CTRI/2021/04/032837 [Registered on: 15/04/2021] Trial Registered Prospectively
Last Modified On:
08/02/2022
Post Graduate Thesis
Yes
Type of Trial
Interventional
Type of Study
Drug
Study Design
Single Arm Study
Public Title of Study
A clinical trial to study the safety and efficacy of PEGylated Factor VIII (BAX 855) in previously untreated patients (PUPs) 6 years with severe hemophilia A (FVIII 1%)
Scientific Title of Study
Phase 3, prospective, multi-center, open label study to investigate safety, immunogenicity, and hemostatic efficacy of PEGylated Factor VIII (BAX 855) in previously untreated patients (PUPs) less than 6 years with severe hemophilia A (FVIII less than 1%)
Trial Acronym
BAX855 PUP
Secondary IDs if Any
Secondary ID
Identifier
Protocol no 261203 version 3.0 dated 26 Nov 2015
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Dr Inderjeet Singh
Designation
Clinical Development Lead Takeda India
Affiliation
Baxalta Bioscience India Pvt. Ltd.
Address
6th Floor Tower C Building No 8
DLF Cyber City DLF Phase-II
Gurgaon 122 002 Haryana India
Gurgaon HARYANA 122002 India
Phone
8146095015
Fax
Email
inderjeet.singh@takeda.com
Details of Contact Person Public Query
Name
Anoop Singh
Designation
Study Site Engagement Lead SSEL APAC & ICMEA Clinical Development Services Takeda India
Affiliation
Baxalta Bioscience India Pvt. Ltd.
Address
6th Floor Tower C Building No 8
DLF Cyber City DLF Phase-II
Gurgaon 122 002 Haryana India
Gurgaon HARYANA 122002 India
Phone
8105536000
Fax
Email
anoop.singh@takeda.com
Source of Monetary or Material Support
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna,
Austria
Primary Sponsor
Name
Baxalta Innovations GmbH
Address
Industriestrasse 67
A-1221 Vienna,
Austria
Type of Sponsor
Contract research organization
Details of Secondary Sponsor
Name
Address
Baxalta Bioscience India Pvt Ltd
Baxalta Bioscience India Pvt. Ltd.
6th Floor, Tower-C,
Building No.8,
DLF Cyber City,
DLF Phase-II,
Gurgaon-122 002,
Haryana, India
Tel: 0124-4559100
Countries of Recruitment
India
Sites of Study
No of Sites = 7
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr Neeraj Sidharthan
Amrita Institute of Medical Sciences and Research Centre
Ponekkara, Edappally, Ernakulam, Kochi -682041, Kerala, India Ernakulam KERALA
9946047464
neerajsidharthan@aims.amrita.edu
Dr Fauzia Nambiathayil Aboobacker
Christian Medical College
Ida Scudder Road, Vellore- 632004, Tamil Nadu, India Vellore TAMIL NADU
Ethics Committee, N.R.S. Medical College NRS Medical College And Hospital 138, A.J.C Bose Road, Kolkata 700014,West Bengal India
Approved
Institutional Ethics Committee, Amrita Institute of Medical Sciences AIMS-Ponekkara, Edappally, Ernakulam, Kochi -682041, Kerala, India.
Approved
Institutional Ethics Committee, Institute of Medical Sciences and SUM Hospital, SIKSHA ‘O’ ANUSANDHAN (Deemed to be University), Sector-8, Kalinga Nagar, Ghatikia, Bhubaneshwar-751003, Odisha, India
Approved
Institutional Ethics Committee, St. Johns Medical College Hospital, Sarjapur Road, Koramangala, Bengaluru (Bangalore) Urban- 560034, Karnataka, India.
Submittted/Under Review
INSTITUTIONAL REVIEW BOARD CHRISTIAN MEDICAL COLLEGE THORAPADI POST BAGAYAM VELLORE Tamil Nadu -632012,India
Approved
Nirmal Hospital Ethics Committee, Nirmal Hospital Pvt. Ltd., 2/1423-8-6 Sagrampura, Ring Road, Near Centre Point, Surat-395002, Gujarat, India.
