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Trial registered on ANZCTR


Registration number
ACTRN12620001152910
Ethics application status
Approved
Date submitted
5/09/2020
Date registered
3/11/2020
Date last updated
2/02/2022
Date data sharing statement initially provided
3/11/2020
Date results information initially provided
2/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Understanding the blood level of a new coagulant factor VIIa in participants with congenital Haemophilia A
Scientific title
Pharmacokinetic Evaluation of Coagulation Factor VIIa (Recombinant) in Subjects with Congenital Hemophilia A with or without Inhibitors to Factor VIII
Secondary ID [1] 302103 0
Protocol number: LFB-FVIIA-009-19
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Congenital Hemophilia A in subjects with or without Inhibitors to Factor VIII 318722 0
Condition category
Condition code
Blood 316738 316738 0 0
Clotting disorders
Human Genetics and Inherited Disorders 317256 317256 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Within 14 days of screening, eligible subjects will return to the study site for the single-day dosing period (Day 1). Subjects will be randomized (1:1) to receive one of the following intravenous single doses of LR769: 75 or 225 µg/kg. Randomization will be stratified by FVIII inhibitor status (with or without) with a minimum of 2 and a maximum of 5 subjects with inhibitors to FVIII enrolled in each treatment group.

LR769 will be administered by a qualified health care professional in a clinic or hospital setting as an intravenous bolus injection within 2 minutes according to the Instruction for Use (IFU). The study staff will record the date, start, and stop times, dose, and actual volume of infusion of the LR769 IV administration in source documents and on the appropriate electronic case report form (eCRF) pages. In addition, IMP accountability logs will be completed by the study staff. The study monitor will review these logs, and any discrepancies will be documented.

Hemophilia A is an inherited coagulation disorder due to deficiency of coagulation factor FVIII. Thus, the current standard of care for treatment of individuals with hemophilia A consists of replacing FVIII. However, in hemophilia A patients, inhibitor development is a major concern. When foreign (non-self) factor proteins are introduced, the immune system produces inhibitors (antibodies that inactivate clotting proteins), resulting in the infusion being ineffective. Individuals with severe hemophilia A develop inhibitors more often (up to 30%) than those with hemophilia B (<5%), although reasons for this are unclear.

LR769, a transgenically produced recombinant human factor VIIa (rhFVIIa) derived from a transgenic rabbit line, is part of the vitamin K-dependent coagulation factor family. It is developed for use in hemophilic A or B patients with FVIII or FIX inhibitors. In the presence of both calcium and phospholipids, FVII/VIIa complexed with tissue factor (TF) can activate factor FX to FXa (extrinsic pathway) directly, bypassing the need for FIX or FVIII. This FX to FXa conversion then activates prothrombin to thrombin, which then catalyses conversion of fibrinogen to fibrin and initiate clotting at the bleeding site.

PK data collected thus far in the LR769 clinical program have been affected by small study sample sizes or lack of repeated analyses to confirm findings. As a result, this study has been designed to further characterize the PK of LR769 in subjects with congenital hemophilia A, with or without inhibitors to FVIII.
Intervention code [1] 318419 0
Treatment: Drugs
Comparator / control treatment
Subjects will be randomised to receive either a 75 µg/kg or 225 µg/kg dose of LR769.

However, no comparative statistical tests are planned between the doses. All data collected in this study will be documented using summary tables and subject data listings. Summary tables will present results by dose group (75 or 225 µg/kg).
Control group
Dose comparison

Outcomes
Primary outcome [1] 324884 0
The primary objective of this study is to evaluate the single-dose PK of LR769 at 75 and 225 µg/kg in subjects with hemophilia A, with and without inhibitors to FVIII.

FVIIa concentrations will be determined using a validated activity assay. Noncompartmental and compartmental PK analysis will be performed, and the following PK parameters will be calculated:

- Maximum plasma concentration (Cmax)
- Area under the plasma concentration-time curve from Time 0 (dosing) to the time of the last measurable concentration (AUC0-last)
- Area under the plasma concentration-time curve from Time 0 (dosing) extrapolated to infinity (AUC0-inf)
- Time to Cmax (tmax)
- Terminal elimination half-life(t1/2): alpha (distribution) and beta (elimination) phases, for compartmental analysis
- Clearance (CL)
- Volume of distribution (Vd)
- Mean residence time (MRT)
- Area under the first moment curve (AUMC)
- Incremental recovery (IR)

