What is the purpose and protocol of the Advocate trial?

The ADVOCATE Trial: Purpose and Protocol

The ADVOCATE trial is a Phase 3, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of lebrikizumab for the treatment of moderate-to-severe atopic dermatitis in adolescents and adults. 1

Trial Overview

The ADVOCATE trial consists of two identically designed studies (ADvocate1 and ADvocate2) with the following key characteristics:

• Duration: 52 weeks total, divided into:

  • 16-week induction period
  • 36-week maintenance period

• Population: Adults (≥18 years) and adolescents (12 to <18 years, weighing ≥40 kg) with moderate-to-severe atopic dermatitis

• Randomization: 2:1 ratio (lebrikizumab:placebo)

• Intervention:

  • Lebrikizumab 250 mg (with loading doses of 500 mg at baseline and week 2)
  • Administered subcutaneously every 2 weeks
  • Placebo comparator with identical administration schedule

Primary and Secondary Outcomes

Primary Outcome

• Investigator's Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin) with a reduction of at least 2 points from baseline at week 16

Secondary Outcomes

• 75% improvement in Eczema Area and Severity Index score (EASI-75)
• Assessment of itch severity
• Evaluation of itch interference with sleep
• Safety assessments

Protocol Design Elements

The ADVOCATE trial follows standard protocol items recommended for interventional trials (SPIRIT guidelines) 2, including:

1. Administrative Information:

   • Trial registration: NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2)
   • Protocol version with date identifier
   • Funding sources and sponsor roles

2. Introduction:

   • Background and rationale for the trial
   • Explanation for choice of lebrikizumab as an IL-13 targeting monoclonal antibody
   • Specific objectives and hypotheses

3. Methods:

   • Eligibility criteria for participants
   • Detailed intervention descriptions including dosing regimens
   • Primary and secondary outcome measures with specific measurement variables
   • Sample size calculations
   • Randomization and blinding procedures

4. Data Collection and Management:

   • Plans for assessment of outcomes
   • Data management procedures
   • Statistical analysis plan

5. Ethics and Dissemination:

   • Research ethics approval
   • Protocol amendments procedures
   • Consent procedures
   • Confidentiality protections
   • Declaration of interests
   • Plans for communicating trial results

Significance of the Trial

The ADVOCATE trial addresses an important clinical need in atopic dermatitis treatment by evaluating lebrikizumab, a high-affinity IgG4 monoclonal antibody that specifically targets interleukin-13. This mechanism prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex 1.

Initial Results

Preliminary results from the induction period showed that lebrikizumab was effective compared to placebo:

• ADvocate1:

  • Primary outcome achieved in 43.1% (lebrikizumab) vs 12.7% (placebo)
  • EASI-75 response in 58.8% vs 16.2%

• ADvocate2:

  • Primary outcome achieved in 33.2% (lebrikizumab) vs 10.8% (placebo)
  • EASI-75 response in 52.1% vs 18.1%

The safety profile showed that most adverse events were mild to moderate, with conjunctivitis being more common in the lebrikizumab group 1.

Clinical Trial Registration and Protocol Access

As recommended by CONSORT guidelines 2, the ADVOCATE trials were registered in a public registry (ClinicalTrials.gov) and the full protocol is available for transparency and to prevent selective outcome reporting.