Treatments Comparison for Skin Vasculitis

(ARAMIS Trial)

Recruiting at 8 trial locations

Overseen By Carol McAlear, MA

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Disqualifiers: Systemic vasculitis, Auto-immune conditions, Cancer, Infections, others

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

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

Compensation: Varies

Number of Visits: 11

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of three medications—Azathioprine (an immunosuppressant), Colchicine, and Dapsone—for treating skin vasculitis, a condition that inflames blood vessels in the skin. The goal is to determine which treatment works best for individuals with isolated skin vasculitis, without affecting other organs. Participants will be randomly assigned to one of these treatments and may switch if the initial treatment proves ineffective. This trial may suit someone with active or recurring skin vasculitis for at least a month, confirmed by a skin biopsy. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant findings.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but if you are taking prednisone for skin vasculitis, you will need to stop it within 6 weeks after starting the study drug, following a specific tapering schedule. If you are on a low and stable dose of glucocorticoids for other conditions, you can continue that dose during the study.

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

Previous studies have raised safety concerns about azathioprine. It can weaken the immune system, increasing susceptibility to infections. Some individuals have reported skin rashes as a reaction to the drug. Long-term use may also pose a risk of certain cancers, such as skin cancer and lymphoma, a type of blood cancer.

Colchicine, often used for various skin conditions, can also cause side effects. The most common issues include stomach problems like pain, diarrhea, and nausea, affecting up to 80% of those taking the highest dose.

Dapsone is another treatment option, with common side effects such as stomach issues, headaches, and changes in liver function. Some individuals might experience serious reactions like methemoglobinemia, a blood condition.

Discussing these potential side effects with a doctor is important to weigh the benefits and risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for skin vasculitis because they offer diverse approaches compared to traditional options like corticosteroids and immunosuppressants. Azathioprine works by suppressing the immune system more selectively, potentially reducing inflammation with fewer side effects. Colchicine, commonly used for gout, may offer an anti-inflammatory benefit by disrupting white blood cell activity in a novel way for vasculitis. Dapsone, known for treating leprosy, acts as both an anti-inflammatory and an antibacterial agent, providing a unique dual action that might better address the symptoms of skin vasculitis. These varied mechanisms give hope for improved outcomes and personalized treatment strategies.

What evidence suggests that this trial's treatments could be effective for skin vasculitis?

This trial will compare the effectiveness of azathioprine, colchicine, and dapsone for treating skin vasculitis. Research has shown that azathioprine, one of the treatments participants may receive, works well for this condition. Specifically, one study reported that 88% of patients experienced complete symptom resolution after 18 months. Colchicine, another treatment option in this trial, also appears promising. Some reports suggest it quickly controls skin vasculitis when patients resume it after a break, though evidence of its effectiveness is less consistent. Dapsone, the third treatment under study, has effectively managed symptoms in patients with moderate cases. Overall, these treatments have varying levels of success, with azathioprine having the strongest supporting evidence. ^{1 6 7 8 9}

Who Is on the Research Team?

Christian Pagnoux, MD, MPH, MSc

Principal Investigator

University of Toronto/Mount Sinai Hospital

Robert Micheletti, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

Adults with isolated skin vasculitis, confirmed by biopsy, lasting at least 1 month or having multiple flares. Eligible participants have primary skin vasculitis without serious extra-skin symptoms and may have used steroids before joining. Excluded are those with contraindications to the study drugs, systemic vasculitis signs, active cancer in the last 5 years, severe infections or organ insufficiency.

Inclusion Criteria

I have a specific type of skin vasculitis without kidney problems.

I have a skin condition without serious effects on other body parts.

My vasculitis was confirmed by a skin biopsy.

Exclusion Criteria

I cannot take or have not responded to two or three of the drugs in this study.

I have a G6PD deficiency or a history of hemolytic anemia.

My kidneys are not working well, with a creatinine clearance below 60 mL/min.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Stage 1

Participants are randomized to receive one of three medications (colchicine, dapsone, or azathioprine) for 6 months

6 months

Visits at months 1, 3, and 6

Follow-up

Participants are monitored for response to treatment and side effects

6 months

Visits at months 9 and 12

Treatment Stage 2

Participants who discontinue the initial treatment are re-randomized to receive one of the remaining two medications for another 6 months

6 months

Visits at months 1, 3, and 6 of stage 2

What Are the Treatments Tested in This Trial?

