Evaluation of a Recombinant Factor IX Product, APVO101, in Previously-Treated Pediatric Patients With Hemophilia B

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.

Study Overview

• Status: Completed
• Conditions: Hemophilia B
• Intervention / Treatment: Drug: APVO101

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Campinas, Brazil, 13083-878
    • Universidade Estadual de Campinas - Centro de Hematologia e Hemoterapia
  • Ribeirão Preto, Brazil, 14051-140
    • Hospital Das Clinicas Da Faculdade De Medicina De Ribeirao Preto da Universidade de Sao Paulo
  • Espirito Santo
    • Vitória, Espirito Santo, Brazil, 29040-090
      • Centro Estadual de Hemopterapia e Hematologia do Espirito Santo
• Georgia
  • Tbilisi, Georgia, 0159
    • JSC K Eristavi National Center for Experimental and Clinical Surgery
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, MD-2062
    • PMSI Institute of Mother and Child
• South Africa
  • Johannesburg, South Africa, 2193
    • Haemophilia Comprehensive Care Centre
  • Gauteng
    • Benoni, Gauteng, South Africa, 1500
      • Worthwhile Clinical Trials, Lakeview Hospital
• Turkey
  • Adana, Turkey, 01330
    • Cukurova University School of Medicine
  • İzmir, Turkey, 35100
    • Ege University School ofMedicine
• Ukraine
  • Kyiv, Ukraine, 01135
    • National Specialized Children's Hospital OKHMATDYT
  • Lviv, Ukraine, 79044
    • State Institute: Institute of Blood Pathology and Transfusion Medicine of the National Academy of Medical Sciences of Ukraine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 12 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: APVO101; APVO101: 35 - 75 IU/kg; twice weekly

Drug: APVO101; Subjects will receive a single IV dose of APVO101 twice weekly or at a frequency of infusions as determined appropriate by the investigator for the particular study subject for a total of 50 ED. The starting prophylaxis dose will be based on APVO101 recovery from PK Phase assessments (only pre-infusion and 15-30 minute post-infusion samples).; Other Names: IB1001; Recombinant factor IX; IXINITY

