Emicizumab PUPs and Nuwiq ITI Study

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

Tracking Information

• First Submitted Date: July 21, 2019
• First Posted Date: July 23, 2019
• Last Update Posted Date: December 12, 2019
• Estimated Study Start Date: January 1, 2020
• Estimated Primary Completion Date: July 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current
• Change History: Complete list of historical versions of study NCT04030052 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (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: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Emicizumab PUPs and Nuwiq ITI Study
• Official Title: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Hemophilia A

Intervention

• 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

• 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

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: July 21, 2019): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 2024
• Estimated Primary Completion Date: July 2024 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Robert Sidonio, MD; 404-785-1637; robert.sidonio.jr@emory.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04030052
• Other Study ID Numbers: 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

• 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: Emory University
• Collaborators: Not Provided

Investigators

• Principal Investigator: Robert Sidonio, MD; Emory University

• PRS Account: Emory University
• Verification Date: August 2019