Interventions

• Azathioprine
• Colchicine
• Dapsone

Trial Overview The trial is testing three treatments for skin vasculitis: Colchicine, Dapsone, and Azathioprine. It's a multi-center study where patients are randomly assigned to receive one of these standard care options to compare their effectiveness.

How Is the Trial Designed?

Group I: Stage 2 Experimental Treatment 3 Interventions

If the patient has to discontinue the study drug within the (stage 1) 6 month study period or during the subsequent follow-up period (up to month 12) because of a lack of response (or failure), flare or side effect, he/she will be randomized again to receive one of the remaining two study drugs (stage 2, with a 1:1 randomization ratio, colchicine 0.6 mg x 2/day; dapsone 150 mg/day; azathioprine 2 mg/kg/day) for 6 months. Endpoint in this second stage will again be the response to treatment at 6 months.

Group II: Stage 1 Experimental Treatment 3 Interventions

Eligible patients will be initially randomized (1:1:1) to receive one of the 3 medications under investigation (colchicine 0.6 mg x 2/day; dapsone 150 mg/day; azathioprine 2 mg/kg/day) for 6 months. Endpoint is response to treatment at month 6 (stage 1).

Azathioprine is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Imuran for:

• Prevention of rejection in organ transplantation
• Treatment of autoimmune diseases such as rheumatoid arthritis

Approved in United States as Imuran for:

• Prevention of rejection in organ transplantation
• Treatment of rheumatoid arthritis

Approved in Canada as Imuran for:

• Prevention of rejection in organ transplantation
• Treatment of rheumatoid arthritis

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Collaborator

Trials

508

Recruited

1,090,000+

Office of Rare Diseases (ORD)

Collaborator

Trials

44

Recruited

12,400+

National Center for Advancing Translational Sciences (NCATS)

Collaborator

Trials

394

Recruited

404,000+

Published Research Related to This Trial

The treatment approach for leukocytoclastic immune-complex vasculitis (LcV) varies based on the presence of IgA in immune complexes, with IgG- or IgM-associated LcV generally having a better prognosis and often requiring only symptomatic treatment.

In cases of severe conditions like ANCA-associated systemic vasculitis and giant cell arteriitis, rapid and aggressive treatment with glucocorticoids is crucial for improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapy of vasculitides and vasculopathies]. Sunderkötter, C., de Groot, K.[2021]

Two patients with a rare form of discoid lupus erythematosus affecting only the palms and soles did not respond to standard treatments, highlighting the challenges in managing this condition.

Both patients showed significant improvement when treated with azathioprine after failing conventional therapies, suggesting that azathioprine may be an effective option for difficult-to-treat cases of this disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resistant discoid lupus erythematosus of palms and soles: successful treatment with azathioprine. Ashinoff, R., Werth, VP., Franks, AG.[2019]

Dapsone, traditionally used for leprosy, showed rapid improvement in two patients with cutaneous dermatomyositis who were unresponsive to other treatments, indicating its potential efficacy in this condition.

Both patients experienced exacerbations of their symptoms upon withdrawal of Dapsone, which improved again when the medication was reintroduced, suggesting a strong therapeutic response linked to Dapsone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous involvement of dermatomyositis can respond to Dapsone therapy. Cohen, JB.[2019]

A woman with severe cutaneous necrotizing vasculitis for over 10 years did not respond to various immunosuppressants, including cyclophosphamide, indicating the complexity and treatment resistance of this condition.

Treatment with DADPS (dapsone) resulted in complete remission of her chronic vasculitic ulcerations, suggesting that dapsone may be an effective option for managing severe cases of cutaneous vasculitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Refractory cutaneous necrotizing vasculitis. Successful sulfone therapy]. Seybold, H., Simon, M., Schuler, G., et al.[2018]

In four patients with pemphigus vulgaris, while high-dose prednisone was initially effective, adding azathioprine did not help reduce steroid doses and even worsened the disease, highlighting its limited efficacy in this context.

The combination of cyclophosphamide and dapsone with prednisone led to clinical and serologic remission without significant side effects, suggesting that cyclophosphamide can be a valuable alternative treatment when azathioprine fails.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of cyclophosphamide in azathioprine failures in pemphigus. Ahmed, AR., Hombal, S.[2019]

Mycophenolate mofetil is emerging as a safer alternative to azathioprine for treating autoimmune bullous diseases like bullous pemphigoid and pemphigus vulgaris, as it has a lower risk of myelosuppression and hepatotoxicity.

