Cardiovascular events and mortality in systemic sclerosis (SSc): a study of the effect of iloprost on these and on disease progression
| ISRCTN | ISRCTN67541323 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN67541323 |
| Secondary identifying numbers | N/A |
- Submission date
- 13/07/2005
- Registration date
- 07/09/2005
- Last edited
- 30/04/2020
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Musculoskeletal Diseases
Plain English summary of protocol
Background and study aims
Systemic sclerosis is a long-term condition that causes thickening and hardening of the skin and can also affect the internal organs. Death from cardiovascular (heart) disease is a significant problem for patients with systemic sclerosis, accounting for one third of all deaths in this population. The drug iloprost, delivered into a vein (intravenous), will be a familiar treatment to many patients with systemic sclerosis. It is used as a prophylactic (preventative) treatment for Raynaud’s phenomenon (spasm of the small blood vessels in the fingers and toes). However, its effect as a blood vessel dilator may also prevent patients with systemic sclerosis from developing cardiovascular disease. The aim of this study is to find out whether oral iloprost treatment is effective at reducing systemic sclerosis disease progression.
Who can participate?
Patients over 40 years of age with systemic sclerosis
What does the study involve?
Participants take a placebo (dummy drug) for one month to ensure that they are compliant with the study medication in that period. Following this phase, all participants are reviewed first at three months (to ensure stability on treatment and absence of serious side effects); at six months; and then six monthly until their final visit at the end of the study. Participants are randomly allocated to take either iloprost or placebo as one tablet (50mcg) daily for one week. This is then increased to one tablet twice daily for a further week, then one tablet three times daily for a further week and, if tolerated, then increased to the maximum desired dose of 200mcg daily (100mcg twice daily) and kept at that dose for the duration of the study. Participants are then followed up to assess disease progression for a period of 4 to 7 years based on when they joined the study.
What are the possible benefits and risks of participating?
This study is important as it takes a medication known to be of use for some aspects of systemic sclerosis and investigates whether it may prevent cardiovascular disease which may result in death. This study involves the collaboration of medical, nursing and other staff with expertise in this area throughout the UK and Eire. It also provides a further opportunity to follow up patients for over 4 years to look at other important aspects of this disease, namely heart, lung and kidney function, to find out whether this treatment is protective of other organs as well. There may be risks involved with participation in this study related to possible side effects of the drug iloprost, which may include flushing, light-headedness, dizziness, faintness or low blood pressure, nausea, and headache. Although iloprost has been used and tested before, side effects may occur which have not been seen previously.
Where is the study run from?
1. Ninewells Hospital (UK)
2. Foresterhill Hospital (UK)
3. Woolmanhill Hospital (UK)
4. Western General Hospital (UK)
5. St John’s Hospital (UK)
6. Glasgow Royal Infirmary (UK)
7. Freeman Hospital (UK)
8. Chapel Allerton Hospital (UK)
9. Royal St James Hospital (UK)
10. Northampton General (UK)
11. Royal Free Hospital (UK)
12. St Vincent’s Hospital (Ireland)
When is the study starting and how long is it expected to run for?
February 2002 to December 2008
Who is funding the study?
Raynaud's and Scleroderma Association (UK)
Who is the main contact?
1. Prof. Jill Belch
J.J.F.Belch@dundee.ac.uk
2. Dr Stephen McSwiggan
s.j.mcswiggan@dundee.ac.uk
Contact information
Scientific
Division of Medicine and Therapeutics
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
| Phone | +44 (0)1382 632457 |
|---|---|
| J.J.F.Belch@dundee.ac.uk |
Scientific
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
| s.j.mcswiggan@dundee.ac.uk |
Study information
| Study design | Randomised placebo-controlled parallel-group trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | Cardiovascular events and mortality in systemic sclerosis (SSc): a study of the effect of iloprost on these and on disease progression |
| Study acronym | SSTEP: Systemic Sclerosis Trial of Events and Progression |
| Study objectives | That oral iloprost therapy is more effective than placebo in reducing SSc disease progression, and coronary and cerebrovascular events in patients with SSc. |
| Ethics approval(s) | Scotland ‘A’ REC, 08/11/2001, ref: MREC 01/0/70 |
| Health condition(s) or problem(s) studied | Systemic sclerosis (SSc) |
| Intervention | Oral iloprost or placebo Added 11/08/2017: The study was a randomised, placebo-controlled clinical trial with a one month placebo run in to ensure patients were compliant with study medication in that period. Following this placebo run in phase, all patients enrolled in the study were reviewed first at three months (to ensure stability on treatment and absence of serious side effects); at six months; and then six monthly until their final visit at the end of the study period. Block randomisation was done for each site in blocks of six (three active versus three placebo) to ensure even distribution, where possible, of active and placebo allocation at each site. Investigators and participants were blinded to treatment. Study drugs and placebo were in small identical capsules of 50 mcg doses. Participants were advised to continue on one tablet (50mcg) daily for one week. This was then increased to one tablet twice daily for a further week, then one tablet three times daily for a further week and, if tolerated, then titrated to the maximum desired dose of 200mcg daily (100mcg bd) and maintained at that dose for the duration of the trial. Participants were then followed up for a period of 4 to 7 years dependent on time of enrolment. Iloprost and placebo composition Active ingredient in the Iloprost capsules was 0.38 mg Iloprost β-cyclodextrin clathrate (50µg Iloprost and 0.33mg β-cyclodextrin) with the following inactive ingredients: 1. Lactose monohydrate 2. Microcrystalline cellulose 3. Methacrylic acid copolymer (Eudragit NE 3OD) 4. Magnesium stearate 5. Titanium dioxide 6. Polyethlene glycol 6000 7. Polysorbate 80 8. Silicon dioxide 9. Hard gelatin capsule (containing titanium dioxide, iron oxide (red) and gelatin) The matched placebo was identical to the Iloprost capsule but lacked the active ingredient, Iloprost β-cyclodextrin clathrate. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Iloprost |
| Primary outcome measure | A composite primary endpoint is sought for this study. 1. Fatal coronary and stroke events plus non fatal myocardial infarction and stroke 2. Vascular disease death 3. SSc disease progression to include: 3.1. Deteriorating renal function as measured by 24-hour urine and blood sampling for creatinine clearance 3.2. Deteriorating lung function as measured by changes in DLCO total lung capacity 3.3. Increase in pulmonary artery pressure measured in millimetres in mercury by echocardiogram 3.4. Skin score assessed using the modified Rodnan Skin Score These will be monitored and percentage change from baseline calculated. If deterioration is indicated by an increasing figure then 30% change will be required. If deterioration is based on a decreasing number then 20% change from baseline will be required. Additionally the Medsger categories will be evaluated. A final decision regarding the primary endpoints will be carried out by the Data and Safety Monitoring Committee approximately 8 months into the study. The definition of the above cardiovascular (CV) events will be made according to the World Health Organisation (WHO) Criteria for the diagnosis of coronary events and stroke (fatal and non-fatal). |
| Secondary outcome measures | The main secondary endpoints are: 1. All cause mortality 2. Non-fatal myocardial infarction and stroke 3. Occurrence of other vascular events including requirement of coronary or peripheral arterial bypass surgery and/or angioplasty, development of angina, claudication or development of critical limb ischaemia 4. Severity of Raynaud's Phenomenon |
| Overall study start date | 07/02/2002 |
| Completion date | 31/12/2008 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | 215 |
| Key inclusion criteria | Subjects will be patients with both limited and diffuse SSc, as our pilot work has shown atherosclerotic vascular disease to occur in both groups. The patients considered for this study will be as follows: 1. Any patient fulfilling Arthritis Research Campaign (ARC) criteria for SSc 2. Any patient with Raynauds Phenomenon and at least 3 other features of limited SSc 3. Any patient with Raynauds Phenomenon and the presence of an SSc-related autoantibody (e.g. anticentromere, antitopo1 [scleroderma 70], anti-U1RNP, anti-ThRNP, anti-U3RNP, anti-PmScl) All will be >40 years of age. These patients will be recruited from Connective Tissue Disease clinics throughout Tayside, Fife, Strathclyde, Lothian, Grampian, Yorkshire, Bath, Northamptonshire and Ireland. Patients with SSc will be invited to attend the clinics to have their vascular risk factors assessed. Volunteers will then be asked to give informed consent and if that consent is given, enter the screening phase of the study |
| Key exclusion criteria | 1. Suspected serious physical illness such as cancer which may be expected to curtail life expectancy 2. Psychiatric illness (reported by GP) 3. Congenital heart disease 4. Any patient who is pregnant or who wishes to become pregnant within the time course of the study |
| Date of first enrolment | 07/02/2002 |
| Date of final enrolment | 28/02/2005 |
Locations
Countries of recruitment
- England
- Ireland
- Scotland
- United Kingdom
Study participating centres
DD1 9SY
United Kingdom
United Kingdom
United Kingdom
United Kingdom
United Kingdom
United Kingdom
United Kingdom
United Kingdom
United Kingdom
United Kingdom
United Kingdom
United Kingdom
Sponsor information
University/education
Research & Innovations Service
University of Dundee
Dundee
DD1 4HN
Scotland
United Kingdom
| Phone | +44 (0)1382 344000 |
|---|---|
| s.g.bell@dundee.ac.uk | |
| Website | http://www.dundee.ac.uk |
"ROR" |
https://ror.org/03h2bxq36 |
Funders
Funder type
Charity
Private sector organisation / Associations and societies (private and public)
- Alternative name(s)
- RSA
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/12/2019 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Stored in repository |
| Publication and dissemination plan | Protocol and statistical plan are available direct on request. The trialists plan to publish the protocol if possible. Planned publication in a high-impact peer reviewed journal of 10-year follow-up data. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository - the local Safe Haven, the Tayside Health Informatics Centre: https://www.dundee.ac.uk/hic. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Basic results | 09/08/2017 | 24/08/2017 | No | No | |
| Results article | results | 01/01/2019 | 17/01/2019 | Yes | No |
| Results article | results | 01/11/2016 | 17/01/2019 | Yes | No |
| Results article | results of a parenting program among women who began childbearing as adolescents and young adults | 01/11/2017 | 17/01/2019 | Yes | No |
| Results article | results of promoting child development through group-based parent support within a cash transfer program | 01/02/2017 | 17/01/2019 | Yes | No |
| Results article | results of stimulating parenting practices in indigenous and non-indigenous Mexican communities | 25/12/2017 | 17/01/2019 | Yes | No |
Additional files
- ISRCTN67541323_BasicResults_09Aug17.pdf
- Uploaded 24/08/2017
Editorial Notes
30/04/2020: Publication reference added.
17/01/2019: Publication references added
24/08/2017: The basic results of this trial have been uploaded as an additional file.
11/08/2017: Added ethics/interventions details, plain English summary, recruitment dates, centres, publication and dissemination plan, IPD sharing statement, contact.
