Cardiac Sarcoidosis Randomized Trial

Sarcoidosis Clinical Trial

— CHASM-CS-RCT  

Official title:

Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03593759
• Other study ID #: UOttawaHI
• Status: Recruiting
• Phase: Phase 3
• Start date: January 15, 2019
• Est. completion date: December 2025

Study information

• Verified date: July 2023
• Source: Ottawa Heart Institute Research Corporation
• Contact: David H Birnie, MD
• Phone: 613-696-7269
• Email: dbirnie[@]ottawaheart.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 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:

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 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 194
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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:

1. Current or recent (within two months) non-topical treatment for sarcoidosis

2. Currently taking Methotrexate or Prednisone for another health condition

3. Intolerance or contra-indication to Methotrexate or Prednisone

4. Patient does not meet all of the above listed inclusion criteria

5. Patient is unable or unwilling to provide informed consent

6. Patient is included in another randomized clinical trial

7. Patient has a contraindication to PET imaging or is unlikely to tolerate due to severe claustrophobia

8. Pregnancy (all women of child bearing age and potential will have a negative BHCG test before enrollment)

9. Breastfeeding

10. Women of childbearing age who refuse to use a highly effective and medically acceptable form of contraception throughout the study

11. Patients for whom the investigator believes that the trial is not in the interest of the patient

Related Conditions & MeSH terms

• Cardiac Sarcoidosis
• Sarcoidosis

Intervention

Drug:
• Prednisone or Prednisolone
Oral prednisone/prednisolone tablet
• Methotrexate
Oral, subcutaneous, or intramuscular methotrexate

Locations

Country	Name	City	State
Canada	Libin Cardiovascular Institute of Alberta	Calgary	Alberta
Canada	QE II Health Sciences Centre	Halifax	Nova Scotia
Canada	St. Joseph's Healthcare Centre	Hamilton	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	CIUSSS-Hopital du Sacre-Coeur de Montreal	Montreal	Quebec
Canada	Montreal Heart Institute	Montreal	Quebec
Canada	University of Ottawa Heart Institute	Ottawa	Ontario
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	Eastern Health Health Sciences Centre	St. John's	Newfoundland and Labrador
Canada	University Health Network	Toronto	Ontario
Canada	St. Paul's Hospital	Vancouver	British Columbia
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	Hokkaido University	Sapporo	Kita 8, Nishi 5, Kita-Ku
Japan	Sapporo Medical University	Sapporo
Japan	Nippon Medical School	Tokyo
United Kingdom	Imperial College Healthcare Trust-NHS-Hammersmith Hospital	London
United Kingdom	King's College Hospital NHS Foundation Trust	London
United States	University of Michigan-Michigan Medicine Cardiovascular Center	Ann Arbor	Michigan
United States	Tufts Medical Center	Boston	Massachusetts
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	University of Minnesota	Minnesota	Minnesota
United States	Yale-New Haven Hospital	New Haven	Connecticut
United States	Montefiore Medical Center	New York	New York
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Virginia Commonwealth University	Richmond	Virginia
United States	University of Utah	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
Ottawa Heart Institute Research Corporation	Canadian Institutes of Health Research (CIHR)

Countries where clinical trial is conducted

United States,  Canada,  Japan,  United Kingdom, 

Outcome

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