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
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

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

Prof Jill Belch
Scientific

Division of Medicine and Therapeutics
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom

Phone +44 (0)1382 632457
Email J.J.F.Belch@dundee.ac.uk
Dr Stephen McSwiggan
Scientific

Ninewells Hospital
Dundee
DD1 9SY
United Kingdom

Email s.j.mcswiggan@dundee.ac.uk

Study information

Study designRandomised placebo-controlled parallel-group trial
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Hospital
Study typeTreatment
Participant information sheet Not available in web format, please use the contact details to request a patient information sheet
Scientific titleCardiovascular events and mortality in systemic sclerosis (SSc): a study of the effect of iloprost on these and on disease progression
Study acronymSSTEP: Systemic Sclerosis Trial of Events and Progression
Study objectivesThat 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) studiedSystemic sclerosis (SSc)
InterventionOral 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 typeDrug
Pharmaceutical study type(s)
PhaseNot Applicable
Drug / device / biological / vaccine name(s)Iloprost
Primary outcome measureA 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 measuresThe 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 date07/02/2002
Completion date31/12/2008

Eligibility

Participant type(s)Patient
Age groupAdult
SexBoth
Target number of participants215
Key inclusion criteriaSubjects 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 Raynaud’s Phenomenon and at least 3 other features of limited SSc
3. Any patient with Raynaud’s 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 criteria1. 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 enrolment07/02/2002
Date of final enrolment28/02/2005

Locations

Countries of recruitment

  • England
  • Ireland
  • Scotland
  • United Kingdom

Study participating centres

Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
Foresterhill Hospital
AB25 2ZG
United Kingdom
Woolmanhill Hospital
AB25 1LD
United Kingdom
Western General Hospital
EH4 2XU
United Kingdom
St John’s Hospital
EH54 6PP
United Kingdom
Glasgow Royal Infirmary
G4 0SF
United Kingdom
Freeman Hospital
NE7 7DN
United Kingdom
Chapel Allerton Hospital
LS7 4SA
United Kingdom
Royal St James Hospital
LS9 7TF
United Kingdom
Northampton General Hospital
NN1 5BD
United Kingdom
Royal Free Hospital
NW3 2QG
United Kingdom
St Vincent’s Hospital
D04 Y8V0
United Kingdom

Sponsor information

University of Dundee (UK)
University/education

Research & Innovations Service
University of Dundee
Dundee
DD1 4HN
Scotland
United Kingdom

Phone +44 (0)1382 344000
Email s.g.bell@dundee.ac.uk
Website http://www.dundee.ac.uk
ROR logo "ROR" https://ror.org/03h2bxq36

Funders

Funder type

Charity

Raynaud's and Scleroderma Association
Private sector organisation / Associations and societies (private and public)
Alternative name(s)
RSA
Location
United Kingdom

Results and Publications

Intention to publish date31/12/2019
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryStored in repository
Publication and dissemination planProtocol 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 planThe 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.