Pragmatic Clinical Trials in Scleroderma

Summary

Systemic Sclerosis (SSc) is an autoimmune connective tissue disease characterized by autoantibodies, fibrosis and microvascular injury and endothelial cell activation that results in vascular damage. Vascular injury induces both innate and acquired immune responses resulting in fibroblast activation and organ fibrosis. SSc may target multiple organs, including: skin, lungs, heart, vascularization, kidneys, the gastrointestinal tract and musculoskeletal structures. Mortality among scleroderma patients is significant, with a 3.5 standardized mortality ratio (SMR) in studies of prevalent cases. This mortality may be increased in the early years of the disease, reaching a SMR of 4 in a multinational inception cohort. In general, treatment strategies target involved organs as early as possible to avoid damage. Many treatment options are available for each manifestation, but evidence with respect to the order of treatment is scarce. Financial costs, the lack of proper outcome measures, difficulty to recruit patients as a rare disease, all prevent the development of new big clinical trials, oppositely to other common diseases such as stroke or cancer. The heterogeneous features of SSc may make trials challenging. The current guidelines available are the British guidelines (2017) , and the updated European League Against Rheumatism (EULAR) guidelines, published in 2017. Management guidelines have some gaps regarding second-line treatment, combinations and there are no proposed algorithms.

With the pragmatic trials, the investigators intend to fill the gap between the complicated randomized clinical trials and the observational studies. Using the treatments that have already been proved useful in SSc, in an open-label randomized way and based on some refined expert-made algorithms, will allow the investigators to establish the order in how to use them.

Patients will be offered to participate with the collection of their clinical data and, if they give their consent, they will be randomized according to the algorithms. There will be an optional part of the study consisting in the collection of blood samples and skin samples for future research.

Conditions

• Scleroderma, Systemic
• Sclerosis, Systemic

Interventions

OTHER

Interstitial lung disease induction algorithm

Patients failing first line mycophenolic acid (MFA) will be randomized to MFA plus rituximab or intravenous cyclophosphamide. If they fail the second line they will be crossed over to the other option.

OTHER

Pulmonary arterial hypertension algorithm

Patients diagnosed with pulmonary arterial hypertension secondary to systemic sclerosis will be randomized to receive anticoagulation (warfarin, rivaroxaban or apixaban)

OTHER

Raynaud's phenomenon algorithm

Patients with mild Raynaud's phenomenon not responding to the first line treatment (nifedipine), will be randomized to receive losartan or nifedipine plus atorvastatin or nifedipine plus losartan. If they fail the second line they will be crossed over to the other options randomly. Patients with severe Raynaud's phenomenon not responding to the first line treatment (nifedipine) or failing the previous mild Raynaud's algorithm, will be randomized to receive nifedipine plus sildenafil or nifedipine plus intravenous iloprost. If they fail the second line they will be crossed over to the other option.

OTHER

Digital ulcer algorithm

Patients with active digital ulcers not healing after 3 months or developing new ones with nifedipine will be randomized to nifedipine plus sildenafil or nifedipine plus intravenous iloprost. If they fail the second line they will be crossed over to the other option. Patients who develop new digital ulcers under treatment with nifedipine will be randomized to nifedipine plus atorvastatin plus standard of care or nifedipine plus standard of care. If they fail the second line they will be crossed over to the other option.

OTHER

Inflammatory arthritis algorithm

Patients with inflammatory arthritis failing methotrexate and/or prednisone and/or hydroxychloroquine and/or sulfasalazine will be randomized to receive intravenous rituximab or subcutaneous tocilizumab. If they fail the second line they will be crossed over to the other option.

OTHER

Gastroesophageal reflux algorithm

Patients with gastroesophageal reflux failing standard doses of proton pump inhibitors (PPI) will be randomized to receive double doses of PPI or standard dose of PPI plus ranitidine or double doses of PPI plus domperidone or double doses of PPI plus prucalopride/erythromycin. If they fail the second line they will be crossed over to the other options randomly.

OTHER

Bacterial overgrowth algorithm

Patients with bacterial overgrowth will be randomized to receive erythromycin or metronidazole or amoxicillin. If they fail the second line they will be crossed over to the other options randomly.

OTHER

Constipation algorithm

Patients with constipation will be randomized to receive bisacodyl or magnesium sulphate or polyethylene glycol or senna.If they fail the second line they will be crossed over to the other options randomly.

OTHER

Skin involvement algorithm

Patients with skin involvement and modified Rodnan skin score \<32 will be randomized to receive methotrexate or mycophenolic acid or methotrexate plus mycophenolic acid. If they fail the second line they will be crossed over to the other option. Patients with skin involvement and modified Rodnan skin score \>32 will be randomized to receive methotrexate plus mycophenolic acid or intravenous cyclophosphamide. If they fail the second line they will be crossed over to the other option.

OTHER

Pain algorithm

Patients with pain failing first line treatment with acetaminophen or celecoxib or ibuprofen will be randomized to receive pregabalin or duloxetine. Patients with skin involvement and modified Rodnan skin score \<32 will be randomized to receive methotrexate or mycophenolic acid or methotrexate plus mycophenolic acid. If they fail the second line they will be crossed over to the other option. In case they fail the second line they will be treated with medical marijuana.

Sponsors & Collaborators

• University of Western Ontario, Canada

  collaborator OTHER

• University of West London

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SEQUENTIAL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2018-10-31

Primary Completion

2021-10-31

Completion

2021-10-31

Countries

• Canada

Study Locations