Approved
Sahyadri Hospitals Ltd. Ethics Committee, Sahyadri Clinical Research & Development Center (A Unit of Sahyadri Hospitals Ltd.), 33/34B, Makarand Bhave Path, Karve Road, Pune- 411004, Maharashtra, India
PEGylated Recombinant Factor VIII
Polyethylene glycol (PEG)-ylated full-length recombinant FVIII (rFVIII)
Dosage form: injection, powder, lyophilized, for solution
Part A (main study):
On-demand: 10-80 IU/kg depending on the severity of the bleeding episode.
Subjects may start with on-demand therapy if they are younger than 3 years
and if they have not experienced two joint bleeds.
Prophylaxis: To be initiated before the age of 3 years or after a maximum of
2 joint bleeds, whichever occurs first, at a dose of 25-80 IU/kg at least once
weekly.
Surgery (Part A):
The dose and frequency of BAX 855 administered will be individualized based
on the subject’s BAX 855 IR and half-life, if available, to obtain the target
level required for the type of the surgery, dental or other invasive procedure
being performed. In general, for major surgery initial FVIII target levels in
plasma should be ≥ 80-100% of normal FVIII level, whereas for minor surgery
target FVIII levels should be ≥ 30-60%.
Part B (ITI): daily 100-200 IU/kg or three times weekly 50 IU/kg. In case of
success, high-dose ITI regimen, if applicable, will be reduced to twice weekly
prophylaxis as follows:
 100±5 IU/kg/day for the first four weeks; then
 50±5 IU/kg/day for a further four weeks; then
 50±5 IU/kg every second day for a further four weeks; then
 50±5 IU/kg administered twice a week, adjusted as needed to maintain
a FVIII trough level of 1%, for a further 3 months.
Subjects receiving low dose ITI therapy with 3 x 50 IU/kg weekly will be
transitioned to twice weekly 50 IU/kg, adjusted as needed to maintain a FVIII
trough level of 1%, for a further 3 months. After this period, a
Completion/Termination Visit will be performed.
Mode of Administration: intravenous bolus
Inclusion Criteria
Age From
1.00 Year(s)
Age To
6.00 Year(s)
Gender
Both
Details
1.Subject is < 6 years old at the time of screening 2. Subject is previously untreated with < 3 EDs to ADVATE, BAX 855 or Fresh Frozen Plasma (FFP) at any time prior to screening 3.
Subject has severe hemophilia A (FVIII < 1%) as determined by the central laboratory, or a historical FVIII level < 1% as determined at any local laboratory, optionally supported by an additional FVIII gene mutation consistent with severe hemophilia A 4.
Subject is immune competent with a CD4+ count > 200 cells/mm3, as confirmed by central laboratory at screening 5. Parent or legally authorized representative is willing and able to comply with the requirements of the protocol
Additional inclusion criteria for Part B (ITI): 1 Parent or legal representative has/have voluntarily provided signed informed consent for ITI portion 2 Subject has a confirmed positive high titer inhibitor (> 5.00 BU) or has a positive confirmed low titer inhibitor (≥ 0.6 BU) as determined by the central laboratory based on a second repeat blood sample with a) poorly controlled bleeding despite increased BAX 855 doses, or b) requires bypassing agents to treat bleeding episodes
ExclusionCriteria
Details
1 Subject has detectable FVIII inhibitory antibodies (≥0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening
2 S2. Subject has a history of FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen modification of the Bethesda assay or the Bethesda assay) at any time prior to screening
3 Subject has been diagnosed with an inherited or acquired hemostatic defect other than
hemophilia A (eg, qualitative platelet defect or von Willebrand’s disease)
4 Subject has been previously treated with cryoprecipitate or any type of FVIII concentrate other
than ADVATE, BAX 855v or FFP, or was administered ADVATE,BAX 855 or FFP for ≥ 3 Eds at any time prior to screening.
5 Subject has received any kind of blood-transfusion such as PRBC, platelets or plasma prior to
screening at any time prior to screening
6 The subject’s weight is < 5 kg
7 Subject’s platelet count is < 100,000/mL
8 Subject has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80
9 Subject has severe chronic hepatic dysfunction [eg, > 5 times upper limit of normal alanine
aminotransferase (ALT), aspartate aminotransferase (AST), or a documented INR > 1.5] in his
medical history or at the time of screening
10 Subject has severe renal impairment (serum creatinine > 1.5 times the upper limit of normal)
11 Subject has current or recent (< 30 days) use of other PEGylated drugs prior to study participation or is scheduled to use such drugs during study participation
1212. Subject is scheduled to receive during the course of the study a systemic immunomodulating
drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or
α-interferon) other than anti-retroviral chemotherapy
13 Subject has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study
14 14. Parent or legally authorized representative has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance
15 Parent, legally authorized representative or subject are a member of the team conducting this
study or is in a dependent relationship with one of the study team members. Dependent
relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as
employees of the investigator or site personnel conducting the study.
