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Hemophilia APhase 3NCT04030052

Emicizumab PUPs and Nuwiq ITI Study

A Phase 3 study testing Nuwiq (low dose protocol), HEMLIBRA and Nuwiq (Atlanta protocol) in people with Hemophilia A, run by Emory University at 8 sites in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages Up to 21 years
Conditions the study is for
Hemophilia A
What is being tested?
Nuwiq (low dose protocol), HEMLIBRA and Nuwiq (Atlanta protocol)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
8 sitesUnited States
Study dates
17 Feb 2022to 19 Jan 2023
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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)
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  • 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)
  • 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)

Who cannot join

  • 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
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  • 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

Trial locations and contacts

8 sites in 1 country.

8 sites in 1 country

United States8 sites

  • Emory University/Children's Healthcare of Atlanta

    Atlanta, Georgia, 30322

  • University of North Carolina - Hemophilia and Thrombosis Center

    Chapel Hill, North Carolina, 27599

  • Rush University Medical Center

    Chicago, Illinois, 60612

  • Children's Hospital of Michigan/ Wayne State University

    Detroit, Michigan, 48201

  • Mindy_L_Simpson@rush.edu

    Indianapolis, Indiana, 46260

  • Children's Hospital Los Angeles

    Los Angeles, California, 90027

  • Verisiti, WI

    Milwaukee, Wisconsin, 53233

  • Weill Cornell Medicine

    New York, New York, 10021

Other trials in United States

About this study

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).

Read the detailed description

Hemophilia A (HA) is a congenital bleeding disorder caused by deficient or dysfunctional factor VIII (FVIII) which leads to bleeding correlated with severity. Management is focused on FVIII replacement in reaction to a bleed or preventive as prophylaxis. Effective treatment is complicated by the: (1) difficulty to administer standard replacement therapy via intravenous injection especially in infants and young children; and (2) development of inhibitors (FVIII neutralizing antibodies). Inhibitors can increase morbidity and mortality and exponentially raise the cost of health care. Although inherited and environmental risk factors for inhibitor formation have been identified, there is no effective strategy to prevent inhibitors from developing. Emicizumab (HEMLIBRA®) was recently approved by the Food and Drug Administration (FDA) in infants, children, and adults with congenital hemophilia A, with and without inhibitors, and offers hemostatic efficacy while reducing the burden of administration since it is given weekly, biweekly (every 2 weeks), or monthly via subcutaneous (SQ) route compared to the intravenous (IV) route of FVIII.

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
Being tested
Nuwiq (low dose protocol), HEMLIBRA, Nuwiq (Atlanta protocol)
Keywords
safety, immunogenicity, hemostatic efficacy, prophylactic, infants, children, hemostasis, hemophilia
Medical subject headings
Hemophilia A

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nuwiq (low dose protocol)Drug

    Also called Simoctocog alfa

    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.

  • HEMLIBRADrug

    Also called Emicizumab, ACE910, and RO5534262

    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.

  • Nuwiq (Atlanta protocol)Drug

    Also called Simoctocog alfa

    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.

Study groups in NCT04030052
Study groupRoleWhat they receive
Untreated/minimally treated moderate HA no inhibitorsExperimentalPreviously untreated patients (PUPs) and minimally treated patients (MTPs) <3 years of age with moderately severe (≤2% FVIII) HA and no inhibitors.
Receives: Drug: Nuwiq (low dose protocol); Drug: HEMLIBRA
Treated any moderate HA with existing inhibitorsExperimentalChildren <21 years of age with moderately severe (≤2% FVIII) HA and with already existing inhibitors (LTI or HTI).
Receives: Drug: HEMLIBRA; Drug: Nuwiq (Atlanta protocol)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Cumulative incidence of inhibitors to FVIII

    Cumulative incidence of inhibitors to FVIII will be recorded

    Measured: Duration of the follow up (up to 36 months)

  2. 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

    Measured: Duration of the follow up (up to 36 months)

  3. 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

    Measured: Duration of the follow up (up to 36 months)

  4. 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

    Measured: Duration of the follow up (up to 36 months)

  5. 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

    Measured: Duration of the follow up (up to 36 months)

  6. 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

    Measured: Duration of the follow up (up to 36 months)

Secondary outcomes (12)

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

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

    Measured: 6 months follow up

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

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

    Measured: 12 months follow up

  3. Annualized bleeding rate (ABR)

    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.

    Measured: Duration of the follow up (up to 36 months)

  4. Number of adverse events

    Number of adverse events (AEs and SAEs) will be recorded to evaluate safety of treatment regiments

    Measured: Duration of the follow up (up to 36 months)

  5. Change in blood levels of anti-FVIII antibodies

    Blood test will be done to evaluate blood levels of anti-FVIII antibodies

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

  6. Change in blood levels of anti-Emicizumab antibodies

    Blood test will be done to evaluate blood levels of anti-Emicizumab antibodies

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

  7. Number of infusions of Nuwiq/Novo7 for treatment of an acute bleeding episode

    Number of infusions of Nuwiq/Novo7 for treatment of an acute bleeding episode will be recorded

    Measured: Duration of the follow up (up to 36 months)

  8. Number of infusions of rFVIII or rFVIIa for treatment of an acute bleeding episode

    Number of infusions of rFVIII or rFVIIa for treatment of an acute bleeding episode will be recorded

    Measured: Duration of the follow up (up to 36 months)

  9. Change in blood levels of emicizumab (HEMLIBRA®) in young children (1 month to 24 months of age)

    Blood levels of emicizumab (HEMLIBRA®) in young children (1 month to 24 months of age) will be measured to study Emicizumab pharmacokinetics

    Measured: Weekly for 4 weeks, monthly for 5 months, and every 3 months until study end (up to 36 months)

  10. Microbiota composition of stool in infants with vs. without inhibitors

    Microbiota composition of stool in infants with vs. without inhibitors will be measured

    Measured: Duration of the follow up (up to 36 months)

  11. Change in CATCH scale score

    Scores are calculated as the mean of scores for all items, if 50% or more of the items are missing, then the score is set at missing.

    CATCH scores range from 0 to 100, with the following interpretation:

    • Higher score = Higher the perceived risk to have a bleed while doing daily activities
    • Higher score = Higher impact of hemophilia on daily activities
    • Higher score = Higher the perceived risk to have a bleed while doing social activities
    • Higher score = Higher impact of hemophilia on social activities
    • Higher score = Higher the perceived risk to have a bleed while doing recreational activities
    • Higher score = Higher impact of hemophilia on recreational activities
    • Higher score = Higher impact of hemophilia on work/school activities
    • Higher score = Greater preoccupation related to hemophilia
    • Higher score = Greater perceived burden of the hemophilia treatment

    Measured: Baseline, 36 months

  12. Change in Adapted Inhib-QoL scale score

    Adapted Inhib-QoL scores range from 0 to 100, with lower scores reflecting better health-related quality of life

    Measured: Baseline, 36 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Jul 2019
  2. Study start17 Feb 2022
  3. Primary completion19 Jan 2023
  4. Study completion19 Jan 2023

Why it stopped: The Emi PUPs and Nuwiq ITI study has been closed due to slow enrollment and study site startup.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04030052
Sponsor's protocol ID
IRB00111805
Status last verified
Jan 2024
First submitted
21 Jul 2019
Last updated
5 Jan 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: All of the individual participant data that underlie the results reported in the article, after deidentification (text, tables, figures and appendices) will be shared.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Nuwiq (low dose protocol), HEMLIBRA and Nuwiq (Atlanta protocol) in people with Hemophilia A, run by Emory University at 8 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 5 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Cumulative incidence of inhibitors to FVIII (time frame: Duration of the follow up (up to 36 months)). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04030052.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jan 2024.

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