Overview

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

Eligibility

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.