AIRCHILL-FIRST Protocol · First product-specific human airway safety study

AIRCHILL-FIRST

First product-specific human airway safety and performance study

Protocol status: planning synopsis · version 0.1 · 24 August 2026
Not a recruitment notice. Population, dose, sample size, stopping rules and procedures require regulator, ethics, investigator, medical-monitor and independent safety agreement before clinical use.

Development objective

Show and quantify whether AIRCHILL can deliver a clinically useful respiratory thermal dose through an endotracheal circuit while preserving ventilation, gas exchange, airway integrity and cardiovascular stability, and determine whether any small acute airway changes recover after exposure.

Prerequisites

Human exposure begins only after completion of the relevant device verification, risk-management work, biocompatibility/gas-path assessment, prolonged large-animal endotracheal safety package and an agreed clinical investigation pathway. COLD-DOSE human mechanistic results should inform biomarker selection where available.

Design

Prospective staged early-feasibility/safety investigation with sentinel enrolment and independent cohort review.

Provisional planning ladder

• Cohort A: 6–10 participants at −10 °C
• independent Safety Review Committee review
• Cohort B: 6–10 at −15 °C
• independent review
• Cohort C: 6–10 at −20 °C
• expansion: approximately 20–40 additional participants at the selected qualified exposure

All numbers and temperatures are ASSUMPTIONS, not regulatory commitments. −20 °C is the current provisional first-generation lower setpoint because it has the strongest AIRCHILL-specific prolonged endotracheal preclinical anchor; it is not asserted to be a biological human injury threshold.

Initial population

The first product-specific study should start in a controlled intubated clinical setting in which consent, baseline assessment, continuous ventilation monitoring and post-exposure airway follow-up are feasible. The exact elective population should be selected with investigators and regulators to minimise unrelated risk and confounding.

Emergency post-cardiac-arrest patients should not be used to discover the basic airway dose-response curve. They belong in a subsequent feasibility study after the product-specific exposure is qualified.

Primary endpoints

Ventilation and airway performance

• clinically significant treatment interruption attributable to AIRCHILL
• airway resistance and dynamic/static compliance
• peak and plateau airway pressures
• tidal and minute ventilation
• FiO2 delivery accuracy
• SpO2 and arterial/appropriate gas exchange
• bronchospasm requiring intervention

Device-related safety

Device-related serious adverse events and prespecified airway/pulmonary adverse events through the defined follow-up period.

Biological safety endpoints

• CC16 and prespecified epithelial-injury markers
• inflammatory biomarkers
• FeNO where interpretable
• secretion quantity/viscosity and suction burden
• optional bronchoscopy/mucosal scoring only when ethically justified
• BAL or sputum only in a justified mechanistic subset
• prespecified mucociliary/ciliary-function assessment

Recovery endpoint

AIRCHILL-FIRST explicitly tests reversibility. Physiological and biomarker measurements continue after exposure to determine whether acute deviations return toward baseline. Persistent or delayed changes are safety signals even when the participant remains clinically asymptomatic.

Cardiovascular surveillance

Continuous ECG/arrhythmia monitoring, blood pressure and haemodynamic assessment appropriate to the population are included. This prevents the programme from treating airway safety as the only relevant cold-exposure risk. External facial/oronasal cold-air cardiovascular studies are hazard-identification evidence, not direct evidence for an endotracheal AIRCHILL circuit.

Exposure reconstruction

For every participant store:

• device set temperature
• patient-side inspired gas temperature
• absolute humidity
• flow and peak inspiratory flow
• minute ventilation
• FiO2
• airway pressure/resistance
• exposure duration
• interruptions
• cumulative respiratory thermal/water-loss dose
• core/brain-surrogate temperature trajectory where appropriate

Temperature alone is not an adequate exposure descriptor.

Escalation governance

Each temperature step opens only after independent review of the preceding cohort. The Safety Review Committee receives blinded/unblinded data as specified in its charter and reviews adverse events, airway mechanics, gas exchange, epithelial/inflammatory responses, secretion/mucociliary findings, cardiovascular data, recovery and device deficiencies.

Numerical stopping boundaries must be defined in the final protocol based on the actual population, device verification data and medical-monitor/regulatory agreement. They should not be reverse-engineered from healthy-athlete studies.

Statistical framework

This is a safety/performance study, not an efficacy trial. Report cohort-specific estimates and confidence intervals, individual trajectories and repeated-measures changes from baseline. Model delivered dose continuously in addition to nominal cohort temperature. Do not interpret absence of statistical significance as proof of safety.

The expansion cohort can improve precision around common adverse events and physiological/biomarker response but cannot exclude very rare harms. The final protocol should state the detectable/upper-bound event-rate logic explicitly.

Visit / assessment schedule

Pre-exposure: consent/eligibility, baseline pulmonary status, ECG/vitals, blood/biomarkers and planned airway measurements.
Exposure: continuous device, ventilator, gas-exchange and cardiovascular capture.
Immediate recovery: airway mechanics, gas exchange, symptoms where assessable, biomarkers/airway assessment according to schedule.
Later recovery: repeated biomarker and mucociliary assessment at biologically justified intervals.
Follow-up: delayed pulmonary/device adverse events and confirmation of recovery.

CRF minimum dataset

Eligibility; relevant pulmonary/cardiac history; procedural indication; baseline ventilation; exposure dataset; all device settings; temperatures/humidity; airway mechanics; blood gases; oxygenation; ECG/vitals; biomarkers; secretions/suction; bronchoscopy/BAL if performed; mucociliary endpoint; concomitant medication; adverse events; device deficiencies; protocol deviations; recovery status.

Registration-ready outcome definitions

Primary safety/performance outcome (proposed ASSUMPTION): occurrence of a prespecified AIRCHILL-related airway/ventilation safety event during exposure through the defined acute recovery window. The final event definition should include clinically significant bronchospasm, treatment interruption for respiratory safety, clinically relevant deterioration in airway pressure/resistance/compliance or gas exchange, and device-related serious adverse events. Components must also be reported individually.

Key secondary outcomes: continuous airway mechanics; delivered tidal/minute ventilation and FiO2 accuracy; arterial/appropriate gas exchange; CC16 and epithelial/inflammatory change from baseline; secretion/suction burden; mucociliary/ciliary recovery; cardiovascular events; device deficiencies; delivered respiratory thermal dose; thermal response; and proportion returning to prespecified baseline/recovery limits.

Schedule of assessments

Sample-size and precision plan

The staged 6–10 participants per dose plus a 20–40 participant expansion remains an ASSUMPTION. AIRCHILL-FIRST is not powered for efficacy. The final synopsis should select cohort size using safety precision and stopping-rule operating characteristics. For orientation, when zero events are observed, the classical rule-of-three gives an approximate 95% upper confidence bound of 3/N for the underlying event rate; this is a DERIVED planning heuristic, not proof of safety. Exact/binomial confidence intervals and Bayesian or sequential operating characteristics can be prespecified with the statistician.

Independent Safety Review Committee / DSMB charter

• independent chair, anaesthesia/critical-care physician, pulmonary/airway expert and statistician; add device-engineering expertise as non-voting support where useful;
• review each sentinel participant/group and a formal aggregate review before −15 °C and −20 °C cohorts;
• receive AEs/SAEs, device deficiencies, ventilation/gas exchange, haemodynamics/ECG, airway mechanics, biomarkers, secretions/mucociliary findings and recovery trajectories;
• authority to continue, expand, modify exposure duration, de-escalate, pause or terminate;
• no escalation while a potentially related serious event or unresolved delayed airway signal is under evaluation;
• documented recommendation before the next cohort opens.

Protocol-level stopping framework

Stop the individual exposure for any prespecified clinically significant deterioration in ventilation/gas exchange, bronchospasm, airway pressure/resistance, cardiovascular stability, device essential performance, or other investigator-defined safety event. Pause cohort escalation for a related SAE, recurrent clinically important event, unexpected epithelial/mucociliary injury pattern, failure to recover within the prespecified window, or a device deficiency capable of causing serious harm. Exact numerical limits remain DATA GAP pending final population, device verification and regulator/ethics agreement.

Progression criteria

The programme advances to emergency feasibility when the qualified AIRCHILL setting has reproducible delivery, preserved essential ventilation performance, acceptable acute biological/physiological response, recovery compatible with the prespecified safety criteria and no unresolved device-related safety pattern.

The first emergency cohort then uses the already qualified exposure; it does not simultaneously escalate to a colder setting.

Regulatory role

AIRCHILL-FIRST is intended to provide direct product-specific human evidence supporting the clinical evaluation/risk-management package and later emergency investigation. External cold-air challenge and athlete studies support state-of-the-art and hazard identification. AIRCHILL’s prolonged endotracheal animal work provides route-relevant preclinical support. None substitutes for this direct product-specific clinical evidence.

Positive development framing

The programme is designed to show and size a usable human respiratory-cooling window, establish sensitive monitoring endpoints and provide a defensible bridge to early emergency treatment studies. Evidence boundaries remain explicit so later efficacy claims can be built on a traceable safety foundation.