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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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Acquired Thrombotic Thrombocytopenic Purpura
Interventions Biological: Caplacizumab
Biological: Placebo
Enrollment 145
Recruitment Details A total of 145 subjects was randomized at 55 sites located in Europe (34 sites; 91 subjects), Asia (4 sites, 6 subjects), Australia (3 sites, 3 subjects), and North America (14 sites; 45 subjects). Consent was obtained from the first subject on 19 November 2015; the last subject completed the final visit on 16 August 2017.
Pre-assignment Details Of the 149 subjects screened, 4 were screen failures and 145 were randomly assigned to treatment (Intent-to-treat [ITT] population). All, except 1 subject who withdrew consent, received study drug and were included in the safety population and in the modified ITT (mITT) population.
Arm/Group Title Caplacizumab Placebo
Hide Arm/Group Description

Caplacizumab 10 mg once daily

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 once daily

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.
Period Title: Overall Treatment Period + Follow-up
Started 72 73
Received Study Drug 71 73
Completed 58 50
Not Completed 14 23
Reason Not Completed
Withdrawn by legal representative             0             1
Physician Decision             2             4
Non-compliance with study drug             0             1
Death             1             3
Adverse Event             6             5
Withdrawal by Subject             4             5
Lost to Follow-up             0             1
Diagnosed as non-TTP patient             1             1
Protocol Violation             0             1
Withdrew treatment, agreed for ET visit             0             1
Period Title: Double-blind (DB) Treatment Period
Started 71 [1] 73
Completed 68 65
Not Completed 3 8
[1]
One patient withdrew consent prior to first dosing and did not start the DB treatment period.
Period Title: Open-label (OL) Treatment Period
Started 2 [1] 26 [2]
Completed 2 22
Not Completed 0 4
[1]
2 patients on caplacizumab had a recurrence of TTP during the DB period and started OL treatment.
[2]
26 patients on placebo had a recurrence of TTP during the DB period and started OL treatment.
Arm/Group Title Caplacizumab Placebo Total
Hide Arm/Group Description

Caplacizumab 10 mg once daily

Caplacizumab:

  • First day of treatment: 10 mg intravenous (i.v.) injection prior to 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 once daily

