Octapharma’s FVIII concentrates in previously untreated and minimally treated haemophilia A patients
| ISRCTN | ISRCTN11492145 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11492145 |
| ClinicalTrials.gov number | NCT03695978 |
| Secondary identifying numbers | GENA-25 |
- Submission date
- 16/04/2019
- Registration date
- 29/05/2019
- Last edited
- 06/06/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Haematological Disorders
Plain English Summary
Background and study aims
Haemophilia A results from an abnormality in the blood that affects its ability to clot. Blood clotting is the process that controls bleeding. It changes blood from a liquid to a solid form. This is a complex process involving many different blood chemicals or proteins, known as clotting factors. When certain clotting factors are missing or don't work properly, clotting of blood doesn't occur as it should.
In people with severe haemophilia A, an important clotting factor called factor VIII (FVIII) is missing or doesn't work the way it should. This causes people with haemophilia A to bleed for a longer time than people whose blood FVIII levels are normal. The preferred treatment for haemophilia A is a FVIII replacement therapy. Octapharma’s FVIII concentrates have been tested in clinical trials and registered for treatment of haemophilia A; however, as haemophilia A is a rare disease, only small numbers of patients have been treated. For previously untreated patients (PUPs), who are typically young children, and for minimally treated patients (MTPs), who have been exposed to only minimal FVIII dosages, more information is needed on treatment effectiveness and safety, specifically related to inhibitor development. Also, for PUPs, treatment algorithms are not standardized, e.g. with respect to utilisation, dosage, frequency or optimal start age of FVIII. The aim of this study is thus to evaluate product utilisation, effectiveness and safety, including inhibitor development, in severe haemophilia A PUPs and MTPs, who have been prescribed Octapharma’s FVIII concentrates.
Who can participate?
Patients with severe haemophilia A who have been prescribed Octapharma’s FVIII concentrate and who have never received a FVIII product before or have received a FVIII product for fewer than 5 days
What does the study involve?
This is an observational study, where treatment of severe haemophilia A patients is documented. For the FVIII concentrates evaluated, effectiveness is measured as the number of breakthrough bleeds during prophylactic treatment, and further FVIII utilization pattern (on-demand, surgery). Safety is assessed as the occurrence of hypersensitivity reactions and FVIII inhibitor development after treatment with any of Octapharma’s FVIII concentrates. In addition to the documentation of the individual treatment, there are sub-studies related to blood samples (taken during routine visits). The sub-study samples are analysed in central laboratories. The sub-studies provide additional information on the background of inhibitor development as well as on inhibitor eradication.
Each patient is observed for 100 exposure days to the chosen FVIII product. Frequency of treatment may vary from every other day to every two weeks. In patients developing a FVIII inhibitor, and where an immune tolerance induction is initiated, the maximum observational time is 3 years.
What are the possible benefits and risks of participating?
Participation in this study will help to obtain additional information on the effectiveness and safety of the prescribed FVIII product, and the dosage regimens used, and may contribute towards the development of effective treatment strategies for future haemophilia A patients. Because this is a non-interventional study assessing a routine treatment, no additional risks are expected from being in the study. The FVIII product has been licensed. The study doctor will inform participants about possible risks, side effects and discomfort as part of the routine treatment information.
Where is the study run from?
Prof. Johannes Oldenburg, University Hospital Bonn (Germany)
When is the study starting and how long is it expected to run for?
January 2017 to June 2030
Who is funding the study?
Octapharma AG (Switzerland)
Who is the main contact?
