# Clinical Study Planner

> Interactive AIRCHILL clinical-development planner for turning mechanism and preclinical signals into powered studies that test and size patient benefit, recruitment, follow-up and budget.

- Canonical: https://www.medicalcooling.com/clinical-study-planner/
- Markdown: https://www.medicalcooling.com/clinical-study-planner/index.md
- Language: en
- Last modified: 2026-08-29T14:25:54+00:00

Clinical development · planning tool

# From hypothesis to powered efficacy study.

AIRCHILL already has measured mechanism and preclinical safety signals. The next clinical programme is designed to test whether those effects translate to patients and to estimate the magnitude in the right phenotype. This page turns that objective into explicit study-design assumptions that can be challenged: control event rate, expected absolute benefit, statistical power, attrition, recruitment speed, follow-up and cost. The output is planning arithmetic, not a protocol or regulatory decision.

Development logic

## Three gates before an efficacy claim.

Gate 1 · early feasibility

### Can the intended thermal dose be delivered safely?

Technical performance, airway/pulmonary safety, workflow, temperature trajectory, ventilation stability and stopping rules. Typically tens of patients, not powered for clinical benefit.

Gate 2 · dose / signal finding

### Which population and thermal strategy deserve a pivotal test?

Randomized multicentre work to select timing, target, duration and phenotype. Biomarkers and clinical endpoints can estimate event rates and plausible effect size for the confirmatory study.

Gate 3 · confirmatory efficacy

### Patient-relevant endpoint, prespecified estimand, adequate power.

The pivotal question must match the intended claim. Final sample size should be locked with a statistician and regulators using validated software and current control-event data.

Regulatory frame. EU MDR Annex XV requires an appropriate clinical investigation plan, scientific validity and justified statistical methodology. ISO 14155:2026 covers good clinical practice for medical-device investigations. FDA recommends early interaction on pivotal device-study design; a life-supporting investigational ventilator study would need an explicit IDE / significant-risk assessment before US enrolment.

Airway-safety programme · cold-air dose escalation

## Do not jump directly to the coldest technically achievable gas.

The literature does not support a single minimum safe inspired temperature. AIRCHILL should therefore qualify a multidimensional respiratory thermal dose and use a staged safety programme. The provisional −20 °C first-generation lower setpoint is a planning decision anchored to the existing six-hour porcine endotracheal evidence, not a human injury threshold.

StageTemperature strategyPopulation / modelRequired safety evidenceEscalation gate

Bench / airway modelMap +5 to −30 °C across expected flows, FiO₂ and humidityBreathing circuit + validated airway/lung modelsPatient-side temperature, absolute humidity, heat extraction, condensation/ice, resistance, pressure, FiO₂ accuracy, alarm/failure modes.No unsafe condensate/occlusion; reproducible delivered dose; ventilator essential performance preserved.

Preclinical confirmatory−20 °C reference; add −25 °C dose-finding only after reference replicationLarge-animal prolonged endotracheal ventilationHistology + bronchoscopy, BAL/inflammation, epithelial injury, mucociliary/cilia endpoint, secretions, gas exchange, mechanics, haemodynamics.Independent pathology/safety review supports proceeding; −25 °C does not become a human setting merely because technically feasible.

Human performance / safetySequential −10 → −15 → −20 °C; cohort escalationStart in controlled elective/intubated setting where consent and airway assessment are feasible; final population to be agreed with regulators/ethics.Continuous airway pressure/flow/compliance, gas exchange, ECG/ischemia, haemodynamics, secretions; pre/post epithelial and inflammatory biomarkers; bronchoscopy/BAL only where ethically justified; mucociliary/ciliary assessment in mechanistic subset.DSMB/Safety Review Committee approves each step. Stop/hold for predefined bronchospasm, pressure/resistance, oxygenation/ventilation, epithelial-injury, secretion or cardiovascular signals.

Early emergency feasibilityUse the qualified setting; do not escalate temperature in the first emergency cohortSelected intubated emergency patientsDevice-related SAE, ventilation stability, thermal trajectory, airway safety, ECG/arrhythmia/haemodynamics, workflow and handover.Performance + safety threshold met before any dose-ranging or neurological efficacy expansion.

Later dose optimizationTemperature × humidity × flow × duration optimizationRandomized / adaptive clinical programmeCompare achieved thermal effect and safety rather than “coldest wins”.Select lowest-risk dose that achieves the required thermal performance.

