Clinical trial NCT03593759: Cardiac Sarcoidosis Randomized Trial
Official title: Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Cardiac Sarcoidosis
Sarcoidosis
Keywords: Cardiac Sarcoidosis
Prednisone (or Prednisolone)
Methotrexate
Lead sponsor: Ottawa Heart Institute Research Corporation
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2018-07-20
Enrollment: 194
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, open-label, non-inferiority, randomized controlled with blinded end-point analysis.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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) 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

Exclusion Criteria:

1. Current or recent (within two months) non-topical treatment for sarcoidosis
2. Current Oral/IV treatment of duration greater than 5 days
3. Currently taking Methotrexate or Prednisone for another health condition
4. Intolerance or contra-indication to Methotrexate or Prednisone
5. Patient does not meet all of the above listed inclusion criteria
6. Patient is unable or unwilling to provide informed consent
7. Patient is included in another randomized clinical trial
8. Patient has a contraindication to PET imaging or is unlikely to tolerate due to severe claustrophobia
9. Pregnancy (all women of child bearing age and potential will have a negative BHCG test before enrollment)
10. Breastfeeding
11. Women of childbearing age who refuse to use a highly effective and medically acceptable form of contraception throughout the study
12. Patients for whom the investigator believes that the trial is not in the interest of the patient

Primary outcomes:
measure: Summed perfusion rest score (SPRS) on FDG-PET scan
timeFrame: 6 months
Secondary outcomes:
measure: Mortality
timeFrame: 6 months
measure: Cardiovascular hospitalizations
timeFrame: 6 months
measure: Medication related adverse events
timeFrame: 6 months
measure: Modified Cleveland Clinic Glucocorticoid Toxicity Score
timeFrame: 6 months
measure: Glucocorticoid Toxicity Index
timeFrame: 6 months
measure: Patient reported symptoms related to medication
timeFrame: 6 months
measure: Medication compliance
timeFrame: 6 months
measure: Generic Quality of Life (SF 36)
timeFrame: 6 months
measure: Disease Specific Quality of Life (KSQ and SAT)
timeFrame: 6 months
measure: BMI
timeFrame: 6 months
measure: Blood pressure
timeFrame: 6 months
measure: HbA1C
timeFrame: 6 months
measure: T-score on bone density scan
timeFrame: 6 months
measure: FDG-PET and myocardial perfusion
timeFrame: 6 month scan
measure: Ventricular arrhythmia burden
timeFrame: 6 months
measure: Complete heart block
timeFrame: 6 months
measure: LVEF and RVEF assessed on echocardiogram
timeFrame: 6 months
measure: Highly sensitive Troponin I levels and BNP levels
timeFrame: 6 months
measure: CMR Endpoints
timeFrame: 6 months
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale-New Haven Hospital
state: Connecticut
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan-Michigan Medicine Cardiovascular Center
state: Michigan
city: Minnesota
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Montefiore Medical Center
state: New York
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Calgary
country: Canada
facility: Libin Cardiovascular Institute of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: St. John's
country: Canada
facility: Eastern Health Health Sciences Centre
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: QE II Health Sciences Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: University of Ottawa Heart Institute
state: Ontario
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Montreal
country: Canada
facility: CIUSSS-Hopital du Sacre-Coeur de Montreal
state: Quebec
city: Quebec City
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
state: Quebec
city: Sherbrooke
country: Canada
facility: CIUSSS de l'Estrie - CHUS - Hôpital Fleurimont
state: Quebec
city: Sapporo
country: Japan
facility: Hokkaido University
state: Kita 8, Nishi 5, Kita-Ku
city: Chiba
country: Japan
facility: Chiba University
city: Fukui
country: Japan
facility: University of Fukui
city: Kawasaki
country: Japan
facility: St. Marrianna University
city: Nagoya
country: Japan
facility: Nagoya City University
city: Osaka
country: Japan
facility: National Cerebral and Cardiovascular Center (NCVC)
city: Sapporo
country: Japan
facility: Sapporo Medical University
city: Tokyo
country: Japan
facility: Nippon Medical School
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare Trust-NHS-Hammersmith Hospital
Study officials:
affiliation: Ottawa Heart Institute Research Corporation
name: David H Birnie, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Birnie D, Beanlands RSB, Nery P, Aaron SD, Culver DA, DeKemp RA, Gula L, Ha A, Healey JS, Inoue Y, Judson MA, Juneau D, Kusano K, Quinn R, Rivard L, Toma M, Varnava A, Wells G, Wickremasinghe M, Kron J. Cardiac Sarcoidosis multi-center randomized controlled trial (CHASM CS- RCT). Am Heart J. 2020 Feb;220:246-252. doi: 10.1016/j.ahj.2019.10.003. Epub 2019 Oct 20.