Condition category
Musculoskeletal Diseases
Date applied
13/07/2005
Date assigned
07/09/2005
Last edited
24/08/2017
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

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 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

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

http://www.dundee.ac.uk

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

Editorial Notes

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.