Why this ladder is evidence-aligned. Brief human research exposures reach approximately −35 to −40 °C, but those extreme studies did not establish tissue safety. At −15 °C for 50 minutes, high ventilation can produce epithelial-stress signals; around −23 °C for longer exposure, lower-airway inflammatory changes have been reported. The first clinical programme should therefore optimize therapeutic thermal transfer per unit airway stress, not maximize coldness.

Primary airway endpoints

### Mechanics + gas exchange

Peak/plateau pressure, resistance, compliance, tidal/minute ventilation, SpO₂, PaO₂/PaCO₂, bronchospasm and clinically significant treatment interruption.

Biological safety endpoints

### Epithelium + inflammation

CC16 plus prespecified epithelial/inflammatory markers; sputum/BAL only where feasible; optional bronchoscopic mucosal scoring in a mechanistic cohort.

Mucociliary endpoints

### Cilia + secretions

Secretion volume/viscosity, suction burden and a prespecified mucociliary/ciliary-function endpoint. The literature supports temperature-dependent slowing, not a −32 °C destruction threshold.

Cardiovascular endpoints

### Do not make this a lung-only trial

Continuous ECG, arrhythmia, ST/ischemia surveillance where appropriate, blood pressure, vasopressor dose and haemodynamics. Short −15 °C facial cold-air exposure has altered coronary microvascular response in obstructive CAD, although the route differs from an endotracheal circuit.

Exposure reconstruction

### Temperature alone is insufficient

Store patient-side temperature, absolute humidity, flow, minute ventilation, FiO₂, pressure and cumulative duration so each participant's respiratory thermal/water-loss dose can be reconstructed.

Current external trial benchmark

### CLARINET · NCT07220928

Completed 60-person −15 °C study with asthma and healthy adults; registry has no posted results as reviewed 23 Aug 2026. Its mechanics + symptom + epithelial/inflammatory endpoint architecture should be copied where appropriate.

Cold-air evidence register and sources: [Cold-Air Inhalation Safety Evidence](https://www.medicalcooling.com/cold-air-safety/) · Jaeger et al. PMID 7453516 · Hartung et al. PMID 7417121 · Eklund et al. PMID 36053365 · Clary-Meinesz et al. PMID 1305479 · Marain et al. European Respiratory Review 2026 · ClinicalTrials.gov NCT07220928. The −10/−15/−20 °C sequence is a development ASSUMPTION requiring regulator, ethics, investigator and DSMB agreement.

Indication concepts

## What an efficacy study would need to prove.

IndicationResearch populationComparatorPreferred patient-relevant endpointFollow-upKey design issue

Cardiac arrestAdults requiring invasive ventilation after OHCA; phenotype/timing prespecified.Same ventilation and guideline-based temperature care without active AIRCHILL cooling.Favourable neurological outcome at ~90 days; blinded outcome assessment.3 monthsVery early randomisation, emergency-consent pathway, avoid mixing fundamentally different arrest phenotypes.

Ischaemic strokeIntubated LVO patients undergoing EVT; randomise before or at thrombectomy.Standard anaesthesia/ventilation and temperature management.90-day mRS; ordinal shift is generally preferable to a dichotomy.3 monthsThe web calculator uses mRS 0–2 as a binary approximation; a pivotal ordinal design should be simulation-based.

Neonatal HIESeparate paediatric programme only; eligible neonates receiving current standard whole-body cooling.Current standard servo-controlled neonatal hypothermia.Death or moderate/severe neurodevelopmental impairment.18–24 monthsAIRCHILL is not neonatal-validated; paediatric engineering and a separate regulatory programme are prerequisites.

Heat strokeSelected severe/intubated patients where adjunct respiratory cooling can ethically be studied.Best available rapid active cooling.Clinical recovery / organ-failure-free survival; mortality as key secondary or larger confirmatory endpoint.30 daysWater immersion remains best-supported for exertional heat stroke when feasible; recruitment is seasonal and sparse.

Severe TBIIntubated severe TBI with prespecified phenotype, bleeding and haemodynamic safeguards.Guideline-based neurocritical care without active AIRCHILL cooling.GOSE at 6 months; ordinal analysis preferred.6 monthsICP reduction is not sufficient; function and safety must drive the claim.

Concussion / mild TBISeparate non-invasive technology pathway, not the current AIRCHILL ventilator.Usual concussion management.Persistent symptom burden / time to clinical recovery or return to activity.1–3 monthsTypical patients are not intubated; this should not be used as an AIRCHILL efficacy programme.

