| 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 | 19.1 |
| 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 co-primary objectives of the study are:
1. To determine the safety of BAX 855 based on the incidence of FVIII inhibitory antibody development
2. To determine the efficacy of BAX 855 based on the annualized bleed rate (ABR) of spontaneous bleeding episodes |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy
1. To determine the total ABR (spontaneous and traumatic bleeding episodes)
2. To determine the overall hemostatic efficacy rating of BAX 855 for treatment of breakthrough bleeding episodes
3. To determine the length of intervals between bleeding episodes
4. To characterize the hemostatic efficacy of BAX 855 for treatment of bleeding episodes by the number of BAX 855 infusions for treatment
5. To determine total weight-adjusted consumption of BAX 855 for prophylaxis and for treatment of bleeding episodes
6. To assess Patient Reported Outcomes (PROs) over time for subjects receiving BAX 855
Safety
1. To determine the safety of BAX 855, as assessed by the occurrence of adverse events (AEs) and changes in vital signs and clinical laboratory parameters
2. To determine the immunogenicity of BAX 855 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects transitioning from other BAX855 studies:
Subjects transitioning from other BAX 855 studies who meet ALL of the following criteria are eligible for this study:
1. Subject has completed a previous BAX 855 study and is willing to immediately transition into this continuation study.
2. Subject is ≤ 75 years of age at screening of the previous BAX 855 study.
3. Subject continues to have a Karnofsky (for subjects aged ≥ 16 years) or Lansky (for subjects aged < 16 years) performance score of ≥ 60
4. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm3, as confirmed by central laboratory at screening.
5. Subject is hepatitis C virus negative (HCV-) by antibody or PCR testing (if positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis.
6. 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.
7. Subject and/or legally authorized representative is willing and able to comply with the requirements of the protocol.
BAX 855 naïve subjects
BAX 855 naïve subjects who are ≥ 12 years of age can only be enrolled in this continuation study after enrollment in the phase 2/3 pivotal study is closed. BAX 855 naïve subjects who are < 12 years of age can only be enrolled in this continuation study after enrollment in the pediatric PTP study is closed.
Enrolment of BAX 855 naïve subjects will only start once the sponsor has notified the study sites
accordingly.
BAX 855 naïve subjects who meet ALL of the following criteria are eligible for this study:
1. Subject is ≤75 years of age at screening.
2. Subject is naïve to BAX 855.
3. Subject has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory at screening after at least a 72-hour washout period.
4. Subject aged ≥ 6 years has documented previous treatment with plasma-derived FVIII concentrates or rFVIII for ≥ 150 EDs.
5. Subject aged < 6 years has documented previous treatment with plasma derived FVIII concentrates or rFVIII for ≥ 50 EDs.
6. Subject is currently receiving prophylaxis or on-demand therapy with FVIII.
7. Subject has a Karnofsky (for subjects aged ≥ 16 years) or Lansky (for subjects aged < 16 years) performance score of ≥ 60
8. Subject is HIV-; or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm3, as confirmed by central laboratory at screening.
9. Subject is HCV- by antibody or PCR testing (if positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis.
10. 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.
11. Subject and/or legally authorized representative is willing and able to comply with the requirements of the protocol. |
|
| E.4 | Principal exclusion criteria |
Subjects transitioning from other BAX855 studies:
Subjects transitioning from other BAX 855 studies who meet ANY of the following criteria are not eligible for this study:
1. Subject had 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 developed FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen modification of the Bethesda assay as determined at central laboratory in a previous BAX 855 study).
3. Subject has acquired a hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand’s disease) in a previous BAX 855 study.
4. Subject has severe chronic hepatic dysfunction (eg, ≥ 5 times upper limit of normal alanine aminotransferase [ALT], as confirmed by central laboratory at screening).
5. Subject has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening.
6. Subject experienced a life-threatening or gastrointestinal bleeding episode within 3 months prior to study entry.
7. Subject is scheduled to use other PEGylated drugs during study participation.
8. Subject is planning to take part in any other clinical study during the course of the continuation study, with the exception of any other parallel BAX 855 study.
9. Subject has medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance.
10. Subject is a family member or employee of the investigator.
BAX 855 naïve subjects
BAX 855 naïve subjects who meet ANY of the following criteria are not eligible for this study:
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 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 known hypersensitivity towards mouse or hamster proteins, PEG, or Tween 80.
5. Subject has severe chronic hepatic dysfunction (eg, ≥ 5 times upper limit of normal ALT, as confirmed by central laboratory at screening).
6. Subject has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening.
7. Subject experienced a life-threatening or gastrointestinal bleeding episode within 3 months prior to study entry.
8. Subject has current or recent (< 30 days) use of other PEGylated drugs prior to study participation or scheduled use of such drugs during study participation.
9. Subject has participated in another clinical study involving an IP other than BAX 855 or 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.
10. Subject has medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance.
11. Subject is a family member or employee of the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety: Development of inhibitory antibodies to FVIII
Efficacy: Spontaneous ABR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| All subjects will continue on study until a minimum of 100 EDs per subject have been achieved across all BAX 855 studies in which each subject participated. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
1. Total ABR (spontaneous and traumatic bleeding episodes)
2. Overall hemostatic efficacy rating of BAX 855 for treatment of breakthrough bleeding episodes
3. Number of BAX 855 infusions to treat bleeding episodes
4. Time intervals between bleeding episodes
5. Weight-adjusted consumption of BAX 855
Safety
1. Occurrence of AEs and serious adverse events (SAEs)
2. Changes in vital signs and clinical laboratory parameters (hematology, clinical chemistry, and lipids)
3. Immunogenicity
a. Binding antibodies (IgG and IgM) to FVIII, BAX 855, and PEG
b. Anti-Chinese hamster ovary (CHO) antibodies
Patient Reported Outcomes (PROs)
Changes from baseline in parent study, if applicable, in the following:
1. Bleed and pain severity as measured using the Haemo-SYM questionnaire
2. Health-related quality of life (HRQoL) as assessed using the SF-36/PedsQL questionnaires |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All subjects will continue on study until a minimum of 100 EDs per subject have been achieved across all BAX 855 studies in which each subject participated. |
|
| 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 | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 |
| Czech Republic |
| Germany |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Lithuania |
| Malaysia |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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