Emicizumab PUPs and Nuwiq ITI Study
- Conditions
- Hemophilia A
- Interventions
- Registration Number
- NCT04030052
- Lead Sponsor
- Emory University
- 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).
- 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).
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Treated any moderate HA with existing inhibitors HEMLIBRA Children \<21 years of age with moderately severe (≤2% FVIII) HA and with already existing inhibitors (LTI or HTI). Untreated/minimally treated moderate HA no inhibitors Nuwiq (low dose protocol) Previously untreated patients (PUPs) and minimally treated patients (MTPs) \<3 years of age with moderately severe (≤2% FVIII) HA and no inhibitors. Treated any moderate HA with existing inhibitors Nuwiq (Atlanta protocol) Children \<21 years of age with moderately severe (≤2% FVIII) HA and with already existing inhibitors (LTI or HTI). Untreated/minimally treated moderate HA no inhibitors HEMLIBRA Previously untreated patients (PUPs) and minimally treated patients (MTPs) \<3 years of age with moderately severe (≤2% FVIII) HA and no inhibitors.
- Primary Outcome Measures
Name Time Method Cumulative incidence of inhibitors to FVIII Duration of the follow up (up to 36 months) Cumulative incidence of inhibitors to FVIII will be recorded
Number of Immune Tolerance Induction (ITI) success cases 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 hNumber of Immune Tolerance Induction (ITI) partial success cases 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 hNumber of Immune Tolerance Induction (ITI) partial response cases 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 hNumber of Immune Tolerance Induction (ITI) partial failure cases 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 hNumber of Immune Tolerance Induction (ITI) failure cases 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
- Secondary Outcome Measures
Name Time Method Change in blood levels of anti-Emicizumab antibodies 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 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 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
Number of joint bleeding events over time (≥3 bleeds in the same joint over the last 24 weeks) 6 months follow up Number of joint bleeding events over time (≥3 bleeds in the same joint over the last 24 weeks) will be recorded
Annualized bleeding rate (ABR) 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.
Change in blood levels of emicizumab (HEMLIBRA®) in young children (1 month to 24 months of age) Weekly for 4 weeks, monthly for 5 months, and every 3 months until study end (up to 36 months) Blood levels of emicizumab (HEMLIBRA®) in young children (1 month to 24 months of age) will be measured to study Emicizumab pharmacokinetics
Number of target joint bleeding events over time (≥3 bleeds in the same joint over the last 24 weeks) 12 months follow up 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 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
Change in blood levels of anti-FVIII antibodies 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
Microbiota composition of stool in infants with vs. without inhibitors Duration of the follow up (up to 36 months) Microbiota composition of stool in infants with vs. without inhibitors will be measured
Change in CATCH scale score Baseline, 36 months 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 treatmentChange in Adapted Inhib-QoL scale score Baseline, 36 months Adapted Inhib-QoL scores range from 0 to 100, with lower scores reflecting better health-related quality of life
Trial Locations
- Locations (8)
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Weill Cornell Medicine
🇺🇸New York, New York, United States
Mindy_L_Simpson@rush.edu
🇺🇸Indianapolis, Indiana, United States
Emory University/Children's Healthcare of Atlanta
🇺🇸Atlanta, Georgia, United States
University of North Carolina - Hemophilia and Thrombosis Center
🇺🇸Chapel Hill, North Carolina, United States
Verisiti, WI
🇺🇸Milwaukee, Wisconsin, United States
Children's Hospital of Michigan/ Wayne State University
🇺🇸Detroit, Michigan, United States