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

Ablynx, a Sanofi company75 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

Conditions

Acquired Thrombotic Thrombocytopenic Purpura

Interventions

CaplacizumabBIOLOGICAL

* Subjects received a first intravenous (i.v.) bolus of 10 mg (filled at 5 mg/mL) caplacizumab via push injection within 6 hours to 15 minutes prior to the first PE on study. The first PE on study could either be the very first PE session for the current episode of aTTP (if the subject was randomized prior to the initiation of PE) or the second PE session (if the subject was randomized after a single PE session). * The first PE on study was followed by subcutaneous (s.c.) administration of 10 mg study drug within 30 minutes after the end of the PE procedure. * All subsequent study drug administrations were daily s.c. injections within 30 minutes after the end of the PE procedure (if applicable) or within 24 hours of the previous dose. * Subjects received caplacizumab up to 30 days after the last PE session.

PlaceboBIOLOGICAL

* Subjects received a first i.v. bolus of placebo via push injection within 6 hours to 15 minutes prior to the first PE on study. The first PE on study could either be the very first PE session for the current episode of aTTP (if the subject was randomized prior to the initiation of PE) or the second PE session (if the subject was randomized after a single PE session). * The first PE on study was followed by s.c. administration of placebo within 30 minutes after the end of the PE procedure. * All subsequent study drug administrations were daily s.c. injections within 30 minutes after the end of the PE procedure (if applicable) or within 24 hours of the previous dose. * Subjects received placebo up to 30 days after the last PE session.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (51)

Outcomes

Primary Outcomes

Time-to-response of Treatment Defined by a Confirmed Recovery of Platelets ≥ 150,000/µL

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').

Time frame: From the day of first study drug administration up to 30 days after first study drug administration

Secondary Outcomes

Number and Percentage of Subjects With Complete Remission Following Initial Daily Plasma Exchange (PE)

Number and percentage of subjects with complete remission (defined as confirmed platelet count response and absence of exacerbation) following initial daily PE.

Time frame: From the day of first study drug administration up to 30 days after first study drug administration

Number and Percentage of Subjects With Exacerbations of TTP

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.

Time frame: Within 30 days of last day of initial daily PE

Number and Percentage of Subjects With Relapse of TTP

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.

Time frame: Later than 30 days after the last daily PE

Data from ClinicalTrials.gov

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Investigator Site

Los Angeles, California, United States

Investigator Site

Washington D.C., District of Columbia, United States

Investigator Site

Atlanta, Georgia, United States

Investigator Site

St Louis, Missouri, United States

Investigator Site

New York, New York, United States

Investigator Site

Rochester, New York, United States

Investigator Site

Valhalla, New York, United States

Investigator Site

Durham, North Carolina, United States

Investigator Site

Winston-Salem, North Carolina, United States

Investigator Site

Columbus, Ohio, United States

...and 41 more locations

Number of Daily PE Sessions During the Initial Daily PE Period

Number of daily PE sessions during the initial daily PE period which could include more than 1 PE per day was evaluated.

Time frame: During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days

Total Volume of Plasma Administered During the Initial Daily PE Period

The total volume of plasma administered during the initial daily PE period was measured.

Time frame: During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days

Number of Days With at Least One PE Administration During the Total Course of the Study

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.

Time frame: During the total course of the study (from Screening till the 12-month follow-up [FU] visit)

The Maximum Number of Consecutive Days Per Subject Where There Was no Interruption of PE During the Initial Daily PE Period

The maximum number of consecutive days per subject where there was no interruption of PE during the initial daily PE period.

Time frame: During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days

Resolution of Non-focal Neurological Symptoms

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.

Time frame: From Baseline till the 12-month FU visit

Number of Participants With Resolution of TTP-related Signs or Symptoms

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".

Time frame: 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

Mortality

Total mortality up to 1 month follow-up.