Long-term follow up of patients in European Vasculitis Study Group clinical trials
| ISRCTN | ISRCTN52952998 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN52952998 |
| EudraCT/CTIS number | 2006-001663-33 |
- Submission date
- 16/02/2010
- Registration date
- 07/05/2010
- Last edited
- 13/03/2020
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English summary of protocol
Background and study aims
Small vessel vasculitis is an inflammation of small blood vessels. This is often associated with circulating antibodies to substances normally found in the white blood cells; ANCA (anti neutrophil cytoplasmic antibodies), hence called ANCA-associated vasculitis (AAV). Any organ in the body could be affected by this inflammation. However, most commonly the upper and lower respiratory tract (nose to lungs) and kidneys are involved. Untreated the inflammation of the blood vessel could result in organ failure for example kidney failure with need for dialysis or transplantation or respiratory insufficiency and in worst cases death. In the past, the outlook for patients has been poor, but, after the introduction of immunosuppressive therapy patient survival has improved dramatically. However, the side effects of the treatment have caused short and long term problems for patients. Therefore, a European network started in the 1990’s ‘European Vasculitis Society (EUVAS)’ with the aim to harmonize and improve the outcome from treatment of AAV. Several prospective randomized clinical trials (RCTs) have been conducted under EUVAS leadership (NORAM, CYCAZAREM, CYLOPS, MEPEX). The follow-up within these RCT was 12-18 months. As the recurrence rate of AAV is high, the side-effects of immunosuppression still was considerable and sometimes delayed a five year follow up of patients within the first four EUVAS’ trials were launched 2004. The results from the 5-year follow up revealed that the risks of death and kidney failure and other complications remain high. Therefore there is need to both follow-up a more recently recruited cohort to assess whether outcomes are improving and also to obtain longer follow up on the original cohort in order to obtain robust data, particularly regarding the cumulative incidence of cancer and cardiovascular events.
Who can participate? What does the study involve?
This is a prolonged follow-up study of patients who have participated in EUVAS randomized controlled studies. A questionnaire regarding patient- and kidney survival, incidence of cancer and cardiovascular disease is to be completed by the physician responsible for the patient in the initial RCT. Details on patient outcome will then be transferred as coded data (the patient identity is not revealed) into a data set for further statistical analyses.
What are the possible risks and benefits of participating?
Participation in this long term follow up study will not generate any direct benefits to the patients There should not be any risks as the data retrieved from the patients respectively are coded and anonymized when transferred to the data set. Ethical approvals were obtained for all the initial RCTs and have also been applied for according to national laws and rules and regarding this long term follow up. The investigation is conducted in accordance with the 1964 Declaration of Helsinki and its subsequent amendments
Where is the study run up from?
The study is run from the EUVAS’ centers which have participated in the previous EUVAS randomized clinical trials
When is study starting and how long is it expected to run for?
This long term follow up study started 2004, and is now prolonged to a 10 year or longer follow up during 2018-2019
Who is funding the study?
Skane University Hospital Malmö-Lund is the sponsor.
Who is the main contact?
Dr. Kerstin Westman, Department of Nephrology, Skane University Hospital Malmö-Lund
kerstin.westman@skane.se
Contact information
Scientific
Dept. of Nephrology
Skane University Hospital Malmö-Lund
Njurmottagningen, Inga Marie Nilssonsgata 8B, Malmö
Malmo
205 02
Sweden
| Phone | +46 40 338336 |
|---|---|
| kerstin.westman@skane.se |
Study information
| Study design | Current study design as of 05/04/2019: Observational long-term follow up of patients who participated in EUVAS’ multi-centre randomised controlled trials after 10 years or longer Previous study design: Observational long-term follow up of patients who participated in four multi-centre randomised controlled trials after median follow- up of five years |
|---|---|
| Primary study design | Observational |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details below to request a patient information sheet |
| Scientific title | Long-term follow up of patients who participated in previous Vasculitis trials |
| Study objectives | Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), Granulomtaosis with Polyangiitis (GPA, previously Wegener’s granulomatosis ;WG, updated 05/04/2019) and microscopic polyangiitis (MPA) are primary vasculitides of unknown cause characterised by necrotising inflammation involving predominantly small blood vessels and the presence of circulating anti-neutrophil cytoplasm antibodies (ANCA) in the majority of patients at diagnosis. They are often grouped as ANCA-AAV because of striking similarities in histology, absence of immune deposits, response to therapy and the likely contribution of ANCA to the pathogenesis. The primary aim of this study is to determine the long-term survival of patients with ANCA-AAV, who participated in randomised controlled trials conducted by the European Vasculitis Study Group (EUVAS) compared to the general population with a median follow-up greater than five years. Secondary aims are to investigate the survival with independent renal function and renal function at five years follow up in addition to the frequency of other severe organ failure such as blindness and oxygen dependency. The survival without disease relapse and the severity and organ involvement of disease relapses will be studied. Important adverse events such as the frequency and nature of malignant disease, cardiovascular disease, serious infections and skeletal fractures will be investigated. The causes of death will be noted. Prognostic factors at entry and at 1 year on long-term survival and renal outcome will be identified including the predictive value of renal histology at presentation. The performance of currently used disease assessment tools like the Birmingham Vasculitis Activity Score (BVAS) for disease activity, the Vasculitis Damage Index (VDI) for damage and the Short-form 36 (SF-36) for quality of life will be assessed. This study will help define the natural history of AAV, will serve as a reference base for new clinical trials and identify the major long-term goals and challenges for the management of AAV. Publications from original trials: 1. de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009 May 19;150(10):670-80. 2. De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005 Aug;52(8):2461-9. 3. Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44. 4. Jayne DR, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J AmSocNephrol. 2007 2007/07//;18(7):2180-8. (added 02/07/2019): 5. Jones RB, Cohen Tervaert JW, Hauser T et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363:211-220. 6. Hiemstra TF, Walsh M, Mahr A et al. Mycophenolate Mofetil vs Azathioprine for Remission Maintenance in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Controlled Trial. JAMA. 2010;304(21):2381-8 7. Jones RB, Hiemstra TF, Ballarin J al. Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial. Ann Rheum Dis. 2019;78:399-405 |
| Ethics approval(s) | 1. West Midlands Multi-centre Research Ethics Committee approved amendment 1 on 22/09/2004 (ref: MREC/98/7/37) 2. Swedish Ethical Committee Lund Dnr 2013/272 (added 02/07/2019) |
| Health condition(s) or problem(s) studied | Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), granulomatosis with polyangiitis (GPA, Wegener’s granulomatosis (WG)) or microscopic polyangiitis (MPA) |
| Intervention | Current interventions as of 05/04/2019: 1. Survival 2. Renal survival (including incidence and latency to start of renal replacement and time to transplant) 3. Immunosuppressive therapy including cumulative cyclophosphamide exposure during 10 years of follow up 4.Incidence and nature of malignancies including non-melanoma skin cancers and myelodysplasia 5. Relapse and renal relapse 6. Cardiovascular events (CVA, MI, PVD, thrombo-embolic events) 7. Diabetes mellitus 8. Infections requiring hospitalisation 9. Skeletal fractures 10. Cause of death 11. Vasculitis Damage Index at 5 years and latest time of follow up Previous interventions: A questionnaire will be send to all participating investigators and data collected on the occurrence and time to event of the following outcomes: 1. Survival 2. Renal survival (including incidence and latency to start of renal replacement and time to transplant) 3. Renal function at 5 years as assessed by 4 factor Modification of Diet in Renal Disease (MDRD) formula 4. Organ failure (such as blindness, pulmonary disease requiring long-term oxygen therapy etc) 5. Immunosuppressive therapy including cumulative cyclophosphamide exposure 6. Incidence and nature of malignancies including non-melanoma skin cancers and myelodysplasia 7. Relapse and renal relapse 8. Cardiovascular events (CVA, MI, PVD, thrombo-embolic events) 9. Diabetes mellitus 10. Infections requiring hospitalisation 11. Skeletal fractures 12. Cause of death 13. Vasculitis Damage Index at 5 years |
| Intervention type | Other |
| Primary outcome measure | Long-term survival of patients with ANCA associated vasculitis compared to age, sex, year and country matched background population (Kaplan Meier analysis, comparison to background population according to Hakkulinen method) |
