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Pragmatic Clinical Trials in Scleroderma (PCTS)

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ClinicalTrials.gov Identifier: NCT03610217
Recruitment Status : Not yet recruiting
First Posted : August 1, 2018
Last Update Posted : August 6, 2018
Sponsor:
Collaborator:
University of Western Ontario, Canada
Information provided by (Responsible Party):
Andreu Fernandez Codina, University of Western Ontario, Canada

Brief 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.


Condition or disease Intervention/treatment Phase
Scleroderma, Systemic Sclerosis, Systemic 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 Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pragmatic Clinical Trials in Scleroderma
Estimated Study Start Date : October 2018
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : October 2021


Arm Intervention/treatment
Experimental: Interstitial lung disease induction 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.

Experimental: Pulmonary arterial hypertension 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)

Experimental: Raynaud's phenomenon 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.


Experimental: Digital ulcers 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.


Experimental: Inflammatory arthritis 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.

Experimental: Gastroesophageal reflux 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.

Experimental: Bacterial overgrowth 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.

Experimental: Constipation 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.

Experimental: Skin involvement 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.


Experimental: Pain 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.




Primary Outcome Measures :
  1. Forced vital capacity % [ Time Frame: 1 year ]
    Variation of the forced vital capacity %

  2. Bleeding [ Time Frame: 1 year ]
    Documentation of bleeding

  3. Raynaud's phenomenon visual analog scale [ Time Frame: 3 months ]
    Raynaud's phenomenon visual analog scale variation ranging from 0 to 100 mm (0 no Raynaud's phenomenon, 100 very intense Raynaud`s phenomenon)

  4. Time to the healing of a digital ulcer [ Time Frame: 1 year ]
    Time to the healing of a digital ulcer

  5. Time to the development of a new digital ulcer [ Time Frame: 1 year ]
    Time to the development of a new digital ulcer

  6. Disease activity score 28 [ Time Frame: 3 months ]
    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

  7. GERD-HRQL [ Time Frame: 3 months ]
    Variation of the Gastro-esophageal reflux disease-health related quality of life questionnaire, ranging from 0 (no symptoms) to 75 (worst symptoms)

  8. Diarrhea visual analog scale [ Time Frame: 3 months ]
    Diarrhea visual analog scale variation ranging from 0 to 100 mm (0 no diarrhea, 100 very intense diarrhea)

  9. Constipation visual analog scale [ Time Frame: 3 months ]
    constipation visual analog scale variation ranging from 0 to 100 mm (0 no constipation, 100 very intense constipation)

  10. Modified Rodnan skin score [ Time Frame: 1 year ]
    Modified Rodnan skin score variation. Ranging from a total of 0 (no induration) to 51 (maximum induration)

  11. Pain visual analog scale [ Time Frame: 3 months ]
    Pain visual analog scale variation, ranging from 0 to 100 mm (0 no pain, 100 very intense pain)



Information from the National Library of Medicine

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

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03610217


Contacts
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Contact: Janet E Pope, MD, MPH, FRCPSC 15196466332 Janet.Pope@sjhc.london.on.ca
Contact: Andreu Fernandez-Codina, MD, MSc 151964661023 doccodina@gmail.com

Locations
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Canada, Ontario
Saint Joseph's Health Care London Not yet recruiting
London, Ontario, Canada, n6a 4v2
Contact: Janet E Pope, MD, MPH, FRCPSC    15196466332    Janet.Pope@sjhc.london.on.ca   
Contact: Andreu Fernandez-Codina    151964661023    doccodina@gmail.com   
Sponsors and Collaborators
University of West London
University of Western Ontario, Canada

Additional Information:
Publications of Results:
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Responsible Party: Andreu Fernandez Codina, Principal investigator, University of Western Ontario, Canada
ClinicalTrials.gov Identifier: NCT03610217     History of Changes
Other Study ID Numbers: 111419
First Posted: August 1, 2018    Key Record Dates
Last Update Posted: August 6, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Additional relevant MeSH terms:
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Scleroderma, Systemic
Scleroderma, Diffuse
Scleroderma, Localized
Connective Tissue Diseases
Skin Diseases
Mycophenolic Acid
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action