Pragmatic Clinical Trials in Scleroderma

Study Overview
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Brief Summary
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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.

Official Title
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Pragmatic Clinical Trials in Scleroderma

Conditions
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Scleroderma, Systemic, Sclerosis, Systemic

Intervention / Treatment
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* Other: Interstitial lung disease induction algorithm
* Other: Pulmonary arterial hypertension algorithm
* Other: Raynaud's phenomenon algorithm
* Other: Digital ulcer algorithm
* Other: Inflammatory arthritis algorithm
* Other: Gastroesophageal reflux algorithm
* Other: Bacterial overgrowth algorithm
* Other: Constipation algorithm
* Other: Skin involvement algorithm
* Other: Pain algorithm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient with an age >18 years meeting the 2013 SSc classification criteria managed at the Rheumatology division, St. Joseph's Healthcare London. Patients who refuse to be randomized for treatments but wish to provide their data for the registry will also be included, after signing the informed consent form. Exclusion Criteria: Refusal to participate or to sign an informed consent form.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interstitial lung disease induction<br> | Other: Interstitial lung disease induction algorithm<br>* 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.<br>|
| Experimental: Pulmonary arterial hypertension<br> | Other: Pulmonary arterial hypertension algorithm<br>* Patients diagnosed with pulmonary arterial hypertension secondary to systemic sclerosis will be randomized to receive anticoagulation (warfarin, rivaroxaban or apixaban)<br>|
| Experimental: Raynaud's phenomenon<br> | Other: Raynaud's phenomenon algorithm<br>* 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.<br>|
| Experimental: Digital ulcers<br> | Other: Digital ulcer algorithm<br>* 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.<br>|
| Experimental: Inflammatory arthritis<br> | Other: Inflammatory arthritis algorithm<br>* 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.<br>|
| Experimental: Gastroesophageal reflux<br> | Other: Gastroesophageal reflux algorithm<br>* 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.<br>|
| Experimental: Bacterial overgrowth<br> | Other: Bacterial overgrowth algorithm<br>* 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.<br>|
| Experimental: Constipation<br> | Other: Constipation algorithm<br>* 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.<br>|
| Experimental: Skin involvement<br> | Other: Skin involvement algorithm<br>* 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.<br>|
| Experimental: Pain<br> | Other: Pain algorithm<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced vital capacity % | Variation of the forced vital capacity % | 1 year | 
| Bleeding | Documentation of bleeding | 1 year | 
| Raynaud's phenomenon visual analog scale | Raynaud's phenomenon visual analog scale variation ranging from 0 to 100 mm (0 no Raynaud's phenomenon, 100 very intense Raynaud's phenomenon) | 3 months | 
| Time to the healing of a digital ulcer | Time to the healing of a digital ulcer | 1 year | 
| Time to the development of a new digital ulcer | Time to the development of a new digital ulcer | 1 year | 
| Disease activity score 28 | Disease activity score 28 accounting for tender and swollen joints over 28 possible joints. Values <2.6 remission, values <3.2 low disease activity, values >5.1 high disease activity | 3 months | 
| GERD-HRQL | Variation of the Gastro-esophageal reflux disease-health related quality of life questionnaire, ranging from 0 (no symptoms) to 75 (worst symptoms) | 3 months | 
| Diarrhea visual analog scale | Diarrhea visual analog scale variation ranging from 0 to 100 mm (0 no diarrhea, 100 very intense diarrhea) | 3 months | 
| Constipation visual analog scale | constipation visual analog scale variation ranging from 0 to 100 mm (0 no constipation, 100 very intense constipation) | 3 months | 
| Modified Rodnan skin score | Modified Rodnan skin score variation. Ranging from a total of 0 (no induration) to 51 (maximum induration) | 1 year | 
| Pain visual analog scale | Pain visual analog scale variation, ranging from 0 to 100 mm (0 no pain, 100 very intense pain) | 3 months |