External design benchmark · PRINCESS2

## The most useful lesson is how a signal becomes a definitive trial.

PRINCESS2 provides a highly relevant development template for AIRCHILL even though it tests a different cooling technology: a narrow cardiac-arrest phenotype, on-scene randomisation, a time-critical intervention, treatment continuity into hospital care, blinded neurological follow-up, a prespecified pilot phase and independent safety/futility oversight. AIRCHILL can use that architecture while generating its own product-specific safety, thermal-performance and efficacy evidence.

1 · Phenotype before power

### Define the arrest phenotype before powering.

PRINCESS2 restricts the confirmatory question to OHCA with an initial shockable rhythm after earlier studies generated a subgroup signal. For AIRCHILL, intended population and timing phenotype should be frozen before pivotal powering; materially different arrest phenotypes should be separated or prospectively stratified.

2 · Time is part of the dose

### Record the clock, not just the temperature.

The protocol randomises at the scene and requires transnasal cooling within 20 minutes of EMS arrival. AIRCHILL feasibility work should prospectively capture emergency call, CPR, airway management, randomisation, device start, ROSC, transport, hospital handover and the first measurable thermal effect. Delay is an exposure variable, not background noise.

3 · Bridge the care transition

### Prehospital treatment cannot end at the ambulance door.

PRINCESS2 continues the assigned cooling intervention through transport and hospital arrival until transition to institutional temperature management. AIRCHILL should likewise prespecify device-to-ICU handover, ventilation continuity, temperature trajectory and rewarming so that treatment gaps do not become an uncontrolled co-intervention.

4 · Pilot before pivotal

### Test conduct and safety before testing efficacy.

The first 100 PRINCESS2 participants formed a prespecified pilot focused on protocol adherence and safety; primary and secondary efficacy endpoints were deliberately not analysed. AIRCHILL should use the same logic: predefined feasibility and safety gates before a larger patient-outcome trial.

5 · Control downstream bias

### Standardise what happens after ROSC.

Post-resuscitation care, neuroprognostication and withdrawal-of-life-support procedures are protocolised, while the 90-day neurological assessment is blinded to treatment allocation. This matters because downstream ICU decisions can otherwise overwhelm the effect of an early device intervention.

6 · Engineer for trial reality

### Ambulance operations are part of device performance.

The 2026 pilot reported 92% overall protocol adherence and no device-related serious adverse events, but it also documented minor treatment interruptions during real-world prehospital and in-hospital use. AIRCHILL pilot testing should therefore stress fixation, energy/gas reserve, circuit handling, condensation, alarms, transport vibration, reserve runtime and handover—not only benchtop cooling capacity.

Use PRINCESS2 as a design benchmark; power AIRCHILL from its own claim and Phase 1/2 data. PRINCESS2 plans 1,022 participants around an external 45% versus 54% complete-neurological-recovery assumption, with an interim analysis and 2.5% loss-to-follow-up allowance. That nine-percentage-point assumption is shown here only as an external study-design benchmark. It is not an AIRCHILL effect estimate and should not be used as the calculator default. AIRCHILL powering must come from its final claim, comparator, endpoint, population and observed phase-1/2 event rates.

Study-family sources: [PRINCESS2 protocol v1.1](https://cdn.clinicaltrials.gov/large-docs/23/NCT06025123/Prot_000.pdf) · [PRINCESS2 design paper](https://pubmed.ncbi.nlm.nih.gov/38417773/) · [PRINCESS2 100-patient pilot (2026)](https://pubmed.ncbi.nlm.nih.gov/41680915/) · [PRINCESS randomized trial](https://jamanetwork.com/journals/jama/fullarticle/2732572) · [time-to-cooling subanalysis](https://pubmed.ncbi.nlm.nih.gov/32514590/) · [PRINCE + PRINCESS pooled analysis](https://pubmed.ncbi.nlm.nih.gov/34103095/). These studies test transnasal evaporative cooling, not AIRCHILL.

Study-by-study lessons learned

## What the frequently cited trials should change in an AIRCHILL protocol.

The research register contains many relevant studies, but not every frequently cited study had previously been translated into a concrete protocol lesson. The matrix below separates efficacy signals from design lessons. External cooling studies inform population, timing, dose, endpoint, safety and analysis choices; none of them validate AIRCHILL.

Study familyWhat it showedWhat AIRCHILL should learnProtocol consequence

PRINCESS / PRINCESS2Prehospital transnasal cooling is operationally feasible; PRINCESS was neutral overall, while PRINCESS2 deliberately narrows the phenotype and uses a pilot-before-pivotal architecture.Time-to-treatment and phenotype are part of the intervention. Conduct quality and handover can dilute a biologically plausible effect.Freeze the intended phenotype before pivotal powering; capture every treatment clock; use a prespecified feasibility/safety gate; blind neurological follow-up and standardise post-ROSC care.

TTM2In 1,900 comatose OHCA patients, 33°C did not improve mortality or functional outcome versus normothermia/fever prevention and increased haemodynamically significant arrhythmias.Cooling depth by itself is not a sufficient hypothesis. A new trial must test a distinct treatment contrast such as substantially earlier delivery, different thermal distribution or a defined phenotype.Do not power AIRCHILL against an assumed generic hypothermia effect. Prespecify the estimand, timing contrast, adverse-event surveillance and a clinically meaningful patient-centred endpoint.

Kim et al. 2014 · prehospital cold salineUp to 2 L of 4°C saline after ROSC lowered temperature and brought patients to target about an hour earlier, but did not improve survival or neurological status.Earlier cooling is not enough if the delivery method adds a competing physiological burden. Thermal effect and delivery burden must be separated.Capture fluid balance, pulmonary oedema, haemodynamics, ventilation and actual thermal separation. Historical context: Fabian Temme's WO2008017456A1, priority 7 Aug 2006, describes an infusion system for changing infusion-fluid temperature. It predates the Kim trial enrolment/publication, but no connection or influence between the patent family and the Kim study is claimed. [Patent reference](https://patents.google.com/patent/WO2008017456A1/en).

HYPERION + later IPD evidenceHYPERION reported a 4.5-pp neurological signal in non-shockable arrest, but later individual-patient meta-analysis with TTM2 did not confirm improved survival or function.Single positive trials can be fragile when event rates are low and populations heterogeneous.Treat subgroup signals as hypothesis-generating; stratify or enrich prospectively rather than retrospectively; avoid using +4.5 pp as an AIRCHILL default effect.

COTTISA small matched analysis reported a very large mRS signal after peri-EVT cooling, but the authors explicitly call the effect surprisingly large and request randomized confirmation.Feasibility plus a striking observational effect is not enough for effect-size transfer.For stroke, randomise before/at EVT, use 90-day ordinal mRS as the main analysis, model anaesthesia/door-to-reperfusion/cooling delay, and power from contemporary randomized control rates rather than the +38.7-pp signal.

NICHD neonatal HIEWhole-body cooling started within 6 hours and continued for 72 hours reduced death or moderate/severe disability versus then-standard care.The therapeutic concept can work in a tightly defined biological window, but a future device would be incremental to an established standard rather than a cooling-vs-no-cooling comparison.Any neonatal programme requires separate paediatric engineering, transport timing, servo-controlled comparator care and 18–24-month neurodevelopmental follow-up. Do not transfer the historical 18-pp effect.

POLAREarly prophylactic 33–35°C hypothermia in severe TBI produced essentially identical favourable GOSE to normothermia.Very early cooling is not automatically neuroprotective in an unselected severe-TBI population.Use 0 pp as the evidence-aligned reference; enrich by mechanism/phenotype only prospectively; collect 6-month GOSE with blinded assessment and explicit pulmonary/bleeding safety endpoints.

Eurotherm3235Hypothermia successfully reduced intracranial pressure but worsened mortality/functional outcome.A physiological surrogate can improve while patients do worse.ICP or temperature change can be feasibility/secondary endpoints but cannot substitute for GOSE, mortality and safety. Rewarming, infection, haemodynamics and co-interventions must be protocolised.

LTH / long-duration TBI studiesSome earlier studies and selected subgroups suggested benefit from longer, slower-rewarmed hypothermia, while larger modern trials were neutral or harmful.Thermal dose is multidimensional: onset, depth, duration, phenotype and rewarming may interact.Early AIRCHILL work should reconstruct individual thermal dose and avoid collapsing all exposure into one target temperature. Any subgroup hypothesis must be prespecified before confirmatory testing.

Exertional heat-stroke CWI evidenceRapid whole-body cooling, especially cold-water immersion, consistently achieves high cooling rates and very low mortality in exertional heat stroke; current critical-care guidance prioritises active rapid cooling.For early heat-stroke research, cooling rate and time-above-dangerous-temperature are more defensible first endpoints than an assumed survival effect.Benchmark AIRCHILL against best available rapid cooling, not passive care. Primary early-feasibility metrics should include °C/min, time to