A Randomized Multicenter Study for Isolated Skin Vasculitis
A Randomized Multicenter Study for Isolated Skin Vasculitis
Multi-center sequential multiple assignment randomized trial comparing the effectiveness of
 three different standard of care treatment options for patients with isolated skin
 vasculitis.
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.
Inclusion Criteria:

 1. 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.

 2. 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).

 3. 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).

 4. 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).

 5. 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).

 6. 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).

 7. Participant age 18 years or greater.

 Exclusion Criteria:

 1. 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.

 2. 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.

 3. 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.

 4. 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%).

 5. 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.

 6. 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%).

 7. 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).

 8. Evidence of significant hepatic insufficiency or liver function tests > 2 times the
 upper limit of normal.

 9. Evidence of significant renal insufficiency or creatinine clearance < 60 mL/min.

 10. Evidence of significant or symptomatic anemia or Hb < 10 g/dL.

 11. 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).

 12. 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).

 13. Active uncontrolled or serious infection that may compromise or contra-indicate the
 use of the study medications.

 14. Patient unable to consent.

 15. Pregnant or lactating women.