For this study, the PK parameters of primary interest are Cmax and AUC0-inf.
Timepoint [1] 324884 0
Blood samples (approximately 4.5 mL per time point) for assessment of FVIIa serum concentrations will be collected at the following time periods:

Day 1:
- Before dosing
- 5 (±1) minutes after infusion
- 15 (±2) minutes after infusion
- 30 (±5) minutes after infusion
- 1 hour (±10 minutes) after infusion
- 2 hours (±10 minutes) after infusion
- 4 hours (±10 minutes) after infusion
- 6 hours (±10 minutes) after infusion
- 8 hours (±10 minutes) after infusion
- 12 hours (±10 minutes) after infusion
Secondary outcome [1] 386096 0
The secondary objective of this study is to characterize safety data collected before and after administration of a single dose of LR769.

Safety endpoints will include, but not limited to, the frequency and severity of treatment-emergent AEs (TEAEs). Subjects will be evaluated after administration of the investigational medicinal product (IMP) for TEAEs throughout the study.

Information on the subject’s medical history will be obtained at the screening visit. A physical examination, including vital signs, will be performed, and blood samples will be obtained for clinical laboratory assessments. Before administration of IMP during the treatment period (Day 1), vital signs will be collected from all subjects. Subjects will also be interviewed for AEs, and concomitant medications at every visit.
Timepoint [1] 386096 0
Subjects will be monitored for AEs/SAEs from the time of informed consent to the end of the safety follow-up (Day 4, ± 1 day), including when at the site for dosing (Day 1). A follow-up telephone call will be made to the subject on Day 4 (±1 day) to determine the subject’s safety status. To summarise, these are the timepoints:

Days -14 to -1:
- Screening

Day 1:
- Before dose
- 0 min
- 5 (±1) minutes after infusion
- 15 (±2) minutes after infusion
- 30 (±5) minutes after infusion
- 1 hour (±10 minutes) after infusion
- 2 hours (±10 minutes) after infusion
- 4 hours (±10 minutes) after infusion
- 6 hours (±10 minutes) after infusion
- 8 hours (±10 minutes) after infusion
- 12 hours (±10 minutes) after infusion

Day 4 ± 1 day:
- Safety follow-up/ early termination

Eligibility
Key inclusion criteria
1. Have the ability to provide informed consent, including privacy authorization, before study participation
2. Be judged by the investigator as willing and able to comply with the study procedures and visit schedules
3. Be a male, aged 18 to 75 years, inclusive, at the time of informed consent
4. Have a confirmed diagnosis of congenital hemophilia A (with or without inhibitors to FVIII) of any severity and not be experiencing an active bleeding episode
5. If enrolled with a medical history of inhibitors to FVIII, have a positive inhibitor test result (5 Bethesda Units (BU) and above) at the local laboratory during the 14 day screening period
Minimum age
18 Years
Maximum age
75 Years
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Have any other known coagulation or hematologic disorder(s) or condition(s) in addition to hemophilia A
2. Be immunosuppressed (i.e., the patient may not be receiving systemic immunosuppressive medication; cluster of differentiation 4 (CD4) counts at screening must be >200/µL)
3. Have undergone a major surgical procedure (e.g., orthopedic, abdominal) within 1 month
before administration of LR769
4. Be currently receiving treatment for active, ongoing bleeding, or if treatment for a bleeding was stopped within 24 hours of the time of LR769 administration
5. Have a medical history of malignancy within the past 5 years (except for nonmelanoma
skin cancer)
6. Have a clinically significant cardiac arrhythmia/dysrhythmia or unstable cardiac disease,
based on medication use, recent (< 6 months) medical history or intervention, or ECG
results during screening
7. Have positive serology during the 14 day screening period for hepatitis B (hepatitis B
surface antigen), hepatitis C virus (except patients with history of cured Hepatitis C proven
by a documented HCV RNA negative RT-PCR performed at least 24 weeks after completion of the Hepatitis C treatment, and with normal liver function tests), or human
immunodeficiency virus
8. Be currently taking or have taken within 7 days prior to LR769 administration (Day 1) known or suspected anticoagulants, antiplatelet medications, supplements, dietary ingredients, or other medications that may alter platelet aggregation including, but not limited to, the following:
• Aspirin
• Nonsteroidal anti-inflammatory drugs (commonly known as NSAIDs)
• Herbal or natural medications
• Supplements or vitamins
• Other platelet-inhibiting drugs
9. Have any life-threatening disease, or other disease or condition that, in the investigator’s judgment, could pose a potential hazard to the subject or interfere with study participation or study outcome (e.g., a history of no response to bypassing products or thromboembolic disease)
10. Have any known or suspected hypersensitivity to the active substance in LR769 or to any of its excipients
11. Have any known or suspected allergy or hypersensitivity to rabbits or rabbit proteins
12. Have received a Factor VII- or FVIIa-containing product (either plasma derived or recombinant) within 24 hours prior to administration of LR769
13. Have received an investigational drug within 30 days prior to LR769 administration, or be expected to receive such drug during participation in this study
14. Have platelet count <100,000/µL
15. Have abnormal renal or hepatic function as defined by the following laboratory results at screening:
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN)
• Serum creatinine concentration >2 times the ULN

