| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
KOVALTRY, indicated for use in adults and children with hemophilia A (congenital Factor VIII
deficiency) for:
- Routine prophylaxis to reduce the frequency of bleeding episodes
- On-demand treatment and control of bleeding episodes
- Perioperative management of bleeding
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of hemophilia A patients (lacking of native FVIII) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060612 |
| E.1.2 | Term | Hemophilia A |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071818 |
| E.1.2 | Term | Bleeding prophylaxis |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A (PTPs):
Evaluate the efficacy of prophylaxis treatment with KOVALTRY in Chinese children (<12 years) and adolescents/adults (≥12 years) with severe hemophilia A
Part B (PUPs/MTPs):
Assess the efficacy of KOVALTRY within 48 hours of previous prophylaxis infusion in previously untreated/minimally treated Chinese children (<6 years of age) with severe hemophilia A |
|
| E.2.2 | Secondary objectives of the trial |
Part A (PTPs):
Efficacy
• Evaluate efficacy of KOVALTRY for treatment of bleedings
• Assess efficacy within 48 hours of previous prophylaxis infusion
• Evaluate in vivo recovery of KOVALTRY
• Hemostatic control for minor surgeries
Safety
• Assess safety of KOVALTRY for prophylaxis and treatment of bleeding episodes in Chinese children (<12 years) and adolescents/adults (≥12 years) with severe hemophilia A
Pharmacokinetics (PK)
• Evaluate PK of KOVALTRY in Chinese children (<12 years) and adolescents/adults (≥12 to 65 years) severe hemophilia A patients
Part B (PUPs/MTPs):
Efficacy
• Evaluate efficacy of prophylaxis treatment with KOVALTRY
• Assess efficacy of KOVALTRY for treatment of bleeding episodes
• Evaluate in vivo recovery of KOVALTRY
• Hemostatic control for minor surgeries
Safety
• Assess safety of KOVALTRY for prophylaxis and treatment of bleeding episodes in previously untreated/minimally treated Chinese children (<6 years) with severe hemophilia A
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A (PTPs):
Participants are eligible to be included if all of the following criteria apply:
1. Participants enrolled as children must be <12 years at the time of their parent or legal representative’s signature of informed consent on participant’s behalf, or if enrolled as adolescents/adults, must be ≥ age 12 to 65 years at time of signed informed consent.
2. Chinese participants with severe hemophilia A (defined as FVIII:C <1% with one-stage clotting assay documented at the time of screening). If screening results show FVIII:C as equal to or higher than 1%, then severe hemophilia A may be confirmed by documented historical evidence from a (certified) clinical laboratory demonstrating <1% FVIII:C as determined by a one-stage clotting assay.
3. Currently receiving on-demand or any type of prophylaxis treatment regimen with any FVIII product (excluding treatment with fresh-frozen plasma and cryo-precipitate).
4. For participants <12 years of age, ≥50 exposure days (ED); for participants ≥12 to 65 years of age, ≥150 ED with any Factor VIII product (excluding treatment with fresh-frozen plasma and cryo-precipitate).
5. No current evidence of inhibitor antibody as measured by the Nijmegen-modified Bethesda assay [<0.6 Bethesda units (BU)/mL] in 2 consecutive samples and absence of clinical signs or symptoms of decreased response to FVIII administration. (First negative sample can be historical if obtained within 3 months prior to screening with a result of <0.6 BU/mL by classical Bethesda assay. The testing for a second negative, confirmatory sample must, in all cases, be performed by a central laboratory using the Nijmegen-modified Bethesda test. If a first recent sample is not available,
then testing for 2 negative samples must be performed by central laboratory at least 1 week apart). Participants may not receive FVIII within 72 hours prior to the collection of samples for inhibitor testing.
6. No history of FVIII inhibitor formation. Documentation of negative result in medical records is required (Nijmegen-modified Bethesda assay or classical Bethesda assay); participants with a maximum historical titer of 1.0 BU/mL on no more than 1 occasion with classical Bethesda assay but at least 3 successive negative results (<0.6 BU/mL) thereafter are eligible.