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Bleeding Rate (ABR)	The primary efficacy variable was the ABR while on prophylaxis to prevent bleeding episodes. The ABR was defined as the number of bleeding episodes per year.	Exposure Day 1 up to 50 exposure days (approximately 6 months)
Annualized Bleeding Rate (ABR) Overall	The primary efficacy variable was the ABR while on prophylaxis to prevent bleeding episodes. The ABR was defined as the number of bleeding episodes per year.	Exposure Day 1 through study completion (up to 2.5 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration (Cmax)	Maximum post-infusion plasma concentration of FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.	Pre-infusion to 50 hours post-infusion
Area Under the Curve (0-inf)	Area under plasma concentration curve, FIX activity-time profile from time zero extrapolated to infinity. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.	Pre-infusion to 50 hours post-infusion
Mean Residence Time (MRT)	MRT is the average time the molecules of drug reside in the body before elimination.	Pre-infusion to 50 hours post-infusion
Terminal Half-Life (t 1/2)	Terminal half-life is the length of time required for the concentration of drug to decrease by one half of its starting dose in the body. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.	Pre-infusion to 50 hours post-infusion
Clearance (CL)	Clearance is a measure of the volume of plasma from which FIX activity is removed per unit time. Weight normalized clearance calculated as CL=Dose/AUC 0-inf. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.	Pre-infusion to 50 hours post-infusion
Volume of Distribution at Steady-State (Vdss)	Volume of distribution is defined as the theoretical volume in which the total amount of FIX would need to be uniformly distributed to produce the observed plasma concentration of FIX. Steady state volume of distribution (Vdss) is the apparent volume of distribution at steady-state. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.	Pre-infusion to 50 hours post-infusion
Incremental Recovery (IR)	Incremental recovery was the increase in circulating FIX activity for every international unit (IU) of APVO101 administered per kilogram of body weight of participant. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.	Pre-infusion to 50 hours post-infusion
Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase)	Subjects rated APVO101 efficacy for each bleeding episode based on a four-point scale: Excellent: a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size; Good: pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution;; Fair: probable or slight beneficial response usually requiring one of more additional infusions for resolution;; Poor: no improvement or condition worsens.	Exposure Day 1 up to 50 exposure days (approximately 6 months)
Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall)	Subjects rated APVO101 efficacy for each bleeding episode based on a four-point scale: Excellent: a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size; Good: pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution;; Fair: probable or slight beneficial response usually requiring one of more additional infusions for resolution;; Poor: no improvement or condition worsens.	Exposure Day 1 through study completion (up to 2.5 years)
Investigator Rating of APVO101 Prophylaxis Efficacy (Treatment Phase)	The investigator will indicate the overall assessment of APVO101 prophylaxis efficacy, considering the absence of bleeding episodes, site, severity and types of bleeding episodes treated, and other factors that might influence the therapeutic response. The investigator's efficacy assessment categories for prophylaxis will include: 'effective', 'partially effective' and 'not effective'.	Exposure Day 1 up to 50 exposure days (approximately 6 months)
Investigator Rating of APVO101 Prophylaxis Efficacy (Overall)	The investigator will indicate the overall assessment of APVO101 prophylaxis efficacy, considering the absence of bleeding episodes, site, severity and types of bleeding episodes treated, and other factors that might influence the therapeutic response. The investigator's efficacy assessment categories for prophylaxis will include: 'effective', 'partially effective' and 'not effective'.	Exposure Day 1 through study completion (up to 2.5 years)
Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Treatment Phase)	Of the bleeding episodes requiring treatment, the investigator considered the site, severity and type of the bleeding episode while evaluating efficacy for control and management of the bleeding episode. The investigator's efficacy assessment categories control of bleeding episodes included: 'effective', 'partially effective' and 'not effective'.	Exposure Day 1 up to 50 exposure days (approximately 6 months)
Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Overall)	Of the bleeding episodes requiring treatment, the investigator considered the site, severity and type of the bleeding episode while evaluating efficacy for control and management of the bleeding episode. The investigator's efficacy assessment categories control of bleeding episodes included: 'effective', 'partially effective' and 'not effective'.	Exposure Day 1 through study completion (up to 2.5 years)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spontaneous Annualized Bleeding Rate (Treatment Phase)	Includes annualized bleeding rate for spontaneous bleeding (i.e. bleeds that occur without obvious cause).	Exposure Day 1 up to 50 exposure days (approximately 6 months)
Spontaneous Annualized Bleeding Rate (Overall)	Includes annualized bleeding rate for spontaneous bleeding (i.e. bleeds that occur without obvious cause).	Exposure Day 1 through study completion (up to 2.5 years)
Occurrence of Inhibitory Factor IX Antibodies (Overall)	Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins [CHOP])	Exposure Day 1 through study completion (up to 2.5 years)
Occurrence of Non-Inhibitory Factor IX Antibodies (Overall)	Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins [CHOP])	Exposure Day 1 through study completion (up to 2.5 years)
Occurrence of Anti-CHOP Antibodies (Overall)	Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins [CHOP])	Exposure Day 1 through study completion (up to 2.5 years)
Thrombogenicity Assessment - D-Dimer	This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk.	Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion
Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex	This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk.	Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion
Thrombogenicity Assessment - Prothrombin Fragment 1+2	This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk.	Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion

Collaborators and Investigators

• Sponsor: Medexus Pharma, Inc.
• Investigators: Study Chair: Khaled Mohamed, Medexus Pharma, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2020
• Primary Completion (Actual): July 4, 2022
• Study Completion (Actual): July 4, 2022

Study Registration Dates

• First Submitted: February 25, 2019
• First Submitted That Met QC Criteria: February 25, 2019
• First Posted (Actual): February 26, 2019

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: APVO101-903

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No