Mrs Martina Jansen
martina.jansen@octapharma.com
Contact information
Public
Oberlaaerstrasse 235
Vienna
1100
Austria
| Phone | +43 664 9227867 |
|---|---|
| martina.jansen@octapharma.com |
Study information
| Study design | Post-marketing prospective and retrospective non-interventional study (NIS) |
|---|---|
| Primary study design | Observational |
| Secondary study design | Epidemiological study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN11492145_PIS_23Jan19_v1.3.0.pdf |
| Scientific title | Practical utilization of Octapharma FVIII concentrates in previously untreated and minimally treated haemophilia A patients entering routine clinical treatment (with Nuwiq, Octanate or Wilate) |
| Study acronym | Protect-NOW |
| Study hypothesis | The purpose of this study is to evaluate FVIII utilisation, effectiveness and safety in previously untreated (PUPs) and minimally treated (MTPs) severe haemophilia A patients prescribed with Octapharma’s FVIII products in a real-world setting, to understand real life treatment patterns and facilitate life-cycle benefit-risk profiling. |
| Ethics approval(s) | Approved 18/09/2017, Rheinische Friedrich-Wilhelms-University Ethics Committee (Biomedical Center, Sigmund-Freud-Str. 25, 53127 Bonn, Germany; Tel: +49 (0)228 287 51 282; Email: ethik@uni-bonn.de), ref: 207/17 |
| Condition | Haemophilia A |
| Intervention | This is an observational study, where treatment of severe haemophilia A patients is documented. For the FVIII concentrates evaluated, effectiveness will be measured as the number of breakthrough bleeds during prophylactic treatment, and further FVIII utilization pattern (on-demand, surgery). Safety will be assessed as the occurrence of hypersensitivity reactions and FVIII inhibitor development post-treatment with any of Octapharma’s FVIII concentrates. In addition to the documentation of the individual treatment, patients' parents are offered to join sub-studies, which are related to blood samples (taken during routine visits). The sub-study samples are analysed in central laboratories. The sub-studies will evaluate parameters to provide additional information on the background of inhibitor development as well as on inhibitor eradication. Each patient will be observed for 100 exposure days to the chosen FVIII product. Frequency of treatment may vary from every other day to every two weeks. In patients developing a FVIII inhibitor, and an immune tolerance induction is initiated, the maximum observational time will be 3 years. |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Nuwiq, octanate, wilate |
| Primary outcome measure | Products’ effectiveness in the treatment of bleeding episodes (BEs) and as prophylactic treatment: 1. Prophylactic treatment effectiveness is measured using the annualized rate of all bleeding episodes (BEs) (Annualized Bleeding Rate, ABR), including and differentiated into all spontaneous, all traumatic and all joint BEs. Patients’ parents have a diary, where all BEs need to be documented. These BEs are reviewed by the treating physician (together with the parents), and transcribed into the eCRF. The observational period is 100 exposure days (EDs) for patients treated prophylactically or on demand. For patients undergoing immune tolerance therapy after inhibitor to FVIII development may be up to 3 years. 2. The effectiveness of treatment at the end of a BE will be assessed by the patient’s parent or legal guardian as applicable, or by the treating physician in case of treatment at the treatment centre, using a scale including the four items ‘excellent,’ ‘good,’ moderate,’ and ‘none': Excellent: Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single infusion Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 – 12 hours after an infusion requiring up to 2 infusions for complete resolution Moderate: Probable or slight beneficial effect within approximately 12 hours after the first infusion requiring more than two infusions for complete resolution None: No improvement within 12 hours, or worsening of symptoms, requiring more than 2 infusions for complete resolution The observational period is 100 exposure days (EDs) for patients treated prophylactically or on demand. The observational period for patients undergoing immune tolerance therapy after inhibitor to FVIII development may be up to 3 years. |
| Secondary outcome measures | 1. Products’ utilization patterns, including dosage and frequency of application. To assess usage of Octapharma’s FVIII concentrates in the treatment of PUPs and MTPs with severe haemophilia A in real life, individual patient information on concentrate selection, dosage, duration and treatment frequency, as well as changes over time of Octapharma’s FVIII concentrates will be collected and analysed. Patients’ observational period will vary – depending from the treatment intensity: patients will stay for 100 EDs, or for a max. of 3 years, if they developed an inhibitor to FVIII and initiated immune tolerance induction therapy. 