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

Acquired Thrombotic Thrombocytopenic Purpura Clinical Trial

— TITAN  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01151423
• Other study ID #: ALX0681-2.1/10
• Secondary ID: 2010-019375-30
• Status: Completed
• Phase: Phase 2
• Start date: January 2011
• Est. completion date: March 2014

Study information

• Verified date: May 2019
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 75
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acquired Thrombotic Thrombocytopenic Purpura
• Purpura
• Purpura, Thrombocytopenic
• Purpura, Thrombotic Thrombocytopenic

Intervention

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.
• 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.

Locations

Country	Name	City	State
Australia	Investigator Site	Garran	Australian Capital Territory
Australia	Investigator Site	Liverpool
Australia	Investigator Site	Melbourne
Australia	Investigator Site	Woolloongabba
Austria	Investigator Site	Graz
Austria	Investigator Site	Vienna
Belgium	Investigator Site	Antwerp
Belgium	Investigator Site	Brussels
Belgium	Investigator Site	Leuven
Belgium	Investigator Site	Namur
Bulgaria	Investigator Site	Sofia
France	Investigator Site	Caen
Germany	Investigator Site	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	Ulm	Baden-Wuerttemberg
Israel	Investigator Site	Haifa
Israel	Investigator Site	Jerusalem
Israel	Investigator Site	Petach Tikva
Italy	Investigator Site	Catania
Italy	Investigator Site	Foggia
Italy	Investigator Site	Milan
Italy	Investigator Site	Reggio Emilia
Italy	Investigator Site	Rome
Romania	Investigator Site	Bucharest
Spain	Investigator Site	Badalona
Spain	Investigator Site	Sevilla
Spain	Investigator Site	Valencia
Switzerland	Investigator Site	Bern
Switzerland	Investigator Site	Lausanne
Switzerland	Investigator Site	Zurich
United Kingdom	Investigator Site	Liverpool
United Kingdom	Investigator Site	London
United States	Investigator Site	Atlanta	Georgia
United States	Investigator Site	Columbus	Ohio
United States	Investigator Site	Dallas	Texas
United States	Investigator Site	Durham	North Carolina
United States	Investigator Site	Los Angeles	California
United States	Investigator Site	New York	New York
United States	Investigator Site	Pittsburgh	Pennsylvania
United States	Investigator Site	Rochester	New York
United States	Investigator Site	Saint Louis	Missouri
United States	Investigator Site	Salt Lake City	Utah
United States	Investigator Site	Valhalla	New York
United States	Investigator Site	Washington	District of Columbia
United States	Investigator Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Ablynx, a Sanofi company

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Bulgaria,  France,  Germany,  Israel,  Italy,  Romania,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	Mortality	Total mortality up to 1 month follow-up.	From the start of the study up to 1 month follow-up
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).