Study to investigate the effectiveness of emicizumab under real-world conditions in paediatric, adolescent, adult and elderly participants with haemophilia A with and without Factor VIII (FVIII) inhibitors
| ISRCTN | ISRCTN58752772 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN58752772 |
| Secondary identifying numbers | ML40914 |
- Submission date
- 14/01/2022
- Registration date
- 09/02/2022
- Last edited
- 04/12/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Haematological Disorders
Plain English Summary
Background and study aims
Haemophilia A is an inherited disorder in which the blood does not clot due to a deficiency of clotting factor VIII (FVIII; a protein that help the blood to clot). Common signs of hemophilia A include easy bruising, prolonged bleeding after trauma or surgery, spontaneous bleeding into joints, muscles or soft tissues, and intracranial haemorrhage (bleeding inside the skull). The severity of haemophilia A is directly related to the FVIII activity. There is no cure for haemophilia A and those with the disorder require life-long treatment.
Treatment involves replacing the missing clotting factor. Factor VIII can be obtained from blood donations but is now usually created artificially in a lab. This is called recombinant factor VIII. Replacement therapy may be administered as regular continuous treatment or as episodic (on-demand) treatment given at the time of bleeding. People with severe haemophilia A usually receive prophylactic treatment to help prevent bleeding episodes and complications. One of the most severe treatment-related complications that occurs in some people is the development of certain proteins that neutralise FVIII called FVIII inhibitors. As FVIII can no longer be used to control bleeding, people with inhibitors are treated with bypassing agents (BPAs, treatments that “bypass” the need for clotting factor treatment) such as recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). This type of treatment is short-acting and needs to be administered frequently.
Emicizumab (Hemlibra® ) is a drug that was approved by health authorities for the routine prophylaxis of bleeding episodes in adults, adolescents, and children with Haemophilia A with factor VIII inhibitors and for severe Haemophilia A without factor VIII inhibitors. The aims of this study are to:
1. To find out the long-term effectiveness of emicizumab prophylaxis in actual conditions in participants with congenital (present from birth) Haemophilia A. Two groups of participants will be observed: participants with severe Haemophilia A without FVIII inhibitors and participants with Haemophilia A (any severity) with FVIII inhibitors
2. To determine the percentage of participants with zero treated bleeds
3. To determine the annualised bleeding rate and the percentage of participants with zero bleeds as compared to those with treated spontaneous bleeds, treated joint bleeds and treated target joint (one particular joint has recurrent bleeding) bleeds
4. To assess the type, dosing, and frequency of haemostatic medication (medicines to stop bleeding) besides emicizumab used to treat bleeding events or for other purposes
5. To assess the participants’ perceived physical and mental health over time using the health-related quality of life questionnaires which are specific to different age groups such as children, adolescents, adults, and elderly
6. To determine the preferred dosing regimen for emicizumab prophylaxis such as once a week, every 2 weeks, every 4 weeks etc
7. To determine the blood levels of emicizumab in actual conditions
8. To assess the health of joints using a scale known as the Hemophilia Joint Health Score
9. To assess descriptively the number and reasons for invasive surgical procedures
10. To assess the usage of pain medications
11. To assess the disability caused by haemophilia A in performing the functions of any occupation
12. To evaluate the participants’ use of health resources related to Haemophilia A by assessing the number of contacts to site (visits and telephone calls), unscheduled visits at site, number of emergency room (ER) visits, number of hospitalisations related to Haemophilia A, including length of stay, and number of physiotherapies received
13. To find out the frequency of newly occurring FVIII inhibitors in participants undergoing Emicizumab prophylaxis and additionally treated with FVIII
14. To find out the level of FVIII inhibitors over time
15. To find out the percentage of participants receiving immune tolerance induction (ITI, a process that helps to achieve permanent elimination of the inhibitors) and the frequency of FVIII injections for ITI
16. To assess the occurrences of side effects in participants of all age groups.
17. To determine the occurrence and significance of neutralizing anti-drug antibodies (ADAs, proteins that prevent the drug activity) under actual conditions in all participants
Who can participate?
Participants of any age with congenital haemophilia A with FVIII inhibitors or severe haemophilia A without FVIII inhibitors.
What does the study involve?
This study is being conducted in Germany and Switzerland at about 25 specialised haemophilia centres. The duration of the study is 5 years. Participants will be observed for a minimum of 1 year to a maximum of 5 years.
During the study, the participants’ regular visits are recorded by the study doctor in a standardised form either on paper or electronically. In addition, participants will be asked to fill out two questionnaires about their quality of life at the beginning of the data collection and every 6 months. The contents of the questionnaire do not go beyond the information requested in the context of normal medical practice. The questionnaires will be handed out to participants by the doctor during a routine visit with a request for an answer. Filling out a questionnaire may take about 5-10 minutes. The joint health of the participants will be documented once a year at the beginning of the data collection and during the study period.
The type and duration of treatment that the participants are receiving will not get influenced by study participation.
