Cardiac Sarcoidosis Randomized Trial (CHASM-CS-RCT)

• ClinicalTrials.gov Identifier: NCT03593759
• Recruitment Status: Recruiting
• First Posted: July 20, 2018
• Last Update Posted: July 25, 2023
• Sponsor: Ottawa Heart Institute Research Corporation
• Collaborator: Canadian Institutes of Health Research (CIHR)
• Information provided by (Responsible Party): Ottawa Heart Institute Research Corporation

Tracking Information

• First Submitted Date: June 27, 2018
• First Posted Date: July 20, 2018
• Last Update Posted Date: July 25, 2023
• Actual Study Start Date: January 15, 2019
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 10, 2018)

Summed perfusion rest score (SPRS) on FDG-PET scan [ Time Frame: 6 months ]

Measure of myocardial scarring and fibrosis (blinded core lab analysis)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 10, 2018)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cardiac Sarcoidosis Randomized Trial
• Official Title: Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial

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 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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Prospective, open-label, non-inferiority, randomized controlled with blinded end-point analysis.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Cardiac Sarcoidosis
• Sarcoidosis

Intervention

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

Study Arms

• Active Comparator: 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

  Intervention: Drug: Prednisone or Prednisolone
• Experimental: 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 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.

  Interventions:

  • Drug: Prednisone or Prednisolone
  • Drug: Methotrexate

• Publications *: 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 10, 2018): 194
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

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) 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: David H Birnie, MD; 613-696-7269; dbirnie@ottawaheart.ca

Contact: Janine Ryan, BAH, CCRP; 613-696-7000 ext 17077; jryan@ottawaheart.ca

• Listed Location Countries: Canada, Japan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03593759
• Other Study ID Numbers: UOttawaHI
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Ottawa Heart Institute Research Corporation
• Original Responsible Party: Same as current
• Current Study Sponsor: Ottawa Heart Institute Research Corporation
• Original Study Sponsor: Same as current
• Collaborators: Canadian Institutes of Health Research (CIHR)

Investigators

• Principal Investigator: David H Birnie, MD; Ottawa Heart Institute Research Corporation

• PRS Account: Ottawa Heart Institute Research Corporation
• Verification Date: July 2023