Comparison of apremilast versus betamethasone oral-mini pulse therapy in the treatment of progressive non-segmental vitiligo: An open label non-inferiority randomized trial

Title: Comparison of apremilast versus betamethasone oral-mini pulse therapy in the treatment of progressive non-segmental vitiligo: An open label non-inferiority randomized trialResearch hypothesis:·      Apremilast can halt the progression of spreading vitiligo.

·      Apremilast is non-inferior to oral mini-pulse therapy (OMP) with Betamethasone sodium monophosphate, in halting the disease progression in progressive non-segmental vitiligo.

Aims and objectives:

A. Primary Objective:

a.     To compare the effect of daily apremilast with weekly OMP therapy with betamethasone in achieving stability in patients with progressive non-segmental vitiligo.

B.    Secondary Objectives:

a)     To evaluate the re-pigmentation achieved in patients of progressive non-segmental vitiligo

b)    To compare the improvement in quality of life in the two subsets of patients.

c)     To compare the side-effect profile of apremilast as compared to OMP

d)    To evaluate the change in Th1, Th2, Th17 and Tregs in the lesional skin of non-segmental vitiligo patients

Study design:Open label randomized non-inferiority trial

Study subjects:A.   Inclusion criteria: 1.     Patients >18 years of age with progressive non-segmental vitiligo (developing new lesions in the past 1 month and/or extension of pre-existing lesions in the past 1 month, VIDA score +4) affecting body surface area >2%.B.    Exclusion criteria:1.     Patients with segmental or stable vitiligo

2.     Patients with non-segmental vitiligo involving body surface area <2%.

3.     Pregnant and lactating females

4.     Patients with known contra-indications to corticosteroids, ie, patients with evidence of active infection; diabetes; hypertension.

5.     Patient with a known hypersensitivity to apremilast

6.     On topical treatment for last 2 weeks.

7.     On systemic treatment and /or phototherapy for last 4 weeks.

Duration of study:3 years

 Sample sizeAssuming anticipated success rate of 80% in the OMP arm and 95% in the apremilast arm at 6 months, taking the power of study at 80%, the alpha error 5% and the non-inferiority margin at 5%, the sample size required to be studied is 32 patients in each arm. Taking approximate 20% attrition, total sample size is estimated at 40 patients in each arm.

Detailed clinical history and clinical examination will be done, as well as vitiligo specific examination to note the body surface area involvement. VIDA score would be calculated and noted in the proforma at baseline and at every follow-up visit. Re-pigmentation will be calculated by the VASI score at every follow-up visit. Photographs of the whole body using fixed settings will be taken at baseline and at every follow-up visit. The photographs will be evaluated by 2 investigators blinded to the treatment arm for Vitiligo extent score - plus (Annexure 5, permission to use: Annexure 6) and percentage re-pigmentation on a Likert scale: -1, worse from baseline, 0: no change, +1: <25% re-pigmentation, +2: 25-49%, +3: 50-74%, +4: 75-89%, and +5: 90-100% re-pigmentation. Vitiligo Impact Score-22 (VIS-22) would be evaluated at baseline and at the end of 6 months. Blood investigations including baseline complete blood count, liver function tests, kidney function tests, chest X-ray, fasting blood sugar levels will be done at baseline, 1, 3 and 6 months. Five millilitres of venous blood will be drawn under aseptic precautions at 4 visits (baseline, 1, 3 and 6 months).A 3mm punch biopsy from one of the representative vitiligo lesions at a non-acral site will be taken at the baseline and at 6 months in a subset of patients (n=20, 10 patients in each arm). The skin biopsy specimen will be subjected to analysis of mRNA expression of Th1 (IL-2, IFN-gamma), Th2 (IL-4, IL-13), Th17 (IL-17, IL-22) and T-regulatory (FoxP3) cell specific-markers by real time PCR.

Patients would be randomized using random number tables (simple randomization); to be included in one of the two groups, ie,

a.     Group 1: Patient who would receive 2.5mg betamethasone tablet after breakfast on Saturdays and Sundays for 6 months.

b.     Group 2: Patients receiving tablet Apremilast, slowly build up daily (10 mg on day 1, 10 mg twice daily on day 2, 20 mg in the morning and 10 mg in the evening on day 3, 20 mg twice daily on day 4, 30 mg in the morning and 20 mg in the evening on day 5, 30 mg twice daily on day 6 and henceforth) for 6 months. For patients not able to tolerate 30 mg twice daily Apremilast, dose would be reduced to 30mg once a day. If apremilast is still not tolerated by the patient, they would be excluded from the study.

h.     Patients would be followed up every two weeks for the 1st month, then monthly for the next 6 months.