| Secondary outcome measures | 1. Prognostic factors at presentation-multi-variable analysis 2. Cumulative damage according to Vasculitis Damage Index at 1 and 5 years 3. Relapse rate and relapse free survival by Kaplan Meier method 4. Renal function as survival with independent renal function by Kaplan Meier method and estimated glomerular filtration rate (eGFR) at 5 year follow up. 5. Incidence and time point of severe organ failure (eg blindness, oxygen dependency) 6. Cumulative incidence of malignancies including non-melanoma skin cancer and myelodysplasia 7. Cardiovascular morbidity and mortality |
| Overall study start date | 01/09/2004 |
| Completion date | 31/12/2019 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | 875 |
| Key inclusion criteria | Current participant inclusion criteria as of 11/07/2019: 1. Patients with newly diagnosed Anti-Neutrophil Cytoplasm Antibody Vasculitis recruited into one of EUVAS’ randomized controlled trials, NORAM, CYCAZAREM, MEPEX, CYCLOPS, RITUXVAS, IMPROVE, MYCYC performed by European Vasculitis Society (EUVAS) Previous participant inclusion criteria: 1. Patients with newly diagnosed Anti-Neutrophil Cytoplasm Antibody Vasculitis recruited into one of four randomised controlled trials, NORAM, CYCAZAREM, MEPEX, CYCLOPS performed by European Vasculitis Study Group 2. The patients were recruited during the period of 1995 to 2002 |
| Key exclusion criteria | 1. Patients withdrawn from original study due to incorrect diagnosis 2. Consent withheld by patient |
| Date of first enrolment | 01/09/2004 |
| Date of final enrolment | 24/01/2020 |
Locations
Countries of recruitment
- Belgium
- Czech Republic
- Denmark
- Finland
- France
- Germany
- Ireland
- Italy
- Mexico
- Netherlands
- Spain
- Sweden
- Switzerland
- United Kingdom
Study participating centre
205 02
Sweden
Sponsor information
Hospital/treatment centre
Skane University Hospital
Malmö-Lund
SE-221 85
Sweden
| Phone | +46 46 173931 |
|---|---|
| kerstin.tollstam@skane.se | |
"ROR" |
https://ror.org/02z31g829 |
Funders
Funder type
Research council
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- The Vasculitis Foundation, VF
- Location
- United States of America
No information available
Government organisation / Local government
- Location
- Sweden
Results and Publications
| Intention to publish date | 01/01/2021 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Results to be published in scientific medical journals |
| IPD sharing plan | The current data sharing plans for this study are unknown and will be available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/03/2011 | Yes | No | |
| Results article | results | 01/04/2011 | Yes | No | |
| Results article | results | 01/05/2011 | Yes | No | |
| Results article | results | 01/08/2011 | Yes | No | |
| Results article | results | 01/12/2011 | Yes | No | |
| Results article | results | 01/02/2012 | Yes | No | |
| Results article | results | 01/06/2012 | Yes | No | |
| Results article | results | 01/10/2012 | Yes | No | |
| Results article | results | 01/01/2013 | Yes | No | |
| Results article | results | 01/06/2013 | Yes | No | |
| Results article | results | 01/08/2013 | Yes | No | |
| Results article | results | 01/01/2015 | Yes | No | |
| Results article | results | 01/03/2015 | Yes | No | |
| Results article | results | 01/03/2015 | Yes | No | |
| Results article | results | 01/04/2015 | Yes | No | |
| Results article | results | 14/12/2016 | Yes | No | |
| Results article | results | 01/05/2017 | Yes | No | |
| Results article | results | 01/12/2017 | Yes | No |
Editorial Notes
13/03/2020: Internal review.
14/01/2020: The recruitment end date was changed from 31/12/2019 to 24/01/2020.
11/07/2019: The participant inclusion criteria were updated.
02/07/2019: The following changes were made to the trial record:
1. The study hypothesis was updated.
2. The EudraCT number was added.
3. The ethics approval was updated.
4. The target number of participants was changed from 535 to 875.
5. The funder "European League Against Rheumatism (EULAR) (Europe)" was removed and three new funders were added.
6. The publication and dissemination plan was added.
7. The intention to publish date was added.
8. The participant level data was changed from "Not provided at time of registration" to "To be made available at a later date".
9. The plain English summary was added.
05/04/2019 The following changes were made to the trial record to reflect that the research project has been extended to a 10-year study:
1. The study hypothesis has been updated
2. The condition has been changed from "Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV); Wegeners granulomatosis (WG); microscopic polyangiitis (MPA)" to "Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV); granulomatosis with polyangiitis (GPA, Wegener’s granulomatosis (WG)); microscopic polyangiitis (MPA) ".
3. The interventions have been changed
4. The overall end date was changed from 31/01/2007 to 31/12/2019
5. The recruitment end date was changed from 31/01/2007 to 31/12/2019
6. The sponsor was changed from University of Birmingham/University Hospital NHS Foundation Trust (UK) to Skane University Hospital Malmö-Lund, Sweden
7. Publication references added.
