Study of Recombinant Factor IX Product, IB1001, in Subjects With Hemophilia B

Conditions

Hemophilia B

Brief summary

Primary Objective: To evaluate the safety (acute effects associated with infusions, and inhibitor development), pharmacokinetics (PK), and efficacy with respect to breakthrough bleeding during prophylaxis and with respect to control of hemorrhaging in both the prophylaxis and on demand groups of IB1001 in subjects with hemophilia B. Key Secondary Objectives: To evaluate the ability of IB1001 to provide coverage against bleeding under surgical circumstances; To evaluate the long-term safety and efficacy of IB1001

Martinowitz U, Shapiro A, Quon DV, Escobar M, Kempton C, Collins PW, Chowdary P, Makris M, Mannucci PM, Morfini M, Valentino LA, Gomperts E, Lee M.

2012-07-0521 citations

10.1111/j.1365-2516.2012.02897.x

Interventions

BIOLOGICALIB1001

Study Part 1: Randomized, double-blind, cross-over study with IB1001 and nonacog alfa; Study Part 2: Non-randomized, open-label evaluation of prophylaxis and on demand IB1001; Surgical Sub-study: Open-label evaluation of IB1001 during major surgery

BIOLOGICALnonacog alfa

Study Part 1: Randomized, double-blind, cross-over study with IB1001 and nonacog alfa

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

SUPPORTIVE_CARE

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

Study Part 1 only

Intervention model description

Study Part 1: Randomized, double-blind, cross-over study of pharmacokinetics; Study Part 2: Non-randomized, open-label study of safety and efficacy; Surgical sub-study: Non-randomized, open-label study of safety and efficacy during major surgery

Eligibility

Sex/Gender

ALL

Age

5 Years to No maximum

Healthy volunteers

No

Inclusion criteria

1. Patient must be willing to give written Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent, make the required study visits, and follow instructions while enrolled in the study 2. Severe (factor IX activity ≤2 U/dL) hemophilia B subjects on demand therapy with a minimum of 3 bleeding episodes over the preceding 6 months or 6 bleeding episodes over the preceding 12 months; subjects on prophylaxis with a bleeding pattern as above demonstrated prior to starting prophylaxis 3. Immunocompetent (CD4 count \>400/mm3) and not receiving immune modulating or chemotherapeutic agents 4. Previously treated patients with a minimum of 150 exposure days to a factor IX preparation 5. Platelet count at least 150,000/mm3 6. Liver function: alanine transaminase \[ALT\] and aspartate transaminase \[AST\] ≤2 times the upper limit of the normal range 7. Total bilirubin ≤1.5 times the upper limit of the normal range 8. Renal function: serum creatinine ≤1.25 times the upper limit of the normal range 9. Willingness to participate in the trial for up to 12-15 months 10. European Union (EU), Israel, and Canada: Age of at least 12 years and body weight of ≥40 kilograms to participate in any PK Study or the Surgical Sub-study \[the Surgical Sub-study does not apply to the UK\]; age of at least 12 years for the prophylaxis and on demand components of the Treatment Phase and Continuation Study United States (US): Age of at least 12 years and body weight of ≥40 kilograms to participate in any PK Study or the Surgical Sub-study; age of at least 5 years for the prophylaxis and on demand components of the Treatment Phase and Continuation Study 11. Hemoglobin ≥7 g/dL at the time of the blood draw

Exclusion criteria

1. History of factor IX inhibitor ≥0.6 Bethesda units (BU) 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. On medications that could impact hemostasis, such as aspirin 6. History of poor compliance, 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 7. 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

Design outcomes

Primary

Measure	Time frame	Description
Degree of Hemorrhage Control by Treatment Regimen	Prophylaxis Group Duration of Treatment: 17.9 ± 9.6 months; On Demand Group Duration of Treatment: 15.9 ± 11.5 months	Subject rating of bleed control within 6 hours of the time bleeding has stopped: 1. Excellent: a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size; 2. Good: pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution; 3. Fair: probable or slight beneficial response usually requiring one or more additional infusions for resolution; 4. Poor: no improvement or condition worsens.