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.
Total of all reporting groups
Overall Number of Baseline Participants 72 73 145
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants 73 participants 145 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
68
  94.4%
65
  89.0%
133
  91.7%
>=65 years
4
   5.6%
8
  11.0%
12
   8.3%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 72 participants 73 participants 145 participants
44.9  (13.46) 47.3  (14.07) 46.1  (13.78)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants 73 participants 145 participants
Female
49
  68.1%
51
  69.9%
100
  69.0%
Male
23
  31.9%
22
  30.1%
45
  31.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants 73 participants 145 participants
Hispanic or Latino
4
   5.6%
2
   2.7%
6
   4.1%
Not Hispanic or Latino
65
  90.3%
62
  84.9%
127
  87.6%
Unknown or Not Reported
3
   4.2%
9
  12.3%
12
   8.3%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants 73 participants 145 participants
Hungary
4
   5.6%
3
   4.1%
7
   4.8%
United States
10
  13.9%
22
  30.1%
32
  22.1%
Czechia
2
   2.8%
2
   2.7%
4
   2.8%
United Kingdom
13
  18.1%
8
  11.0%
21
  14.5%
Switzerland
1
   1.4%
0
   0.0%
1
   0.7%
Spain
8
  11.1%
6
   8.2%
14
   9.7%
Canada
7
   9.7%
6
   8.2%
13
   9.0%
Austria
3
   4.2%
1
   1.4%
4
   2.8%
Netherlands
1
   1.4%
0
   0.0%
1
   0.7%
Turkey
4
   5.6%
5
   6.8%
9
   6.2%
Belgium
5
   6.9%
3
   4.1%
8
   5.5%
Italy
6
   8.3%
4
   5.5%
10
   6.9%
Israel
4
   5.6%
2
   2.7%
6
   4.1%
Australia
1
   1.4%
2
   2.7%
3
   2.1%
France
3
   4.2%
9
  12.3%
12
   8.3%
1.Primary Outcome
Title Time to Platelet Count Response
Hide Description 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.
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)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population (for the respective study period, i.e., DB treatment period)
Arm/Group Title Caplacizumab Placebo
Hide Arm/Group Description:
Caplacizumab 10 mg once daily
Placebo once daily
Overall Number of Participants Analyzed 71 73
Median (95% Confidence Interval)
Unit of Measure: days
2.69
(1.89 to 2.83)
2.88
(2.68 to 3.56)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Caplacizumab, Placebo
Comments Time to platelet count response in the caplacizumab arm and placebo arm was compared by conducting a two-sided stratified log-rank test based on a KM analysis, with severity of neurological involvement (according to the Glasgow coma scale [GCS] category, stratification factor used in randomization: ≤12 / 13-15) as stratification factor.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.0099
Comments The resulting p-value was compared with a significance level of 5%.
Method Log Rank
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Caplacizumab, Placebo
Comments Time to platelet count response was analyzed using a Cox proportional hazards regression model with time to platelet count response as dependent variable, and treatment group and GCS category as independent variables. The hazard (or platelet count normalization rate) ratio from the Cox model was reported along with 95% CI.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.55
Confidence Interval (2-Sided) 95%
1.095 to 2.195
Estimation Comments The HR was estimated from a Cox proportional Hazards regression model.
2.Secondary Outcome
Title Number and Percentage of Subjects With TTP-Related Death, Recurrence of TTP, or a Major Thromboembolic Event During the Study Drug Treatment Period
Hide Description 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).
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.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population (for the respective study period, i.e., overall treatment period)
Arm/Group Title Caplacizumab Placebo
Hide Arm/Group Description:
Caplacizumab 10 mg once daily
Placebo once daily
Overall Number of Participants Analyzed 71 73
Measure Type: Count of Participants
Unit of Measure: Participants
9
  12.7%
36
  49.3%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Caplacizumab, Placebo
Comments A Cochran-Mantel-Haenszel (CMH) test was conducted with adjustment for GCS category (stratification factor used in randomization).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments The resulting p-value was compared with a significance level of 5%.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
3.Secondary Outcome
Title Number and Percentage of Subjects With a Recurrence of TTP in the Overall Study Period
Hide Description 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).
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.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population (for the respective study period, i.e., overall study period)
Arm/Group Title Caplacizumab Placebo
Hide Arm/Group Description:
Caplacizumab 10 mg once daily
Placebo once daily
Overall Number of Participants Analyzed 71 73
Measure Type: Count of Participants
Unit of Measure: Participants
9
  12.7%
28
  38.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Caplacizumab, Placebo
Comments A CMH test was conducted with adjustment for GCS category (stratification factor used in randomization).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.0004
Comments The resulting p-value was compared with a significance level of 5%.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
4.Secondary Outcome
Title Number and Percentage of Subjects With Refractory Disease
Hide Description 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 Frame The study drug treatment period, a median (min, max) of 36 (2, 82) days.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population (for the respective study period, i.e., overall treatment period)
Arm/Group Title Caplacizumab Placebo
Hide Arm/Group Description:
Caplacizumab 10 mg once daily
Placebo once daily
Overall Number of Participants Analyzed 71 73
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
3
   4.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Caplacizumab, Placebo
Comments A CMH test was conducted with adjustment for GCS category (stratification factor used in randomization).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.0572
Comments The resulting p-value was compared with a significance level of 5%.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
5.Secondary Outcome
Title Time to Normalization of Organ Damage Marker Levels
Hide Description

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).

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.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population (for the respective study period, i.e., overall study period) with biomarker level data available
Arm/Group Title Caplacizumab Placebo
Hide Arm/Group Description:
Caplacizumab 10 mg once daily
Placebo once daily
Overall Number of Participants Analyzed 65 66
Median (95% Confidence Interval)
Unit of Measure: days
2.86
(1.93 to 3.86)
3.36
(1.88 to 7.71)
6.Other Pre-specified Outcome
Title Number of Days of Plasma Exchange
Hide Description 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).
Time Frame Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population (for the respective study period, i.e., overall treatment period)
Arm/Group Title Caplacizumab Placebo
Hide Arm/Group Description:
Caplacizumab 10 mg once daily
Placebo once daily
Overall Number of Participants Analyzed 71 73
Mean (Standard Error)
Unit of Measure: days
5.8  (0.51) 9.4  (0.81)
7.Other Pre-specified Outcome
Title Total Volume of Plasma Exchange
Hide Description 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).
Time Frame Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population (for the respective study period, i.e., overall treatment period)
Arm/Group Title Caplacizumab Placebo
Hide Arm/Group Description:
Caplacizumab 10 mg once daily
Placebo once daily
Overall Number of Participants Analyzed 71 73
Mean (Standard Error)
Unit of Measure: liter(s)
21.33  (1.619) 35.93  (4.169)
8.Other Pre-specified Outcome
Title Number of Days in Intensive Care Unit
Hide Description 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).
Time Frame Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population (for the respective study period, i.e., overall treatment period)
Arm/Group Title Caplacizumab Placebo
Hide Arm/Group Description:
Caplacizumab 10 mg once daily
Placebo once daily
Overall Number of Participants Analyzed 71 73
Mean (Standard Error)
Unit of Measure: days
3.4  (0.40) 9.7  (2.12)
9.Other Pre-specified Outcome
Title Number of Days in Hospital
Hide Description 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).
Time Frame Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population (for the respective study period, i.e., overall treatment period)
Arm/Group Title Caplacizumab Placebo
Hide Arm/Group Description:
Caplacizumab 10 mg once daily
Placebo once daily
Overall Number of Participants Analyzed 71 73
Mean (Standard Error)
Unit of Measure: days
9.9  (0.70) 14.4  (1.22)
Time Frame From time of first study drug administration until the subject's study completion/discontinuation date, a median (min, max) of 65 (2, 110) days.
Adverse Event Reporting Description

Double-Blind Caplacizumab/Double-Blind placebo groups (subjects randomized to caplacizumab/placebo, respectively): adverse events (AEs) starting in DB or FU Periods for subjects with no OL Period. Only AEs starting in the DB Period for subjects with an OL Period.

OL Caplacizumab group (all subjects with OL Period): AEs starting in the OL or FU Periods.

The 3 subjects who died in the placebo group died during treatment and the subject who died in the caplacizumab group died during follow-up.

 
Arm/Group Title Double-blind Caplacizumab Double-blind Placebo Open-label Caplacizumab
Hide Arm/Group Description Caplacizumab 10 mg once daily Placebo once daily In case an exacerbation during the 30-day treatment period or a relapse during the treatment extension period occurred (first exacerbation or relapse), subjects were to receive open label caplacizumab 10 mg daily together with re-initiation of daily PE and optimized immunosuppressive treatment. Caplacizumab treatment schedule and visit schedule were the same as for the initial study drug treatment period (covering daily PE [variable duration] and 30-day post-daily PE period) and the possible treatment extension period.
All-Cause Mortality
Double-blind Caplacizumab Double-blind Placebo Open-label Caplacizumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/71 (1.41%)      3/73 (4.11%)      0/28 (0.00%)    
Hide Serious Adverse Events
Double-blind Caplacizumab Double-blind Placebo Open-label Caplacizumab
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   28/71 (39.44%)      39/73 (53.42%)      7/28 (25.00%)    
Blood and lymphatic system disorders       
Thrombotic thrombocytopenic purpura  1  9/71 (12.68%)  9 29/73 (39.73%)  29 4/28 (14.29%)  4
Thrombotic microangiopathy  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Cardiac disorders       
Myocardial infarction  1  1/71 (1.41%)  1 1/73 (1.37%)  1 0/28 (0.00%)  0
Arteriospasm coronary  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Cardiac tamponade  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Cardiogenic shock  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Ventricular fibrillation  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Gastrointestinal disorders       
Gingival bleeding  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Upper gastrointestinal hemorrhage  1  1/71 (1.41%)  1 0/73 (0.00%)  0 1/28 (3.57%)  1
Colitis  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Gastric ulcer hemorrhage  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Gastrointestinal necrosis  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Hematemesis  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Intestinal ischemia  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Intestinal perforation  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Small intestinal obstruction  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
General disorders       
Asthenia  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Systemic inflammatory response syndrome  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Hepatobiliary disorders       
Bile duct stone  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Cholecystitis  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Gallbladder necrosis  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Immune system disorders       
Serum sickness  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Infections and infestations       
Septic shock  1 [1]  0/71 (0.00%)  0 2/73 (2.74%)  2 0/28 (0.00%)  0
Bacteremia  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Device related sepsis  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Diverticulitis  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Injury, poisoning and procedural complications       
Anaphylactic transfusion reaction  1  0/71 (0.00%)  0 3/73 (4.11%)  3 0/28 (0.00%)  0
Subarachnoid hemorrhage  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Investigations       
Gamma-glutamyltransferase increased  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Platelet count decreased  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Pain in extremity  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Arthropathy  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Nervous system disorders       
Headache  1  2/71 (2.82%)  2 0/73 (0.00%)  0 0/28 (0.00%)  0
Seizure  1  0/71 (0.00%)  0 0/73 (0.00%)  0 1/28 (3.57%)  1
Cerebral ischemia  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Encephalopathy  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Hemorrhagic transformation stroke  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Hemiparesis  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Reproductive system and breast disorders       
Menorrhagia  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Hemorrhagic ovarian cyst  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Epistaxis  1  4/71 (5.63%)  4 0/73 (0.00%)  0 0/28 (0.00%)  0
Dyspnoea  1  0/71 (0.00%)  0 0/73 (0.00%)  0 1/28 (3.57%)  1
Hypoxia  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Respiratory failure  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Pulmonary embolism  1  1/71 (1.41%)  1 0/73 (0.00%)  0 0/28 (0.00%)  0
Skin and subcutaneous tissue disorders       
Rash erythematosus  1  0/71 (0.00%)  0 0/73 (0.00%)  0 1/28 (3.57%)  1
Vascular disorders       
Deep vein thrombosis  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
Jugular vein thrombosis  1  0/71 (0.00%)  0 1/73 (1.37%)  1 0/28 (0.00%)  0
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
[1]
Verbatim term of serious adverse event (SAE) with fatal outcome: septic shock
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Double-blind Caplacizumab Double-blind Placebo Open-label Caplacizumab
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   67/71 (94.37%)      65/73 (89.04%)      25/28 (89.29%)    
Blood and lymphatic system disorders       
Anemia  1  4/71 (5.63%)  4 6/73 (8.22%)  9 4/28 (14.29%)  8
Cardiac disorders       
Sinus tachycardia  1  4/71 (5.63%)  4 3/73 (4.11%)  5 1/28 (3.57%)  4
Tachycardia  1  2/71 (2.82%)  2 4/73 (5.48%)  4 1/28 (3.57%)  1
Eye disorders       
Vision blurred  1  5/71 (7.04%)  6 5/73 (6.85%)  5 0/28 (0.00%)  0
Gastrointestinal disorders       
Nausea  1  10/71 (14.08%)  12 7/73 (9.59%)  8 2/28 (7.14%)  2
Gingival bleeding  1  12/71 (16.90%)  13 1/73 (1.37%)  1 4/28 (14.29%)  5
Constipation  1  7/71 (9.86%)  7 5/73 (6.85%)  6 4/28 (14.29%)  6
Diarrhoea  1  7/71 (9.86%)  7 5/73 (6.85%)  5 4/28 (14.29%)  7
Abdominal pain  1  5/71 (7.04%)  5 4/73 (5.48%)  4 2/28 (7.14%)  4
Vomiting  1  3/71 (4.23%)  3 4/73 (5.48%)  5 2/28 (7.14%)  2
Abdominal pain upper  1  1/71 (1.41%)  1 1/73 (1.37%)  1 4/28 (14.29%)  8
Dyspepsia  1  2/71 (2.82%)  2 1/73 (1.37%)  1 2/28 (7.14%)  2
Hematochezia  1  2/71 (2.82%)  5 0/73 (0.00%)  0 2/28 (7.14%)  2
Lip hemorrhage  1  0/71 (0.00%)  0 0/73 (0.00%)  0 2/28 (7.14%)  2
General disorders       
Catheter site hemorrhage  1  5/71 (7.04%)  6 5/73 (6.85%)  5 8/28 (28.57%)  10
Fatigue  1  10/71 (14.08%)  10 6/73 (8.22%)  6 2/28 (7.14%)  2
Pyrexia  1  10/71 (14.08%)  12 6/73 (8.22%)  6 1/28 (3.57%)  1
Oedema peripheral  1  4/71 (5.63%)  4 7/73 (9.59%)  8 1/28 (3.57%)  2
Asthenia  1  2/71 (2.82%)  3 4/73 (5.48%)  4 2/28 (7.14%)  3
Chest pain  1  1/71 (1.41%)  1 5/73 (6.85%)  6 1/28 (3.57%)  1
Catheter site pain  1  1/71 (1.41%)  1 5/73 (6.85%)  5 0/28 (0.00%)  0
Injection site pain  1  1/71 (1.41%)  1 4/73 (5.48%)  4 1/28 (3.57%)  1
Injection site hematoma  1  1/71 (1.41%)  1 3/73 (4.11%)  4 2/28 (7.14%)  2
Pain  1  4/71 (5.63%)  7 1/73 (1.37%)  1 0/28 (0.00%)  0
Injection site erythema  1  1/71 (1.41%)  1 1/73 (1.37%)  1 2/28 (7.14%)  4
Injection site pruritus  1  2/71 (2.82%)  2 0/73 (0.00%)  0 2/28 (7.14%)  2
Injection site reaction  1  1/71 (1.41%)  1 0/73 (0.00%)  0 2/28 (7.14%)  2
Face oedema  1  0/71 (0.00%)  0 0/73 (0.00%)  0 2/28 (7.14%)  2
Infections and infestations       
Urinary tract infection  1  4/71 (5.63%)  4 4/73 (5.48%)  4 0/28 (0.00%)  0
Viral upper respiratory tract infection  1  4/71 (5.63%)  4 0/73 (0.00%)  0 0/28 (0.00%)  0
Injury, poisoning and procedural complications       
Contusion  1  5/71 (7.04%)  7 10/73 (13.70%)  24 2/28 (7.14%)  10
Investigations       
Hepatic enzyme increased  1  0/71 (0.00%)  0 1/73 (1.37%)  1 2/28 (7.14%)  2
Metabolism and nutrition disorders       
Hypokalemia  1  6/71 (8.45%)  6 14/73 (19.18%)  15 2/28 (7.14%)  2
Hyperglycemia  1  4/71 (5.63%)  5 4/73 (5.48%)  4 1/28 (3.57%)  2
Hypocalcemia  1  1/71 (1.41%)  1 5/73 (6.85%)  8 2/28 (7.14%)  3
Musculoskeletal and connective tissue disorders       
Pain in extremity  1  4/71 (5.63%)  5 6/73 (8.22%)  7 0/28 (0.00%)  0
Arthralgia  1  4/71 (5.63%)  4 3/73 (4.11%)  3 3/28 (10.71%)  4
Back pain  1  5/71 (7.04%)  5 3/73 (4.11%)  3 1/28 (3.57%)  1
Muscular weakness  1  4/71 (5.63%)  5 2/73 (2.74%)  2 0/28 (0.00%)  0
Myalgia  1  2/71 (2.82%)  2 1/73 (1.37%)  1 2/28 (7.14%)  3
Nervous system disorders       
Headache  1  14/71 (19.72%)  18 6/73 (8.22%)  10 6/28 (21.43%)  6
Dizziness  1  7/71 (9.86%)  8 8/73 (10.96%)  8 2/28 (7.14%)  3
Paresthesia  1  8/71 (11.27%)  9 6/73 (8.22%)  6 0/28 (0.00%)  0
Psychiatric disorders       
Insomnia  1  6/71 (8.45%)  7 8/73 (10.96%)  8 0/28 (0.00%)  0
Anxiety  1  4/71 (5.63%)  4 6/73 (8.22%)  6 1/28 (3.57%)  1
Agitation  1  5/71 (7.04%)  6 4/73 (5.48%)  4 0/28 (0.00%)  0
Renal and urinary disorders       
Hematuria  1  5/71 (7.04%)  7 2/73 (2.74%)  2 2/28 (7.14%)  2
Reproductive system and breast disorders       
Vaginal hemorrhage  1  4/71 (5.63%)  5 2/73 (2.74%)  2 1/28 (3.57%)  1
Respiratory, thoracic and mediastinal disorders       
Epistaxis  1  21/71 (29.58%)  32 2/73 (2.74%)  2 5/28 (17.86%)  5
Dyspnoea  1  7/71 (9.86%)  10 2/73 (2.74%)  2 2/28 (7.14%)  2
Skin and subcutaneous tissue disorders       
Urticaria  1  12/71 (16.90%)  14 5/73 (6.85%)  8 1/28 (3.57%)  1
Rash  1  5/71 (7.04%)  6 9/73 (12.33%)  11 4/28 (14.29%)  4
Pruritus  1  5/71 (7.04%)  6 6/73 (8.22%)  6 2/28 (7.14%)  4
Petechiae  1  4/71 (5.63%)  4 5/73 (6.85%)  5 3/28 (10.71%)  5
Ecchymosis  1  2/71 (2.82%)  2 4/73 (5.48%)  4 3/28 (10.71%)  3
Vascular disorders       
Hypertension  1  4/71 (5.63%)  4 8/73 (10.96%)  8 1/28 (3.57%)  1
Hematoma  1  3/71 (4.23%)  7 2/73 (2.74%)  2 2/28 (7.14%)  2
Hypotension  1  4/71 (5.63%)  4 2/73 (2.74%)  3 1/28 (3.57%)  1
Hot flush  1  0/71 (0.00%)  0 0/73 (0.00%)  0 2/28 (7.14%)  2
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Publication of any results from this study will be according to the principles of the Declaration of Helsinki, in particular point 30, and will require prior review and written agreement of the Sponsor.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Monitor
Organization: Ablynx
Phone: +32 (9) 262 00 00
EMail: clinicaltrials@ablynx.com
Layout table for additonal information
Responsible Party: Ablynx
ClinicalTrials.gov Identifier: NCT02553317    
Other Study ID Numbers: ALX0681-C301
2015-001098-42 ( EudraCT Number )
First Submitted: September 14, 2015
First Posted: September 17, 2015
Results First Submitted: February 25, 2019
Results First Posted: May 22, 2019
Last Update Posted: May 22, 2019