Additional exclusion criteria for Part B (ITI)
1 Spontaneous disappearance of the inhibitor prior to ITI
2 FVIII inhibitor titer ≥ 0.6 BU is not confirmed by a second new blood sample drawn within
2 weeks of study site notification of inhibitor and determined at the central laboratory
3 Inability or unwillingness to comply with the protocol
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
Incidence of FVIII inhibitor development Success rate of Immune tolerance induction (ITI)
Throughout Part A of the study, approximately 5 years
Up to 33 months
Secondary Outcome
Outcome
TimePoints
Safety:• Binding IgG and IgM antibodies to FVIII, PEG-FVIII and PEG
• AEs and SAEs
• Clinically significant changes in vital signs and clinical laboratory parameters (hematology and clinical chemistry)
Throughout Part A of the study, approximately 5 years
Throughout Part A and Part B of the study, approximately 7 years
Throughout Part A and Part B of the study, approximately 7 years
Efficacy •Annualized bleeding rate (ABR) for prophylactic and on-demand treatment
•Number of BAX 855 infusions per bleeding episode
•Overall hemostatic efficacy rating at 24 h after initiation of treatment and at resolution of bleed
•Weight-adjusted consumption of BAX 855 per month, per year and per event (prophylaxis, treatment of bleeding episode and surgery) and the number of infusions per month and per year
Throughout Part A of the study, approximately 5 years
24 h after initiation of treatment and at resolution of bleed
Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)
Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)
Pre-infusion within 30 minutes; and post-infusion at 15-30 minutes and 24-48 hours
ost-infusion: 15-30 minutes and 24-48 hours
• Assessment of intra-, post- and perioperative hemostatic efficacy in case of surgery
• Intra- and postoperative blood loss in case of surgery
• IR at baseline and over time
• Half-life at baseline (optional). This is based on an abbreviated PK using 2 post-infusion timepoints: 15-30 minutes and 24–48 hours
Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first
Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)
Pre-infusion within 30 minutes; and post-infusion at 15-30 minutes and 24-48 hours
Additional Outcome Measures for ITI: Primary: The success rate of ITI therapy with BAX 855, success being defined as 1) a persistently negative inhibitor titer 0.6 BU (confirmed by central laboratory with second blood specimen obtained within 2 months); 2) a FVIII IR 66% of baseline value following a wash-out period of
84-96 h, and 3) a FVIII half-life of ≥ 6 hours.
If no baseline IR is available, the IR value is indicative of an adequate clinical response following a wash-out period of 84-96 h.
•ABR during ITI
•Weight-adjusted consumption of BAX 855 per month and per year for each ITI regimen employed
•Catheter-related complications
•Binding IgG and IgM antibodies to FVIII, PEG-FVIII, and PEG
•The rate of partial success and failure of ITI with BAX 855
Up to 33 months
Target Sample Size
Total Sample Size="12" Sample Size from India="12" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This study is a Phase 3, prospective, open-label, multicenter study to assess the safety, immunogenicity and hemostatic efficacy of BAX 855 in PUPs < 6 years of age with severe hemophilia A (baseline FVIII level < 1%) and < 3 EDs to ADVATE, BAX 855viii or plasma in at least 100 evaluable subjects. Subjects will receive prophylactic and/or on demand therapy with BAX 855 for at least 100 EDs or until they have developed a confirmed FVIII inhibitor (Part A). During Part A, subjects can undergo surgical or invasive procedures under a protocol-defined regimen for BAX 855. Subjects who develop a high titer FVIII inhibitor or subjects with low titer FVIII inhibitors where ITI therapy is necessary because of poorly controlled bleeding despite increased BAX 855 doses or bypassing agents are required to treat bleeding may enter Part B (ITI portion) of the study to undergo ITI therapy with BAX 855.