Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura

Acquired Thrombotic Thrombocytopenic Purpura Clinical Trial

— HERCULES  

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02553317
• Other study ID #: ALX0681-C301
• Secondary ID: 2015-001098-42
• Status: Completed
• Phase: Phase 3
• Start date: November 2015
• Est. completion date: August 2017

Study information

• Verified date: May 2019
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: August 2017
• Est. primary completion date: August 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acquired Thrombotic Thrombocytopenic Purpura
• Purpura
• Purpura, Thrombocytopenic
• Purpura, Thrombotic Thrombocytopenic

Intervention

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.
• 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.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Ablynx, a Sanofi company

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  France,  Germany,  Hungary,  Israel,  Italy,  Netherlands,  Spain,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.
Other	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.
Other	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.
Other	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.
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.