Cabotegravir & Rilpivirine: 96-Week HIV Treatment Results in Africa | CARES Trial

Rigorous ‌Sample ⁤Size Justification for a‍ Long-Acting HIV Therapy Trial

Determining the appropriate sample size is a cornerstone of any clinical trial, ensuring both scientific validity and ethical resource allocation. In our recent study evaluating a‌ novel ⁣long-acting HIV therapy, we employed a meticulous approach to⁤ sample size calculations, driven ​by‍ the need to demonstrate non-inferiority for ​key outcomes and gather robust safety data. This article details the‍ rationale behind our chosen ‍sample sizes for the primary,secondary,and substudy analyses.

Primary Outcome: Demonstrating Non-Inferiority

for the primary endpoint,we aimed to ‌demonstrate non-inferiority with ⁣a 10% margin,using a 5% two-sided meaning level and achieving 90% power. These parameters led us to a required sample size of 238 participants ‍- 119 in each⁣ treatment arm. Importantly, the power to detect non-inferiority for this primary outcome, given our chosen parameters, was exceptionally high, ⁤approaching 100%. ⁣

Key Secondary Outcome: Accounting for Hierarchical Testing

The key secondary outcome, virological failure, required ​a more conservative approach. Based on data ‌from previous 8-weekly long-acting trials³³, we anticipated a failure rate of 1.7% in both treatment groups.

* We utilized a ‍hierarchical ⁣testing procedure to control for multiple comparisons.
* This⁤ necessitated a 4% non-inferiority margin, a 5% two-sided significance level, and 85% power.
*⁢ these criteria indicated a need for 512 participants (256 per group).

To ensure adequate power for both the primary and secondary analyses, and to bolster the safety data available for broader adoption of long-acting ‌therapy, we opted to proceed⁤ with the larger sample ⁢size of 512 participants. This decision prioritized thorough​ data collection and maximized confidence in our ⁤findings.

DEXA Substudy: Assessing Body⁢ Composition Changes

A dedicated substudy focused on changes ⁤in body composition, specifically trunk fat mass, using Dual-energy X-ray absorptiometry (DEXA) scans. ​

* We targeted a minimum of 120 participants across four study sites.
* ‌ This sample⁤ size was calculated‍ to provide ‌at⁣ least ‌90% power to detect⁢ a clinically meaningful difference of 1.2 kg⁤ between treatment arms.
* The calculation was based on a standard deviation ⁤of ‍2 kg, informed by body composition data from treatment-naive individuals initiating HIV treatment in Africa², and a 5% alpha level.

Recognizing the inherent uncertainties in sample size estimations – particularly regarding attrition and the potential for exploring additional body composition outcomes -​ we ‍allowed sites to enroll beyond the minimum target.This versatility ensured a robust dataset for comprehensive analysis.

Analytical Approach & ‌Transparency

All ​statistical analyses were performed using Stata version 16.1 (statacorp),with the ⁣exception of efficacy analyses involving proportion differences,wich were conducted in R version 4.3.3. A detailed ‍statistical analysis plan is available in ‍the Supplementary Information.⁣ Further details regarding research design are provided ⁤in the Nature Portfolio Reporting Summary.

References:

³³ Jaeger, H. et al.Long-acting cabotegravir and rilpivirine dosed every⁤ 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results:‍ a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet HIV 8, e679-e689 (2021).

² Venter,W. ​D. F. et al. Dolutegravir​ with ⁢emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate ⁣versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority ⁣trial. Lancet HIV 7, e666-e676 (2020).