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

NCT02878603 | Completed Phase 3 Results DMC

• 3 other identifiers: LTS163712016-001503-23ALX0681-C302
• Study Type: interventional
• Target: 104
• Locations: 13 countries
• Sites: 45

Brief Summary

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).

Conditions

Acquired Thrombotic Thrombocytopenic Purpura

Outcome Measures

Primary Outcomes (23)

• 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

Study Arms (1)

caplacizumab

EXPERIMENTAL

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

Interventions

Caplacizumab BIOLOGICAL

caplacizumab

Standard of Care OTHER

• 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).

caplacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• Sanofi: lead

Study Sites (45)

Investigator site

St Louis, Missouri, 63110, United States

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Valhalla, New York, 10595, United States

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Durham, North Carolina, 27710, United States

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Columbus, Ohio, 43210, United States

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Oklahoma City, Oklahoma, 73104, United States

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Pittsburgh, Pennsylvania, 15232, United States

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Charleston, South Carolina, 29425, United States

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Greenville, South Carolina, 27834, United States

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Vienna, Austria

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Antwerp, Belgium

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Brussels, Belgium

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La Louvière, Belgium

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Leuven, Belgium

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Halifax, Canada

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Québec, Canada

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Toronto, Canada

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Brno, Czechia

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Olomouc, Czechia

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Caen, France

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Lille, France

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Marseille, France

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Paris, France

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Paris, France

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Budapest, Hungary

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Debrecen, Hungary

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Haifa, Israel

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Jerusalem Region, Israel

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Nahariya, Israel

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Catania, Italy

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Milan, Italy

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Pesaro, Italy

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Rome, Italy

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Vicenza, Italy

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Barcelona, Spain

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Barcelona, Spain

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Seville, Spain

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Valencia, Spain

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Valencia, Spain

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Bern, Switzerland

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Ankara, Turkey (Türkiye)

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Istanbul, Turkey (Türkiye)

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Kayseri, Turkey (Türkiye)

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Bristol, United Kingdom

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Liverpool, United Kingdom

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London, United Kingdom

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Related Publications (1)

• Scully M, de la Rubia J, Pavenski K, Metjian A, Knobl P, Peyvandi F, Cataland S, Coppo P, Kremer Hovinga JA, Minkue Mi Edou J, De Passos Sousa R, Callewaert F, Gunawardena S, Lin J. Long-term follow-up of patients treated with caplacizumab and safety and efficacy of repeat caplacizumab use: Post-HERCULES study. J Thromb Haemost. 2022 Dec;20(12):2810-2822. doi: 10.1111/jth.15892. Epub 2022 Oct 21.

  PMID: 36138517 DERIVED

MeSH Terms

Conditions

Purpura, Thrombotic Thrombocytopenic

Interventions

caplacizumab; Standard of Care

Condition Hierarchy (Ancestors)

Purpura, Thrombocytopenic; Purpura; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Cytopenia; Thrombophilia; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Skin Manifestations; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Medical Director Ablynx, MD

  Ablynx NV

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2016
• First Posted: August 25, 2016
• Study Start: October 6, 2016
• Primary Completion: October 23, 2020
• Study Completion: October 23, 2020
• Last Updated: March 28, 2022
• Results First Posted: November 22, 2021

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

IT (5); BE (4); GB (3); CA (3); FR (5); HU (2); ES (5); IL (3); US (8); AU (1); TU (3); CH (1); CZ (2)