E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe hemophilia A (FVIII <1%) |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
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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 |
To determine safety including immunogenicity of BAX 855 based on the
incidence of inhibitor development to FVIII (≥ 0.6 Bethesda unit (BU)/mL using the Nijmegen modification of the Bethesda assay) |
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E.2.2 | Secondary objectives of the trial |
Safety
1. To determine the immunogenicity of BAX 855 in terms of binding IgG and IGM antibodies to FVIII, PEG-FVIII and PEG
2. To determine the safety of BAX 855 based on adverse events (AEs) and serious adverse events (SAEs)
Hemostatic Efficacy
3. To assess the efficacy of prophylactic treatment with BAX 855
4. To characterize the efficacy of BAX 855 in the control of bleeding episodes
Pharmacokinetics
6. To determine the incremental recovery (IR) of BAX 855 at baseline and over time
7. To determine half-life of BAX 855 at baseline (optional) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is < 6 years old at the time of screening
2. Subject is previously untreated with <3 EDs to ADVATE, BAX 855 or plasma transfusion 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 and an optional 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 |
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E.4 | Principal exclusion criteria |
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 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 or BAX 855, or was administered ADVATE or BAX 855 or plasma transfusion for ≥ 3 EDs at any time prior to screening
5. Subject receives > 2 EDs of ADVATE in total during the periods prior to enrollment and during the screening period, up until the baselineinfusion.
6. The subject’s weight is anticipated to be < 5 kg at the baseline visit
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
12. 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. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of FVIII inhibitor development
The success rate of ITI therapy with BAX 855 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The set of subjects to be analyzed includes all subjects who developed a confirmed inhibitor (at any time) based on a second repeat blood sample within 2 weeks of sitenotification of an inhibitor and all subjects who did not develop an inhibitor and had ≥ 100 EDs. |
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E.5.2 | Secondary end point(s) |
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)
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 and treatment of bleeding episode) and the number of infusions per month and per year
Pharmacokinetics:
-IR at baseline and over time
-Half-life at baseline (optional) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Binding antibodies to FVIII, BAX 855 and PEG and all other secondary safety outcome measures will be analyzed descriptively.
The ABR will be analyzed by point and interval estimates derived from a negative binomial model with treatment regimen (on-demand vs. prophylaxis) as a covariate and the duration of the observation period as an offset. Other secondary efficacy outcome measures as well as IR over time will be analyzed descriptively. |
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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 | 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) | 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 | 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 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Austria |
Belgium |
Bulgaria |
Czech Republic |
France |
Germany |
Hong Kong |
Hungary |
India |
Italy |
Korea, Republic of |
Malaysia |
Netherlands |
Norway |
Poland |
Romania |
Singapore |
Spain |
Taiwan |
Thailand |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 25 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |