| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hemophilia A is a rare but serious bleeding disorder which affects males and is characterized by a deficiency in the plasma protein known as coagulation Factor VIII. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
| 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 | 10060612 |
| E.1.2 | Term | Hemophilia A |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To characterize the pharmacokinetic (PK) profile of CSL627
To demonstrate efficacy in the prevention and treatment of bleeding events
To demonstrate the efficacy of routine prophylaxis treatment over on-demand treatment
To demonstrate the efficacy of CSL627 in surgical prophylaxis.
To characterize the rate of inhibitor formation.
|
|
| E.2.2 | Secondary objectives of the trial |
To characterize the safety profile of CSL627.
To establish the PK comparison of CSL627 to octocog alfa. |
|
| 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 |
An evaluation of the safety and efficacy of CSL627 in the prevention and treatment of bleeding during surgical procedures.
Main objective of substudy: to demonstrate the efficacy of CSL627 in surgical procedures.
|
|
| E.3 | Principal inclusion criteria |
- Diagnosis of severe hemophilia A defined as <1% FVIII:C documented in medical records.
- Males between ≥ 12 and 65 years of age (Part 3).
- Subjects who have received or are currently receiving FVIII products (plasma-derived and/or recombinant FVIII) and have had
>150 EDs with a FVIII product
- Written informed consent for study participation obtained before undergoing any study specific procedures. |
|
| E.4 | Principal exclusion criteria |
- Any history of or current FVIII inhibitors
- Any first order family history of FVIII inhibitors
- Use of an Investigational Medicinal Product within 30 days prior to the first CSL627 administration
- Not capable of receiving treatment at home
- Administration of any cryoprecipitate, whole blood or plasma within 30 days prior to administration of CSL627 or reference product.
- Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein.
- Any known congenital or acquired coagulation disorder other than congenital FVIII deficiency.
- Platelet count < 100,000/μL at screening.
- HIV positive subjects with a CD4 count < 200/mm3, in their medical history or at screening if available results are older than one year. (HIV positive subjects may participate in the study and antiviral therapy are permitted, at the discretion of the Investigator).
- Subject currently receiving IV immunomodulating agents such as chronic systemic corticosteroid treatment.
- Subject with serum aspartate aminotransferase or serum alanine aminotransferase values > 5 times (x) the upper limit of normal (ULN) at Screening.
- Subjects with serum creatinine values > 2 x ULN at Screening.
- Evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months prior to Day 1.
- Experienced life-threatening bleeding episode or had major surgery or an orthopedic surgical procedure during the 3 months prior to Day 1.
- Demonstrated inability (e.g., language problem or mental condition) or unwillingness to comply with study procedures or history of noncompliance.
- Employee at the study site, or spouse/partner or relative of the investigator.
- Re-entry of subjects previously enrolled or participating in the current study.
- Suspected inability (eg, language problems) or unwillingness to comply with study procedures.
- Mental condition rendering the subject (or subject's legally acceptable representative[s])unable to understand the nature, scope and possible consequences of the study.
- Any condition that is likely to interfere with evaluation of the IMP or satisfactory conduct of the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The rate of treatment success for bleeding episodes defined as a rating of “excellent” or “good” on the investigator’s overall clinical assessment of hemostatic efficacy four-point scale.
Annualized spontaneous bleeding rate (AsBR).
The rate of inhibitor formation to FVIII evaluated from the time of first dose through the End of Study visit.
For surgical sub-study the primary efficacy endpoint:
-the rate of treatment success during the peri-operative surgical sub-study defined as an investigator rating of “excellent” or “good” on the four-point efficacy evaluation of surgical treatment scale. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The study design includes a 28 day screening period. Subjects participating in Part 3 will be dosed for at least 50 EDs. Subjects enrolled in Part 3 may continue treatment with CSL627 until an extension study is available, if necessary which may extend treatment up to 24 months. |
|
| E.5.2 | Secondary end point(s) |
PK parameters for the repeat assessment of CSL627 collected during Part 3 of the study including incremental recovery, AUC0–t, AUC0–∞, percent of area extrapolated, Cmax, Tmax, elimination constant, half-life (t1/2), AUMC0–∞, mean residence time (MRT), clearance (CL), and volume of distribution at steady-state (Vss).
Annualized bleeding rate (ABR) for total bleeds, traumatic bleeds, and joint bleeds.
The proportion of bleeding episodes requiring 1, 2, 3 or > 3 infusions of CSL627 to achieve hemostasis.
The safety assessment of CSL627 including AEs, SAEs, laboratory safety parameters (serum chemistry and hematology), antibodies to CSL627, pre- and post-infusion vital signs, and physical examination.
Safety data include: vital signs measurement (sitting blood pressure, heart rate and temperature), standard safety laboratory data (hematology and chemistry [including liver function tests]), and physical examination.
Inhibitors to FVIII and antibodies to CSL627 will be assessed prior to the first exposure to CSL627, 14 days after the first dose of CSL627, and every 4 weeks thereafter.
A four day wash out period should occur before inhibitor and antibody assessments.
Following the month six evaluation subjects wil return to the clinic for visits every 3 months.
The overal assessment of efficacy will include all spontaneous bleeding events (regardless of the treatment regimen), and will include the dose administered, the number of infusions required to achieve hemostasis for a bleeding event and the subject and investigator's assessment if efficacy. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood draws for the PK analysis -Part 3 will be at pre-dose (immediately prior to the initial dose), then at intervals after infusion over 96 hours (10-15 min., 0.5, 1, 3, 6, 9, 24, 28, 32, 48, 72 and 96 hours).
|
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Canada |
| European Union |
| Japan |
| Korea, Republic of |
| Lebanon |
| Malaysia |
| Philippines |
| Russian Federation |
| South Africa |
| Switzerland |
| Ukraine |
| United States |
|
| 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
|
| The end of the trial is defined as the last-patient-last-visit. |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
