Clinical trial NCT03855280: Evaluation of a Recombinant Factor IX Product, APVO101, in Previously-Treated Pediatric Patients With Hemophilia B
Official title: Evaluation of a Recombinant Factor IX Product, APVO101, in Previously-Treated Pediatric Patients With Hemophilia B
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia B
Lead sponsor: Medexus Pharma, Inc.
Sponsor class: INDUSTRY
First posted: 2019-02-26
Enrollment: 21
Sex: ALL
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Phase 3/4, single arm, open-label study with three defined phases:

* PK Phase: Initial PK evaluation - single dose of APVO101
* Treatment Phase: APVO101 prophylaxis treatment for 50 ED
* Continuation Phase: After completion of the Treatment Phase, subjects may continue APVO101 prophylaxis treatment (for an additional ≥ 50 ED)
Primary purpose: TREATMENT

Brief summary: Phase 3/4, single arm, open-label study to evaluate PK, safety, and efficacy of APVO101 prophylaxis in severe or moderately severe hemophilia B subjects \< 12 years of age.

Detailed description: Study APVO101-903 is a Phase 3/4, single arm, open-label clinical trial. The purpose of the study is to evaluate pharmacokinetics (PK), safety, and efficacy of APVO101 prophylaxis in severe or moderately severe hemophilia B subjects \< 12 years of age. The study is designed to gather information in two age groups of previously treated (with a minimum of 50 previous ED to factor IX replacement therapy) pediatric patients, specifically those \< 6 years of age and 6 to \<12 years of age.

Study APVO101-903 consists of three distinct phases:

* PK Phase - PK evaluation will consist of administration of a single 75 ± 5 IU/kg dose, followed by factor IX activity and safety assessments up to 50 hours post-infusion.
* Treatment Phase - subjects will receive APVO101 prophylaxis (starting prophylaxis dose to be determined based on APVO101 recovery; ideally within the recommended dose range: 35 - 75 IU/kg; twice weekly) for 50 ED (approximately 6 months).
* Continuation Phase - subjects may continue to receive APVO101 prophylaxis (recommended dose range: 35 - 75 IU/kg; twice weekly) for an additional ≥ 50 ED.

Eligibility criteria: Inclusion Criteria:

1. Age: \< 11.5 years of age at the time of the first dose and \< 12 years throughout the Treatment Phase of the study (for at least 50 ED).
2. Informed consent: subject's parent or legal guardian written Institutional Review Board (IRB)/Ethics Committee (EC)-approved informed consent. An assent form (IRB/EC-approved) will be obtained, when required by local regulations/guidelines.
3. Willingness and ability to make the required study visits, and follow instructions while enrolled in the study (for at least 50 ED; approximately 6 months).
4. Documented severe or moderately severe hemophilia B diagnosis (factor IX activity ≤ 2 IU/dL); in addition, severity may be indicated by the occurrence of one or more joint bleeding episode(s) at any point in the child's medical history requiring infusion(s) to replace factor IX.
5. Subjects must be on prophylaxis or switch to a prophylaxis regimen for the duration of the study.
6. Previously treated patients with a minimum of 50 ED (as documented and determined by the investigator) to a preparation/blood components containing factor IX.
7. Willingness to adhere to the 4-day washout period of any factor IX replacement therapy prior to PK evaluation. In case of previous exposure to a factor IX product with a prolonged half-life, a washout period of 3 half-lives is required in order to achieve steady state factor IX level prior to exposure to APVO101.
8. Immunocompetent (CD4 count \> 400/mm3) and not receiving immune modulating or chemotherapeutic agents.
9. Platelet count at least 150,000/mm3.
10. Liver function: alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2 times the upper limit of the normal range.
11. Total bilirubin ≤ 1.5 times the upper limit of the normal range.
12. Renal function: serum creatinine ≤ 1.25 times the upper limit of the normal range.
13. Hemoglobin ≥ 7 g/dL.

Exclusion Criteria:

1. History of factor IX inhibitor ≥ 0.6 Bethesda Units (BU); confirmed by the screening result.
2. Existence of another coagulation disorder.
3. Evidence of thrombotic disease, fibrinolysis, or disseminated intravascular coagulation (DIC).
4. Use of an investigational drug within 30 days prior to study entry.
5. Previous use of APVO101.
6. Use of medications that could impact hemostasis, such as aspirin.
7. Known hypersensitivity to the active substance or to any of the excipients in the investigational products.
8. Known allergic reaction to hamster proteins.
9. History of poor compliance, geographic isolation, unreliable transportation, a serious medical or social condition, or any other circumstance that, in the opinion of the investigator, would interfere with participation or compliance with the study protocol.
10. History of adverse reaction to either plasma-derived factor IX or recombinant factor IX that interfered with the subject's ability to treat bleeding episodes with a factor IX product.
11. History of any medical condition that would impact the efficacy evaluation and/or safety evaluation of the study product.