Secondary

Measure	Time frame	Description
Concentration (Max)	Pre-infusion to 72 hours following infusion	Factor IX levels were assessed at the following time points: Pre-infusion, post-infusion at 30 min ± 5 min, 1 hour ± 5 min, 3 hours ± 30 min, 6 hours ± 1 hour, 9 hours ± 1 hour, 12 hours ± 2 hours, 24 hours ± 3 hours, 36 hours ± 3 hours, 48 hours ± 3 hours, 60 hours ± 3 hours, and 72 hours ± 3 hours.
Clearance	Pre-infusion to 72 hours following infusion	Factor IX levels were assessed at the following time points: Pre-infusion, post-infusion at 30 min ± 5 min, 1 hour ± 5 min, 3 hours ± 30 min, 6 hours ± 1 hour, 9 hours ± 1 hour, 12 hours ± 2 hours, 24 hours ± 3 hours, 36 hours ± 3 hours, 48 hours ± 3 hours, 60 hours ± 3 hours, and 72 hours ± 3 hours.
Volume of Distribution (Steady State)	Pre-infusion to 72 hours following infusion	Factor IX levels were assessed at the following time points: Pre-infusion, post-infusion at 30 min ± 5 min, 1 hour ± 5 min, 3 hours ± 30 min, 6 hours ± 1 hour, 9 hours ± 1 hour, 12 hours ± 2 hours, 24 hours ± 3 hours, 36 hours ± 3 hours, 48 hours ± 3 hours, 60 hours ± 3 hours, and 72 hours ± 3 hours.
Annualized Bleed Rate	Prophylaxis Group Duration of Treatment: 17.9 ± 9.6 months; On Demand Group Duration of Treatment: 15.9 ± 11.5 months	Measure was assessed during the Treatment Study
Area Under the Curve (0-inf)	Pre-infusion to 72 hours following infusion	Factor IX levels were assessed at the following time points: Pre-infusion, post-infusion at 30 min ± 5 min, 1 hour ± 5 min, 3 hours ± 30 min, 6 hours ± 1 hour, 9 hours ± 1 hour, 12 hours ± 2 hours, 24 hours ± 3 hours, 36 hours ± 3 hours, 48 hours ± 3 hours, 60 hours ± 3 hours, and 72 hours ± 3 hours.
Area Under the Curve (0-72 hr)	Pre-infusion to 72 hours following infusion	Factor IX levels were assessed at the following time points: Pre-infusion, post-infusion at 30 min ± 5 min, 1 hour ± 5 min, 3 hours ± 30 min, 6 hours ± 1 hour, 9 hours ± 1 hour, 12 hours ± 2 hours, 24 hours ± 3 hours, 36 hours ± 3 hours, 48 hours ± 3 hours, 60 hours ± 3 hours, and 72 hours ± 3 hours.
Terminal Half-life	Pre-infusion to 72 hours following infusion	Factor IX levels were assessed at the following time points: Pre-infusion, post-infusion at 30 min ± 5 min, 1 hour ± 5 min, 3 hours ± 30 min, 6 hours ± 1 hour, 9 hours ± 1 hour, 12 hours ± 2 hours, 24 hours ± 3 hours, 36 hours ± 3 hours, 48 hours ± 3 hours, 60 hours ± 3 hours, and 72 hours ± 3 hours.
Incremental Recovery	Pre-infusion to 72 hours following infusion	Factor IX levels were assessed at the following time points: Pre-infusion, post-infusion at 30 min ± 5 min, 1 hour ± 5 min, 3 hours ± 30 min, 6 hours ± 1 hour, 9 hours ± 1 hour, 12 hours ± 2 hours, 24 hours ± 3 hours, 36 hours ± 3 hours, 48 hours ± 3 hours, 60 hours ± 3 hours, and 72 hours ± 3 hours.
Mean Residence Time	Pre-infusion to 72 hours following infusion	Factor IX levels were assessed at the following time points: Pre-infusion, post-infusion at 30 min ± 5 min, 1 hour ± 5 min, 3 hours ± 30 min, 6 hours ± 1 hour, 9 hours ± 1 hour, 12 hours ± 2 hours, 24 hours ± 3 hours, 36 hours ± 3 hours, 48 hours ± 3 hours, 60 hours ± 3 hours, and 72 hours ± 3 hours.

Other

Measure	Time frame	Description
Number of Surgeries Requiring Blood Transfusions	During the surgical procedure	Measure was assessed during Surgical Substudy.
Hemostasis Following Surgery	12 and 24 hours after surgery	Surgeon assessment of hemostasis at 12 and 24 hours after surgery using the following descriptors: superior, adequate, or poorly controlled. Measure was assessed during Surgical Substudy.
Blood Loss During Surgery	During the surgical procedure	Surgeon assessment of blood loss during the procedure using the following descriptors: less than expected, expected, or more than expected. Measure was assessed during Surgical Substudy.

Countries

France, India, Israel, Italy, Poland, United Kingdom, United States

Participant flow

Pre-assignment details

Subjects could enter the study at any part and could leave at any time. Of the 77 subjects in the total study population, 32 entered during the PK part, 35 entered during the Treatment part, and 10 entered during the Surgical Substudy. Nine subjects participated only in one Part: 3 only in the PK study and 6 only in the Surgical Substudy

Participants by arm

Arm	Count
IB1001 Safety Population Study Population exposed to at least one infusion of IB1001.	77
Total	77

Baseline characteristics

Characteristic	IB1001 Safety Population
Age, Continuous	30.8 years STANDARD_DEVIATION 14.54
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	73 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race/Ethnicity, Customized Race American Indian/Alaska Native	0 Participants
Race/Ethnicity, Customized Race Asian	8 Participants
Race/Ethnicity, Customized Race Black or African American	3 Participants
Race/Ethnicity, Customized Race Caucasian	61 Participants
Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander	2 Participants
Race/Ethnicity, Customized Race Other	3 Participants
Sex: Female, Male Female	1 Participants
Sex: Female, Male Male	76 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	58 / 77
serious Total, serious adverse events	10 / 77

Outcome results

Primary

Degree of Hemorrhage Control by Treatment Regimen

Subject rating of bleed control within 6 hours of the time bleeding has stopped: 1. Excellent: a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size; 2. Good: pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution; 3. Fair: probable or slight beneficial response usually requiring one or more additional infusions for resolution; 4. Poor: no improvement or condition worsens.

Time frame: Prophylaxis Group Duration of Treatment: 17.9 ± 9.6 months; On Demand Group Duration of Treatment: 15.9 ± 11.5 months

Population: The 68 patients in the Treatment Study (Part 2) were assigned to an initial treatment regimen as follows: prophylaxis (n=58), on demand (n=9), and unassigned (n=1). Patients were allowed to switch regimens during the course of the study. As a result 61 patients were treated with prophylaxis and 12 patients were treated on demand.

Arm	Measure	Category	Value (COUNT_OF_UNITS)
IB1001 (On Demand)	Degree of Hemorrhage Control by Treatment Regimen	Good	105 Bleeding Episodes
IB1001 (On Demand)	Degree of Hemorrhage Control by Treatment Regimen	Fair	25 Bleeding Episodes
IB1001 (On Demand)	Degree of Hemorrhage Control by Treatment Regimen	Poor	3 Bleeding Episodes
IB1001 (On Demand)	Degree of Hemorrhage Control by Treatment Regimen	Not Rated	36 Bleeding Episodes
IB1001 (On Demand)	Degree of Hemorrhage Control by Treatment Regimen	Excellent	53 Bleeding Episodes
IB1001 (Prophylaxis)	Degree of Hemorrhage Control by Treatment Regimen	Not Rated	59 Bleeding Episodes
IB1001 (Prophylaxis)	Degree of Hemorrhage Control by Treatment Regimen	Excellent	116 Bleeding Episodes
IB1001 (Prophylaxis)	Degree of Hemorrhage Control by Treatment Regimen	Good	74 Bleeding Episodes
IB1001 (Prophylaxis)	Degree of Hemorrhage Control by Treatment Regimen	Poor	9 Bleeding Episodes
IB1001 (Prophylaxis)	Degree of Hemorrhage Control by Treatment Regimen	Fair	28 Bleeding Episodes

Secondary

Annualized Bleed Rate

Measure was assessed during the Treatment Study

Time frame: Prophylaxis Group Duration of Treatment: 17.9 ± 9.6 months; On Demand Group Duration of Treatment: 15.9 ± 11.5 months

Population: The 68 patients in the Treatment Study (Part 2) were assigned to an initial treatment regimen as follows: prophylaxis (n=58), on demand (n=9), and unassigned (n=1). Patients were allowed to switch regimens during the course of the study. As a result 61 patients were treated with prophylaxis and 12 patients were treated on demand.

Arm	Measure	Value (MEDIAN)
IB1001 (On Demand)	Annualized Bleed Rate	16.10 Bleeds/year
IB1001 (Prophylaxis)	Annualized Bleed Rate	1.52 Bleeds/year

Secondary

Area Under the Curve (0-72 hr)

Factor IX levels were assessed at the following time points: Pre-infusion, post-infusion at 30 min ± 5 min, 1 hour ± 5 min, 3 hours ± 30 min, 6 hours ± 1 hour, 9 hours ± 1 hour, 12 hours ± 2 hours, 24 hours ± 3 hours, 36 hours ± 3 hours, 48 hours ± 3 hours, 60 hours ± 3 hours, and 72 hours ± 3 hours.