Acquired Thrombotic Thrombocytopenic Purpura
Conditions
Brief 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
Interventions
BIOLOGICALCaplacizumab
* 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.
BIOLOGICALPlacebo
* 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.
Sponsors
Ablynx, a Sanofi company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Platelet Count Response | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Subjects With TTP-Related Death, Recurrence of TTP, or a Major Thromboembolic Event During the Study Drug Treatment Period | 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 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). |
| Number and Percentage of Subjects With a Recurrence of TTP in the Overall Study Period | 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 a recurrence of TTP during the Overall Study Period (i.e., including follow-up \[FU\]) (i.e., second key secondary endpoint). |
| Number and Percentage of Subjects With Refractory Disease | The study drug treatment period, a median (min, max) of 36 (2, 82) days. | 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 to Normalization of Organ Damage Marker Levels | 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. | 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Total Volume of Plasma Exchange | Overall study drug treatment period, a median (min, max) of 36 (2, 82) days. | 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). |
| Number of Days in Intensive Care Unit | Overall study drug treatment period, a median (min, max) of 36 (2, 82) days. | 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). |
| Number of Days in Hospital | Overall study drug treatment period, a median (min, max) of 36 (2, 82) days. | 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). |
| Number of Days of Plasma Exchange | Overall study drug treatment period, a median (min, max) of 36 (2, 82) days. | 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). |
Countries
Australia, Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Netherlands, Spain, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Caplacizumab 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. | 72 |
| Placebo 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. | 73 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Treatment Period + Follow-up | Adverse Event | 6 | 5 |
| Overall Treatment Period + Follow-up | Death | 1 | 3 |
| Overall Treatment Period + Follow-up | Diagnosed as non-TTP patient | 1 | 1 |
| Overall Treatment Period + Follow-up | Lost to Follow-up | 0 | 1 |
| Overall Treatment Period + Follow-up | Non-compliance with study drug | 0 | 1 |
| Overall Treatment Period + Follow-up | Physician Decision | 2 | 4 |
| Overall Treatment Period + Follow-up | Protocol Violation | 0 | 1 |
| Overall Treatment Period + Follow-up | Withdrawal by Subject | 4 | 5 |
| Overall Treatment Period + Follow-up | Withdrawn by legal representative | 0 | 1 |
| Overall Treatment Period + Follow-up | Withdrew treatment, agreed for ET visit | 0 | 1 |
Baseline characteristics
| Characteristic | Caplacizumab | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 12 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 68 Participants | 133 Participants | 65 Participants |
| Age, Continuous | 44.9 years STANDARD_DEVIATION 13.46 | 46.1 years STANDARD_DEVIATION 13.78 | 47.3 years STANDARD_DEVIATION 14.07 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 6 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 65 Participants | 127 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 12 Participants | 9 Participants |
| Region of Enrollment Australia | 1 Participants | 3 Participants | 2 Participants |
| Region of Enrollment Austria | 3 Participants | 4 Participants | 1 Participants |
| Region of Enrollment Belgium | 5 Participants | 8 Participants | 3 Participants |
| Region of Enrollment Canada | 7 Participants | 13 Participants | 6 Participants |
| Region of Enrollment Czechia | 2 Participants | 4 Participants | 2 Participants |
| Region of Enrollment France | 3 Participants | 12 Participants | 9 Participants |
| Region of Enrollment Hungary | 4 Participants | 7 Participants | 3 Participants |
| Region of Enrollment Israel | 4 Participants | 6 Participants | 2 Participants |
| Region of Enrollment Italy | 6 Participants | 10 Participants | 4 Participants |
| Region of Enrollment Netherlands | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Spain | 8 Participants | 14 Participants | 6 Participants |
| Region of Enrollment Switzerland | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Turkey | 4 Participants | 9 Participants | 5 Participants |
| Region of Enrollment United Kingdom | 13 Participants | 21 Participants | 8 Participants |
| Region of Enrollment United States | 10 Participants | 32 Participants | 22 Participants |
| Sex: Female, Male Female | 49 Participants | 100 Participants | 51 Participants |
| Sex: Female, Male Male | 23 Participants | 45 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 71 | 3 / 73 | 0 / 28 |
| other Total, other adverse events | 67 / 71 | 65 / 73 | 25 / 28 |
| serious Total, serious adverse events | 28 / 71 | 39 / 73 | 7 / 28 |
Outcome results
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.
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)
Population: Intent-to-treat (ITT) population (for the respective study period, i.e., DB treatment period)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Caplacizumab | Time to Platelet Count Response | 2.69 days |
| Placebo | Time to Platelet Count Response | 2.88 days |
Comparison: 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.p-value: =0.0099Log Rank
Comparison: 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.95% CI: [1.095, 2.195]
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).
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.
Population: ITT Population (for the respective study period, i.e., overall study period)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Caplacizumab | Number and Percentage of Subjects With a Recurrence of TTP in the Overall Study Period | 9 Participants |
| Placebo | Number and Percentage of Subjects With a Recurrence of TTP in the Overall Study Period | 28 Participants |
Comparison: A CMH test was conducted with adjustment for GCS category (stratification factor used in randomization).p-value: =0.0004Cochran-Mantel-Haenszel
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).
Time frame: The study drug treatment period, a median (min, max) of 36 (2, 82) days.
Population: ITT Population (for the respective study period, i.e., overall treatment period)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Caplacizumab | Number and Percentage of Subjects With Refractory Disease | 0 Participants |
| Placebo | Number and Percentage of Subjects With Refractory Disease | 3 Participants |
Comparison: A CMH test was conducted with adjustment for GCS category (stratification factor used in randomization).p-value: =0.0572Cochran-Mantel-Haenszel
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).
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.
Population: ITT Population (for the respective study period, i.e., overall treatment period)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Caplacizumab | Number and Percentage of Subjects With TTP-Related Death, Recurrence of TTP, or a Major Thromboembolic Event During the Study Drug Treatment Period | 9 Participants |
| Placebo | Number and Percentage of Subjects With TTP-Related Death, Recurrence of TTP, or a Major Thromboembolic Event During the Study Drug Treatment Period | 36 Participants |
Comparison: A Cochran-Mantel-Haenszel (CMH) test was conducted with adjustment for GCS category (stratification factor used in randomization).p-value: <0.0001Cochran-Mantel-Haenszel
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).
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.
Population: ITT Population (for the respective study period, i.e., overall study period) with biomarker level data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Caplacizumab | Time to Normalization of Organ Damage Marker Levels | 2.86 days |
| Placebo | Time to Normalization of Organ Damage Marker Levels | 3.36 days |
Other Pre-specified
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).
Time frame: Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Population: ITT Population (for the respective study period, i.e., overall treatment period)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caplacizumab | Number of Days in Hospital | 9.9 days | Standard Error 0.7 |
| Placebo | Number of Days in Hospital | 14.4 days | Standard Error 1.22 |
Other Pre-specified
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).
Time frame: Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Population: ITT Population (for the respective study period, i.e., overall treatment period)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caplacizumab | Number of Days in Intensive Care Unit | 3.4 days | Standard Error 0.4 |
| Placebo | Number of Days in Intensive Care Unit | 9.7 days | Standard Error 2.12 |
Other Pre-specified
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).
Time frame: Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Population: ITT Population (for the respective study period, i.e., overall treatment period)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caplacizumab | Number of Days of Plasma Exchange | 5.8 days | Standard Error 0.51 |
| Placebo | Number of Days of Plasma Exchange | 9.4 days | Standard Error 0.81 |
Other Pre-specified
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).
Time frame: Overall study drug treatment period, a median (min, max) of 36 (2, 82) days.
Population: ITT Population (for the respective study period, i.e., overall treatment period)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caplacizumab | Total Volume of Plasma Exchange | 21.33 liter(s) | Standard Error 1.619 |
| Placebo | Total Volume of Plasma Exchange | 35.93 liter(s) | Standard Error 4.169 |