Emicizumab PUPs and Nuwiq ITI Study

NCT04030052 | Withdrawn Phase 3 DMC FDA Drug

• 1 other identifier: IRB00111805
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 8

Brief Summary

This study prospectively investigates the safety, FVIII immunogenicity, and hemostatic efficacy of prophylactic HEMLIBRA® given with a concomitant low dose recombinant factor VIII (rFVIII) known as 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).

Conditions

Hemophilia A

Keywords

safety; immunogenicity; hemostatic efficacy; prophylactic; infants; children; hemostasis; hemophilia

Outcome Measures

Primary Outcomes (6)

• Cumulative incidence of inhibitors to FVIII

  Cumulative incidence of inhibitors to FVIII will be recorded

  Duration of the follow up (up to 36 months)

• Number of Immune Tolerance Induction (ITI) success cases

  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

  Duration of the follow up (up to 36 months)

• Number of Immune Tolerance Induction (ITI) partial success cases

  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

  Duration of the follow up (up to 36 months)

• Number of Immune Tolerance Induction (ITI) partial response cases

  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

  Duration of the follow up (up to 36 months)

• Number of Immune Tolerance Induction (ITI) partial failure cases

  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

  Duration of the follow up (up to 36 months)

• Number of Immune Tolerance Induction (ITI) failure cases

  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

  Duration of the follow up (up to 36 months)

Secondary Outcomes (12)

• Number of joint bleeding events over time (≥3 bleeds in the same joint over the last 24 weeks)

  6 months follow up

• Number of target joint bleeding events over time (≥3 bleeds in the same joint over the last 24 weeks)

  12 months follow up

• Annualized bleeding rate (ABR)

  Duration of the follow up (up to 36 months)

• Number of adverse events

  Duration of the follow up (up to 36 months)

• Change in blood levels of anti-FVIII antibodies

  Weekly x4 (±3 days), then monthly (±7 days) up to 36 months

Study Arms (2)

Untreated/minimally treated moderate HA no inhibitors

EXPERIMENTAL

Previously untreated patients (PUPs) and minimally treated patients (MTPs) \<3 years of age with moderately severe (≤2% FVIII) HA and no inhibitors.

Drug: Nuwiq (low dose protocol); Drug: HEMLIBRA

Treated any moderate HA with existing inhibitors

EXPERIMENTAL

Children \<21 years of age with moderately severe (≤2% FVIII) HA and with already existing inhibitors (LTI or HTI).

Drug: HEMLIBRA; Drug: Nuwiq (Atlanta protocol)

Interventions

Nuwiq (low dose protocol) DRUG

After receiving HEMLIBRA® for 1-6 months, rFVIII (NUWIQ®) will be given at low dose (25 ±5 units/kg/dose) every 7-14 days as part of a low dose 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.

Also known as: Simoctocog alfa

Untreated/minimally treated moderate HA no inhibitors

HEMLIBRA DRUG

Four weekly subcutaneous (SQ) injections of HEMLIBRA® loading doses of 3 mg/kg will be given. A total of 12 mg/kg within the first month is allowed for the loading doses. Maintenance dosing will follow, and will either be 1.5 mg/kg/dose weekly, 3 mg/kg/dose biweekly (every 2 weeks), or 6 mg/kg/dose every 4 weeks depending on the recommended dosing.

Also known as: Emicizumab, ACE910, and RO5534262

Treated any moderate HA with existing inhibitors; Untreated/minimally treated moderate HA no inhibitors

Nuwiq (Atlanta protocol) DRUG

After completing HEMLIBRA® loading doses, participants will receive intravenous (IV) infusions of NUWIQ® 3 times per week, 100 units/kg the Atlanta protocol. Infusions will be given at least 36 hours from the previous NUWIQ® injection. Participants will continue on the HEMLIBRA® SQ - NUWIQ® IV treatment regimen for up to 12 months of NUWIQ® treatment.

Also known as: Simoctocog alfa

Treated any moderate HA with existing inhibitors

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Moderately severe (≤2% FVIII) hemophilia A
• \<3 Years of age at the time of informed consent
• Caregiver (parent or legal guardian) has provided written informed consent
• ≤2 EDs to pdFVIII, rFVIII, or a single dose of FFP, Cryoprecipitate or PRBCs.
• Adequate hematologic function (HgB \>8 g/dL and platelet count \>100,000 µL)
• 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 ≥30 mL/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 \*Participants will be encouraged to co-enroll in the ATHN 8 Study
• Moderately severe (≤2% FVIII) hemophilia A
• \<21 Years of age at the time of informed consent
• Documented on 2 occasions a persistent low (\>0.6 BU/mL) titer inhibitor with a 72-hour washout within 24 weeks of enrollment or historical high titer inhibitor (\>5 BU/mL) and a single occasion of a low titer inhibitor (\>0.6 BU/mL) with a 72-hour washout within 24 weeks of enrollment after either the first time ITI or after single attempt of \<6 months of continuous 3x/week factor ITI
• Has completed loading doses of HEMLIBRA® (weekly for 4 weeks, dose 3 mg/kg, a total of 12 mg/kg/dose will also be allowed)
• Caregiver and/or participant provided written informed consent
• Adequate hematologic function (HgB \>8 g/dL and platelet count \>100,000 µL)

You may not qualify if:

• Inherited or acquired bleeding disorder other than severe hemophilia A (participants with previous documentation of low von Willebrand factor (vWF) defined as vWF antigen and vWF ristocetin cofactor both between 40-50 will be permitted)
• Previous or current treatment for thromboembolic disease or signs of thromboembolic disease
• Conditions that may increase the 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 HEMLIBRA® injection (with the exception of rituximab)
• Known HIV infection with CD4 count \<200 cells/µL within 24 weeks prior to screening. Testing is not required if can demonstrate negative testing in the 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 an 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 HEMLIBRA® as part of a prior investigational study; an investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of the last drug administration; a non-hemophilia-related investigational drug concurrently, within the last 30 days or 5 half-lives, whichever is shorter

Sponsors & Collaborators

• Emory University: lead
• Genentech, Inc.: collaborator

Study Sites (8)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Emory University/Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Mindy_L_Simpson@rush.edu

Indianapolis, Indiana, 46260, United States

Location

Children's Hospital of Michigan/ Wayne State University

Detroit, Michigan, 48201, United States

Location

Weill Cornell Medicine

New York, New York, 10021, United States

Location

University of North Carolina - Hemophilia and Thrombosis Center

Chapel Hill, North Carolina, 27599, United States

Location

Verisiti, WI

Milwaukee, Wisconsin, 53233, United States

Location

MeSH Terms

Conditions

Hemophilia A

Interventions

Factor VIII; Clinical Protocols; simoctocog alfa (Nuwiq); emicizumab

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors; Therapeutics; Epidemiologic Study Characteristics; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation

Study Officials

• Robert Sidonio, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 21, 2019
• First Posted: July 23, 2019
• Study Start: February 17, 2022
• Primary Completion: January 19, 2023
• Study Completion: January 19, 2023
• Last Updated: January 5, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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 Traci Leong (tleong@emory.edu), the statistician.

Locations

US (8)