E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Haemophilia A (Factor VIII deficiency) |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018937 |
E.1.2 | Term | Haemophilia 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 demonstrate safety of GreenGene™ F with respect to inhibitor development (neutralizing anti-Factor VIII antibodies) and
long-term safety
•To evaluate the hemostatic efficacy in prophylaxis (rate of breakthrough bleeding) and on demand treatment in the management of acute bleeding events;
•To evaluate the physicians and subjects rating of response for on demand treatment of bleeding episodes; and
•To evaluate peri-operative hemostatic control of GreenGene™ F during surgical and invasive diagnostic procedures.
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E.2.2 | Secondary objectives of the trial |
Please see main objective above. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic sub-study (not applicable for Poland). This is described in the main clinical study protocol. Objectives are:
•To demonstrate pharmacokinetic (PK) profile of GreenGene™ F;
•To compare the PK profile of GreenGene™ F to an approved recombinant Factor VIII product (Refacto AF); and
•To determine the PK parameters for GreenGene™ F after 50 exposure days in a cohort of subjects who participated in the initial PK analysis and compare these parameters to those recorded at the beginning of the study.
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E.3 | Principal inclusion criteria |
1.Male or female subjects age ≥ 12 years at time of informed consent
2.Body weight ≥ 35 kg
3.Diagnosed with severe hemophilia A. All subjects must have severe hemophilia A with baseline FVIII <1% activity; <0.01 IU/mL
4.Have ≥ 150 previous exposure days to FVIII concentrates, as documented in the subject’s medical records
5.Subjects included in the on-demand treatment cohort must have a verifiable record of at least three bleeding episodes per month on average in the last 6 months prior to enrollment
6.Negative assays for FVIII inhibitor at both local and central laboratories at inclusion (<0.6BU Nijmegen assay)
7.Negative assays for FVIII inhibitor in subject files (<0.6BU Nijmegen assay) No history of positive inhibitor is allowed
8.Normal liver and kidney function.
9.Platelet count ≥ 100,000 μL
10.Normal prothrombin time or International Normalized Ratio (INR) < 1.5
11.Subjects receiving therapy for human immunodeficiency virus (HIV) or hepatitis must be on a stable treatment regimen
12.Subjects must be able to withhold FVIII infusions for approximately 72 h prior to each FVIII activity and inhibitor assay
13.Absolute CD4 lymphocyte cell count ≥ 200 μL
14.Signed the written informed consent form or informed consent was obtained from the subject’s legal guardian
15.Females must not be lactating or pregnant at Screening or Baseline
16.All females will be considered to be of childbearing potential unless they are postmenopausal or have been sterilized surgically
17.Willing and able to comply with all aspects of the protocol |
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E.4 | Principal exclusion criteria |
1.Presence at Screening of FVIII inhibitor ≥ 0.6 BU as tested with the Nijmegen modification of the Bethesda assay in either central or local laboratory
2.History of FVIII inhibitor of ≥ 0.6 BU as measured using the Nijmegen modification of the Bethesda assay
3.History of FVIII inhibitor ≥ 1.0 BU if the subject has been tested routinely using the original Bethesda assay, or history of periods with low recovery and no response to Factor VIII treatment
4.Demonstrated an inability to respond to conventional doses of FVIII therapy
5.History of incremental recovery of Factor VIII <1.35% per IU/kg infused
6.Hematological disorders or blood coagulation diseases (e.g., idiopathic thrombocytopenic purpura, von Willebrand disease, etc.) other than hemophilia A
7.Laboratory or clinical evidence of portal vein hypertension including,(but not limited to, an INR > 1.4, the presence of splenomegaly and/or spider angiomata on physical examination and/or a history of esophageal hemorrhage or documented esophageal varices
8.Uncontrolled hypertension (diastolic blood pressure >100 mm Hg)
9.Hemoglobin < 10 g.dL
10.HIV disease symptoms regardless of presence of HIV antibodies
11.Routine administration (or planned routine administration during the course of the study), of immunosuppressive or immunomodulating drugs other than anti-retroviral therapy (e.g., steroids, beta-interferon)
12.Severe renal dysfunction (creatinine > 2x upper limit of normal [ULN], total bilirubin > 2x the ULN)
13.Liver disease (alanine aminotransferase [ALT], aspartate aminotransferase [ AST] > 3x the ULN)
14.History of diabetes or other metabolic disease
15.History of hypersensitivity or serious adverse reaction to recombinant or plasma-derived FVIII concentrate
16.History of pretreatment prior to the administration of FVIII products (e.g., of antihistamines)
17.Regular use of antifibrinolytics or medications affecting platelet function
18.Hypersensitivity to hamster-or mouse derived proteins
19.Blood transfusions within 30 days of enrollment into the study
20.Current participation in another investigational drug or device study, or participated in a clinical study involving an investigational drug or device within 30 days of enrollment into the study
21.Unable or unwilling to cooperate with study procedures
22.Females who are pregnant (positive β-hCG test) or breastfeeding |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and efficacy; The primary safety objective is to demonstrate a sufficiently low incidence of inhibitor associated with the use GreenGene™ F.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety and efficacy; Following a minimum 50 exposure days for both prophylaxis and on demand patients |
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E.5.2 | Secondary end point(s) |
Safety and efficacy;
• Frequency of breakthrough bleeds (total, trauma and joint);
• Subject evaluation of efficacy;
• Number of infusions per bleeding episodes;
• Units of FVIII per infusion per bleeding episode;
• Units of FVIII per bleeding; and
• Units of FVIII per prophylaxis treatment.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety and efficacy; Following a minimum 50 exposure days for both prophylaxis and on demand patients. |
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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 | 3 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Canada |
Croatia |
Hungary |
Moldova, Republic of |
New Zealand |
Poland |
Romania |
Russian Federation |
Ukraine |
United Kingdom |
United States |
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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
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
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 |