 PE) were treated with caplacizumab initial 10 milligrams (mg) intravenous dose followed by a daily 10 mg subcutaneous injections during the period of PE and for 30 days after stop of PE (and eventually 28-day extension period, if needed). Participants with or without recurrence were followed up twice yearly up to maximum of 36 months in LTS16371.

Biological: Caplacizumab; Other: Standard of Care; • PE with plasma (e.g., fresh frozen plasma, solvent detergent/viral-inactivated plasma, cryosupernatant), • Corticosteroid treatment and • Use of other immunosuppressive agents (e.g., rituximab).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Acquired Thrombotic Thrombocytopenic Purpura (aTTP) Related Events	aTTP-related events were defined as: aTTP-related death, recurrence of aTTP (defined as recurrent thrombocytopenia requiring initiation of daily PE) or at least one major thromboembolic event (e.g., myocardial infarction, cerebrovascular accident, pulmonary embolism, or deep venous thrombosis). Percentage of participants with at least one aTTP-related events during the study were reported in this outcome measure.	From Baseline up to 36 months
Number of Acquired Thrombotic Thrombocytopenic Purpura-related Events	aTTP-related events were defined as: aTTP-related death, recurrence of aTTP (defined as recurrent thrombocytopenia requiring initiation of daily PE) or at least one major thromboembolic event (e.g., myocardial infarction, cerebrovascular accident, pulmonary embolism or deep venous thrombosis).	From Baseline up to 36 months
Time to First Acquired Thrombotic Thrombocytopenic Purpura-related Events	Time to first aTTP-related events was defined as the duration of time (in days) from Baseline up to first aTTP-related event in LTS16371. Participants without an event during LTS16371 were censored at the end of the study. Kaplan-Meier method was used for the analysis.	From Baseline up to 36 months
Number of Participants With aTTP Related Deaths Reported During the Study		From Baseline up to 36 months
Percentage of Participants With Recurrence of Disease (aTTP)	Recurrence of aTTP was defined as recurrent thrombocytopenia requiring initiation of daily PE.	From Baseline up to 36 months
Number of Disease (aTTP) Recurrence Reported During the Study	Recurrence of aTTP was defined as recurrent thrombocytopenia requiring initiation of daily PE.	From Baseline up to 36 months
Time to Recurrence of Disease (aTTP)	Time to first recurrence of disease (aTTP) was defined as the duration of time (in days) from Baseline up to first recurrence of aTTP event in LTS16371. Recurrence of aTTP: defined as recurrent thrombocytopenia requiring initiation of daily PE. Participants without an event during LTS16371 were censored at the end of the study. Kaplan-Meier method was used for the analysis.	From Baseline up to 36 months
Percentage of Participants With Major Thromboembolic Events Including Thrombotic Thrombocytopenic Purpura (TTP)	Major thromboembolic events (e.g., myocardial infarction, cerebrovascular accident, pulmonary embolism, or deep venous thrombosis) were assessed based on Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ). Reported major thromboembolic events included TTP recurrences.	From Baseline up to 36 months
Number of Major Thromboembolic Events Including Thrombotic Thrombocytopenic Purpura	Major thromboembolic events (e.g., myocardial infarction, cerebrovascular accident, pulmonary embolism, or deep venous thrombosis) were assessed based on SMQ. Reported major thromboembolic events included TTP recurrences.	From Baseline up to 36 months
Time to First Major Thromboembolic Event	Time to first major thromboembolic event was defined as the duration of time (in days) from Baseline up to first major thromboembolic event in LTS16371. Participants without an event during LTS16371 were censored at the end of the study. Kaplan-Meier method was used for the analysis.	From Baseline up to 36 months
Cognitive Function: Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Absolute Scores at Baseline, 36 Months Follow-up Visit, and Change From Baseline in RBANS Total Score at 36 Months Follow-up Visit	The RBANS is a 30-minute comprehensive screening test with five individual domains (immediate memory, delayed memory, attention, language, and visuospatial ability) to examine the cognitive mental status of a participant. Scores from all individual domain were aggregated into a total score and thus RBANS total score ranged from 40 to 160, where higher scores reflected better performance.	Baseline, 36 Months follow-up visit
