Rationale and Design of a Novel, Phase 3, External and Synthetic Placebo-Controlled Clinical Trial of Ritlecitinib 50 mg and 100 mg for Alopecia Areata.

INTRODUCTION

Despite recent advancements in treating severe alopecia areata (AA), many patients do not achieve target efficacy with approved therapies. Ritlecitinib is an oral Janus kinase 3 (JAK3)/tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinase inhibitor approved to treat severe AA at a dose of 50-mg once daily (QD). A new phase 3 clinical trial (NCT06873945) described herein evaluates a higher dose of ritlecitinib (100-mg QD) in patients with AA. The study employs an innovative design using patient-level data from patients with similar baseline characteristics from previous AA ritlecitinib studies to form an external placebo control group, a synthetic placebo control group (extrapolating for outcomes over a longer timeframe than captured previously), and an external ritlecitinib 50-mg nonresponders group, eliminating the need to randomize patients to placebo.

METHODS

This randomized, double-blind clinical trial investigates the efficacy and safety of ritlecitinib in patients aged ≥ 12 years with AA and ≥ 50% scalp hair loss. Patients are randomized to ritlecitinib 100-mg or 50-mg QD. Those randomized to ritlecitinib 100-mg continue the 100-mg dose through week 48. Patients randomized to ritlecitinib 50-mg with a Severity of Alopecia Tool (SALT) score ≤ 20 at week 24 (responders) continue ritlecitinib 50-mg through week 48; nonresponders at week 24 are rerandomized 2:1 to increase to ritlecitinib 100-mg or continue ritlecitinib 50-mg through week 48.

PLANNED OUTCOMES: The primary end point is a SALT score ≤ 20 at week 24 for ritlecitinib 100-mg versus external placebo. Key secondary end points include SALT score ≤ 20 at week 24 for ritlecitinib 50-mg versus external placebo and week 36 for ritlecitinib 100-mg versus synthetic placebo, and SALT score change from baseline at week 24 for ritlecitinib 100-mg versus 50-mg. An external ritlecitinib 50-mg nonresponders control group augments the ritlecitinib 50-mg nonresponders at week 24 rerandomized to ritlecitinib 50-mg to support comparative analyses at week 48.

GOV REGISTRATION: NCT06873945. Video Abstract (MP4 303790 kb).