# AIRCHILL Statistical Analysis Plan

> Shared development Statistical Analysis Plan for AIRCHILL cardiac-arrest and stroke clinical investigations, with indication-specific primary models and interim strategy.

- Canonical: https://www.medicalcooling.com/airchill-statistical-analysis-plan/
- Markdown: https://www.medicalcooling.com/airchill-statistical-analysis-plan/index.md
- Language: en-US
- Last modified: 2026-08-29T14:23:47+00:00

Statistics · development SAP v0.1

# AIRCHILL Statistical Analysis Plan

This shared SAP framework defines common principles and indication-specific primary analyses. It must be finalised and signed before database lock and, for confirmatory work, before any sponsor access to unblinded comparative results.

## 1. Analysis populations

- ITT: all randomised participants analysed according to assignment; primary efficacy population.
- Safety: participants analysed according to actual AIRCHILL exposure for device-related safety, while preserving ITT safety summaries in parallel.
- Per-protocol: prespecified major-deviation-free subset, supportive only.
- Thermal-exposure set: participants with interpretable device telemetry for mechanistic dose-response analyses.

## 2. Primary estimands

Cardiac arrest: treatment-policy effect of assignment to early AIRCHILL strategy on the locked 90-day neurological endpoint, with death incorporated according to endpoint definition and crossover/treatment interruption retained under assignment.

Stroke: treatment-policy effect on 90-day ordinal mRS; death remains mRS 6. Crossovers and incomplete exposure are handled under assignment.

## 3. Primary models

CA: if dichotomous favourable outcome is confirmatory, adjusted binomial/logistic model with absolute risk difference, risk ratio/odds ratio and 95% CI reported; full ordinal mRS remains key supportive analysis. Stroke: proportional-odds ordinal logistic regression, adjusted common OR with 95% CI, formal assessment of proportional-odds assumption and prespecified robust alternative if materially violated.

## 4. Covariate adjustment

Use a small prespecified set of strong baseline prognostic factors. CA candidates: age, initial rhythm, witnessed arrest, bystander CPR, time-to-ROSC. Stroke candidates: age, baseline NIHSS, ASPECTS/core burden, onset/last-known-well to randomisation. Avoid adjusting the primary model for post-randomisation mediators.

## 5. Multiplicity

One primary endpoint per pivotal study. Key secondary outcomes are ordered in a hierarchical gatekeeping sequence if confirmatory claims are intended. Imaging, biomarkers, dose-response and most subgroup analyses remain supportive/exploratory unless promoted prospectively.

## 6. Missing data

Primary prevention strategy is operational: central follow-up, multiple contact routes, blinded outcome assessors and retrieval from routine records. Missing-data analysis includes multiple imputation under plausible MAR assumptions plus prespecified tipping-point/worst-reasonable-case sensitivity. Death is an outcome, not ordinary missing data.

## 7. Intercurrent events

Device interruption, crossover, rescue temperature therapy, withdrawal of consent, WLST and protocol deviations are explicitly classified. The primary treatment-policy estimand generally retains these events; hypothetical or principal-stratum analyses, if used, are supportive and clearly labelled.

## 8. Interim analysis

One formal confirmatory interim near 50% information is the base design. A group-sequential alpha-spending approach preserves overall type-I error. Futility is non-binding. Exact spending function and boundaries are generated before first unblinded DSMB review.

## 9. Sample-size re-estimation

Blinded nuisance-parameter updates may use pooled control/event distributions, mRS distribution or missingness if prospectively specified. Any unblinded effect-based adaptation requires a fully defined adaptive method preserving type-I error.

## 10. Subgroups

Interaction tests—not within-subgroup p-values—drive interpretation. Prespecified candidates include treatment-start time, achieved thermal exposure, age, sex and baseline temperature. CA additionally initial rhythm/time-to-ROSC; stroke additionally baseline core/ASPECTS, reperfusion status and collateral grade where available. Findings are supportive unless separately powered.

## 11. Safety analyses

Summarise treatment-emergent AE/SAE, serious adverse device effects, device deficiencies, ventilation compromise, arrhythmia/hemodynamic events, pneumonia and mortality with exposure-adjusted summaries where useful. Stroke adds sICH and treatment-attributable reperfusion delay.

## 12. Sensitivity analyses

- Unadjusted versus adjusted primary model.
- Per-protocol and as-treated supportive analyses.
- Alternative missing-data assumptions.
- Centre/random-effects sensitivity where site heterogeneity is material.
- CA ordinal neurological outcome sensitivity.
- Stroke generalized-odds or win/utility-weighted sensitivity if proportional odds is untenable.

## 13. Reporting

Effect estimates with confidence intervals take precedence over isolated p-values. All deviations from the signed SAP are dated, justified and reported. Statistical code is version controlled and independently validated for the primary analysis.

[← Clinical Investigation Package](https://www.medicalcooling.com/airchill-clinical-investigation-package/)