7. Male participants only
8. signed informed consent
Other
9. Willingness and ability of participants, parents, or caregiver to comply with prophylaxis schedule and complete training on use of the study electronic patient diary (EPD) and to use the diary to document bleeding and infusion information during the study.
Part B (PUPs/MTPs):
Participants are eligible to be included if all of the following criteria apply:
1. Participants must be <6 years of age at the time of their parent or legal representative’s signature of informed consent on the participant’s behalf.
Type of Participant and Disease Characteristics
2. Chinese participants with severe hemophilia A (defined as FVIII:C <1% with one-stage clotting assay documented at the time of screening). If screening results show FVIII:C as equal to or higher than 1%, then severe hemophilia A may be confirmed by documented historical evidence from a (certified) clinical laboratory demonstrating FVIII:C <1% as determined by a one-stage clotting assay.
3. PUPs must have no previous exposure to any FVIII product. MTPs must have no more than 3 EDs with any FVIII product including FFP,
cryoprecipitate, purified FVIII concentrate and recombinant FVIII. MTPs treated for surgical procedures or treated with intensive treatment e.g., mean
dose >35 IU/kg for bleeding episodes during the first 3 EDs are not eligible for the study.
4. MTPs must have no current evidence of inhibitor antibody as measured by the Nijmegen-modified Bethesda assay (<0.6 BU/mL) in 2 consecutive samples and must have absence of clinical signs or symptoms of decreased response to FVIII administration. Testing for the 2 negative samples must be performed by the central laboratory at least 1 week but not more than 2 weeks apart. Participants may not receive FVIII product within 72 hours prior to the collection of samples for inhibitor testing.
5. PUPs & MTPs must observe a 6-month washout period if they have received emicizumab (bispecific monoclonal antibody) for subcutaneous factor substitution therapy.
6. PUPs may be included if they will receive their first FVIII dose KOVALTRY for treatment of first bleeds and agree to start prophylaxis as part of their care. MTPs may be included if they agree to start prophylaxis as part of their care.
7. Male participants only
8. The parents or a legal representative of the participant must be able to provide a signed informed consent on behalf of participant
9. The participant’s parent/caregiver must be willing/able to comply with the prophylaxis schedule and to complete training on use of study EPD and use the EPD to document bleeding and treatment information during the study. |
|
| E.4 | Principal exclusion criteria |
Part A (PTPs) Exclusion Criteria
Participants are excluded from Part A of the study if any of the following criteria apply:
Medical Conditions
1. Any other bleeding disease that is different from hemophilia A (e.g., von Willebrand
disease, hemophilia B).
2. Platelet count <100 000/mm3 based on screening laboratory assessments.
3. Impaired renal function (serum creatinine >2.0 mg/dL) or active liver disease (alanine
aminotransferase/aspartate aminotransferase [ALT/AST] >5x ULN) based on
screening laboratory.
4. Human immunodeficiency virus (HIV) positive with an absolute CD4 lymphocyte cell
count <250 cells/μL.
5. Known hypersensitivity to the active substance, mouse or hamster protein.
Prior/Concomitant Therapy
6. Receiving chemotherapy or immune modulatory drugs (e.g., intravenous [IV]
immunoglobulin, cyclosporine) other than anti-retroviral chemotherapy or chronic use
of oral or intravenous (IV) corticosteroids (>14 days) within the last 3 months. Brief
courses of prednisone/methylprednisolone (<14 days) for treatment of disorders such
as synovitis, asthma, etc. are allowed at the discretion of the treating physician
7. Requiring any pre-medication to tolerate FVIII infusions (e.g., antihistamines).
Prior/Concurrent Clinical Study Experience
8. Currently participating in another investigational drug study, or having previously
participated in a clinical study involving an investigational drug within 30 days of
signing informed consent or participated in completed interventional clinical studies
with BAY 81-8973 (KOVALTRY).
Other Exclusions
9. Unwilling to comply with study visits or other protocol requirements or is not suitable
for participation in this study for any reason, according to the Investigator.
10. Planned major surgery, defined as surgery with respiratory assistance and/or general
anesthesia.
11. Close affiliation with the investigational site; e.g., a close relative of the investigator,
dependent person (e.g., employee or student of the investigational site).
Part B (PUPs/MTPs) Exclusion Criteria
Participants are excluded from Part B of the study if any of the following criteria apply:
Medical Conditions
1. Any other bleeding disorder that is different from hemophilia A (e.g., von Willebrand
disease, hemophilia B).
2. Platelet count <100 000/mm3 based on screening laboratory assessments.
3. Impaired renal function (serum creatinine >2× upper limit of normal [ULN]) or active
liver disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]
>5× ULN) based on screening laboratory assessments.
4. MTPs with history of FVIII inhibitor formation.
5. Known hypersensitivity to the active substance, mouse or hamster protein.
6. First treatment with KOVALTRY for high risk bleeding situations (e.g., surgery,
intracranial bleed etc.) or requiring intensive or prolonged treatment.
7. Planned major surgery, defined as surgery with respiratory assistance and/or general
anesthesia
Prior/Concomitant Therapy
8. Receiving chemotherapy or immune modulatory drugs (e.g., IV immunoglobulin,
cyclosporine) other than anti-retroviral chemotherapy or chronic use (>14 days) of
oral or IV corticosteroids within the last 3 months. Brief courses (<14 days) of
prednisone/methylprednisolone for treatment of disorders such as synovitis, asthma,
etc. are allowed at the discretion of the treating physician.
9. Requiring any pre-medication to tolerate FVIII infusions (e.g., antihistamines).
Prior/Concurrent Clinical Study Experience
10. Currently participating, or have participated within 30 days of signing informed
consent, in another clinical study involving an investigational drug.
Other Exclusions
11. Unwilling to comply with study visits or other protocol requirements or is not suitable
for participation in this study for any reason, according to the investigator’s judgment.
12. Close affiliation with the investigational site (e.g., a close relative of the investigator,
dependent person [e.g., employee or student of the investigational site]).
13. Unable to tolerate volume of blood draws required for study participation (see
Section 10.2).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
All efficacy analyses will be performed on the mITT population. In case of PP population
(Part A only), more than 5% of participants in one arm (children or adolescents/adults) are
excluded from the mITT population, and analyses for primary and secondary endpoints will
be repeated in the PP population. As the non-adherence to the EPD documentation is
considered independent from the treatment efficacy, the exclusion of participants without
bleeding/infusion data from the EPD does not interfere with the intention-to-treat principle.
These participants are excluded in order not to dilute the treatment effect.
The primary endpoint in Part A is the ABR of all bleeding episodes during prophylaxis
treatment, and it will be summarized by age group (<12 y, ≥12 y) separately.
The primary endpoint in Part B is the ABR of all bleeding episodes within 48 hours of a
previous prophylaxis infusion. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for primary and secondary endpoints for part A are evaluated after completion of 6 months of treatment with Kovaltry, and for part B of the study after completion of 50 EDs of Kovaltry. |
|
| E.5.2 | Secondary end point(s) |
Spontaneous bleeding episodes, trauma bleeding episodes, joint bleeding episodes, and other
bleeding episodes types will be summarized separately.
Other efficacy variables are:
- ABR of treated bleeding episodes
- ABR of target joint bleeding episodes
- ABR of bleeding episodes within 48h of previous prophylaxis infusion (total, joint,
spontaneous, trauma) [for Part A]
- ABR of all bleeding episodes during prophylaxis treatment [for Part B]
- Study participant’s/caregiver’s assessment of response to treatment of bleeding
episodes (excellent, moderate, good, or poor)
- Physician’s assessment of the response to treatment of bleeding episodes in minor
surgery (excellent, moderate, good, or poor)
- Evaluate proportion of patients without bleeding episodes
- The number of infusions per bleeding episode
- Factor VIII usage (expressed as number of infusions and IU/kg per year, as well as IU/kg per event)
- Incremental recovery
All details of the analysis will be provided in the SAP. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for primary and secondary endpoints for part A are evaluated after completion of 6 months of treatment with Kovaltry, and for part B of the study after completion of 50 EDs of Kovaltry. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study itself will be considered complete after the last visit of the last participant for all centers has occurred. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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