Clinical trial NCT01151423: Study to Assess Efficacy and Safety of Anti-von Willebrand Factor (vWF) Nanobody in Patients With Acquired Thrombotic Thrombocytopenic Purpura (aTTP)
Official title: A Phase II, Single-blind, Randomized, Placebo-controlled Trial to Study the Efficacy and Safety of Anti-von Willebrand Factor Nanobody Administered as Adjunctive Treatment to Patients With Acquired Thrombotic Thrombocytopenic Purpura
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acquired Thrombotic Thrombocytopenic Purpura
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2010-06-28
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: Time-to-response of Treatment Defined by a Confirmed Recovery of Platelets ≥ 150,000/µL
timeFrame: From the day of first study drug administration up to 30 days after first study drug administration
Secondary outcomes:
measure: Number and Percentage of Subjects With Complete Remission Following Initial Daily Plasma Exchange (PE)
timeFrame: From the day of first study drug administration up to 30 days after first study drug administration
measure: Number and Percentage of Subjects With Exacerbations of TTP
timeFrame: Within 30 days of last day of initial daily PE
measure: Number and Percentage of Subjects With Relapse of TTP
timeFrame: Later than 30 days after the last daily PE
measure: Number of Daily PE Sessions During the Initial Daily PE Period
timeFrame: During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days
measure: Total Volume of Plasma Administered During the Initial Daily PE Period
timeFrame: During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days
measure: Number of Days With at Least One PE Administration During the Total Course of the Study
timeFrame: During the total course of the study (from Screening till the 12-month follow-up [FU] visit)
measure: The Maximum Number of Consecutive Days Per Subject Where There Was no Interruption of PE During the Initial Daily PE Period
timeFrame: During the initial daily PE period, with a median (min, max) duration of exposure to study drug of 6 (2, 36) days
measure: Resolution of Non-focal Neurological Symptoms
timeFrame: From Baseline till the 12-month FU visit
measure: Number of Participants With Resolution of TTP-related Signs or Symptoms
timeFrame: 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
measure: Mortality
timeFrame: From the start of the study up to 1 month follow-up
measure: Number of PE Related Adverse Events
timeFrame: From the start of the study up to 1 month follow-up
measure: Number and Percentage of Subjects With PE Related AEs
timeFrame: From the start of the study up to 1 month follow-up
measure: Number of Treatment-emergent Adverse Events (TEAEs) by Severity
timeFrame: From the start of the study up to 1 month follow-up
measure: Number and Percentage of Subjects With TEAEs by Severity
timeFrame: From the start of the study up to 1 month follow-up
measure: Number of TEAEs and Their Relationship to Study Drug
timeFrame: From the start of the study up to 1 month follow-up
measure: Number of Participants Who Developed Treatment-emergent Anti-Drug Antibodies (ADA)
timeFrame: From the start of the study until last follow-up visit
measure: Plasma Concentrations of Caplacizumab
timeFrame: 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).
measure: Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time
timeFrame: 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).
measure: Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time
timeFrame: 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).
measure: PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time
timeFrame: 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).
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Investigator Site
state: California
city: Washington
country: United States
facility: Investigator Site
state: District of Columbia
city: Atlanta
country: United States
facility: Investigator Site
state: Georgia
city: Saint Louis
country: United States
facility: Investigator Site
state: Missouri
city: New York
country: United States
facility: Investigator Site
state: New York
city: Rochester
country: United States
facility: Investigator Site
state: New York
city: Valhalla
country: United States
facility: Investigator Site
state: New York
city: Durham
country: United States
facility: Investigator Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Investigator Site
state: North Carolina
city: Columbus
country: United States
facility: Investigator Site
state: Ohio
city: Pittsburgh
country: United States
facility: Investigator Site
state: Pennsylvania
city: Dallas
country: United States
facility: Investigator Site
state: Texas
city: Salt Lake City
country: United States
facility: Investigator Site
state: Utah
city: Garran
country: Australia
facility: Investigator Site
state: Australian Capital Territory
city: Liverpool
country: Australia
facility: Investigator Site
city: Melbourne
country: Australia
facility: Investigator Site
city: Woolloongabba
country: Australia
facility: Investigator Site
city: Graz
country: Austria
facility: Investigator Site
city: Vienna
country: Austria
facility: Investigator Site
city: Antwerp
country: Belgium
facility: Investigator Site
city: Brussels
country: Belgium
facility: Investigator Site
city: Leuven
country: Belgium
facility: Investigator Site
city: Namur
country: Belgium
facility: Investigator Site
city: Sofia
country: Bulgaria
facility: Investigator Site
city: Caen
country: France
facility: Investigator Site
city: Ulm
country: Germany
facility: Investigator Site
state: Baden-Wuerttemberg
city: Aachen
country: Germany
facility: Investigator Site
city: Berlin
country: Germany
facility: Investigator Site
city: Dortmund
country: Germany
facility: Investigator Site
city: Hannover
country: Germany
facility: Investigator Site
city: Köln
country: Germany
facility: Investigator Site
city: Mainz
country: Germany
facility: Investigator Site
city: Mannheim
country: Germany
facility: Investigator Site
city: Munchen
country: Germany
facility: Investigator Site
city: Haifa
country: Israel
facility: Investigator Site
city: Jerusalem
country: Israel
facility: Investigator Site
city: Petach Tikva
country: Israel
facility: Investigator Site
city: Catania
country: Italy
facility: Investigator Site
city: Foggia
country: Italy
facility: Investigator Site
city: Milan
country: Italy
facility: Investigator Site
city: Reggio Emilia
country: Italy
facility: Investigator Site
city: Rome
country: Italy
facility: Investigator Site
city: Bucharest
country: Romania
facility: Investigator Site
city: Badalona
country: Spain
facility: Investigator Site
city: Sevilla
country: Spain
facility: Investigator Site
city: Valencia
country: Spain
facility: Investigator Site
city: Bern
country: Switzerland
facility: Investigator Site
city: Lausanne
country: Switzerland
facility: Investigator Site
city: Zurich
country: Switzerland
facility: Investigator Site
city: Liverpool
country: United Kingdom
facility: Investigator Site
city: London
country: United Kingdom
facility: Investigator Site
Study officials:
affiliation: Ablynx NV
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Peyvandi F, Cataland S, Scully M, Coppo P, Knoebl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Minkue Mi Edou J, De Winter H, Callewaert F. Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis. Blood Adv. 2021 Apr 27;5(8):2137-2141. doi: 10.1182/bloodadvances.2020001834.
citation: Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knobl P, Wu H, Artoni A, Westwood JP, Mansouri Taleghani M, Jilma B, Callewaert F, Ulrichts H, Duby C, Tersago D; TITAN Investigators. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2016 Feb 11;374(6):511-22. doi: 10.1056/NEJMoa1505533.
citation: Holz JB. The TITAN trial--assessing the efficacy and safety of an anti-von Willebrand factor Nanobody in patients with acquired thrombotic thrombocytopenic purpura. Transfus Apher Sci. 2012 Jun;46(3):343-6. doi: 10.1016/j.transci.2012.03.027. Epub 2012 Apr 3.