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Emicizumab PUPs and Nuwiq ITI Study

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ClinicalTrials.gov Identifier: NCT04030052
Recruitment Status : Not yet recruiting
First Posted : July 23, 2019
Last Update Posted : December 12, 2019
Sponsor:
Information provided by (Responsible Party):
Robert Sidonio, Emory University

Tracking Information
First Submitted Date  ICMJE July 21, 2019
First Posted Date  ICMJE July 23, 2019
Last Update Posted Date December 12, 2019
Estimated Study Start Date  ICMJE January 1, 2020
Estimated Primary Completion Date July 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 21, 2019)
  • Annualized bleeding rate (ABR) [ Time Frame: Duration of the follow up (up to 36 months) ]
    Number of bleeding events over time (bleed rate) will be recorded to calculate ABR to determine hemostatic efficacy of treatment regiments. Annualized bleeding rate (bleeds/year) is calculated as the number of bleeding events divided by length of time of the treatment regimen.
  • Number of target joint bleeding events over time (≥3 bleeds in the same joint over the last 24 weeks) [ Time Frame: 6 months follow up visit ]
    Number of target joint bleeding events over time (≥3 bleeds in the same joint over the last 24 weeks) will be recorded
  • Number of target joint bleeding events over time (≥3 bleeds in the same joint over the last 24 weeks) [ Time Frame: 12 months follow up visit ]
    Number of target joint bleeding events over time (≥3 bleeds in the same joint over the last 24 weeks) will be recorded
  • Number of adverse events [ Time Frame: Duration of the follow up (up to 36 months) ]
    Number of adverse events (AEs and SAEs) will be recorded to evaluate safety of treatment regiments
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT04030052 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 21, 2019)
  • Change in blood levels of anti-FVIII antibodies [ Time Frame: Weekly x4 (±3 days), then monthly (±7 days) up to 36 months ]
    Blood test will be done to evaluate blood levels of anti-FVIII antibodies
  • Change in blood levels of anti-Emicizumab antibodies [ Time Frame: Weekly x4 (±3 days), then monthly (±7 days) up to 36 months ]
    Blood test will be done to evaluate blood levels of anti-Emicizumab antibodies
  • Number of infusions of Nuwiq/Novo7 for treatment of an acute bleeding episode [ Time Frame: Duration of the follow up (up to 36 months) ]
    Number of infusions of Nuwiq/Novo7 for treatment of an acute bleeding episode will be recorded
  • Number of infusions of rFVIII or rFVIIa for treatment of an acute bleeding episode [ Time Frame: Duration of the follow up (up to 36 months) ]
    Number of infusions of rFVIII or rFVIIa for treatment of an acute bleeding episode will be recorded
  • Change in blood levels of Emicizumab [ Time Frame: Weekly for 4 weeks, monthly for 5 months, and every 3 months until study end (up to 36 months) ]
    Blood levels of Emicizumab will be measured to study Emicizumab pharmacokinetics
  • Number of Immune Tolerance Induction (ITI) success cases [ Time Frame: Duration of the follow up (up to 36 months) ]
    ITI success case is confirmed if three of below are criteria met:
    1. Inhibitor titre < 0.6 BU/mL for at least 2 consecutive measurements
    2. FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg BW approximately 15 to 30 min post-injection
    3. Half-life of FVIII ≥ 6 h
  • Number of Immune Tolerance Induction (ITI) partial success cases [ Time Frame: Duration of the follow up (up to 36 months) ]
    ITI partial success case is confirmed if two of below criteria are met:
    1. Inhibitor titre < 0.6 BU/mL for at least 2 consecutive measurements
    2. FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg BW approximately 15 to 30 min post-injection
    3. Half-life of FVIII ≥ 6 h
  • Number of Immune Tolerance Induction (ITI) partial response cases [ Time Frame: Duration of the follow up (up to 36 months) ]
    ITI partial response case is confirmed if one of below criteria is met:
    1. Inhibitor titre < 0.6 BU/mL for at least 2 consecutive measurements
    2. FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg BW approximately 15 to 30 min post-injection
    3. Half-life of FVIII ≥ 6 h
  • Number of Immune Tolerance Induction (ITI) partial failure cases [ Time Frame: Duration of the follow up (up to 36 months) ]
    ITI partial failure case is confirmed if none of below criteria are met, but participant who initially had a high-titre inhibitor (≥ 5 BU/mL) has a low-titre inhibitor (< 5 BU/mL) at end of ITI.
    1. Inhibitor titre < 0.6 BU/mL for at least 2 consecutive measurements
    2. FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg BW approximately 15 to 30 min post-injection
    3. Half-life of FVIII ≥ 6 h
  • Number of Immune Tolerance Induction (ITI) failure cases [ Time Frame: Duration of the follow up (up to 36 months) ]
    ITI failure case is confirmed if none of below criteria are met:
    1. Inhibitor titre < 0.6 BU/mL for at least 2 consecutive measurements
    2. FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg BW approximately 15 to 30 min post-injection
    3. Half-life of FVIII ≥ 6 h
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Emicizumab PUPs and Nuwiq ITI Study
Official Title  ICMJE Emicizumab PUPs and Nuwiq ITI Study
Brief Summary This study prospectively investigates the safety, immunogenicity and hemostatic efficacy of prophylactic Emicizumab given with a concomitant low dose rFVIII (Nuwiq) in HA infants and children <3 years old who have had little to no previous exposure to FVIII. In addition,the study investigates the safety and efficacy of a novel FVIII ITI regimen in children <21 with existing low and high titer inhibitors (LTI and HTI)
Detailed Description

