Prednisone/Prednisolone Dosing for Cardiac Sarcoidosis

(CHASM-CS-RCT Trial)

Recruiting at 32 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treating cardiac sarcoidosis, a heart condition that can cause heart rhythm problems and weakness. Researchers aim to determine if a lower dose of Prednisone (a medication used to reduce inflammation) combined with Methotrexate (another anti-inflammatory drug) is as effective as a higher dose of Prednisone alone, but with fewer side effects. Individuals diagnosed with active cardiac sarcoidosis and experiencing heart rhythm issues or heart weakness might be suitable candidates. Participants should not have received recent non-topical treatment for sarcoidosis or be currently taking Methotrexate or Prednisone for another condition. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Methotrexate and Prednisone (or Prednisolone) have been studied for safety in treating sarcoidosis, including its impact on the heart. Methotrexate carries a lower risk of causing infections compared to azathioprine. One study found a 6.8% infection risk with Methotrexate over six months, compared to a 12% risk with azathioprine, suggesting Methotrexate is relatively safe for people with sarcoidosis.

Prednisone (or Prednisolone) is often used to treat heart-related sarcoidosis. It is effective, but high doses over a long period can cause side effects. The study aims to determine if using a lower dose with Methotrexate can reduce these side effects while maintaining effectiveness.

Overall, research supports that these treatments are generally well-tolerated. However, it is important to consult a doctor about any concerns before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for cardiac sarcoidosis because they explore different dosing strategies and combinations of existing medications to improve patient outcomes. Methotrexate, combined with varying doses of Prednisone or Prednisolone, offers a potentially more effective approach by using a lower steroid dose, which can reduce side effects. Additionally, the trial includes specific dosing adjustments for Japanese patients, acknowledging and addressing potential regional differences in drug metabolism and response. This tailored approach might lead to more personalized and effective treatment plans for patients with this challenging heart condition.

What evidence suggests that this trial's treatments could be effective for cardiac sarcoidosis?

In this trial, participants will receive either Prednisone (or Prednisolone) or Methotrexate as part of their treatment for cardiac sarcoidosis. Research has shown that prednisone, a type of steroid, effectively treats cardiac sarcoidosis and can help reduce long-term health problems in patients with good heart function. However, prednisone can cause serious side effects, especially at higher doses. Methotrexate, used in this trial alongside a reduced dose of prednisone, can help manage cardiac sarcoidosis. Studies suggest that methotrexate may help control the condition and lower the risk of recurrence. Using a lower dose of prednisone with methotrexate might provide effective treatment while reducing side effects. ^{6 7 8 9 10}

Who Is on the Research Team?

David H Birnie, MD

Principal Investigator

Ottawa Heart Institute Research Corporation

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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 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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39724230/

Comparative effectiveness of disease-modifying antirheumatic ... Among patients with cardiac sarcoidosis at baseline, the risk of serious cardiac outcomes was similar for patients who initiated therapy with ...

2. resmedjournal.com resmedjournal.com/article/S0954-6111(25)00188-X/fulltext

Durable remission of cardiac sarcoidosis following ... Cardiac relapse after MTX discontinuation occurred in 1 of 12 patients (16.7 %). ... Extra-cardiac relapse occurred in 4 of 12 patients (33.3 %).

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9195226/

Effectiveness of methotrexate as a second-line treatment ... Although methotrexate has been widely used as a second-line therapy for cardiac sarcoidosis (CS), it is not clear if it has a direct anti-inflammatory effect.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2352906724001398

Cardiac sarcoidosis treated with nonsteroidal ... Clinical outcomes were observed in 11 patients (42.3 %). Detected events included all-cause death in five patients (19.2 %), FVAE in four (15.4 %), and ...

5. jacc.org jacc.org/doi/10.1016/j.jcmg.2023.11.017

Methotrexate in Cardiac Sarcoidosis: Absence of Evidence ... In a retrospective experience, Rosenthal et al2 demonstrated a beneficial CS-sparing effect of MTX in cardiac sarcoidosis at 20 mg weekly.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8247001/

Infection risk in sarcoidosis patients treated with ... The 6-month infection risk was 43% lower in patients with sarcoidosis who initiated methotrexate compared to those who started azathioprine.

7. sciencedirect.com sciencedirect.com/science/article/pii/S095461112500188X

Durable remission of cardiac sarcoidosis following ... Our study found that after more than three years of MTX, then a trial of therapy discontinuation, only 1/12 patients had a cardiac relapse (with extra-cardiac ...

8. jacc.org jacc.org/doi/10.1016/j.jcmg.2024.02.004

Methotrexate in Cardiac Sarcoidosis: Absence of Evidence ... This prospective study is the first to evaluate MTX in patients who have poorly responded to prednisolone, and safety is an important consideration.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9437759/

Controversies in the Treatment of Cardiac Sarcoidosis - PMC The adjusted 6-month risk of infection in the methotrexate group was 6.8% compared to 12% in the azathio-prine group(86). The recommended starting/maintenance ...

10. journal.houstonmethodist.org journal.houstonmethodist.org/articles/10.14797/mdcvj.1068

State-of-the-Art Treatments for Sarcoidosis Additionally, MTX has proven effective in neurosarcoidosis, cardiac disease, skin, eye, and disrupted calcium metabolism. It is given at a total dose of 15 mg ...