Prednisone/Prednisolone Dosing for Cardiac Sarcoidosis

(CHASM-CS-RCT Trial)

Recruiting at 30 trial locations

Overseen By David H Birnie, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Ottawa Heart Institute Research Corporation

Must not be taking: Methotrexate, Prednisone

Disqualifiers: Pregnancy, Breastfeeding, Claustrophobia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 6 months

194 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you are not currently taking Methotrexate or Prednisone for another health condition, and you must not have received non-topical treatment for sarcoidosis recently (within two months). If you are on these medications, you may need to stop them to participate.

What data supports the effectiveness of the drug combination of Prednisone and Methotrexate for treating cardiac sarcoidosis?

Prednisone is commonly used as a first-line treatment for cardiac sarcoidosis based on clinician experience and small observational studies, while Methotrexate is increasingly used as a steroid-sparing agent in other forms of sarcoidosis. In pulmonary sarcoidosis, Methotrexate has shown significant improvement in symptoms, allowing for the reduction or discontinuation of corticosteroids. ^{1 2 3 4 5}

What safety data exists for Prednisone/Prednisolone in humans?

Prednisone is commonly used for various inflammatory conditions, but it can have side effects like high blood pressure, diabetes, weight gain, bone thinning, and increased risk of infections. Methotrexate, often used as a second-line treatment, generally has fewer side effects compared to Prednisone. ^{3 4 6 7 8}

How does the drug combination of Methotrexate, Prednisone, and Prednisolone for cardiac sarcoidosis differ from other treatments?

This drug combination is unique because it uses Methotrexate as a steroid-sparing agent to potentially reduce the side effects associated with long-term use of glucocorticoids like Prednisone and Prednisolone, which are commonly used in sarcoidosis treatment. While glucocorticoids are the standard treatment, Methotrexate is increasingly used for its better tolerance and fewer side effects. ^{3 4 5 9 10}

What is the purpose of this trial?

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).

Research Team

David H Birnie, MD

Principal Investigator

Ottawa Heart Institute Research Corporation

Eligibility Criteria

This trial is for patients with acute active cardiac sarcoidosis, confirmed by PET scans and biopsies, who haven't been treated yet. They should have specific heart issues like arrhythmias or reduced heart function but can't be pregnant, breastfeeding, or on Methotrexate/Prednisone for other conditions.

Inclusion Criteria

Positive biopsy for Sarcoid (either EMB or extra-cardiac)

My recent PET scan shows active cancer.

I have heart issues due to sarcoidosis, like irregular heartbeats or weak heart muscles.

Exclusion Criteria

Patient is included in another randomized clinical trial

Patient does not meet all of the above listed inclusion criteria

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either low dose Prednisone/Methotrexate combination or standard dose Prednisone for 6 months

6 months

4 visits (in-person) at 4 weeks, 8 weeks (methotrexate arm only), 12 weeks, and 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

1 visit (in-person) at 6 months

Open-label extension (optional)

Further management will be at the treating physician's discretion after the 6-month visit

Treatment Details

Interventions

• Methotrexate
• Prednisone
• Prednisone or Prednisolone

Trial Overview The study compares a low dose combo of Prednisone (or Prednisolone) with Methotrexate to a standard dose of Prednisone alone in treating cardiac sarcoidosis. The goal is to see if the combo works as well while improving life quality and causing less toxicity.

Participant Groups

Group I: Methotrexate Experimental Treatment 2 Interventions

\[Dose everywhere except Japan\] 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.

Group II: Prednisone (or Prednisolone) Active Control 1 Intervention

\[Dose everywhere except Japan\] 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 is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Trexall for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in Canada as Mexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in European Union as Methotrexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis
• Crohn's disease
• Ulcerative colitis

Who Is Running the Clinical Trial?

Ottawa Heart Institute Research Corporation

Lead Sponsor

Trials

200

Recruited

95,800+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Findings from Research

Corticosteroids, particularly prednisone and inhaled budesonide, are the primary treatments for sarcoidosis, showing effectiveness in managing symptoms and improving lung function, especially when used in a tapered regimen over 6 months.

For chronic or resistant cases of sarcoidosis, alternative treatments like methotrexate and infliximab have demonstrated significant benefits, allowing some patients to discontinue corticosteroids and achieve long-lasting remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapeutic management of pulmonary sarcoidosis. Fazzi, P.[2019]

Corticosteroids are commonly used to treat sarcoidosis, especially in cases involving cardiac, neurologic, or eye disease, but some patients may not respond well or may experience adverse effects.

Methotrexate and azathioprine are preferred alternative treatments for sarcoidosis due to their safety and efficacy, although there is no clear consensus on when to use these cytotoxic agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Non-steroid therapy for sarcoidosis]. Konishi, M., Yoneda, K., Takahashi, K., et al.[2013]

In a study of 61 newly diagnosed cardiac sarcoidosis patients, treatment with prednisone, methotrexate, or a combination of both led to significant reductions in myocardial FDG uptake, indicating effective metabolic response after 6 months.

No significant differences in clinical outcomes or major adverse cardiovascular events were observed among the treatment groups, suggesting that methotrexate may be a viable steroid-sparing option in managing cardiac sarcoidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prednisone vs methotrexate in treatment naïve cardiac sarcoidosis. Vis, R., Mathijssen, H., Keijsers, RGM., et al.[2023]

The CHASM CS-RCT is the first randomized controlled trial aimed at evaluating treatment strategies for cardiac sarcoidosis, comparing a low-dose prednisone/methotrexate combination to standard-dose prednisone in 194 patients with active cardiac involvement.

The study hypothesizes that the combination therapy will not only be equally effective but also improve patients' quality of life by reducing the side effects commonly associated with higher doses of prednisone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac Sarcoidosis multi-center randomized controlled trial (CHASM CS- RCT). Birnie, D., Beanlands, RSB., Nery, P., et al.[2021]

In a study of 58 sarcoidosis patients, 55 were successfully treated with prednisolone therapy over one to two years, indicating its efficacy in managing the condition.

Synthetic ACTH was safely administered to 23 patients either alone or with corticosteroids, showing no side effects and suggesting it can effectively replace corticosteroids in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sarcoidosis therapy with cortisone and ACTH--the role of ACTH therapy. Mariani, B.[2013]

In a survey of 56 patients with pulmonary sarcoidosis, those taking prednisone reported significantly more side effects (78%) compared to those on methotrexate (49%), suggesting that methotrexate may be a safer alternative.

The study highlights the need for a larger prospective study to confirm these findings, as methotrexate appears to have fewer and less bothersome side effects than the first-line treatment, prednisone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient reported side-effects of prednisone and methotrexate in a real-world sarcoidosis population. Kahlmann, V., Moor, CC., Veltkamp, M., et al.[2021]

In a study of 200 sarcoidosis patients, both methotrexate and azathioprine effectively reduced the need for prednisone, with 70% of patients achieving a decrease of at least 10 mg in their daily prednisone dose after one year.

While both treatments improved lung function, methotrexate and azathioprine had similar side effects, except that the azathioprine group experienced a higher rate of infections (34.6% vs 18.1%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Vorselaars, ADM., Wuyts, WA., Vorselaars, VMM., et al.[2017]

Prednisone has been effectively used for over 60 years to treat inflammatory conditions like rheumatoid arthritis, and recent clinical trials have shifted its use towards long-term low-dose regimens.

Current research is focusing on the safety and effectiveness of these low-dose treatments, including insights from the 2nd Circadian Administration of Prednisone trial, which explores the benefits of modified-release formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The current relevance and use of prednisone in rheumatoid arthritis. Krasselt, M., Baerwald, C.[2015]

Glucocorticosteroids, particularly prednisolone at doses of 30-60 mg/day, are the primary treatment for sarcoidosis, with various administration routes available, including oral and inhaled options for pulmonary cases.

Other steroid-sparing medications like methotrexate and azathioprine can be effective alternatives, especially for patients requiring long-term treatment, which may last from 6 months to a lifetime depending on disease activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of sarcoidosis. Selroos, O.[2013]

In a trial involving 40 sarcoidosis patients treated with intramuscular triamcinolone acetonide (Kenacort A), the treatment showed a higher rate of improvement in chest findings compared to oral prednisolone, indicating its efficacy.

The intramuscular treatment also resulted in fewer side effects and a significant improvement in ocular lesions, suggesting it may be a safer alternative to oral corticosteroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parenteral treatment of sarcoidosis with triamcinolone. Mikami, R., Hiraga, Y., Yotsumoto, H., et al.[2013]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacotherapeutic management of pulmonary sarcoidosis. [2019]

2. Japan pubmed.ncbi.nlm.nih.gov

[Non-steroid therapy for sarcoidosis]. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Prednisone vs methotrexate in treatment naïve cardiac sarcoidosis. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Cardiac Sarcoidosis multi-center randomized controlled trial (CHASM CS- RCT). [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Sarcoidosis therapy with cortisone and ACTH--the role of ACTH therapy. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Patient reported side-effects of prednisone and methotrexate in a real-world sarcoidosis population. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Methotrexate vs azathioprine in second-line therapy of sarcoidosis. [2017]

8. England pubmed.ncbi.nlm.nih.gov

The current relevance and use of prednisone in rheumatoid arthritis. [2015]

9. Italy pubmed.ncbi.nlm.nih.gov

Treatment of sarcoidosis. [2013]

10. Germany pubmed.ncbi.nlm.nih.gov

Parenteral treatment of sarcoidosis with triamcinolone. [2013]