Hemophilia A (HA) is a congenital bleeding disorder caused by deficient or dysfunctional factor VIII (FVIII) which leads to bleeding correlating with severity. Treatment options depend on the age of the patient and severity of the disease. In children with severe hemophilia A (SHA), management is focused on FVIII replacement given prophylactically or in reaction to a bleed. Effective treatment with FVIII replacement is complicated by the development of FVIII neutralizing antibodies (inhibitors).

This study prospectively investigates the safety, immunogenicity and hemostatic efficacy of prophylactic Emicizumab given with a concomitant low dose rFVIII (Nuwiq) in HA infants and children <3 years old who have had little to no previous exposure to FVIII. In addition,the study investigates the safety and efficacy of a novel FVIII ITI regimen in children <21 with existing low and high titer inhibitors (LTI and HTI).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Hemophilia A
Intervention  ICMJE
  • Drug: Nuwiq (low dose protocol)
    After receiving Emicizumab for 3-6 months, Nuwiq will be given as part of a low (25 units/kg) dose biweekly factor exposure program and for on demand use for acute bleeding episodes/procedures. Nuwiq will be administered intravenously (IV) via peripheral infusion. If the infant has a central line such as a PICC line or mediport this can be used.
    Other Name: Simoctocog alfa
  • Drug: Emicizumab
    Weekly subcutaneous (SQ) injections of Emicizumab include 4 weekly loading 3 mg/kg doses followed by weekly maintenance doses of 1.5 mg/kg.
    Other Name: ACE910, Hemlibra and RO5534262
  • Drug: Nuwiq (Atlanta protocol)
    After completing Emicizumab loading, participants will receive intravenous (IV) infusions of Nuwiq 100 units/kg/dose 3 times a week for 12 months per the Atlanta protocol. Infusions will be given at least 36 hours from the previous Nuwiq injection.
    Other Name: Simoctocog alfa
Study Arms  ICMJE
  • Experimental: Untreated/minimally treated severe HA with no inhibitors
    Previously untreated patients (PUPs) and minimally treated patients (MTPs) <3 years of age with severe hemophilia A (SHA, baseline FVIII <1%) and no inhibitors.
    Interventions:
    • Drug: Nuwiq (low dose protocol)
    • Drug: Emicizumab
  • Experimental: Treated any severity HA with existing inhibitors
    Children <21 years of age with any severity of hemophilia A (HA) and with already existing inhibitors (LTI or HTI).
    Interventions:
    • Drug: Emicizumab
    • Drug: Nuwiq (Atlanta protocol)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 21, 2019)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2024
Estimated Primary Completion Date July 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria - Part A:

  • Severe hemophilia A, defined as FVIII level <0.01 IU/ml in the central laboratory
  • <3 Years of age at time of informed consent
  • Caregiver (parent or legal guardian) has provided written informed consent
  • <2 EDs to either pdFVIII/rFVIII or FFP, Cryoprecipitate or prbcs.
  • Adequate hematologic function (hgb >8 g/dL and platelet count >100,000 uL)
  • Adequate hepatic function (total bilirubin ≤1.5x ULN and both AST/ALT ≤3x ULN at screening (excluding known Gilbert's)
  • Adequate renal function (≤2.5 x ULN and CrCl ≥30ml/min)
  • Negative test for inhibitor (<0.6 BU/mL) with a 72 hour washout within 4 weeks of enrollment
  • No documented FVIII inhibitor since birth
  • Age <3 years of age at time of informed consent
  • Encourage co-enrollment in ATHN 8

Inclusion Criteria - Part B

  • Any severity hemophilia A.
  • <21 Years of age at time of informed consent
  • Documented on 2 occasions a low (>0.6 BU/mL) or high titer inhibitor (>5 BU/mL) with a 72-hour washout within 8 weeks of enrollment
  • Caregiver has provided written informed consent
  • Adequate hematologic function (hgb >8 g/dL and platelet count >100,000 uL)
  • Adequate hepatic function (total bilirubin ≤1.5x ULN and both AST/ALT ≤3x ULN at screening (excluding known Gilbert's)
  • Adequate renal function (≤2.5 x ULN and CrCl ≥30ml/min)

Exclusion Criteria - Parts A and B:

  • Inherited or acquired bleeding disorder other than hemophilia A
  • Previous or current treatment for thromboembolic disease or signs of thromboembolic disease
  • Conditions that may increase risk of bleeding or thrombosis. Will not require or request a thrombophilia evaluation
  • History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
  • Known HIV infection with CD4 count <200 cells/mcL) within 24 weeks prior to screening. Testing not required if can demonstrate negative testing in mother prior to pregnancy.
  • Use of systemic immunomodulators at enrollment or planned use during the study
  • Participants who are at high risk for thrombotic microangiopathy (TMA) (for example, have a previous medical or family history of TMA), in the investigator's judgment
  • Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose additional risk, or would, in the opinion of the investigator, preclude the participant's safe participation in and completion of the study
  • Planned surgery (excluding minor procedures or central line placement) during the study
  • Receipt of emicizumab in a prior investigational study; an investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration; a non-hemophilia-related investigational drug concurrently, within last 30 days or 5 half-lives, whichever is shorter
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Robert Sidonio, MD 404-785-1637 robert.sidonio.jr@emory.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04030052
Other Study ID Numbers  ICMJE IRB00111805
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: All of the individual participant data that underlie the results reported in the article, after deidentification (text, tables, figures and appendices) will be shared.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Data will become available beginning 9 months and ending 36 months after publication
Access Criteria: Data will be shared with investigators/researchers involved in the study approved by the steering committee following verification of sound science for the purpose of achieving aims of the study, meta-analysis and for sound scientific evaluation deemed by the steering committee. Proposal may be submitted up to 36 months following publication and can be accessed following steering committee approval directed to courtney.mccracken@emory.edu, the lead statistician.
Responsible Party Robert Sidonio, Emory University
Study Sponsor  ICMJE Emory University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Robert Sidonio, MD Emory University
PRS Account Emory University
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP