A Randomized Multicenter Study for Isolated Skin Vasculitis

Study Overview
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Brief Summary
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Multi-center sequential multiple assignment randomized trial comparing the effectiveness of three different standard of care treatment options for patients with isolated skin vasculitis.

Detailed Description
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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). If the patient has to discontinue the study drug within the 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) for 6 months. Endpoint in this second stage will again be the response to treatment at 6 months.

Official Title
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A Randomized Multicenter Study for Isolated Skin Vasculitis

Conditions
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Primary Cutaneous Vasculitis, Cutaneous Polyarteritis Nodosa, IgA Vasculitis, Henoch-Schönlein Purpura

Intervention / Treatment
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* Drug: Colchicine
* Drug: Dapsone
* Drug: Azathioprine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with primary skin vasculitis, not associated with any significant extra-cutaneous involvement that would require specific immunosuppressive therapy. Eligible patients will have a diagnosis of either: Isolated cutaneous small vessel (SV) or medium-sized vessel (MV) vasculitis or cutaneous polyarteritis nodosa (PAN) IgA vasculitis (IgA, formerly Henoch-Schönlein purpura), without active and/or progressing renal involvement (stable glomerular filtration rate (GFR) >60 ml/min; absence of, or mild-and-stable microscopic hematuria without red blood cell casts; absence of, or mild-and-stable proteinuria (<1g/24 hours); not requiring systemic immunosuppressive therapy). These conditions, when skin-limited, are all currently treated in similar manners in practice. Mild arthralgias, myalgias, peripheral limb edema, fatigue, weight loss ≤6 lbs or 3 kg within past 3 months, low-grade fever, and mild anemia (Hb ≥ 10 g/dL) will be allowed. The diagnosis of vasculitis must have been confirmed by skin biopsy prior to enrollment (earlier, at diagnosis, and/or just prior to enrollment) that has included an immunofluorescence study (in the case of small vessel vasculitis). Patients must have active cutaneous vasculitis lasting for at least 1 month continuously and/or have had 2 or more flares over the six months preceding enrollment (post-inflammatory lesions such as hyperpigmentation or healing ulceration(s) are not to be considered active vasculitis). Patients must have active / ongoing cutaneous vasculitis lesions at the time of enrollment (post-inflammatory lesions such as hyperpigmentation or healing ulceration(s) are not to be considered active vasculitis). Patients may have a contra-indication to one of the study drug or have been treated prior to enrollment with one of the study medications but failed to respond to it (according to the study definitions of failure and if they have been on the drug at the target dose or higher for 3 months or longer) or had to stop it because of an adverse event. Such patients can be enrolled directly in the second stage of the study and be randomized to receive one of the two other study drugs. The number of such patients enrolled directly in stage 2 will be capped at 10 (10% of the total recruitment target). Patients may have received systemic glucocorticoids for their cutaneous vasculitis before enrollment. For the patients on prednisone at the time of enrollment, prednisone should be stopped within a maximum of 6 weeks after enrollment and initiation of the study drug, following a pre-defined tapering schedule. Patients on long-term, low and stable dose of glucocorticoids (≤5 mg/day prednisone-equivalent) for other conditions (e.g., asthma or adrenal insufficiency) can be enrolled if the likelihood of requiring a dose increase for this other condition is low during the 6 month study period (these patients will remain on that low and stable dose during the study period, with the option to receive one short course of prednisone at higher doses for skin vasculitis flare during the first 3 months of the study period, like any other patients enrolled). Participant age 18 years or greater. Exclusion Criteria: Presence of significant extra-cutaneous manifestations suggestive of a systemic vasculitis or more diffuse condition. The presence of mild arthralgias, myalgias, peripheral limb edema, fatigue, weight loss ≤6 lbs or 3 kg within past 3 months, low-grade fever, and mild anemia [Hb ≥ 10 g/dL] are not exclusion criteria. Mild and stable microscopic hematuria without RBC casts and/or mild and stable proteinuria (<1g/24 hours) are not exclusion criteria. These latter patients must not require systemic immunosuppressive therapy because of possible renal involvement and their GFR must be >60 ml/min. Known systemic and/or non-skin-isolated vasculitis, such as granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, cryoglobulinemic vasculitis, systemic polyarteritis nodosa, central nervous system vasculitis and patients with detectable antineutrophil cytoplasmic antibody (ANCA) by immunofluorescence or ELISA. Hypocomplementemic urticarial vasculitis, cryoglobulinemic vasculitis, and other known secondary skin vasculitides such as those secondary to systemic lupus erythematosus, Sjögren syndrome, another auto-immune condition, a cancer, a hematological disorder, an ongoing active infection, or an ongoing medication. Investigators should consider such underlying diagnoses and perform and interpret appropriate laboratory work-up where indicated based on clinical presentation. History of significant intolerance, allergy or serious adverse events to any of the study medications: such patients can be enrolled directly in the second stage of the study and be randomized to receive one of the two other study drugs. The number of patients enrolled directly in stage 2 of the study will be capped at 10 (10%). Patients who have contra-indications to two or three of the study drugs (azathioprine, colchicine, or dapsone), or have been treated prior to enrollment with two or three of the study drugs but failed to respond to them, or had to stop two or three of them because of adverse events. Deficit in glucose-6-phosphate dehydrogenase (G6PD) or history of hemolytic anemia (all patients must be tested for G6PD at the screening visit to assess for their eligibility): such patients can be enrolled directly in the second stage of the study and be randomized to receive one of the two other study drugs (azathioprine or colchicine). The number of patients enrolled directly in stage 2 of the study will be capped at 10 (10%). Low or absent thiopurine methyltransferase (TPMT) activity (if known, not a requirement for study entry): Patients known to have low or absent TPMT can be enrolled directly in the second stage of the study and be randomized to receive one of the two other study drugs (dapsone or colchicine). Evidence of significant hepatic insufficiency or liver function tests > 2 times the upper limit of normal. Evidence of significant renal insufficiency or creatinine clearance < 60 mL/min. Evidence of significant or symptomatic anemia or Hb < 10 g/dL. Comorbid condition that has moderate or high likelihood of requiring intermittent courses of prednisone within the study period, according to the investigator (e.g. chronic obstructive pulmonary disease (COPD), unstable or severe asthma). Active cancer or history of malignancy within the previous 5 years (patient in remission of a cancer >5 years, or with non-metastatic prostate cancer or treated basal or squamous cell carcinoma of the skin can be enrolled). Active uncontrolled or serious infection that may compromise or contra-indicate the use of the study medications. Patient unable to consent. Pregnant or lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1<br>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). | Drug: Colchicine<br>* Randomized to colchicine 0.6 mg x 2/day<br>* Other names: Colcrys;Drug: Dapsone<br>* Randomized to dapsone 150 mg/day<br>* Other names: Diaminodiphenylsulfone;Drug: Azathioprine<br>* Randomized to azathioprine 2 mg/kg/day<br>* Other names: Imuran;|
| Experimental: Stage 2<br>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. | Drug: Colchicine<br>* Randomized to colchicine 0.6 mg x 2/day<br>* Other names: Colcrys;Drug: Dapsone<br>* Randomized to dapsone 150 mg/day<br>* Other names: Diaminodiphenylsulfone;Drug: Azathioprine<br>* Randomized to azathioprine 2 mg/kg/day<br>* Other names: Imuran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of the study drugs for the treatment of skin vasculitis. | Compare response to therapies. | Response to therapy at month 6 of the pooled study stages 1 and 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rates for each of the study drugs | Proportion of patient with complete response and significant response to therapy at months 3, 6 and 12 | Response evaluated months 3, 6 and 12 | 
| Physician's global assessment of response | Health-related quality of life as measured using physician's global assessment scale. | Assessed at months 0, 1, 3, 6, 9, and 12. | 
| Patient's global assessment of response | Health-related quality of life as measured using patient's global assessment scale. | Assessed at months 0, 1, 3, 6, 9, and 12. | 
| Skindex29 score | Disease activity measured by response to therapy at months 1, 3, 6, and 12 | Assessed at months 1, 3, 6, 9, and 12. | 
| Health-related quality of life | Health-related quality of life as measured using SF-36 and Patient-Reported Outcomes Measurement Information System (PROMIS) | Assessed at months 1, 3, 6, 9, and 12. |