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
21/11/2020
Actual
16/02/2021
Date of last participant enrolment
Anticipated
10/05/2021
Actual
28/07/2021
Date of last data collection
Anticipated
Actual
27/08/2021
Sample size
Target
28
Accrual to date
Final
28
Recruitment outside Australia
Country [1] 22877 0
New Zealand
State/province [1] 22877 0
Country [2] 22878 0
South Africa
State/province [2] 22878 0
Country [3] 22879 0
Ukraine
State/province [3] 22879 0

Funding & Sponsors
Funding source category [1] 306524 0
Commercial sector/Industry
Name [1] 306524 0
LFB Biotechnologies
Country [1] 306524 0
France
Primary sponsor type
Commercial sector/Industry
Name
LFB USA, Inc.
Address
175 Crossing Blvd, Framingham, MA 01702, USA
Country
United States of America
Secondary sponsor category [1] 307053 0
Commercial sector/Industry
Name [1] 307053 0
Covance New Zealand Limited
Address [1] 307053 0
RSM New Zealand (Auckland), level 2, Bldg 5, 60 Highbrook Drive, East Tamaki, Auckland 2013, New Zealand
Country [1] 307053 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306725 0
Health and Disability Ethics Committees
Ethics committee address [1] 306725 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 306725 0
New Zealand
Date submitted for ethics approval [1] 306725 0
05/08/2020
Approval date [1] 306725 0
31/08/2020
Ethics approval number [1] 306725 0

Summary
Brief summary
This is an open-label, randomized, parallel, single-dose, PK study of coagulation factor VIIa (Recombinant), LR769, in subjects with hemophilia A, with or without inhibitors to FVIII. This study is designed to evaluate the PK and safety of a single intravenous dose of 75 or 225 µg/kg in 28 male subjects aged 18 to 75 years, inclusive, with confirmed diagnoses of hemophilia A (with or without inhibitors to FVIII), and who are not experiencing an active bleeding event.

This study consists of a screening visit (Day -14 to Day -1), a single-day dosing period (Day 1), and a follow-up phone call (Day 4, ± 1 day). Total study participation may last up to 19 days.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104802 0
Dr Dean Richard Quinn
Address 104802 0
P3 Research Ltd
Level 1, 121 Adelaide Rd
Mount Cook, Wellington 6021
New Zealand
Country 104802 0
New Zealand
Phone 104802 0
+64 4 8010002
Fax 104802 0
+64 4 3897468
Email 104802 0
[email protected]
Contact person for public queries
Name 104803 0
Mr Eric Carbonnelle, Ph.D.
Address 104803 0
LFB Biotechnologies
3 avenue des Tropiques - BP 50052 - 91942 Courtaboeuf Cedex, France
Country 104803 0
France
Phone 104803 0
+33 1 69 82 17 29
Fax 104803 0
Email 104803 0
[email protected]
Contact person for scientific queries
Name 104804 0
Mr Hakim Bendjenana, M.D.
Address 104804 0
LFB Biotechnologies
3 avenue des Tropiques - BP 50052 - 91942 Courtaboeuf Cedex, France
Country 104804 0
France
Phone 104804 0
+33 1 69 82 72 08
Fax 104804 0
Email 104804 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Due to the very small number of patients with this rare disease, it will not be possible to adequately deidentify individual participant data for distribution.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.