Clinical trial NCT03708718: Prednisolone in Early Diffuse Systemic Sclerosis
Official title: A Phase II Randomised Study of Oral Prednisolone in Early Diffuse Cutaneous Systemic Sclerosis (Initially Double-blind, Then Switched to Open-label Because of Covid-19)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Systemic Sclerosis
Keywords: Diffuse cutaneous systemic sclerosis (dcSSc)
Prednisolone
Randomised Controlled Trial
Disability
Pain
Fatigue
Lead sponsor: University of Manchester
Sponsor class: OTHER
Collaborators: name: Versus Arthritis
First posted: 2018-10-17
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients are allocated to received either prednisolone or matched placebo for the duration of the trial. The allocation is randomised 1:1.

From August 2020: Under the open-label design, patients are allocated to receive prednisolone or no additional treatment. The randomisation allocation is 1:1.
Primary purpose: TREATMENT

Brief summary: This is a randomised placebo-controlled study of moderate dose prednisolone for 6 months in patients with early diffuse cutaneous systemic sclerosis (dcSSc). Seventy-two patients within 3 years of the onset of skin thickening will be recruited from 14 UK centres over 3 years. Co-primary end-points will be the Health Assessment Questionnaire Disability Index (HAQ-DI) and the modified Rodnan skin score (mRSS). Patients will be assessed 5 times: screening, baseline, 6 weeks, 3 and 6 months, with a code-break on exit from the study at 6 months.

Please note: From August 2020, the trial was re-started following halt due to Covid-19 as open-label. The placebo arm is the 'no treatment' arm and there is no longer a code-break at study exit.

Detailed description: The study is a non-commercial phase II randomised, double-blind, placebo-controlled, multi-centre study to test moderate dose prednisolone versus placebo in patients with early diffuse cutaneous systemic sclerosis (dcSSc).

Our aim is to investigate whether treatment with the steroid prednisolone is beneficial in patients with early diffuse cutaneous systemic sclerosis (also termed "scleroderma"). This is a controversial subject. Although it is very possible that prednisolone can help relieve the severe pain, itching, and disability (due to contractures and musculoskeletal involvement) of early diffuse scleroderma, doctors are often reluctant to prescribe prednisolone because of possible side effects, particularly an increased risk of serious kidney problems. Our proposed trial, treating patients with either prednisolone or placebo therapy for 6 months, should provide clinicians with a long awaited answer to the important clinical question: Can prednisolone be used as a therapy in this group of patients?

The study, funded by Arthritis Research UK, aims to determine:

1. Is moderate dose prednisolone effective in reducing pain, disability and skin thickening in patients with early diffuse scleroderma?
2. Is moderate dose prednisolone a safe therapy in patients with early diffuse scleroderma (with particular reference to kidney function)?

If the answer to both is 'yes', then prednisolone therapy will be much more widely prescribed for this patient group.

The patient population will be selected from individuals with early dcSSc, as defined by skin involvement of less than 3 years, who are considered potentially able to benefit from this treatment. Following screening, to minimise bias, eligible patients will be randomised at the baseline visit to receive either daily moderate dose prednisolone (as determined by body weight) or a matched placebo. To further eliminate subjective and unrecognised bias both the research team and patients will be blind to the randomisation. A placebo control, as opposed to an active treatment control, will be administered. This is necessary as the study treatment is adjunctive to and not a substitute for any other therapies which may be prescribed, such as immunosuppressant therapies.

Patients will attend on 5 occasions (screen, baseline, 6 weeks, 3 and 6 months). All patients will be considered off-study at the end of the 6 month visit whereupon the treatment code will be broken. At each visit a number of measurements will be taken including functional ability, degree of skin involvement (skin score), mood and kidney function. This will allow us to determine whether 'active' (prednisolone) therapy is effective and free from serious side-effects.

Please note: from August 2020, due to Covid-19 the trial was re-designed and re-started following trial halt as open-label. A placebo is no longer required. The aims, primary outcome measures and number of visits remain unchanged. However, to further mitigate the ongoing impact of Covid-19, the screen and baseline assessments may now be conducted at the same visit. Remote visits can also be carried out at 6 weeks and 6 months, if necessary.