Participants may also be asked to keep a bleeding diary to record important information about each bleeding episode. The following data will be collected from the bleeding diary:
1. Place of bleeding
2. Type of bleeding
3. Reason for bleeding
4. Time of each individual bleeding (day of onset of bleeding)
5. Symptoms of bleeding
6. Treatment of bleeding (medicines, onset and end, dose) and other treatments directly related to bleeding (e.g., additional painkillers, if consumed, due to bleeding)
7. Number of bleedings treated in the last 6 months before the first hemlibra® administration
The following information will be collected from participants’ medical records during the course of the study:
1. Body weight if there are changes
2. Data about haemophilia and the medicines given to prevent or treat bleeding
3. Data on treated bleeding from bleeding diary
4. Details of treatment with Hemlibra® (dosage, frequency) and changes, if any
5. Data on other conditions and/or other medicines participants may be taking
6. Details of the use of medical services due to haemophilia (frequency of contacts with the haemophilia centre, frequency of hospitalisations/stays in the intensive care unit and frequency of prescriptions for physiotherapy)
7. Possible occupational disability due to haemophilia, if any
8. Results of the questions on quality of life
9. Data of joint health, once a year
10. Results of blood tests
11. Data on side effects, illnesses, accidents, injuries, and other events affecting the health of participants during and after emicizumab treatment
In order to fully record possible side effects, a doctor will document events that occur from the first dose of emicizumab to the end of the observation period of this study. Participants who discontinue emicizumab will be monitored for adverse events for a period of 6 months.
What are the possible benefits and risks of participating?
Participants will not receive any benefit from participating in this study, but the information that is learned from this study may help researchers and doctors to learn more about haemophilia A in general and other people who have a similar medical condition may benefit from the results of such research in the future. There are no risks from participating in the study as it is observational.
Where is the study run from?
Roche (Germany)
When is the study starting and how long is it expected to run for?
February 2019 to January 2025
Who is funding the study?
Roche (Germany)
Who is the main contact?
global.trial_information@roche.com
Contact information
Public
Emil-Barell-Str. 1
Grenzach-Wyhlen
79639
Germany
| Phone | +41 616878333 |
|---|---|
| global.trial_information@roche.com |
Study information
| Study design | Single-arm two-cohort prospective multicentre non-interventional study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Cohort study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | No participant information sheet available |
| Scientific title | Non-interventional study to investigate the effectiveness of emicizumab under real-world conditions in pediatric, adolescent, adult and elderly patients with hemophilia A with and without FVIII inhibitors |
| Study acronym | EMIIL |
| Study hypothesis | The purpose of this study is to evaluate the long-term effectiveness of emicizumab prophylaxis in pediatric, adolescent, adult, and elderly patients with hemophilia A with and without FVIII inhibitors under real-world conditions. |
| Ethics approval(s) | Approved 10/05/2019, Ethics Committee of Rhenish Friedrich Wilhelm University of Bonn (Sigmund-Freud-Str. 25, 53127 Bonn, Germany; +49 228 287 51931; ethik@uni-bonn.de), ref: 151/19 |
| Condition | Haemophilia A |
| Intervention | Cohort A: The participants with congenital severe haemophilia A without Factor VIII (FVIII) inhibitors who are undergoing emicizumab treatment as described in the Hemlibra® (Emicizumab) summary of product characteristics (SPC), will be observed and asked to complete questionnaires every 6 months at the study centre until the end of study if emicizumab treatment is not discontinued (maximum up to 5 years). Cohort B: The participants with congenital haemophilia A (any severity) with FVIII inhibitors who are undergoing emicizumab treatment as described in the Hemlibra® (Emicizumab) SPC, will be observed and asked to complete questionnaires every 6 months at the study centre until the end of study if emicizumab treatment is not discontinued (maximum up to 5 years). |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Emicizumab |
| Primary outcome measure | Annualized bleeding rates (ABRs) of treated bleeds estimated using nature and number of treated bleeds in the past 24 weeks prior to the emicizumab treatment, derived from participant’s files and treatment diaries from baseline until the end of the study (up to 5 years) |
| Secondary outcome measures | 1. Percentage of participants with zero treated bleeds estimated using nature and number of treated bleeds in the past 24 weeks prior to the emicizumab treatment, derived from participant’s files and treatment diaries from baseline until the end of the study (up to 5 years) 2. ABRs of treated spontaneous bleeds, treated joint bleeds, treated target joint bleeds estimated using nature and number of treated bleeds in the past 24 weeks prior to the emicizumab treatment, derived from participant’s files and treatment diaries from baseline until the end of the study (up to 5 years) 3. Percentage of participants with zero treated spontaneous bleeds, treated joint bleeds, treated target joint bleeds estimated using nature and number of treated bleeds in the past 24 weeks prior to the emicizumab treatment, derived from participant’s files and treatment diaries from baseline until the end of the study (up to 5 years) 4. Number of doses and frequency of haemostatic medication besides emicizumab used to treat bleeding events or for other purposes, derived from participant’s files and treatment diaries from baseline until the end of the study (up to 5 years) 5. Percentage of participants with different dosing regimens of emicizumab, derived from participant’s files and treatment diaries from screening up to the end of the study (up to 5 years) 6. Number of invasive surgical procedures, derived from participant’s files and treatment diaries from day 1 up to the end of the study (up to 5 years) 7. Percentage of participants that used pain medication, derived from participant’s files and treatment diaries from day 1 up to end of study (up to 5 years) 8. Percentage of participants with occupational disability related to haemophilia A, derived from participant’s files and treatment diaries from day 1 up to the end of the study (up to 5 years) 9. Number of events of using health resources (number of contacts to the site, unscheduled visits at the site, number of emergency room (er) visits, number of hospitalizations related to haemophilia a, number of physiotherapies received), derived from participant’s files and treatment diaries from day 1 up to end of study (up to 5 years) 10. Number of participants with newly occurring FVIII inhibitors under emicizumab prophylaxis and additionally treated with FVIII in cohort A, derived from participant’s files and treatment diaries from screening until the end of the study (up to 5 years) 11. Level of FVIII inhibitors over time, derived from participant’s files and treatment diaries from screening until the end of the study (up to 5 years) 12. Percentage of participants receiving parallel immune tolerance induction (ITI) inhibitors who develop new FVIII inhibitors, derived from participant’s files and treatment diaries from screening until the end of the study (up to 5 years) 13. Percentage of participants with serious adverse events, non-serious adverse events, and adverse events of special interest, derived from participant’s files and treatment diaries from screening up to the end of the study (up to 5 years) 14. Percentage of participants experiencing thrombotic microangiopathies and thrombotic events (TES), derived from participant’s files and treatment diaries from screening until the end of the study (up to 5 years) 15. Percentage of participants with anti-drug antibodies at baseline and after initiation of study treatment indirectly evident by functional assays and exclusion of non-adherence from screening until the end of the study (up to 5 years) |
| Overall study start date | 13/02/2019 |
| Overall study end date | 31/01/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | All |
| Sex | Male |
| Target number of participants | 168 |
| Participant inclusion criteria | 1. Participants of any age with congenital severe haemophilia A with or without FVIII inhibitors 2. Participants undergoing treatment with emicizumab according to Summary of Product Characteristics (SPC) (start of treatment with emicizumab maximum 3 months prior to study entry) 3. Must sign informed consent by the legal representative or participant or both, as required 4. Selection criteria for Cohort A include participants diagnosed with severe congenital haemophilia A (<1% FVIII activity) and no present FVIII inhibitor at the start of emicizumab treatment, patients who completed successful ITI before the start of Emicizumab treatment are eligible. 5. Selection criteria for Cohort B include participants diagnosed with congenital haemophilia A (any severity) with FVIII inhibitor activity at the start of emicizumab treatment or ongoing ITI at the start of emicizumab treatment |
| Participant exclusion criteria | 1. Participants having bleeding disorder other than congenital haemophilia A 2. Treatment with emicizumab outside of the SPC at study entry 3. Any contraindication for treatment with emicizumab according to current SPC 4. Current participation in an interventional study |
| Recruitment start date | 20/01/2020 |
| Recruitment end date | 23/01/2024 |
Locations
Countries of recruitment
- Germany
- Switzerland
Study participating centres
Hannover
30625
Germany
Hamburg
20246
Germany
Frankfurt
60323
Germany
Giessen
35390
Germany
Hannover
30159
Germany
Regensburg
93053
Germany
Moerfelden Walldorf
64546
Germany
Berlin
13353
Germany
Ringstraße 52
Homburg
66421
Germany
LEIPZIG
04289
Germany
Klinik für Innere Medizin II
Abteilung Hämatologie und Internistische Onkologie
Am Klinikum 1
Jena
07747
Germany
Leipzig
04103
Germany
Heidelberg
69123
Germany
Bonn
53127
Germany
Zürich
8032
Switzerland
Genève
1205
Switzerland
Basel
4056
Switzerland
Bellinzona
6500
Switzerland
Lausanne
1011
Switzerland
Bern
3010
Switzerland
Sponsor information
Industry
Emil-Barell-Str. 1
Grenzach-Wyhlen
79639
Germany
| Phone | +41 616878333 |
|---|---|
| global.trial_information@roche.com | |
| Website | https://www.roche.com/about_roche/roche_worldwide.htm |
"ROR" |
https://ror.org/00sh68184 |
Funders
Funder type
Industry
Government organisation / For-profit companies (industry)
- Alternative name(s)
- F. Hoffmann-La Roche Ltd, F. Hoffmann-La Roche & Co, F. Hoffmann-La Roche AG, Roche Holding AG, Roche Holding Ltd, Roche Holding, Roche Holding A.G., Roche Holding, Limited, F. Hoffmann-La Roche & Co.
- Location
- Switzerland
Results and Publications
| Intention to publish date | 15/12/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal and congresses |
| IPD sharing plan | The datasets generated and/or analysed during the current study are not expected to be made available due to participant-level data not being a regulatory requirement. |
Editorial Notes
04/12/2023: The sponsor and study contact telephone numbers and email addresses were changed.
09/02/2022: Trial's existence confirmed by the Ethics Committee of Rhenish Friedrich Wilhelm University of Bonn.
