Cardiac Sarcoidosis Randomized Trial
- Conditions
- SarcoidosisCardiac Sarcoidosis
- Interventions
- Registration Number
- NCT03593759
- Lead Sponsor
- Ottawa Heart Institute Research Corporation
- Brief Summary
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
Subjects meeting the study inclusion/exclusion criteria will be randomized equally to receive either:
Everywhere but Japan:
1. Prednisone 0.5 mg kg/day for 6-months (MAX dose 30 mg per day) or
2. Methotrexate 15-20 mg po, sc, or IM once a week for 6-months + Folic Acid OD (exact dose and directions at physician) 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:
1. Prednisone or prednisolone 0.5 mg/kg po (max 30mg) for one month then reduce by 5 mg per month for five months or
2. 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 an optional 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, optional 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 194
(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) Nuclear Imaging within six-months of enrollment consisting of FDG-PET scan with FDG uptake suggestive of active CS and myocardial perfusion imaging
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
- Current or recent (within two months) non-topical treatment for sarcoidosis
- Current Oral/IV treatment of duration greater than 5 days
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Prednisone (or Prednisolone) Prednisone or Prednisolone \[Dose everywhere except Japan\] 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 Methotrexate Prednisone or Prednisolone \[Dose everywhere except Japan\] 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 OD (exact dose and directions at physicians discretion) 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. Methotrexate Methotrexate \[Dose everywhere except Japan\] 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 OD (exact dose and directions at physicians discretion) 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.
- Primary Outcome Measures
Name Time Method Summed perfusion rest score (SPRS) on FDG-PET scan 6 months Measure of myocardial scarring and fibrosis (blinded core lab analysis)
- Secondary Outcome Measures
Name Time Method Mortality 6 months All cause deaths
LVEF and RVEF assessed on echocardiogram 6 months Ejection fraction, absolute and delta compared to baseline
Highly sensitive Troponin I levels and BNP levels 6 months Absolute and delta compared to baseline
Patient reported symptoms related to medication 6 months Using medication side-effect questionnaire ( symptom present, yes or no; frequency; intensity)
Disease Specific Quality of Life (KSQ and SAT) 6 months Using Kings Sarcoidosis questionnaire and Sarcoidosis Assessment Tool
BMI 6 months Weight and height combined to report BMI in kg/m2, absolute and delta compared to baseline
Generic Quality of Life (SF 36) 6 months Measuring general QOL using SF-36 questionnaire
Complete heart block 6 months Percentage of patients who are in CHB
Medication related adverse events 6 months Using clinical assessment, medication side-effect and adverse event reporting
Medication compliance 6 months % of days where treatment was taken as prescribed
Blood pressure 6 months Systolic and diastolic, absolute and delta compared to baseline
HbA1C 6 months Absolute and delta compared to baseline
Ventricular arrhythmia burden 6 months Episodes of sustained ventricular arrhythmia or episodes requiring appropriate ICD therapy (shock or anti-tachycardia pacing)
Cardiovascular hospitalizations 6 months Cardiovascular related only
Modified Cleveland Clinic Glucocorticoid Toxicity Score 6 months Summed score of new/worsening diabetes;new/worsening HTN; osteoporosis; change in height and weight (combined and reported as BMI in kg/m2)
Glucocorticoid Toxicity Index 6 months Composite scoring (improvement; no significant change; worsening) compared to baseline
T-score on bone density scan 6 months Absolute and delta compared to baseline
FDG-PET and myocardial perfusion 6 month scan SPRS in mismatched segments; SUVmax, SUVmean and COI; LVEF, RVEF; whole body disease activity
CMR Endpoints 6 months Volume of delayed enhancement
Trial Locations
- Locations (30)
Yale-New Haven Hospital
🇺🇸New Haven, Connecticut, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
University of Michigan-Michigan Medicine Cardiovascular Center
🇺🇸Ann Arbor, Michigan, United States
University of Minnesota
🇺🇸Minnesota, Minnesota, United States
Montefiore Medical Center
🇺🇸New York, New York, United States
The Ohio State University Wexner Medical Center
🇺🇸Columbus, Ohio, United States
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
St. Joseph's Healthcare Centre
🇨🇦Hamilton, Ontario, Canada
London Health Sciences Centre
🇨🇦London, Ontario, Canada
University of Utah
🇺🇸Salt Lake City, Utah, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
Libin Cardiovascular Institute of Alberta
🇨🇦Calgary, Alberta, Canada
St. Paul's Hospital
🇨🇦Vancouver, British Columbia, Canada
Eastern Health Health Sciences Centre
🇨🇦St. John's, Newfoundland and Labrador, Canada
QE II Health Sciences Centre
🇨🇦Halifax, Nova Scotia, Canada
University of Ottawa Heart Institute
🇨🇦Ottawa, Ontario, Canada
Montreal Heart Institute
🇨🇦Montreal, Quebec, Canada
CIUSSS-Hopital du Sacre-Coeur de Montreal
🇨🇦Montreal, Quebec, Canada
Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
🇨🇦Quebec City, Quebec, Canada
CIUSSS de l'Estrie - CHUS - Hôpital Fleurimont
🇨🇦Sherbrooke, Quebec, Canada
Hokkaido University
🇯🇵Sapporo, Kita 8, Nishi 5, Kita-Ku, Japan
Chiba University
🇯🇵Chiba, Japan
University of Fukui
🇯🇵Fukui, Japan
St. Marrianna University
🇯🇵Kawasaki, Japan
Nagoya City University
🇯🇵Nagoya, Japan
National Cerebral and Cardiovascular Center (NCVC)
🇯🇵Osaka, Japan
Sapporo Medical University
🇯🇵Sapporo, Japan
Nippon Medical School
🇯🇵Tokyo, Japan
King's College Hospital NHS Foundation Trust
🇬🇧London, United Kingdom
Imperial College Healthcare Trust-NHS-Hammersmith Hospital
🇬🇧London, United Kingdom