Eligibility criteria: Inclusion Criteria:

1. Patients presenting with dcSSc with skin involvement extending to the proximal limb and/or trunk.
2. Male or female age ≥ 18 years.
3. Skin involvement of less than 3 years defined by patient report or clinician opinion.
4. Patient is able and willing to follow the requirements of the study.
5. Fully written informed consent.

Exclusion Criteria:

1. Patients with significant uncontrolled Stage 1 Hypertension (clinic BP \>140/90mmHg i.e. either \>140mmHg OR \>90mmHg). Patients with previous hypertension which is controlled (clinic BP \<140/90mmHg) for at least 4 weeks are considered eligible.
2. Previous renal crisis or significant renal impairment (estimated Glomerular Filtration Rate (eGFR) \< 40 ml/min).
3. Patients currently on steroid therapy, or previous steroid therapy within the last 4 weeks, with the exception of inhaled steroids for respiratory diseases.
4. Patients currently participating in another randomised controlled trial of an investigational agent or device, or previous participation within the last 30 days.
5. Patients currently receiving an immunosuppressant or biologic therapy the dose of which has changed in the last 4 weeks prior to the baseline visit, or is likely to change during the first 3 months of study treatment.
6. Patients with major myositis or inflammatory arthritis. Patients with low level myositis or inflammatory arthritis are eligible for inclusion (for example, in the case of myositis, a creatine kinase less than 4 times the upper limit of normal or myositis only demonstrable on magnetic resonance imaging).
7. Female patients who are pregnant at time of screening.
8. Female patients who are breastfeeding.
9. Patients with significant inflammatory bowel disease as judged by the investigator.
10. It is important that patients do not suddenly stop taking the study medication. Patients who do not fully understand this, will be excluded.
11. Patients who are unwilling or unable to provide informed consent.

Primary outcomes:
measure: Health Assessment Questionnaire Disability Index (HAQ-DI)
timeFrame: Baseline to 3 months
measure: modified Rodnan Skin Score (mRSS)
timeFrame: Baseline to 3 months
Secondary outcomes:
measure: Quality of life and functional ability - Assessed by Questionnaire
timeFrame: Baseline to 6 weeks and 6 months
measure: Pain and disability
timeFrame: Baseline to 6 weeks and 6 months
measure: Functional ability - Assessed by Questionnaire
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Pain associated with itch - Assessed by Questionnaire
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Hand function - Assessed by Questionnaire
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Fatigue - Assessed by Questionnaire
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Anxiety and depression - Assessed by questionnaire
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Health related quality of life - Assessed by Questionnaire
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Health related quality of life - Assessed by Questionnaire
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Health related quality of Life - Assessed by Questionnaire
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Pain and disability
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Pain and disability
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Assessment of pain - Clinician assessment
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Assessment of pain - Clinician assessment
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Assessment of pain - Clinician assessment
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Pain and disability - Assessed by Questionnaire
timeFrame: Baseline to 6 weeks, 3 months and 6 months
measure: Pain and disability
timeFrame: Baseline to 6 weeks, 3 months and 6 months
Other outcomes:
Locations:
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary - NHS Grampian
state: Aberdeenshire
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital - Cambridge University Hospitals NHS Foundation Trust
state: Cambridgeshire
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
state: Greater Manchester
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary -
state: Lanarkshire
city: Liverpool
country: United Kingdom
facility: Aintree University Hospitals NHS Foundation Trust
state: Merseyside
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre - Nottingham University Hospitals NHS Trust
state: Nottinghamshire
city: Bath
country: United Kingdom
facility: Royal National Hospital For Rheumatic Diseases - Royal United Hospitals Bath NHS Foundation Trust
state: Somerset
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital - Sheffield Teaching Hospitals NHS Foundation Trust
state: South Yorkshire
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital - The Newcastle upon Tyne Hospitals NHS Foundation Trust
state: Tyne And Wear
city: Dudley
country: United Kingdom
facility: The Dudley Group NHS Foundation Trust
state: West Midlands
city: Leeds
country: United Kingdom
facility: Leeds Institute of Rheumatic and Musculoskeletal Medicine
state: West Yorkshire
city: Bristol
country: United Kingdom
facility: Southmead Hospital Bristol - North Bristol NHS Trust
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School - NHS Tayside
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
Study officials:
affiliation: University of Manchester
name: Professor Ariane Herrick
role: PRINCIPAL_INVESTIGATOR
References: