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

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

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 Overview

• Status: Completed
• Conditions: Acquired Thrombotic Thrombocytopenic Purpura
• Intervention / Treatment: Biological: Caplacizumab; Biological: Placebo

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Liverpool, Australia
    • Investigator site
  • Melbourne, Australia
    • Investigator site
  • Woolloongabba, Australia
    • Investigator site
  • Australian Capital Territory
    • Garran, Australian Capital Territory, Australia
      • Investigator site
• Austria
  • Graz, Austria
    • Investigator site
  • Vienna, Austria
    • Investigator site
• Belgium
  • Antwerp, Belgium
    • Investigator site
  • Brussels, Belgium
    • Investigator site
  • Leuven, Belgium
    • Investigator site
  • Namur, Belgium
    • Investigator site
• Bulgaria
  • Sofia, Bulgaria
    • Investigator site
• France
  • Caen, France
    • Investigator site
• Germany
  • Aachen, Germany
    • Investigator site
  • Berlin, Germany
    • Investigator site
  • Dortmund, Germany
    • Investigator site
  • Hannover, Germany
    • Investigator site
  • Köln, Germany
    • Investigator site
  • Mainz, Germany
    • Investigator site
  • Mannheim, Germany
    • Investigator site
  • Munchen, Germany
    • Investigator site
  • Baden-Wuerttemberg
    • Ulm, Baden-Wuerttemberg, Germany
      • Investigator site
• Israel
  • Haifa, Israel
    • Investigator site
  • Jerusalem, Israel
    • Investigator site
  • Petach Tikva, Israel
    • Investigator site
• Italy
  • Catania, Italy
    • Investigator site
  • Foggia, Italy
    • Investigator site
  • Milan, Italy
    • Investigator site
  • Reggio Emilia, Italy
    • Investigator site
  • Rome, Italy
    • Investigator site
• Romania
  • Bucharest, Romania
    • Investigator site
• Spain
  • Badalona, Spain
    • Investigator site
  • Sevilla, Spain
    • Investigator site
  • Valencia, Spain
    • Investigator site
• Switzerland
  • Bern, Switzerland
    • Investigator site
  • Lausanne, Switzerland
    • Investigator site
  • Zurich, Switzerland
    • Investigator site
• United Kingdom
  • Liverpool, United Kingdom
    • Investigator site
  • London, United Kingdom
    • Investigator site
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Investigator site
  • District of Columbia
    • Washington, District of Columbia, United States
      • Investigator site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Investigator site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Investigator site
  • New York
    • New York, New York, United States, 10021
      • Investigator site
    • Rochester, New York, United States, 14642
      • Investigator site
    • Valhalla, New York, United States, 10595
      • Investigator site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Investigator site
    • Winston-Salem, North Carolina, United States, 27157
      • Investigator site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Investigator site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Investigator site
  • Texas
    • Dallas, Texas, United States
      • Investigator site
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Investigator site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo once daily	Biological: Placebo; 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.
Experimental: Caplacizumab; Caplacizumab 10 mg once daily	Biological: Caplacizumab; 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.; Other Names: ALX-0081; anti-vWF Nanobody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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').	From the day of first study drug administration up to 30 days after first study drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	Later than 30 days after the last daily PE
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.	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.	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.	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.	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.	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".	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.	From the start of the study up to 1 month follow-up
Number of PE Related Adverse Events	Number of PE treatment-related adverse events (AEs).	From the start of the study up to 1 month follow-up
Number and Percentage of Subjects With PE Related AEs	Number and percentage of subjects with PE related AEs.	From the start of the study up to 1 month follow-up
Number of Treatment-emergent Adverse Events (TEAEs) by Severity	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.	From the start of the study up to 1 month follow-up
Number and Percentage of Subjects With TEAEs by Severity	Number and percentage of subjects with TEAEs by severity. The severity grades of AEs were defined as: mild, moderate, and severe.	From the start of the study up to 1 month follow-up
Number of TEAEs and Their Relationship to Study Drug	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.	From the start of the study up to 1 month follow-up
Number of Participants Who Developed Treatment-emergent Anti-Drug Antibodies (ADA)	The development of anti-drug antibodies (ADA) was monitored from the start of the study until last follow-up visit.	From the start of the study until last follow-up visit
Plasma Concentrations of Caplacizumab	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.	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).
Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time	The change from baseline in RICO activity was measured at different time points.	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).
Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time	The change from baseline in vWF:Ag concentration was measured at different time points.	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).
PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time	The change from baseline in FVIII:C concentration was measured at different ime points.	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).

Collaborators and Investigators

• Sponsor: Ablynx, a Sanofi company
• Investigators: Study Director: Medical Monitor, Ablynx NV

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2011
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: June 25, 2010
• First Submitted That Met QC Criteria: June 25, 2010
• First Posted (Estimate): June 28, 2010

Study Record Updates

• Last Update Posted (Actual): April 4, 2023
• Last Update Submitted That Met QC Criteria: March 31, 2023
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Hematologic Diseases; Hemorrhage; Blood Coagulation Disorders; Skin Manifestations; Thrombocytopenia; Blood Platelet Disorders; Thrombophilia; Thrombotic Microangiopathies; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic
• Other Study ID Numbers: ALX0681-2.1/10; 2010-019375-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org