CHASM-CS-RCT: Cardiac Sarcoidosis Randomized Trial

• Sponsor: Ottawa Heart Institute Research Corporation (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT03593759
• Collaborator: Canadian Institutes of Health Research (CIHR) (Other)
• Enrollment: 194
• Locations: 18
• Arms: 2
• Anticipated Duration (Months): 70.5
• Patients Per Site: 10.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Cardiac Sarcoidosis; Sarcoidosis	Drug: Prednisone or Prednisolone; Drug: Methotrexate	Phase 3

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 Design

• Study Type: Interventional
• Anticipated Enrollment: 194 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Prospective, open-label, non-inferiority, randomized controlled with blinded end-point analysis.Prospective, open-label, non-inferiority, randomized controlled with blinded end-point analysis.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial
• Actual Study Start Date: Jan 15, 2019
• Anticipated Primary Completion Date: Dec 1, 2023
• Anticipated Study Completion Date: Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
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	Drug: Prednisone or Prednisolone; Oral prednisone/prednisolone tablet
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.	Drug: Prednisone or Prednisolone; Oral prednisone/prednisolone tablet; Drug: Methotrexate; Oral, subcutaneous, or intramuscular methotrexate

Outcome Measures

Primary Outcome Measures

1. Summed perfusion rest score (SPRS) on FDG-PET scan [6 months]

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

Secondary Outcome Measures

1. Mortality [6 months]

   All cause deaths

2. Cardiovascular hospitalizations [6 months]

   Cardiovascular related only

3. Medication related adverse events [6 months]

   Using clinical assessment, medication side-effect and adverse event reporting

4. 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)

5. Glucocorticoid Toxicity Index [6 months]

   Composite scoring (improvement; no significant change; worsening) compared to baseline

6. Patient reported symptoms related to medication [6 months]

   Using medication side-effect questionnaire ( symptom present, yes or no; frequency; intensity)

7. Medication compliance [6 months]

   % of days where treatment was taken as prescribed

8. Generic Quality of Life (SF 36) [6 months]

   Measuring general QOL using SF-36 questionnaire

9. Disease Specific Quality of Life (KSQ and SAT) [6 months]

   Using Kings Sarcoidosis questionnaire and Sarcoidosis Assessment Tool

10. BMI [6 months]

    Weight and height combined to report BMI in kg/m2, absolute and delta compared to baseline

11. Blood pressure [6 months]

    Systolic and diastolic, absolute and delta compared to baseline

12. HbA1C [6 months]

    Absolute and delta compared to baseline

13. T-score on bone density scan [6 months]

    Absolute and delta compared to baseline

14. FDG-PET and myocardial perfusion [6 month scan]

    SPRS in mismatched segments; SUVmax, SUVmean and COI; LVEF, RVEF; whole body disease activity

15. Ventricular arrhythmia burden [6 months]

    Episodes of sustained ventricular arrhythmia or episodes requiring appropriate ICD therapy (shock or anti-tachycardia pacing)

16. Complete heart block [6 months]

    Percentage of patients who are in CHB

17. LVEF and RVEF assessed on echocardiogram [6 months]

    Ejection fraction, absolute and delta compared to baseline

18. Highly sensitive Troponin I levels and BNP levels [6 months]

    Absolute and delta compared to baseline

19. CMR Endpoints [6 months]

    Volume of delayed enhancement

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 (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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale-New Haven Hospital	New Haven	Connecticut	United States	06520
2	University of Michigan-Michigan Medicine Cardiovascular Center	Ann Arbor	Michigan	United States	48109-5853
3	The Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
4	Virginia Commonwealth University	Richmond	Virginia	United States	23298-0053
5	Libin Cardiovascular Institute of Alberta	Calgary	Alberta	Canada	T2N 2T9
6	St. Paul's Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
7	Eastern Health Health Sciences Centre	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
8	St. Joseph's Healthcare Centre	Hamilton	Ontario	Canada	L8N 4A6
9	London Health Sciences Centre	London	Ontario	Canada	N6A 4A5
10	University of Ottawa Heart Institute	Ottawa	Ontario	Canada	K1Y 4W7
11	University Health Network	Toronto	Ontario	Canada	M5G 2C4
12	Montreal Heart Institute	Montreal	Quebec	Canada	H1T 1C8
13	CIUSSS-Hopital du Sacre-Coeur de Montreal	Montreal	Quebec	Canada	H4J 1C5
14	Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval	Quebec City	Quebec	Canada	G1V 4G5
15	CIUSSS de l'Estrie - CHUS - Hôpital Fleurimont	Sherbrooke	Quebec	Canada	J1H 5N4
16	Hokkaido University	Sapporo	Kita 8, Nishi 5, Kita-Ku	Japan	060-0808
17	King's College Hospital NHS Foundation Trust	London		United Kingdom	SE5 9RS
18	Imperial College Healthcare Trust-NHS-Hammersmith Hospital	London		United Kingdom	W12 0HS

Sponsors and Collaborators

• Ottawa Heart Institute Research Corporation
• Canadian Institutes of Health Research (CIHR)

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ottawa Heart Institute Research Corporation
• ClinicalTrials.gov Identifier: NCT03593759
• Other Study ID Numbers: UOttawaHI
• First Posted: Jul 20, 2018
• Last Update Posted: Oct 26, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Keywords provided by Ottawa Heart Institute Research Corporation: Cardiac Sarcoidosis; Prednisone (or Prednisolone); Methotrexate
• Additional relevant MeSH terms: Sarcoidosis; Prednisone; Prednisolone; Methotrexate

Study Results

No Results Posted as of Oct 26, 2021