E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital haemophilia A or B patients with inhitors to Factor VIII or Factor IX |
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E.1.1.1 | Medical condition in easily understood language |
Hereditary haemophilia which is caused by a shortage of Factor VIII (Haemophilia A) or Factor IX (Haemophilia B), which is complicated by inhibitors to factor treatment, making these ineffective. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018938 |
E.1.2 | Term | Haemophilia A (Factor VIII) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018939 |
E.1.2 | Term | Haemophilia B (Factor IX) |
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 assess the efficacy of 2 separate dose regimens (75 µg/kg and 225 µg/kg) of LR769 for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to factor VIII or IX.
To assess the safety of LR769. This includes the immunogenic potential of the drug product. |
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E.2.2 | Secondary objectives of the trial |
To assess the pharmacokinetics of LR769 (from both the original and scaled-up processes) in hemophilia A or B patients with inhibitors to factor VIII or IX, without a current bleeding episode. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. be male with a diagnosis of congenital hemophilia A or B of any severity
2. have one of the following:
a. a positive inhibitor test BU ≥ 5 (as confirmed at screening by the institutional lab), OR
b. a BU <5 but expected to have a high anamnestic response to FVIII or FIX, as demonstrated from the subject's medical history, precluding the use of the factor VIII or IX products to treat bleedings, OR
c. a BU <5 but expected to be refractory to increased dosing of FVIII or FIX, as demonstrated from the subject's medical history, precluding the use of the factor VIII or IX products to treat bleedings
3. be 12 years or older, up to and including 75 years of age
4. have at least 3 bleeding episodes of any severity in the past 6 months
5. be capable of understanding and willing to comply with the conditions of the protocol
6. have read, understood and provided written informed consent (patient and/or parent(s)/legal guardian(s) if <18 years age) |
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E.4 | Principal exclusion criteria |
1. have any coagulation disorder other than hemophilia A or B
2. be immuno-suppressed (i.e., the patient should not be receiving systemic immunosuppressive medication, CD4 counts at screening should be >200/µl)
3. have known allergy or hypersensitivity to rabbits
4. have platelet count <100,000/ml
5. have had within one month prior to first administration of the study drug in this study a major surgical procedure (e.g. orthopedic, abdominal)
6. have received an investigational drug within 30 days of the first study drug administration, or is expected to receive such drug during participation in this study
7. have a clinically relevant hepatic (AST and/or ALT >3 times the upper limit of normal) and/or renal impairment (creatinine >2times the upper limit of normal)
8. have a history of arterial and/or venous thromboembolic events (such as myocardial infarction, ischemic strokes, transient ischemic attacks, deep venous thrombosis or pulmonary embolism) within 2 years prior to first dose of study drug, or current New York Heart Association (NYHA) functional classification score of stage II-IV
9. have an active malignancy (those with non-melanoma skin cancer are allowed)
10. have any life-threatening disease or other disease or condition which, according to the investigator's judgment, could imply a potential hazard to the patient, interfere with the trial participation or trial outcome (e.g., a history of non-responsiveness to bypassing products) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the successful treatment of a bleeding episode. For the primary efficacy endpoint only treatment of mild/moderate bleedings are taken into account. Successful treatment of a bleeding episode is defined as a combination of the following.
- Good or Excellent response noted by patient
- Study drug treatment: Mild/moderate bleeding episodes: No further treatment with study drug beyond time point for this bleeding episode
Severe bleeding episodes: increase of dosing interval or no further treatment with study drug
- No other haemostatic treatment needed for this bleeding episode
- No administration of blood products indicating continuation of bleeding beyond time point
- No increase of pain beyond time point that cannot otherwise be explained
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The time point for the primary evaluation of efficacy will be 12 hours after first administration of study drug |
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E.5.2 | Secondary end point(s) |
- Proportion of mild/moderate bleedings with a "good" or "excellent" patient reported assessment of the response at 12 hours
- Time to assessment of a "good" or "excellent" response of the mild/moderate bleedings by the patient.
- Patient level mean number of administrations and patient level mean total amount of drug administered per mild/moderate bleeding episode. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 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 | Yes |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Same IMP at different dosing regimen |
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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 | 9 |
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 |
Belarus |
Bulgaria |
France |
Georgia |
Israel |
Romania |
Russian Federation |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |