| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe hemophilia A (FVIII <1%) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to compare 2 prophylactic dosing regimens of BAX 855 targeting 2 different FVIII trough levels, by comparing the proportions of subjects achieving a total ABR of 0 in the second 6-month study period. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the 2 prophylactic dosing regimens of BAX 855 targeting 2 different FVIII trough levels with respect to the following:
Proportion of subjects in each prophylactic dosing arm achieving a spontaneous ABR and spontaneous AJBR of 0 in the second 6-m period
Proportion of subjects in each prophylactic dosing arm with a total, spontaneous ABR and AJBR <2
Total, spontaneous, and trauma-related ABRs in the 12-m period
Reduction in ABR between the two treatment arms and the historical ABR prior to study enrolment
Total weight-adjusted consumption of BAX 855 for each prophylactic regimen
Joint status using the HJHS and over time
HRQoL / Pharmacoeconomic outcomes
To determine:
hemostatic efficacy of BAX 855 in control of bleeding episodes
efficacy of BAX 855 for perioperative management
immunogenicity/ safety of BAX 855
PK parameters of BAX 855 at baseline and steady state and the correlation with pre-infusion VWF antigen level
IR over time
To assess the PROs over time |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Subjects Transitioning from Another BAX 855 study:
1. Subject has completed the end of study visit of a BAX 855 study or is transitioning from the ongoing Continuation Study 261302
2. Subject is either receiving on-demand or prophylactic treatment with BAX 855 and had an ABR of ≥ 2 documented and treated during the past 12 months
3. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm3, as confirmed by central laboratory
4. Subject is willing and able to comply with the requirements of the protocol
Inclusion Criteria for Newly Recruited Subjects:
1. Subject is 12 to 65 years old at the time of screening
2. Subject has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory or by historically documented FVIII clotting activity performed by a certified clinical laboratory , optionally supported by a FVIII gene mutation consistent with severe hemophilia A
3. Subject has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥ 150 documented exposure days (EDs)
4. Subject is either receiving on-demand treatment or prophylactic treatment and had an annual bleeding rate of ≥ 2 documented and treated during the past 12 months.
5. Subject has a Karnofsky performance score of ≥ 60 at screening
6. Subject is HIV-; or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm3, as confirmed by central laboratory at screening
7. Subject is hepatitis C virus negative (HCV-) by antibody (if positive, additional PCR testing will be performed), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis
8. If female of childbearing potential, subject presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study
9. Subject is willing and able to comply with the requirements of the protocol. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria for Subjects Transitioning from Another BAX 855 study:
1. Subject has developed a confirmed inhibitory antibody to FVIII with a titer of ≥ 0.6 Bethesda Units (BU) using the Nijmegen modification of the Bethesda assay as determined at the central laboratory during the course of the previous BAX 855 study
2. Subject has been diagnosed with an acquired hemostatic defect other than hemophilia A
3. The subject’s weight is < 35 kg or > 100 kg
4. Subject’s platelet count is < 100,000/mL
5. Subject has an abnormal renal function (serum creatinine > 1.5 times the upper limit of normal)
6. Subject has active hepatic disease with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels ≥ 5 times the upper limit of normal
7. Subject is scheduled to receive systemic immunomodulating drug (eg, corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy during the study
8. Subject has a clinically significant medical, psychiatric, or cognitive illness, or
recreational drug/alcohol use that, in the opinion of the investigator, would affect subject’s safety or compliance
9. Subject is planning to take part in any other clinical study during the course of the study.
10. Subject is 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
Exclusion Criteria for Newly Recruited Subjects
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. Subject has a history of confirmed FVIII inhibitors with a titer ≥ 0.6 BU (as determined by the Nijmegen modification of the Bethesda assay or the assay employed with the respective cut-off in the local laboratory) 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. The subject’s weight is < 35 kg or > 100 kg.
5. Subject’s platelet count is < 100,000/mL.
6. Subject has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80
7. Subject has severe chronic hepatic dysfunction [eg, ≥ 5 times upper limit of normal ALT and/ or AST, as confirmed by central laboratory at screening, or a documented INR > 1.5]
8. Subject has severe renal impairment (serum creatinine > 1.5 times the upper limit of normal)
9. 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
10. Subject is scheduled to receive during the course of the study, a systemic immunomodulating drug (eg, corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α- interferon) other than anti-retroviral chemotherapy.
11. 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
12. Subject 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
13. Subject is 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Presence or absence of any bleedings in the second 6-month study period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The observation period for the primary endpoint will be the second 6 months of prophylaxis (Day 184 to Day 366). If the subject undergoes a surgical procedure the observation period is interrupted starting from the presurgical loading dose until the subject resumes his previous prophylactic treatment regimen, or until rehabilitation or any other surgery specific postoperative measures have been completed, whichever
occurs last. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
1. Total, spontaneous and traumatic ABR, and spontaneous AJBR
2. Total weight-adjusted consumption of BAX 855
3. Overall hemostatic efficacy rating at 8 (± 1) hours after the initiation of treatment and at resolution of bleed
4. Number of BAX 855 infusions needed for the treatment of bleeding episodes
5. HJHS
6. Intra-, post- and perioperative hemostatic efficacy in case of surgery
7. Intra- and postoperative blood loss in case of surgery
Safety
1. Occurrence of AEs and SAEs
2. Clinically significant changes in vital signs and clinical laboratory parameters (hematology, clinical chemistry, and lipids)
3. Inhibitory antibodies to FVIII, and binding antibodies to FVIII, BAX 855, PEG, and CHO protein
Patient Reported Outcomes (PROs)
1. Physical domain and component scores of the SF-36 Health Survey
Pharmacokinetics
1. BAX 855 PK parameters based on FVIII activity at baseline and steady state, if applicable:
a. AUC0-∞ (Area under the plasma concentration versus time curve from time 0 to infinity), IR (incremental recovery) at 15-30 minutes post-infusion, T1/2 (plasma half-life), MRT (mean residence time), CL (clearance), maximum plasma concentration (Cmax) and time to maximum concentration in
plasma (Tmax), Vss (Volume of distribution at steady state)
b. Incremental recovery (IR) over time |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Individual aspects of the following end points will be evaluated at different time points throughout the study:
Efficacy
Safety
PROs
Pharmacokinetics
Please refer to the protocol for details. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Israel |
| Italy |
| Korea, Democratic People's Republic of |
| Malaysia |
| Norway |
| Poland |
| Romania |
| Singapore |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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