Primary outcomes:
measure: Annualized Bleeding Rate (ABR)
timeFrame: Exposure Day 1 up to 50 exposure days (approximately 6 months)
measure: Annualized Bleeding Rate (ABR) Overall
timeFrame: Exposure Day 1 through study completion (up to 2.5 years)
Secondary outcomes:
measure: Concentration (Cmax)
timeFrame: Pre-infusion to 50 hours post-infusion
measure: Area Under the Curve (0-inf)
timeFrame: Pre-infusion to 50 hours post-infusion
measure: Mean Residence Time (MRT)
timeFrame: Pre-infusion to 50 hours post-infusion
measure: Terminal Half-Life (t 1/2)
timeFrame: Pre-infusion to 50 hours post-infusion
measure: Clearance (CL)
timeFrame: Pre-infusion to 50 hours post-infusion
measure: Volume of Distribution at Steady-State (Vdss)
timeFrame: Pre-infusion to 50 hours post-infusion
measure: Incremental Recovery (IR)
timeFrame: Pre-infusion to 50 hours post-infusion
measure: Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase)
timeFrame: Exposure Day 1 up to 50 exposure days (approximately 6 months)
measure: Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall)
timeFrame: Exposure Day 1 through study completion (up to 2.5 years)
measure: Investigator Rating of APVO101 Prophylaxis Efficacy (Treatment Phase)
timeFrame: Exposure Day 1 up to 50 exposure days (approximately 6 months)
measure: Investigator Rating of APVO101 Prophylaxis Efficacy (Overall)
timeFrame: Exposure Day 1 through study completion (up to 2.5 years)
measure: Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Treatment Phase)
timeFrame: Exposure Day 1 up to 50 exposure days (approximately 6 months)
measure: Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Overall)
timeFrame: Exposure Day 1 through study completion (up to 2.5 years)
Other outcomes:
measure: Spontaneous Annualized Bleeding Rate (Treatment Phase)
timeFrame: Exposure Day 1 up to 50 exposure days (approximately 6 months)
measure: Spontaneous Annualized Bleeding Rate (Overall)
timeFrame: Exposure Day 1 through study completion (up to 2.5 years)
measure: Occurrence of Inhibitory Factor IX Antibodies (Overall)
timeFrame: Exposure Day 1 through study completion (up to 2.5 years)
measure: Occurrence of Non-Inhibitory Factor IX Antibodies (Overall)
timeFrame: Exposure Day 1 through study completion (up to 2.5 years)
measure: Occurrence of Anti-CHOP Antibodies (Overall)
timeFrame: Exposure Day 1 through study completion (up to 2.5 years)
measure: Thrombogenicity Assessment - D-Dimer
timeFrame: Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion
measure: Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex
timeFrame: Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion
measure: Thrombogenicity Assessment - Prothrombin Fragment 1+2
timeFrame: Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion
Locations:
city: Vitória
country: Brazil
facility: Centro Estadual de Hemopterapia e Hematologia do Espirito Santo
state: Espirito Santo
city: Campinas
country: Brazil
facility: Universidade Estadual de Campinas - Centro de Hematologia e Hemoterapia
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
city: Tbilisi
country: Georgia
facility: JSC K Eristavi National Center for Experimental and Clinical Surgery
city: Chisinau
country: Moldova, Republic of
facility: PMSI Institute of Mother and Child
city: Benoni
country: South Africa
facility: Worthwhile Clinical Trials, Lakeview Hospital
state: Gauteng
city: Johannesburg
country: South Africa
facility: Haemophilia Comprehensive Care Centre
city: Adana
country: Turkey
facility: Cukurova University School of Medicine
city: İzmir
country: Turkey
facility: Ege University School ofMedicine
city: Kyiv
country: Ukraine
facility: National Specialized Children's Hospital OKHMATDYT
city: Lviv
country: Ukraine
facility: State Institute: Institute of Blood Pathology and Transfusion Medicine of the National Academy of Medical Sciences of Ukraine
Study officials:
affiliation: Medexus Pharma, Inc.
name: Khaled Mohamed
role: STUDY_CHAIR
References: