Cardiac Sarcoidosis Randomized Trial

Study Overview
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Brief Summary
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Prospective randomized controlled trial comparing low dose Prednisone(or Prednisolone)/Methotrexate combination to standard dose Prednisone(or Prednisolone) in patients diagnosed with acute active clinically manifest cardiac sarcoidosis and not yet treated. The Investigators hypothesize that low dose Prednisone(or Prednisolone)/Methotrexate combination will be as effective as standard dose Prednisone(or Prednisolone), and result in significantly better quality of life and less toxicity than standard dose Prednisone(or Prednisolone).

Detailed Description
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Subjects meeting the study inclusion/exclusion criteria will be randomized equally to receive either: Everywhere but Japan: Prednisone 0.5 mg kg/day for 6-months (MAX dose 30 mg per day) or Methotrexate 15-20 mg po, sc, or IM once a week for 6-months + Folic Acid 2 mg OD for 6 months + Prednisone 20 mg day for 1 month, then 10 mg OD for 1 month, then 5 mg OD for one month then STOP In Japan: Prednisone or prednisolone 0.5 mg/kg po (max 30mg) for one month then reduce by 5 mg per month for five months or Methotrexate 5-20mg po, sc or IM once week for 6-months +Folic Acid 2-5 mg OD for 6-months+Prednisone or prednisolone 20mg OD for 1 month then 10mg OD for 1 month then 5 mg OD one month Methotrexate will be initiated at a dose of 15 mg once a week and increased to 20 mg once a week after 4 weeks if tolerated. In case of Methotrexate-induced side-effects general guidelines will be provided, however specific management will be left to the treating physicians. Folic acid will be taken to help reduce methotrexate side-effects. Prior to randomization and study treatment all subjects will have the following baseline tests done: baseline safety blood work; FDG-PET scan with myocardial perfusion imaging; ECG; echo; and a bone mineral density scan. Cardiac MRI (CMR) is optional but strongly encouraged. Blood will be obtained for biomarker core-lab analysis. Biomarkers to be assayed will include highly sensitive Troponin I. Samples will be stored for future novel biomarker discovery. Quality of LIfe (QOL) questionnaires (KSQ, SAT and SF-36) will be completed prior to treatment start. After therapy initiation subjects will be seen at 4 weeks, 8 weeks (methotrexate arm only), and 12 weeks, with a final visit at 6 months. Safety bloodwork and assessment for medication side effects, using a medication side-effect questionnaire, will be completed at all visits. At 12 weeks QOL questionnaires will be completed. The primary endpoint will be assessed at 6-months, when FDG-PET with myocardial perfusion imaging, ECG, echo, bone mineral density scan, QOL questionnaires, blood for biomarkers and device interrogation will be done. CMR may be repeated. Skin, muscle strength testing and neuropsychiatric assessment will be completed at 6 months as part of the composite glucocorticoid toxicity index. After the 6 month visit. further management will be at the treating physician's discretion. Details of the physicians planned treatment following the 6-month PET scan will be collected. Standardized protocols for all aspects of FDG-PET scans (i.e. patient preparation, image acquisition, image processing, transfer to the core lab and analysis at core lab) will be followed.

Official Title
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Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial

Conditions
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Cardiac Sarcoidosis, Sarcoidosis

Intervention / Treatment
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* Drug: Prednisone or Prednisolone
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (i) Cardiac sarcoidosis presenting with one or more of the following clinical findings: advanced conduction system disease (defined as Mobitz II AV block or third degree AV block) significant sinus node dysfunction (defined as average HR less than 40bpm when awake and/or sustained atrial arrhythmias) non- sustained or sustained ventricular arrhythmia left ventricular dysfunction (LVEF < 50%) right ventricular dysfunction (RVEF < 40%) AND (ii) No alternative explanation for clinical features AND (iii) FDG-PET uptake suggestive of active CS within two months of enrollment AND Myocardial Perfusion Imaging (MPI) completed (confirmed by PET core lab read) AND ONE OR BOTH OF FOLLOWING (iv) Positive biopsy for Sarcoid (either EMB or extra-cardiac) (v) CT Chest showing features consistent with pulmonary sarcoidosis and/or mediastinal and/or hilar lymphadenopathy Exclusion Criteria: Current or recent (within two months) non-topical treatment for sarcoidosis Currently taking Methotrexate or Prednisone for another health condition Intolerance or contra-indication to Methotrexate or Prednisone Patient does not meet all of the above listed inclusion criteria Patient is unable or unwilling to provide informed consent Patient is included in another randomized clinical trial Patient has a contraindication to PET imaging or is unlikely to tolerate due to severe claustrophobia Pregnancy (all women of child bearing age and potential will have a negative BHCG test before enrollment) Breastfeeding Women of childbearing age who refuse to use a highly effective and medically acceptable form of contraception throughout the study Patients for whom the investigator believes that the trial is not in the interest of the patient

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: Parallel Assignment
Interventional Model Description: Prospective, open-label, non-inferiority, randomized controlled with blinded end-point analysis.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prednisone (or Prednisolone)<br>[Dose everywhere except Japan] Prednisone 0.5 mg kg/day for 6 months (max dose 30 mg) [Dose in Japan] Prednisone or prednisolone 0.5 mg/kg po (max 30mg) for one month then reduce by 5 mg per month for five months | Drug: Prednisone or Prednisolone<br>* Oral prednisone/prednisolone tablet<br>|
| Experimental: Methotrexate<br>[Dose everywhere except Japan] Methotrexate 15-20 mg orally, sc, or IM once a week for 6 months + Prednisone 20 mg po daily for one month then 10 mg po daily for one month then 5 mg po daily for one month and then stop. Also Folic Acid 2 mg po daily for 6 months. [Dose in Japan] Methotrexate 5-20mg mg orally, sc, or IM once a week for 6 months+ Prednisone or Prednisolone 20mg OD for 1 month then 10mg OD for 1 month then 5 mg OD one month. Also Folic Acid 2 mg po daily for 6 months. | Drug: Prednisone or Prednisolone<br>* Oral prednisone/prednisolone tablet<br>Drug: Methotrexate<br>* Oral, subcutaneous, or intramuscular methotrexate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed perfusion rest score (SPRS) on FDG-PET scan | Measure of myocardial scarring and fibrosis (blinded core lab analysis) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | All cause deaths | 6 months | 
| Cardiovascular hospitalizations | Cardiovascular related only | 6 months | 
| Medication related adverse events | Using clinical assessment, medication side-effect and adverse event reporting | 6 months | 
| Modified Cleveland Clinic Glucocorticoid Toxicity Score | Summed score of new/worsening diabetes;new/worsening HTN; osteoporosis; change in height and weight (combined and reported as BMI in kg/m2) | 6 months | 
| Glucocorticoid Toxicity Index | Composite scoring (improvement; no significant change; worsening) compared to baseline | 6 months | 
| Patient reported symptoms related to medication | Using medication side-effect questionnaire ( symptom present, yes or no; frequency; intensity) | 6 months | 
| Medication compliance | % of days where treatment was taken as prescribed | 6 months | 
| Generic Quality of Life (SF 36) | Measuring general QOL using SF-36 questionnaire | 6 months | 
| Disease Specific Quality of Life (KSQ and SAT) | Using Kings Sarcoidosis questionnaire and Sarcoidosis Assessment Tool | 6 months | 
| BMI | Weight and height combined to report BMI in kg/m2, absolute and delta compared to baseline | 6 months | 
| Blood pressure | Systolic and diastolic, absolute and delta compared to baseline | 6 months | 
| HbA1C | Absolute and delta compared to baseline | 6 months | 
| T-score on bone density scan | Absolute and delta compared to baseline | 6 months | 
| FDG-PET and myocardial perfusion | SPRS in mismatched segments; SUVmax, SUVmean and COI; LVEF, RVEF; whole body disease activity | 6 month scan | 
| Ventricular arrhythmia burden | Episodes of sustained ventricular arrhythmia or episodes requiring appropriate ICD therapy (shock or anti-tachycardia pacing) | 6 months | 
| Complete heart block | Percentage of patients who are in CHB | 6 months | 
| LVEF and RVEF assessed on echocardiogram | Ejection fraction, absolute and delta compared to baseline | 6 months | 
| Highly sensitive Troponin I levels and BNP levels | Absolute and delta compared to baseline | 6 months | 
| CMR Endpoints | Volume of delayed enhancement | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiac Sarcoidosis, Prednisone (or Prednisolone), Methotrexate