Prednisolone in Early Diffuse Systemic Sclerosis (PRedSS)

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)

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.

Study Overview

• Status: Completed
• Conditions: Systemic Sclerosis
• Intervention / Treatment: Drug: Prednisolone 5 mg; Drug: Placebo oral capsule; From August 2020 'no additional treatment'

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Bristol, United Kingdom, BS10 5NB
    • Southmead Hospital Bristol - North Bristol NHS Trust
  • Dundee, United Kingdom, DD1 9SY
    • Ninewells Hospital and Medical School - NHS Tayside
  • London, United Kingdom, NW3 2QG
    • Royal Free London NHS Foundation Trust
  • Aberdeenshire
    • Aberdeen, Aberdeenshire, United Kingdom, AB25 2ZN
      • Aberdeen Royal Infirmary - NHS Grampian
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Addenbrooke'S Hospital - Cambridge University Hospitals Nhs Foundation Trust
  • Greater Manchester
    • Salford, Greater Manchester, United Kingdom, M6 8HD
      • Salford Royal NHS Foundation Trust
  • Lanarkshire
    • Glasgow, Lanarkshire, United Kingdom, G4 0SF
      • Glasgow Royal Infirmary -
  • Merseyside
    • Liverpool, Merseyside, United Kingdom, L9 7AL
      • Aintree University Hospitals NHS Foundation Trust
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG7 2UH
      • Queen's Medical Centre - Nottingham University Hospitals NHS Trust
  • Somerset
    • Bath, Somerset, United Kingdom, BA1 1RL
      • Royal National Hospital for Rheumatic Diseases - Royal United Hospitals Bath NHS Foundation Trust
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
      • Royal Hallamshire Hospital - SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST
  • Tyne And Wear
    • Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE7 7DN
      • Freeman Hospital - THE NEWCASTLE UPON TYNE HOSPITALS NHS FOUNDATION TRUST
  • West Midlands
    • Dudley, West Midlands, United Kingdom, DY1 2HQ
      • The Dudley Group NHS Foundation Trust
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS7 4SA
      • Leeds Institute of Rheumatic and Musculoskeletal Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Prednisolone; Prednisolone 5mg enteric-coated tablets, over-encapsulated in a hard gelatine capsule and filled with lactose BP. The prednisolone will be self-administered, orally with water before or after a meal once a day. Dosing will be continuous for a total of 6 months. The total dose prescribed will be equivalent to approximately 0.3mg/kg/day. The minimum dose prescribed will be 10mg per day (2 capsules) and a maximum of 30mg per day (6 capsules). From August 2020: The prednisolone is no longer over-encapsulated. Prednisolone 5mg enteric-coated tablets will be prescribed and taken as above.	Drug: Prednisolone 5 mg; 5mg prednisolone, once a day for 6 months
PLACEBO_COMPARATOR: Placebo oral capsule; From August 2020 - 'no additional treatment'; The placebo will be a hard gelatine capsule filled with lactose BP and identically matched to the prednisolone capsules. The placebo will be self-administered once a day, orally with water before or after a meal. Dosing will be continuous for a total of 6 months. From August 2020 - no placebo capsule will be administered.	Drug: Placebo oral capsule; From August 2020 'no additional treatment'; Matched placebo capsule, once a day for 6 months; From August 2020 - no additional treatment above standard of care medication

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health Assessment Questionnaire Disability Index (HAQ-DI)	The mean difference in HAQ-DI at 3 months	Baseline to 3 months
modified Rodnan Skin Score (mRSS)	The difference in mRSS at 3 months	Baseline to 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life and functional ability - Assessed by Questionnaire	HAQ-DI	Baseline to 6 weeks and 6 months
Pain and disability	Skin involvement as measured by the mRSS	Baseline to 6 weeks and 6 months
Functional ability - Assessed by Questionnaire	11-point Scleroderma Functional Index	Baseline to 6 weeks, 3 months and 6 months
Pain associated with itch - Assessed by Questionnaire	Assessment of Pruritus	Baseline to 6 weeks, 3 months and 6 months
Hand function - Assessed by Questionnaire	Cochin Hand Function	Baseline to 6 weeks, 3 months and 6 months
Fatigue - Assessed by Questionnaire	Functional Assessment of Chronic Illness Therapy (FACIT)	Baseline to 6 weeks, 3 months and 6 months
Anxiety and depression - Assessed by questionnaire	Hospital Anxiety and Depression Scale (HADS) . This questionnaire has 14 questions, each with 4 options designed to assess aspects of mental health	Baseline to 6 weeks, 3 months and 6 months
Health related quality of life - Assessed by Questionnaire	Helplessness Questionnaire	Baseline to 6 weeks, 3 months and 6 months
Health related quality of life - Assessed by Questionnaire	Short Form (36) Health Survey	Baseline to 6 weeks, 3 months and 6 months
Health related quality of Life - Assessed by Questionnaire	EuroQol 5 Dimensions	Baseline to 6 weeks, 3 months and 6 months
Pain and disability	Patient Global Assessment	Baseline to 6 weeks, 3 months and 6 months
Pain and disability	Physician Global Assessment	Baseline to 6 weeks, 3 months and 6 months
Assessment of pain - Clinician assessment	Digital Ulcer Count: The site and total number of ulcers on the hand are recorded by the patients clinician on a diagram of a hand	Baseline to 6 weeks, 3 months and 6 months
Assessment of pain - Clinician assessment	Tender Friction Rubs - the total number of tendon friction rubs on 12 possible anatomical sites are recorded	Baseline to 6 weeks, 3 months and 6 months
Assessment of pain - Clinician assessment	Joint Count: The number of tender or swollen joints are assessed from 14 anatomical sites (both left and right side) and recorded out of a total of 28 (14 sites, left and right side) tender joints and 28 swollen joints	Baseline to 6 weeks, 3 months and 6 months
Pain and disability - Assessed by Questionnaire	Assessment of Arthritis Index	Baseline to 6 weeks, 3 months and 6 months
Pain and disability	Assessment in percentage change of mRSS	Baseline to 6 weeks, 3 months and 6 months

Collaborators and Investigators

• Sponsor: Prof. Ariane herrick
• Collaborators: Versus Arthritis
• Investigators: Principal Investigator: Professor Ariane Herrick, University of Manchester

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 21, 2017
• Primary Completion (ACTUAL): March 4, 2021
• Study Completion (ACTUAL): May 27, 2021

Study Registration Dates

• First Submitted: October 8, 2018
• First Submitted That Met QC Criteria: October 11, 2018
• First Posted (ACTUAL): October 17, 2018

Study Record Updates

• Last Update Posted (ACTUAL): July 30, 2021
• Last Update Submitted That Met QC Criteria: July 29, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Pain; Fatigue; Prednisolone; Disability; Randomised Controlled Trial; Diffuse cutaneous systemic sclerosis (dcSSc)
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Connective Tissue Diseases; Sclerosis; Scleroderma, Systemic; Scleroderma, Diffuse; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone
• Other Study ID Numbers: 119220

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: IPD will be shared with collaborating centres. It is undecided if this information will be shared with researchers unconnected with the trial.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No