Prednisolone in Early Diffuse Systemic Sclerosis (PRedSS)

• ClinicalTrials.gov Identifier: NCT03708718
• Recruitment Status: Completed
• First Posted: October 17, 2018
• Last Update Posted: July 30, 2021
• Sponsor: Prof. Ariane herrick
• Collaborator: Versus Arthritis
• Information provided by (Responsible Party): Prof. Ariane herrick, University of Manchester

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Systemic Sclerosis	Drug: Prednisolone 5 mg; Drug: Placebo oral capsule; From August 2020 'no additional treatment'	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

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.

• Masking: Triple (Participant, Care Provider, Investigator)

Masking Description

Double-blind. The trial management team are blind to treatment allocation for the duration of the trial. The site research teams and patients are blind to treatment until code-break. At this point the on-site team and patient are unblind to allocation for continuing care. The site pharmacy personnel, PRedSS trial monitor and supervising statistician are unblind throughout.

From August 2020: Open-Label - The patient, site research team and site pharmacy are unblind. The trial management team are unblind for patients recruited from August 2020 onwards but remain blind to patients randomised to trial under the double-blind design. The trial monitor and trial statistician continue to be unblind for all patients randomised to trial.

• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: December 21, 2017
• Actual Primary Completion Date: March 4, 2021
• Actual Study Completion Date: May 27, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Health Assessment Questionnaire Disability Index (HAQ-DI) [ Time Frame: Baseline to 3 months ]
   The mean difference in HAQ-DI at 3 months
2. modified Rodnan Skin Score (mRSS) [ Time Frame: Baseline to 3 months ]
   The difference in mRSS at 3 months

Secondary Outcome Measures :

1. Quality of life and functional ability - Assessed by Questionnaire [ Time Frame: Baseline to 6 weeks and 6 months ]
   HAQ-DI
2. Pain and disability [ Time Frame: Baseline to 6 weeks and 6 months ]
   Skin involvement as measured by the mRSS
3. Functional ability - Assessed by Questionnaire [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
   11-point Scleroderma Functional Index
4. Pain associated with itch - Assessed by Questionnaire [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
   Assessment of Pruritus
5. Hand function - Assessed by Questionnaire [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
   Cochin Hand Function
6. Fatigue - Assessed by Questionnaire [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
   Functional Assessment of Chronic Illness Therapy (FACIT)
7. Anxiety and depression - Assessed by questionnaire [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
   Hospital Anxiety and Depression Scale (HADS) . This questionnaire has 14 questions, each with 4 options designed to assess aspects of mental health
8. Health related quality of life - Assessed by Questionnaire [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
   Helplessness Questionnaire
9. Health related quality of life - Assessed by Questionnaire [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
   Short Form (36) Health Survey
10. Health related quality of Life - Assessed by Questionnaire [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
    EuroQol 5 Dimensions
11. Pain and disability [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
    Patient Global Assessment
12. Pain and disability [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
    Physician Global Assessment
13. Assessment of pain - Clinician assessment [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
    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
14. Assessment of pain - Clinician assessment [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
    Tender Friction Rubs - the total number of tendon friction rubs on 12 possible anatomical sites are recorded
15. Assessment of pain - Clinician assessment [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
    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
16. Pain and disability - Assessed by Questionnaire [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
    Assessment of Arthritis Index
17. Pain and disability [ Time Frame: Baseline to 6 weeks, 3 months and 6 months ]
    Assessment in percentage change of mRSS

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United Kingdom

Aberdeen Royal Infirmary - NHS Grampian

Aberdeen, Aberdeenshire, United Kingdom, AB25 2ZN

Addenbrooke's Hospital - Cambridge University Hospitals NHS Foundation Trust

Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ

Salford Royal NHS Foundation Trust

Salford, Greater Manchester, United Kingdom, M6 8HD

Glasgow Royal Infirmary -

Glasgow, Lanarkshire, United Kingdom, G4 0SF

Aintree University Hospitals NHS Foundation Trust

Liverpool, Merseyside, United Kingdom, L9 7AL

Queen's Medical Centre - Nottingham University Hospitals NHS Trust

Nottingham, Nottinghamshire, United Kingdom, NG7 2UH

Royal National Hospital For Rheumatic Diseases - Royal United Hospitals Bath NHS Foundation Trust

Bath, Somerset, United Kingdom, BA1 1RL

Royal Hallamshire Hospital - Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, South Yorkshire, United Kingdom, S10 2JF

Freeman Hospital - The Newcastle upon Tyne Hospitals NHS Foundation Trust

Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE7 7DN

The Dudley Group NHS Foundation Trust

Dudley, West Midlands, United Kingdom, DY1 2HQ

Leeds Institute of Rheumatic and Musculoskeletal Medicine

Leeds, West Yorkshire, United Kingdom, LS7 4SA

Southmead Hospital Bristol - North Bristol NHS Trust

Bristol, United Kingdom, BS10 5NB

Ninewells Hospital and Medical School - NHS Tayside

Dundee, United Kingdom, DD1 9SY

Royal Free London NHS Foundation Trust

London, United Kingdom, NW3 2QG

Sponsors and Collaborators

Prof. Ariane herrick

Versus Arthritis

Investigators

• Principal Investigator: Professor Ariane Herrick; University of Manchester

More Information

• Responsible Party: Prof. Ariane herrick, Professor of Rheumatology, University of Manchester
• ClinicalTrials.gov Identifier: NCT03708718
• Other Study ID Numbers: 119220
• First Posted: October 17, 2018
• Last Update Posted: July 30, 2021
• Last Verified: July 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: IPD will be shared with collaborating centres. It is undecided if this information will be shared with researchers unconnected with the trial.

• 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

Keywords provided by Prof. Ariane herrick, University of Manchester:

Diffuse cutaneous systemic sclerosis (dcSSc); Prednisolone; Randomised Controlled Trial; Disability; Pain; Fatigue

Additional relevant MeSH terms:

Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis; Pathologic Processes; Connective Tissue Diseases; Skin Diseases; Prednisolone; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents