Emicizumab PUPs and Nuwiq ITI Study
Emicizumab PUPs and Nuwiq ITI 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).
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).
Inclusion Criteria - Part A:

 -  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

 Inclusion Criteria - Part B

 -  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) or high titer inhibitor (>5
 BU/mL) with a 72-hour washout within 8 weeks of enrollment after either the first time
 ITI or after single attempt of <6 months of continuous 3x/week factor ITI

 -  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)

 Exclusion Criteria - Part A and B

 -  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 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 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 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 last drug
 administration; a non-hemophilia-related investigational drug concurrently, within
 last 30 days or 5 half-lives, whichever is shorter