Health-Related Quality of Life (HRQoL): Change From Baseline in Headache Impact Test (HIT-6) Total Scores at Month 12, 24, and 36 Follow-up Visits	HIT-6 is an easy to administer assessment that was used as a clinical evaluation of the impact of headache on a participant's QoL in both clinical practice and clinical research. The questionnaire included 6 questions covering the 6 areas of functioning most impacted in headache sufferers including pain, role functioning (the ability to carry out usual activities), social functioning, vitality (energy/ fatigue), cognitive functioning, and psychological/emotional distress. Total HIT-6 scores (sum of all individual questions) ranged from 36 (best outcome) to 78 (worst outcome), where higher scores indicated worse condition.	Baseline, Month 12, 24, and 36 Follow-up visits
Health-Related Quality of Life: Change From Baseline in 36-Item Short Form Questionnaire (SF-36) Health Survey - Physical Functioning Domain Scores at Month 12, 24, and 36 Follow-up Visits	The SF-36 consisted of 36 items that was summarized into 8 domains: physical functioning, social functioning, role functioning/physical, role functioning/emotional, emotional well-being, energy/fatigue, pain, general health and an additional single item covering change in health status. Physical functioning domain scores ranged from 0 (worst value) to 100 (best value), with higher scores reflecting better health status. Change from baseline in physical functioning domain score at months 12, 24, and 36 were reported in this outcome measure.	Baseline, Month 12, 24, and 36 Follow-up visits
Health-Related Quality of Life: Change From Baseline in 36-Item Short Form Questionnaire Health Survey - Role Functioning/Physical Domain Scores at Month 12, 24, and 36 Follow-up Visits	The SF-36 consisted of 36 items that was summarized into 8 domains: physical functioning, social functioning, role functioning/physical, role functioning/emotional, emotional well-being, energy/fatigue, pain, general health and an additional single item covering change in health status. Role Functioning/Physical domain scores ranged from 0 (worst value) to 100 (best value), with higher scores reflecting better health status. Change from baseline in role functioning/physical domain score at months 12, 24, and 36 were reported in this outcome measure.	Baseline, Month 12, 24, and 36 Follow-up visits
Health-Related Quality of Life: Change From Baseline in 36-Item Short Form Questionnaire Health Survey - Role Functioning/Emotional Domain Scores at Month 12, 24, and 36 Follow-up Visits	The SF-36 consisted of 36 items that was summarized into 8 domains: physical functioning, social functioning, role functioning/physical, role functioning/emotional, emotional well-being, energy/fatigue, pain, general health and an additional single item covering change in health status. Role functioning/emotional domain scores ranged from 0 (worst value) to 100 (best value), with higher scores reflecting better health status. Change from baseline in role functioning/emotional domain score at months 12, 24, and 36 were reported in this outcome measure.	Baseline, Month 12, 24, and 36 Follow-up visits
Health-Related Quality of Life: Change From Baseline in 36-Item Short Form Questionnaire Health Survey - Energy/Fatigue Domain Scores at Month 12, 24, and 36 Follow-up Visits	The SF-36 consisted of 36 items that was summarized into 8 domains: physical functioning, social functioning, role functioning/physical, role functioning/emotional, emotional well-being, energy/fatigue, pain, general health and an additional single item covering change in health status. Energy/fatigue domain scores ranged from 0 (worst value) to 100 (best value), with higher scores reflecting better health status. Change from baseline in energy/fatigue domain score at months 12, 24, and 36 were reported in this outcome measure.	Baseline, Month 12, 24, and 36 Follow-up visits
Health-Related Quality of Life: Change From Baseline in 36-Item Short Form Questionnaire Health Survey - Emotional Well-being Domain Scores at Month 12, 24, and 36 Follow-up Visits	The SF-36 consisted of 36 items that was summarized into 8 domains: physical functioning, social functioning, role functioning/physical, role functioning/emotional, emotional well-being, energy/fatigue, pain, general health and an additional single item covering change in health status. Emotional well-being domain scores ranged from 0 (worst value) to 100 (best value), with higher scores reflecting better health status. Change from baseline in emotional well-being domain score at months 12, 24, and 36 were reported in this outcome measure.	Baseline, Month 12, 24, and 36 Follow-up visits
Health-Related Quality of Life: Change From Baseline in 36-Item Short Form Questionnaire Health Survey - Social Functioning Domain Scores at Month 12, 24, and 36 Follow-up Visits	The SF-36 consisted of 36 items that was summarized into 8 domains: physical functioning, social functioning, role functioning/physical, role functioning/emotional, emotional well-being, energy/fatigue, pain, general health and an additional single item covering change in health status. Social functioning domain scores ranged from 0 (worst value) to 100 (best value), with higher scores reflecting better health status. Change from baseline in social functioning domain score at months 12, 24, and 36 were reported in this outcome measure.	Baseline, Month 12, 24, and 36 Follow-up visits
Health-Related Quality of Life: Change From Baseline in 36-Item Short Form Questionnaire Health Survey - Pain Domain Scores at Month 12, 24, and 36 Follow-up Visits	The SF-36 consisted of 36 items that was summarized into 8 domains: physical functioning, social functioning, role functioning/physical, role functioning/emotional, emotional well-being, energy/fatigue, pain, general health and an additional single item covering change in health status. Pain domain scores ranged from 0 (worst value) to 100 (best value), with higher scores reflecting better health status. Change from baseline in pain domain score at months 12, 24, and 36 were reported in this outcome measure.	Baseline, Month 12, 24, and 36 Follow-up visits
Health-Related Quality of Life: Change From Baseline in 36-Item Short Form Questionnaire Health Survey - General Health Domain Scores at Month 12, 24, and 36 Follow-up Visits	The SF-36 consisted of 36 items that was summarized into 8 domains: physical functioning, social functioning, role functioning/physical, role functioning/emotional, emotional well-being, energy/fatigue, pain, general health and an additional single item covering change in health status. General Health domain scores ranged from 0 (worst value) to 100 (best value), with higher scores reflecting better health status. Change from baseline in general health domain score at months 12, 24, and 36 were reported in this outcome measure.	Baseline, Month 12, 24, and 36 Follow-up visits
Health-Related Quality of Life: Change From Baseline in 36-Item Short Form Questionnaire Health Survey - Change in Health Status Scores at Month 12, 24, and 36 Follow-up Visits	The SF-36 consisted of 36 items that was summarized into 8 domains: physical functioning, social functioning, role functioning/physical, role functioning/emotional, emotional well-being, energy/fatigue, pain, general health and an additional single item covering change in health status. Change in health status scores ranged from 0 (worst value) to 100 (best value), with higher scores reflecting better health status. Change from baseline in change in health status score at months 12, 24, and 36 were reported in this outcome measure.	Baseline, Month 12, 24, and 36 Follow-up visits
Percentage of Participants With Drug-induced Treatment-emergent (TE) Anti-drug Antibodies (ADA) Positive Response	Drug-induced TE ADA positive was based on the outcome of a tiered assay approach that included a modified ADA (mADA) method to eliminate the effects of pre-existing antibodies (pre-Ab). TE ADA responses reported here included both pre-Ab positive and negative responses. A participant was considered as drug-induced TE ADA positive if post-dose samples were positive, regardless of the status of pre-dose samples in the ADA and modified ADA assay.	From Baseline up to 36 months
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a clinical study participant administered a medicinal product and which did not necessarily had to have a causal relationship with the treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event.	From Baseline up to 36 months

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Director: Medical Director Ablynx, MD, Ablynx NV

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2016
• Primary Completion (Actual): October 23, 2020
• Study Completion (Actual): October 23, 2020

Study Registration Dates

• First Submitted: August 4, 2016
• First Submitted That Met QC Criteria: August 22, 2016
• First Posted (Estimate): August 25, 2016

Study Record Updates

• Last Update Posted (Actual): March 28, 2022
• Last Update Submitted That Met QC Criteria: March 21, 2022
• Last Verified: March 1, 2022

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: LTS16371; 2016-001503-23 (EudraCT Number); ALX0681-C302 (Other Identifier: Ablynx)

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