While cyclophosphamide remains effective for severe cases, its high cumulative dose raises safety concerns, highlighting the need for randomized controlled studies to compare its efficacy and safety against newer treatments like rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppressive therapy for autoimmune bullous diseases. Meurer, M.[2021]

Dapsone was used to treat chronic purpuric skin lesions in three children with Henoch-Schönlein purpura, leading to fast and complete healing of the lesions.

One child experienced methemoglobinemia, a known side effect of dapsone, emphasizing the importance of careful prescription and monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Dapsone for chronic skin lesions in 3 children suffering from Henoch-Schönlein vasculitis]. Mazille, N., Lipsker, D., Fischbach, M.[2021]

A 10-year-old boy with immunoglobulin A vasculitis (IgAV) experienced prolonged skin symptoms that were resistant to multiple treatments, but he achieved remission with colchicine after 12 months of illness.

Colchicine was effective in controlling the boy's chronic cutaneous manifestations without causing adverse effects, highlighting its potential as a beneficial treatment for IgAV patients with similar symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of IgA vasculitis with prolonged cutaneous manifestation with colchicine in a 10-year-old boy. Okura, Y., Hiramatsu, Y., Shimomura, M., et al.[2022]

Azathioprine is favored by dermatologists for its good safety profile and effectiveness in treating conditions like bullous pemphigoid and chronic eczematous dermatitides, making it a preferred choice for many skin diseases.

Cyclophosphamide, while more toxic, is justified for severe diseases such as Wegener's granulomatosis due to its greater efficacy, whereas cyclosporine shows promise for conditions like psoriasis but requires careful monitoring due to uncertain long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppressive agents in dermatology. Ho, VC., Zloty, DM.[2013]

Dapsone was effective in treating a female patient with urticarial vasculitis (U.V.) and metabolic syndrome, leading to clinical improvement and normalization of hypocomplementemia after previous treatments failed.

This case suggests that dapsone may serve as a viable alternative treatment for U.V. when systemic corticosteroids and other common medications are contraindicated or ineffective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Urticaria vasculitis and sulfone, a case report]. Wozel, G., Thiele, B.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7672387/

Azathioprine: its uses in dermatology - PMC Cutaneous vasculitis​​ There is significant improvement in vasculitis after 18 months of treatment, and 88% of patients achieved complete ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/1953230/

Prednisone plus azathioprine treatment in patients with ... Prednisone plus azathioprine treatment was associated with a low incidence of relapse of vasculitis, few serious complications, and a relatively low mortality.

3. frontiersin.org frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1059612/full

Treatment of cutaneous vasculitis Azathioprine (usually 2 mg/kg/day divided twice daily) has been reported to be efficacious for cutaneous vasculitis and is frequently used for treatment of ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2468024922012001

A Meta-Analysis of the Safety and Efficacy of Maintenance ... Relapse-free survival was significantly worse with the use of azathioprine (HR: 2.11, 95% CI: 1.19–3.74), methotrexate (HR: 2.51, 95% CI: 1.24–5.08), and ...

5. journals.lww.com journals.lww.com/acgcr/fulltext/2023/04000/azathioprine_induced_hypersensitivity_vasculitis.9.aspx

Azathioprine-Induced Hypersensitivity Vasculitis In this report, we describe the case of a 63-year-old man on azathioprine for autoimmune hepatitis, who developed a delayed systemic hypersensitivity reaction ...

6. drugs.com drugs.com/sfx/azathioprine-side-effects.html

Azathioprine Side Effects: Common, Severe, Long Term This medicine may increase your risk of getting certain types of cancer, especially of the skin, lymph system (lymphoma), or blood (leukemia).

7. hopkinsarthritis.org hopkinsarthritis.org/patient-corner/drug-information/azathioprine-imuran/

Azathioprine (Imuran®) Drug Information Sheet Azathioprine can lower your immune system and increase your risk of getting infections. Notify your doctor if you have signs or symptoms of an infection and ...

8. skinhealthinfo.org.uk skinhealthinfo.org.uk/condition/azathioprine/

Azathioprine - BAD Patient Hub Taking azathioprine for a number of years may possibly increase your risk of getting skin cancer and a type of blood cancer called lymphoma. You should protect ...

9. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK542190/

Azathioprine - StatPearls - NCBI Bookshelf Azathioprine is an immunomodulator associated with several serious adverse effects. Susceptibility to its toxicity varies with age, genetic differences, and ...