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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01151423
Recruitment Status : Completed
First Posted : June 28, 2010
Results First Posted : May 29, 2019
Last Update Posted : May 29, 2019
Sponsor:
Information provided by (Responsible Party):
Ablynx

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).


Condition or disease Intervention/treatment Phase
Acquired Thrombotic Thrombocytopenic Purpura Biological: Caplacizumab Biological: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 75 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Masking Description: A single-blinded study design was initiated because, in the initial versions of the protocol, the dosing regimen could be adjusted dependent on the results of the Ristocetin Cofactor (RICO) test following the initial dose. Therefore, a double-blind design was not feasible because the results of the RICO test effectively unblinded the Investigator. Single-blind design was maintained due to the objective nature of the primary endpoint.
Primary Purpose: Treatment
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
Actual Study Start Date : January 2011
Actual Primary Completion Date : March 2014
Actual Study Completion Date : March 2014


Arm Intervention/treatment
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:
  • anti-vWF Nanobody
  • ALX-0081

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.




Primary Outcome Measures :
  1. Time-to-response of Treatment Defined by a Confirmed Recovery of Platelets ≥ 150,000/µL [ Time Frame: 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 :
  1. Number and Percentage of Subjects With Complete Remission Following Initial Daily Plasma Exchange (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 complete remission (defined as confirmed platelet count response and absence of exacerbation) following initial daily PE.

  2. Number and Percentage of Subjects With Exacerbations of TTP [ Time Frame: 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.


  3. Number and Percentage of Subjects With Relapse of TTP [ Time Frame: 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.

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

  5. Total Volume of Plasma Administered 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 ]
    The total volume of plasma administered during the initial daily PE period was measured.

  6. 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) ]
    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.

  7. 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 ]
    The maximum number of consecutive days per subject where there was no interruption of PE during the initial daily PE period.

  8. Resolution of Non-focal Neurological Symptoms [ Time Frame: 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.

  9. Number of Participants With Resolution of TTP-related Signs or Symptoms [ 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 ]
    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".

  10. Mortality [ Time Frame: From the start of the study up to 1 month follow-up ]
    Total mortality up to 1 month follow-up.

  11. Number of PE Related Adverse Events [ Time Frame: From the start of the study up to 1 month follow-up ]
    Number of PE treatment-related adverse events (AEs).

  12. Number and Percentage of Subjects With PE Related AEs [ Time Frame: From the start of the study up to 1 month follow-up ]
    Number and percentage of subjects with PE related AEs.

  13. Number of Treatment-emergent Adverse Events (TEAEs) by Severity [ Time Frame: 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.

  14. Number and Percentage of Subjects With TEAEs by Severity [ Time Frame: 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.

  15. Number of TEAEs and Their Relationship to Study Drug [ Time Frame: 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.

  16. Number of Participants Who Developed Treatment-emergent Anti-Drug Antibodies (ADA) [ Time Frame: 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.

  17. Plasma Concentrations of Caplacizumab [ Time Frame: 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.

  18. Pharmacodynamics (PD): Ristocetin Cofactor (RICO) Activity Over Time [ Time Frame: 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.

  19. Pharmacodynamics: Von Willebrand Factor Antigen (vWF:Ag) Over Time [ Time Frame: 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.

  20. PD: Coagulation Factor VIII Clotting Activity (FVIII:C) Over Time [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01151423


Locations
Show Show 51 study locations
Sponsors and Collaborators
Ablynx
Investigators
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Study Director: Medical Monitor Ablynx NV
  Study Documents (Full-Text)

Documents provided by Ablynx:
Study Protocol  [PDF] June 24, 2013
Statistical Analysis Plan  [PDF] December 9, 2013

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Ablynx
ClinicalTrials.gov Identifier: NCT01151423    
Other Study ID Numbers: ALX0681-2.1/10
2010-019375-30 ( EudraCT Number )
First Posted: June 28, 2010    Key Record Dates
Results First Posted: May 29, 2019
Last Update Posted: May 29, 2019
Last Verified: May 2019
Additional relevant MeSH terms:
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Purpura
Purpura, Thrombocytopenic
Purpura, Thrombotic Thrombocytopenic
Blood Coagulation Disorders
Hematologic Diseases
Hemorrhage
Pathologic Processes
Skin Manifestations
Thrombotic Microangiopathies
Thrombocytopenia
Blood Platelet Disorders
Immune System Diseases
Thrombophilia