2. Products’ effectiveness in surgical prophylaxis. The overall assessment of the effectiveness of any surgical prophylaxis treatment during the patient’s participation in the project, done by the treating physicians will be assessed using a scale including the four items ‘excellent,’ ‘good,’ moderate,’ and ‘none’: Excellent: No post-operative bleeding or oozing that was not due to complications of surgery. All post-operative bleeding (due to complications of surgery) was controlled with Octapharma’s FVIII concentrate, as anticipated for the type of procedure. Good: No post-operative bleeding or oozing that was not due to complications of surgery. Control of post-operative bleeding due to complications of surgery required increased dosing with Octapharma’s FVIII concentrates or additional infusions, not originally anticipated for the type of procedure. Moderate: Some post-operative bleeding and oozing that was not due to complications of surgery; control of post-operative bleeding required increased dosing with Octapharma’s FVIII concentrates or additional infusions, not originally anticipated for the type of procedure. None: Extensive uncontrolled post-operative bleeding and oozing. Control of post-operative bleeding required use of an alternate FVIII concentrate. The optional sub-studies will aim at assessing factors potentially associated with inhibitor development and inhibitor eradication in patients with severe haemophilia A and will include: 1. Anti-FVIII non-neutralising antibodies measured using modified Bethesda test, please see epitope mapping below for the timepoints 2. F8 gene analysis, measured using standard gene mutation analysis of blood sample taken once during the entire study 3. Epitope mapping performed using a microsphere-based bead assay on a Luminex machine at the following timepoints: 3.1. A baseline sample should be taken prior to first treatment with any FVIII concentrate (background) 3.2. Optional sample after 10 ED, likely without inhibitor 3.3. Optional for patients not developing inhibitors: a sample after the first 50-100 ED (also used for non-neutralising antibody detection) 3.4. Optional for patients developing inhibitors: a sample after inhibitor development (preferably within the 1-10 ED after inhibitor development) 3.5. ITI samples every 3 months during the course of ITI 3.6. For non-neutralising antibody detection, if after successful inhibitor eradiation inhibitor titer is <0.6 BU/ml 4. Product-specific batch selection for Wilate and Octanate (only applicable for patients with inhibitor who undergo immune tolerance induction). If treating physician and patients’ parents agree to start ITI with a selected batch of the plasma-derived product, the Oxford method is used. Timepoints are not defined: the test is done when a specific batch is needed after inhibitor development. During the ITI, a new batch might be required, when the earlier batch was completely used. The same Oxford method applies. |
| Overall study start date | 01/01/2017 |
| Overall study end date | 30/06/2030 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | All |
| Sex | Both |
| Target number of participants | 200 |
| Participant inclusion criteria | 1. Male and female patients of any age and ethnicity 2. Severe haemophilia A (FVIII:C<1%) 3. Decision to prescribe Octapharma’s FVIII concentrate before enrolment into the study 4. Either no previous treatment with FVIII concentrates or other blood products containing FVIII (PUPs) OR less than 5 Exposure Days (EDs) to FVIII concentrates or other blood products containing FVIII (MTPs) 5. Voluntarily given, fully informed written and signed consent obtained before any study-related data documentation is conducted (obtained from the patient’s parent/legal guardian) |
| Participant exclusion criteria | 1. Diagnosis with a coagulation disorder other than haemophilia A 2. Concomitant treatment with any systemic immunosuppressive drug 3. Participation in an interventional clinical trial during the time period evaluated 4. Participation in another non-interventional study of Octapharma |
| Recruitment start date | 11/02/2018 |
| Recruitment end date | 30/06/2030 |
Locations
Countries of recruitment
- Belarus
- Belgium
- Canada
- Croatia
- France
- Germany
- Hungary
- Italy
- Lithuania
- Mexico
- Spain
- United Kingdom
- United States of America
Study participating centre
Bonn
53127
Germany
Sponsor information
Industry
Seidenstrasse 2
Lachen
8853
Switzerland
| Phone | +41 (0)554512166 |
|---|---|
| larisa.belyanskaya@octapharma.com | |
"ROR" |
https://ror.org/002k5fe57 |
Funders
Funder type
Industry
No information available
Results and Publications
| Intention to publish date | 30/12/2030 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Not available yet |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are not expected to be made available except to the authorities, if requested. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version v1.3.0 | 23/01/2019 | 14/06/2019 | No | Yes |
| Participant information sheet | version 2.0 | 21/09/2020 | 17/08/2021 | No | Yes |
| Results article | 10/05/2023 | 15/05/2023 | Yes | No |
Additional files
- ISRCTN11492145_PIS_23Jan19_v1.3.0.pdf
- Uploaded 14/06/2019
- ISRCTN11492145_PIS_v2.0_ 21Sept2020.pdf
Editorial Notes
06/06/2024: The following changes were made:
1. The overall study end date was changed from 31/12/2025 to 30/06/2030.
2. The target number of participants was changed from 140 to 200.
3. The recruitment end date was changed from 30/06/2025 to 30/06/2030.
4. Croatia was added as a country of recruitment.
5. The intention to publish date was changed from 30/06/2022 to 30/12/2030.
6. The study contact was updated.
15/05/2023: Publication reference added.
13/06/2022: Trial participating centre address updated, IPD sharing statement added. Estonia and Russia were removed from the countries of recruitment.
08/06/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/01/2023 to 30/06/2025.
2. The overall trial end date was changed from 30/06/2023 to 31/12/2025.
3. Nuwiq, octanate, wilate were added to the drug names.
17/08/2021: The following changes have been made:
1. The recruitment end date has been changed from 31/12/2021 to 31/01/2023.
2. The overall trial end date has been changed from 30/06/2022 to 30/06/2023 and the plain English summary has been updated to reflect this change.
3. The countries of recruitment "Hungary" and "Mexico" have been added.
4. The participant information sheet has been uploaded as an additional file.
14/06/2019: Participant information sheet uploaded.
18/04/2019: Trial's existence confirmed by Rheinische Friedrich-Wilhelms-University Ethics Committee.
