Study to Assess Efficacy and Safety of Anti-von Willebrand Factor (vWF) Nanobody in Patients With Acquired Thrombotic Thrombocytopenic Purpura (aTTP)

Phase 2

Completed

Conditions: Acquired Thrombotic Thrombocytopenic Purpura

Interventions: Biological: Placebo
Biological: Caplacizumab

Registration Number: NCT01151423

Lead Sponsor: Ablynx, a Sanofi company

Brief Summary: This study was a Phase II, single-blind, randomized, placebo-controlled trial to determine whether anti-vWF Nanobody is safe and effective as adjunctive treatment in patients with aTTP.

Patients received either placebo or anti-vWF Nanobody as adjunctive therapy to plasma exchange (PE).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 75

Inclusion Criteria

18 years of age or older (adults) or aged 12 to < 18 years (adolescents)
Male or female subject, willing to accept an acceptable contraceptive regimen
Subject with a clinical diagnosis of TTP
Requiring PE (one single PE session prior to randomization into the study was allowed)
Subject accessible to follow-up
Subject able to provide signed and dated informed consent and assent (if applicable, for adolescents)

Exclusion Criteria

Platelet count ≥ 100,000/µL
Severe active infection indicated by sepsis (requirement for pressors with or without positive blood cultures)
Clinical evidence of enteric infection with Escherichia coli 0157 or related organism
Anti-phospholipid syndrome
Diagnosis of disseminated intravascular coagulation (DIC)
Pregnancy or breast-feeding
Hematopoietic stem cell or bone marrow transplantation-associated thrombotic microangiopathy
Known with congenital TTP
Active bleeding or high risk of bleeding
Uncontrolled arterial hypertension
Known chronic treatment with anticoagulant treatment that cannot be stopped safely, including but not limited to:
- vitamin K antagonists
- heparin or low molecular weight heparin (LMWH)
- non-acetyl salicylic acid non-steroidal anti-inflammatory molecules
Severe or life threatening clinical condition other than TTP that would impair participation in the study
Subjects with malignancies resulting in a life expectation of less than 3 months
Subjects with known or suspected bone marrow carcinosis
Subjects who cannot comply with study protocol requirements and procedures
Known hypersensitivity to the active substance or to excipients of the study drug
Severe liver impairment, corresponding to grade 3 toxicity defined by the CTCAE scale. For the key liver parameters, this is defined as follows:
- bilirubin > 3 x upper limit of normal (ULN) (needed to differentiate isolated increase in indirect bilirubin due to hemolysis, this was not an exclusion parameter but disease-related)
- alanine transaminase (ALT)/ aspartate transaminase (AST) > 5 x ULN
- alkaline phosphatase (ALP) > 5 x ULN
- gamma-glutamyl transpeptidase (GGT) > 5 x ULN
Severe chronic renal impairment, as defined by glomerular filtration rate < 30 mL/min

Note that the use of another investigational drug or device within 30 days prior to screening was not allowed. Participation in non-interventional/observational studies and registries during the study period was allowed. Participation in another clinical study was not allowed until the end of the follow-up period or within 30 days after the last study treatment in case of early subject withdrawal from the study. Subjects who had already participated in the current study and had either completed the study per protocol or had discontinued prematurely, were not allowed to be re-included.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo once daily
Caplacizumab	Caplacizumab	Caplacizumab 10 mg once daily

Primary Outcome Measures

Name	Time	Method
Time-to-response of Treatment Defined by a Confirmed Recovery of Platelets ≥ 150,000/µL	From the day of first study drug administration up to 30 days after first study drug administration	Time-to-response, defined by the achievement of platelet count response, confirmed at 48 hours after the initial reporting of this response. Platelet response was defined as recovery of platelets ≥ 150,000/µL. This response had to be confirmed at 48 hours after the initial reporting of platelet recovery ≥ 150,000/µL by a de novo measure of platelets ≥ 150,000/µL and lactate dehydrogenase (LDH) ≤ 2x upper limit of normal (ULN) (i.e., 'confirmed platelet response').

Secondary Outcome Measures

Name	Time	Method
Number of Daily PE Sessions During the Initial Daily PE Period	During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days	Number of daily PE sessions during the initial daily PE period which could include more than 1 PE per day was evaluated.
Number of Days With at Least One PE Administration During the Total Course of the Study	During the total course of the study (from Screening till the 12-month follow-up [FU] visit)	Number of days for PE was evaluated. This implies the number of days with at least one PE administration during the total course of the study.
Number of TEAEs and Their Relationship to Study Drug	From the start of the study up to 1 month follow-up	Number of TEAEs and their relationship to study drug were evaluated. Relationship of AEs to study drug was: related, possibly related, and unlikely/not related.
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time	From the start of the study up to 1 month follow-up (i.e., at Baseline, Days 1 and 2 of daily PE, last day of daily PE, Day 1 after daily PE, Weeks 1, 2, 3, and 4 after daily PE, Days 3 and 7 of FU and at the 1-month FU visit).	The change from baseline in RICO activity was measured at different time points.
The Maximum Number of Consecutive Days Per Subject Where There Was no Interruption of PE During the Initial Daily PE Period	During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days	The maximum number of consecutive days per subject where there was no interruption of PE during the initial daily PE period.
Number of Treatment-emergent Adverse Events (TEAEs) by Severity	From the start of the study up to 1 month follow-up	Number and severity of TEAEs were evaluated. The severity grades of AEs were defined as: mild, moderate, and severe. Note: the numbers listed do not include the TEAEs with missing severity.
Number and Percentage of Subjects With TEAEs by Severity	From the start of the study up to 1 month follow-up	Number and percentage of subjects with TEAEs by severity. The severity grades of AEs were defined as: mild, moderate, and severe.
Number of Participants Who Developed Treatment-emergent Anti-Drug Antibodies (ADA)	From the start of the study until last follow-up visit	The development of anti-drug antibodies (ADA) was monitored from the start of the study until last follow-up visit.
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time	From the start of the study drug up to 1 month follow-up (i.e., at Baseline, Days 1 and 2 of daily PE, last day of daily PE, Day 1 after daily PE, Weeks 1, 2, 3, and 4 after daily PE, Days 3 and 7 of FU and at the 1-month FU visit).	The change from baseline in vWF:Ag concentration was measured at different time points.
Resolution of Non-focal Neurological Symptoms	From Baseline till the 12-month FU visit	Resolution of non-focal neurological symptoms as defined by neurocognitive function at complete remission, measured by a Computerised Neuropsychological Test Battery(CNTB) (adults only). The CNTB included 6 modules: word list learning and selective reminding (WLL/SR), choice reaction time (CRT), visual memory (VMEM), simple reaction time (SRT), working memory (WMEM), and word list learning and delayed recall (WLL/DR). The 6 tasks are rated as a percentage correct (for CRT and SRT, the percentage correct corresponds to the percentage hits) and the mean score from these provides the CNTB summary score (range: 0-100). A higher CNTB summary score indicates better neuropsychological functioning.
Number of Participants With Resolution of TTP-related Signs or Symptoms	End of daily PE treatment period (median [min, max] duration of exposure to study drug of 6 [2, 36] days), end of study treatment period (median [min, max] duration of exposure to study drug of 36.5 [2, 90] days) and at 1 month follow-up	Resolution or improvement (improvement of ≥ 1 grade in the Common Terminology Criteria for Adverse Events \[CTCAE\] v4.0 scale) of TTP-related signs and symptoms as captured on physical examination and as adverse events. This endpoint was only evaluated for "resolution".
Mortality	From the start of the study up to 1 month follow-up	Total mortality up to 1 month follow-up.
Number of PE Related Adverse Events	From the start of the study up to 1 month follow-up	Number of PE treatment-related adverse events (AEs).
Plasma Concentrations of Caplacizumab	From the start of the study up to 1 month follow-up (i.e., at Baseline, Days 1 and 2 of daily PE, last day of daily PE, Day 1 after daily PE, Weeks 1, 2, 3, and 4 after daily PE, Days 3 and 7 of FU and at the 1-month FU visit).	The concentration of caplacizumab in plasma was determined at different time points. pharmacokinetics (PK) Population: the PK Population consisted of all subjects who received the study drug and for whom the primary PK data are considered to be sufficient and interpretable.
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time	From the start of the study up to 1 month follow-up (i.e., at Baseline, Days 1 and 2 of daily PE, last day of daily PE, Day 1 after daily PE, Weeks 1, 2, 3, and 4 after daily PE, Days 3 and 7 of FU and at the 1-month FU visit).	The change from baseline in FVIII:C concentration was measured at different ime points.
Number and Percentage of Subjects With Complete Remission Following Initial Daily Plasma Exchange (PE)	From the day of first study drug administration up to 30 days after first study drug administration	Number and percentage of subjects with complete remission (defined as confirmed platelet count response and absence of exacerbation) following initial daily PE.
Number and Percentage of Subjects With Relapse of TTP	Later than 30 days after the last daily PE	Number and percentage of subjects with relapse of TTP (defined as de novo TTP event that occurred later than 30 days after the last daily PE) was evaluated.
Total Volume of Plasma Administered During the Initial Daily PE Period	During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days	The total volume of plasma administered during the initial daily PE period was measured.
Number and Percentage of Subjects With Exacerbations of TTP	Within 30 days of last day of initial daily PE	Number and percentage of subjects with exacerbations of TTP (defined as recurrent thrombocytopenia following a confirmed platelet count response and requiring a re-initiation of daily PE treatment after ≥ 1 day but ≤ 30 days of end of daily PE treatment. Time to first exacerbation of TTP was also examined as part of this end point analysis; the median time to first exacerbation could not be determined because of the small number of events.
Number and Percentage of Subjects With PE Related AEs	From the start of the study up to 1 month follow-up	Number and percentage of subjects with PE related AEs.