Plain English Summary
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
Trial website
Contact information
Type
Scientific
Primary contact
Prof Jill Belch
ORCID ID
Contact details
Division of Medicine and Therapeutics
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
+44 (0)1382 632457
J.J.F.Belch@dundee.ac.uk
Type
Scientific
Additional contact
Dr Stephen McSwiggan
ORCID ID
Contact details
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
-
s.j.mcswiggan@dundee.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
N/A
Study information
Scientific title
Cardiovascular events and mortality in systemic sclerosis (SSc): a study of the effect of iloprost on these and on disease progression
Acronym
SSTEP: Systemic Sclerosis Trial of Events and Progression
Study hypothesis
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
Scotland ‘A’ REC, 08/11/2001, ref: MREC 01/0/70
Study design
Randomised placebo-controlled parallel-group trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
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
Phase
Not Applicable
Drug names
Iloprost
Primary outcome measures
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 trial start date
07/02/2002
Overall trial end date
31/12/2008
Reason abandoned
Eligibility
Participant 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
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
215
Participant 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
Recruitment start date
07/02/2002
Recruitment end date
28/02/2005
Locations
Countries of recruitment
Ireland, United Kingdom
Trial participating centre
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
Trial participating centre
Foresterhill Hospital
AB25 2ZG
Trial participating centre
Woolmanhill Hospital
AB25 1LD
Trial participating centre
Western General Hospital
EH4 2XU
Trial participating centre
St John’s Hospital
EH54 6PP
Trial participating centre
Glasgow Royal Infirmary
G4 0SF
Trial participating centre
Freeman Hospital
NE7 7DN
Trial participating centre
Chapel Allerton Hospital
LS7 4SA
Trial participating centre
Royal St James Hospital
LS9 7TF
Trial participating centre
Northampton General Hospital
NN1 5BD
Trial participating centre
Royal Free Hospital
NW3 2QG
Trial participating centre
St Vincent’s Hospital
D04 Y8V0
Sponsor information
Organisation
University of Dundee (UK)
Sponsor details
Research & Innovations Service
University of Dundee
Dundee
DD1 4HN
United Kingdom
+44 (0)1382 344000
s.g.bell@dundee.ac.uk
Sponsor type
University/education
Website
Funders
Funder type
Charity
Funder name
Raynaud's and Scleroderma Association
Alternative name(s)
RSA
Funding Body Type
private sector organisation
Funding Body Subtype
professional associations and societies
Location
United Kingdom
Results and Publications
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 statement
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.
Intention to publish date
31/12/2019
Participant level data
Stored in repository
Results - basic reporting
See additional file ISRCTN67541323_BasicResults_09Aug17.pdf
Publication summary
Publication citations
Additional files
- ISRCTN67541323_BasicResults_09Aug17.pdf Uploaded 24/08/2017