Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Emicizumab PUPs and Nuwiq ITI Study

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04030052
Recruitment Status : Not yet recruiting
First Posted : July 23, 2019
Last Update Posted : November 19, 2019
Sponsor:
Information provided by (Responsible Party):
Robert Sidonio, Emory University

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)

Condition or disease Intervention/treatment Phase
Hemophilia A Drug: Nuwiq (low dose protocol) Drug: Emicizumab Drug: Nuwiq (Atlanta protocol) Phase 3

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).


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Emicizumab PUPs and Nuwiq ITI Study
Estimated Study Start Date : November 2019
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : July 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia
Drug Information available for: Emicizumab

Arm Intervention/treatment
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.
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

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).
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




Primary Outcome Measures :
  1. 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.

  2. 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

  3. 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

  4. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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



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.


Layout table for eligibility information
Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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): NCT04030052


Contacts
Layout table for location contacts
Contact: Robert Sidonio, MD 404-785-1637 robert.sidonio.jr@emory.edu

Locations
Layout table for location information
United States, Georgia
Emory University/Children's Healthcare of Atlanta Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Robert Sidonio, MD    404-785-1637    robert.sidonio.jr@emory.edu   
Sponsors and Collaborators
Emory University
Investigators
Layout table for investigator information
Principal Investigator: Robert Sidonio, MD Emory University

Layout table for additonal information
Responsible Party: Robert Sidonio, Principal Investigator, Emory University
ClinicalTrials.gov Identifier: NCT04030052     History of Changes
Other Study ID Numbers: IRB00111805
First Posted: July 23, 2019    Key Record Dates
Last Update Posted: November 19, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
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
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
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.

Layout table for additional information
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
Keywords provided by Robert Sidonio, Emory University:
safety
immunogenicity
hemostatic efficacy
prophylactic
infants
children
hemostasis
Additional relevant MeSH terms:
Layout table for MeSH terms
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Antibodies, Bispecific
Immunologic Factors
Physiological Effects of Drugs
Coagulants