Clinical Study Planner
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.
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.
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.
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.
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.
| Stage | Temperature strategy | Population / model | Required safety evidence | Escalation gate |
|---|---|---|---|---|
| Bench / airway model | Map +5 to −30 °C across expected flows, FiO₂ and humidity | Breathing circuit + validated airway/lung models | Patient-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 replication | Large-animal prolonged endotracheal ventilation | Histology + 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 / safety | Sequential −10 → −15 → −20 °C; cohort escalation | Start 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 feasibility | Use the qualified setting; do not escalate temperature in the first emergency cohort | Selected intubated emergency patients | Device-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 optimization | Temperature × humidity × flow × duration optimization | Randomized / adaptive clinical programme | Compare achieved thermal effect and safety rather than “coldest wins”. | Select lowest-risk dose that achieves the required thermal performance. |
Mechanics + gas exchange
Peak/plateau pressure, resistance, compliance, tidal/minute ventilation, SpO₂, PaO₂/PaCO₂, bronchospasm and clinically significant treatment interruption.
Epithelium + inflammation
CC16 plus prespecified epithelial/inflammatory markers; sputum/BAL only where feasible; optional bronchoscopic mucosal scoring in a mechanistic cohort.
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.
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.
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.
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 · 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.
| Indication | Research population | Comparator | Preferred patient-relevant endpoint | Follow-up | Key design issue |
|---|---|---|---|---|---|
| Cardiac arrest | Adults 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 months | Very early randomisation, emergency-consent pathway, avoid mixing fundamentally different arrest phenotypes. |
| Ischaemic stroke | Intubated 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 months | The web calculator uses mRS 0–2 as a binary approximation; a pivotal ordinal design should be simulation-based. |
| Neonatal HIE | Separate 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 months | AIRCHILL is not neonatal-validated; paediatric engineering and a separate regulatory programme are prerequisites. |
| Heat stroke | Selected 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 days | Water immersion remains best-supported for exertional heat stroke when feasible; recruitment is seasonal and sparse. |
| Severe TBI | Intubated 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 months | ICP reduction is not sufficient; function and safety must drive the claim. |
| Concussion / mild TBI | Separate 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 months | Typical 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.
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.
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.
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.
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.
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.
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.
Study-family sources: PRINCESS2 protocol v1.1 · PRINCESS2 design paper · PRINCESS2 100-patient pilot (2026) · PRINCESS randomized trial · time-to-cooling subanalysis · PRINCE + PRINCESS pooled analysis. 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 family | What it showed | What AIRCHILL should learn | Protocol consequence |
|---|---|---|---|
| PRINCESS / PRINCESS2 | Prehospital 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. |
| TTM2 | In 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 saline | Up 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. |
| HYPERION + later IPD evidence | HYPERION 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. |
| COTTIS | A 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 HIE | Whole-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. |
| POLAR | Early 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. |
| Eurotherm3235 | Hypothermia 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 studies | Some 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 evidence | Rapid 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 <40°C / target range, organ-failure trajectory, workflow, ventilation continuity and safety. |
| Concussion cooling studies | Small randomized/non-randomized studies focus on symptom trajectories and return-to-activity, not mortality or severe disability. | The endpoint must match the clinical problem and technology. | Keep this outside the current invasive-ventilator programme; if pursued with a separate non-invasive system, use validated symptom scales and time-to-recovery rather than generic favourable-outcome percentages. |
| HYBRID II · hydrogen | In 73 randomized post-OHCA patients, 2% H₂ for 18 h did not significantly improve the primary 90-day CPC 1–2 endpoint, but secondary mRS and survival signals favoured H₂. | A low inspired gas concentration can be studied within mechanical ventilation and can produce a human signal worth confirming, but early termination makes the observed effect sizes unstable. | If pursued, use a factorial cooling-alone / gas-alone / combination design after dedicated ignition, leak and oxygen-enrichment engineering. Do not use HYBRID II secondary effects as AIRCHILL sample-size defaults. |
| CPAr · argon | The phase-II programme is designed for 120 shockable-rhythm OHCA survivors receiving 70% Ar / 30% O₂ for 4 h, with 48-h NSE as the primary endpoint and later clinical outcomes as secondary endpoints. | Argon provides a current translational template for moving a strong preclinical gas signal into a biomarker-first human study. | Keep biomarker and patient-outcome claims separate. If AIRCHILL studies argon, use stable gas delivery first, then a staged biomarker/safety study before any neurological efficacy claim. |
| Xenon + hypothermia | A 110-patient randomized trial showed less MRI white-matter injury with xenon added to 33°C hypothermia, but no statistically significant six-month neurological benefit. | Combination therapy can produce a measurable target-organ biomarker signal without yet proving patient benefit. Delivery complexity matters: xenon required high concentration and closed-loop ventilation. | Use xenon as the strongest human precedent for gas+cooling biomarker design, but not as the first AIRCHILL gas unless recirculation, monitoring and cost are acceptable. |
| Helium respiratory-cooling study · 2025 | In a porcine arrest model, helium-containing gas improved intra-arrest lung-cooling efficiency; the combined cooling method lowered brain temperature by about 0.8°C within 10 minutes. | Gas composition itself may change AIRCHILL heat transfer independently of any pharmacological neuroprotection. | Run a bench/preclinical carrier-gas comparison at matched FiO₂, flow, pressure and inlet temperature. Measure heat-transfer coefficient, brain/core cooling rate, gas exchange, airway pressure and sensor accuracy before considering a helium clinical claim. |
| Inhaled NO after cardiac arrest | Small human IHCA feasibility work and supportive animal studies suggest deliverability and possible perfusion/neurological signals, but no randomized human neurological efficacy result exists. | A gas may improve pulmonary or circulatory physiology and thereby confound a claimed neuroprotective mechanism. | If revisited, randomize and separate pulmonary-haemodynamic endpoints from neurological endpoints; require NO/NO₂/FiO₂ and methemoglobin monitoring and treat timing during CPR versus after ROSC as a distinct dose variable. |
Health economics by design
Build the economic model into the efficacy programme from the start.
Existing OHCA economic evaluations show that the useful unit is not simply “cost per additional survivor”. Modern evaluations link the acute resuscitation pathway to quality of life, long-term survival and resource use, then propagate uncertainty through decision-tree and Markov or state-transition models.
Update the 2017 German QALY chain instead of starting from zero.
The German Resuscitation Registry model combined incidence, ROSC/admission, discharge, ICU and ward days, rehabilitation, long-term survival and a utility assumption to estimate cost per QALY. Its prices are historical, but the pathway structure is directly reusable with current registry and cost inputs.
Collect EQ-5D and costs prospectively.
The INCEPTION ECPR economic evaluation measured EQ-5D-5L repeatedly through 12 months and calculated incremental costs, QALYs, ICERs and cost-effectiveness acceptability. AIRCHILL confirmatory studies should therefore predefine HRQoL collection rather than infer QALYs retrospectively.
Separate acute and long-term states.
Published ECPR studies use decision trees for the arrest/hospital episode and Markov models for subsequent survival and health states. AIRCHILL should similarly model death, favourable neurological survival and dependent survival beyond the trial horizon, with uncertainty distributions rather than fixed point estimates.
Time and geography belong in the economic model.
German AED-drone modelling couples response-time geography, network coverage, survival and costs. For AIRCHILL, transport time, eligible-case density, site/EMS coverage, device deployment and treatment delay should become explicit implementation variables rather than hidden assumptions.
Capture what later drives cost.
At minimum: EMS time and consumables, device use, ED/ICU/ward days, ventilation days, renal replacement therapy, major complications, procedures, rehabilitation, discharge destination, readmissions, long-term care and return-to-work/productivity where the chosen perspective requires it.
Plan PSA from the beginning.
Report deterministic sensitivity analyses and probabilistic sensitivity analysis, cost-effectiveness planes and acceptability curves. The AIRCHILL effect distribution should remain independent from external cooling-study signals until AIRCHILL-specific data exist.
Economic-design references: German Resuscitation Registry QALY model (Fischer et al., 2017) · INCEPTION trial-based economic evaluation (Delnoij et al., 2024; DOI 10.1093/ehjacc/zuae050) · published ECPR Markov-model analyses · German UAV/AED cost-effectiveness study (Bauer et al., 2021; DOI 10.1136/bmjopen-2020-043791) · systematic review of OHCA economic evaluations. These are methodological templates, not evidence that AIRCHILL is cost-effective.
Protocol knowledge system
Every study assumption should trace back to a structured decision record.
The Hypothermia Research Register now contains a Clinical-Development Knowledge Register with a fixed appraisal schema: population, intervention, comparator, timing, thermal dose, endpoint, effect estimate, safety, limitations, AIRCHILL transferability and the exact protocol variable that should change as a consequence. Sample-size or endpoint assumptions on this planner should be traceable to that register rather than copied from a publication headline.
Operational evidence requirements
A prehospital device study can connect thermal performance to interpretable patient evidence.
For AIRCHILL, usability, timing, measurement quality, ventilation continuity and handover are part of the clinical evidence package. These are not substitutes for patient outcomes; they are the variables that determine whether an efficacy result can be interpreted and reproduced.
Measure a trajectory, not a single temperature.
Prespecify the measurement hierarchy, sampling frequency, clock synchronisation and the thermal variables that matter: time to first measurable effect, rate of change, depth, exposure duration, distribution and rewarming. Continuous device timestamps should be retained so thermal dose can be reconstructed patient by patient.
Use errors and set-up burden are safety data.
Capture critical tasks, set-up time, failed starts, interruptions, alarm handling, circuit changes and recovery from foreseeable use errors in the actual EMS and transport environment. Human-factors engineering should run in parallel with clinical development rather than after the device design is frozen.
The cooling intervention must not degrade the primary life-support function.
Track airway pressure, flow, tidal volume, minute ventilation, FiO2, gas exchange, resistance, condensation and clinically relevant interruptions. Any cooling benefit would be uninterpretable if achieved at the cost of unstable ventilation.
Every important clock should be captured.
Record emergency call, EMS arrival, CPR milestones, airway placement, randomisation, device start, first thermal effect, ROSC, departure, hospital arrival and transition to definitive temperature management. Timing is part of the intervention exposure, not merely a baseline characteristic.
Design the ambulance-to-hospital handover into the protocol.
Prespecify what happens to ventilation and thermal management during transport, emergency-department transfer, imaging or catheter procedures, ICU admission and eventual rewarming. Treatment gaps and crossovers should be measured as protocol variables.
Choose sites that can actually deliver the intended exposure.
Feasibility should include EMS workflow, expected eligible volume, transport times, training burden, hospital handover capability and protocol adherence. A site mix dominated by exposures too short to deliver the intended thermal dose can make a technically valid device look clinically inert.
Conduct and safety before neurological efficacy.
Use a prespecified early-feasibility cohort with go/no-go criteria for device deployment, protocol adherence, ventilation stability, thermal performance and device-related adverse events before expanding into an outcome-powered trial.
Collect resource use alongside efficacy.
For later confirmatory work, prospectively capture ventilation days, ICU and hospital length of stay, major complications and discharge disposition in addition to neurological outcomes. These variables can support later health-economic analyses without changing the primary clinical claim.
Primary references: ISO 14155:2026 · IEC 62366-1:2015 + Amd 1:2020 · FDA human factors guidance · PRINCESS2 pilot · ERC–ESICM 2025 post-resuscitation care.
Interactive power, recruitment & budget lab
Change the assumptions. Watch the trial change.
The calculator uses a two-sided superiority approximation for two independent proportions. It is deliberately transparent and conservative: final protocol power must be reproduced in validated statistical software and adapted to the actual endpoint model.
Sample-size method: normal approximation using Cohen’s h for two independent proportions with the selected allocation ratio, then inflated for attrition. The tool does not adjust for interim analyses, multiplicity, covariates, centre effects, competing risks, ordinal endpoints, cluster randomisation or non-inferiority margins. Those require a protocol-specific statistical model.
Planning framework: EU MDR 2017/745 Annex XV; ISO 14155:2026; ICH E9 / E9(R1); FDA pivotal-device-study guidance and IDE guidance. All default control rates, recruitment speeds and costs on this page are planning anchors and remain editable. They are not regulatory commitments, quotations or AIRCHILL efficacy data. See the site-wide source, assumption and data-gap register.
How the trial size reacts to the effect you assume
The curve is the same arcsine calculation as the fields above, drawn across a range of assumed absolute effects. Move any input and it redraws. The steep left-hand side is the whole reason a trial has to name its effect size before it names its budget.
Both panels are drawn from the inputs above and carry no separate assumptions. Sample size uses the arcsine transformation for two proportions; it is a planning approximation and not a substitute for simulation, which is what an ordinal endpoint would need.
Translational airway programme · athlete comparators
Study programme: separate ventilation load, cold/dry air and sport-specific exposures.
The winter-sport literature suggests that airway risk is not driven by cold alone. High minute ventilation, dryness, duration, repeated exposure, pollutants and individual susceptibility interact. The proposed programme therefore uses cross-country skiers, road cyclists, swimmers and low-exposure controls as natural comparator groups before AIRCHILL-specific human dose escalation.
Cross-sport phenotyping study
Objective: quantify how much airway dysfunction is associated with endurance ventilation itself and how much is associated with the inhaled environment. Four cohorts: elite/competitive cross-country skiing or biathlon, road cycling, swimming/triathlon and healthy non-endurance controls.
Controlled exposure crossover
Objective: estimate the short-term dose-response to temperature, humidity and ventilation under standardized conditions, independent of years of sport-specific exposure.
Product-specific respiratory safety
Objective: after bench and large-animal qualification, test the qualified AIRCHILL respiratory dose in an ethically appropriate intubated human population using sequential −10 → −15 → −20 °C cohorts.
Study A · ATHLETE-AIRWAY
Cross-sport airway phenotype study.
Design: multicentre prospective cross-sectional study with a seasonal longitudinal subset. Planning target n≈160 as an initial research cohort: ~40 cross-country skiers/biathletes, ~40 road cyclists, ~40 swimmers/triathletes and ~40 healthy low-endurance controls. This sample is an ASSUMPTION for biomarker and effect-size estimation, not a confirmatory prevalence trial.
| Domain | Planned measurement | Why it matters |
|---|---|---|
| Clinical phenotype | Physician-diagnosed asthma, medication, allergy/atopy, respiratory symptoms, infection history, smoking/vaping, prior airway disease. | Separates pre-existing susceptibility from training/exposure effects. |
| Objective airway function | Spirometry, bronchodilator reversibility, standardized EIB/EVH or methacholine challenge as prespecified, impulse oscillometry/small-airway measure where available. | Symptoms and bronchial hyperresponsiveness often disagree in elite athletes. |
| Inflammation | FeNO, induced sputum differential cell count, blood eosinophils; optional IL-8 and related cytokines. | Winter-sport disease may be neutrophilic or mixed rather than classic Type-2 asthma. |
| Epithelial stress | CC16 as core biomarker; optional SP-D and exploratory epithelial panel. | HME studies show CC16 responds to cold/dry high-ventilation exposure. |
| Remodeling | Exploratory MMP-9/TIMP-1 panel; no single biomarker used as a diagnostic threshold. | Existing athlete studies suggest remodeling biology is heterogeneous and season-dependent. |
| Exposure reconstruction | Training hours/year, years in sport, typical minute ventilation proxy, winter temperature/humidity exposure, pool/chloramine exposure, road pollution/pollen exposure, altitude, indoor-rink exposure where applicable. | Allows multivariable separation of ventilation load from environment. |
| Seasonal subset | Repeat pre-season and peak-season testing in a subset of skiers and cyclists. | Tests within-person change instead of relying only on between-sport prevalence differences. |
Lower-airway dysfunction composite
Predefine a composite only if diagnostic components are harmonized. Otherwise report asthma, EIB and BHR separately and avoid collapsing incompatible endpoints into one prevalence number.
Natural experiments
XC skiing vs cycling: similar endurance ventilation, different thermal environment. XC skiing vs alpine/ski-jump reference data: similar cold, very different sustained ventilation. Swimming vs cycling: both high ventilation, different irritant environment.
Exposure-response model
Estimate associations between cumulative endurance load, cold/dry exposure and airway markers. The model becomes an input—not a substitute—for AIRCHILL dose selection.
Study B · COLD-DOSE
Randomized crossover dose-response study.
This study directly tests the variables suggested by winter-sport and HME research. The purpose is to identify the combination of inspired temperature, humidity and ventilation that produces the least airway stress for a given thermal load.
| Element | Planning choice | Rationale |
|---|---|---|
| Population | Healthy adults plus a smaller pre-specified asthma/EIB susceptibility cohort after initial healthy-cohort safety is established. | Separates normal physiology from susceptible-airway response. |
| Design | Randomized within-subject crossover with washout; blinded endpoint analysis where feasible. | Greatly reduces between-person variability in airway biomarkers and lung function. |
| Exposure levels | Example research ladder: room-temperature control, 0 °C, −10 °C and −15 °C under standardized ventilation; −20 °C only after safety review and if justified by prior data. | Avoids beginning at the coldest technically achievable level. |
| Humidity factor | At least two absolute-humidity conditions or an HME/no-HME comparison at a fixed temperature. | Tests whether water loss, rather than temperature alone, drives epithelial stress. |
| Ventilation factor | Standardized low/moderate vs high ventilation or controlled EVH target. | Tests the interaction seen in athletes: high ventilation amplifies cold/dry-air effects. |
| Duration | Short initial exposure with staged extension after safety review. | Separates acute response from cumulative dose. |
| Core endpoints | ΔFEV1, airway resistance/small-airway mechanics, symptoms, CC16, FeNO, inflammatory markers, secretion/mucociliary measure where feasible. | Captures physiology, epithelium and symptoms separately. |
| Exposure metric | Temperature, absolute humidity, minute ventilation, peak flow and exposure time recorded continuously or at protocol-defined intervals. | Enables calculation of a respiratory thermal/water-loss dose rather than using temperature alone. |
Study C · AIRCHILL-FIRST
First product-specific human airway-safety study.
Only after Study B and confirmatory large-animal work should the AIRCHILL-specific route be tested clinically. A practical first setting is an elective or otherwise controlled intubated population in which airway management, invasive monitoring and informed consent can be handled prospectively. Final population and exposure require ethics, investigator and authority agreement.
| Stage | Illustrative cohort | Exposure | Decision |
|---|---|---|---|
| Cohort 1 | 6–10 participants | −10 °C qualified patient-side setpoint; short prespecified duration. | Proceed only if no predefined airway, gas-exchange, secretion, epithelial or haemodynamic stopping signal. |
| Cohort 2 | 6–10 participants | −15 °C after independent safety review. | Compare exposure-response against cohort 1; assess whether greater thermal performance materially increases airway stress. |
| Cohort 3 | 6–10 participants | −20 °C only after prior cohort review. | Candidate first-generation lower clinical setpoint if benefit-risk and engineering performance remain acceptable. |
| Expansion | ~20–40 additional participants, planning range | Selected dose, not further automatic escalation. | Improve precision for common device-related airway events and characterize biomarker recovery. |
Ventilation cannot deteriorate
Peak/plateau pressure, resistance, compliance, tidal/minute ventilation, SpO2, PaO2/PaCO2, bronchospasm and treatment interruptions.
Epithelium and recovery
CC16 plus prespecified inflammatory/epithelial markers; secretion burden; mucociliary/ciliary recovery endpoint where technically and ethically feasible.
Particularly relevant for post-arrest translation
Continuous ECG, arrhythmia, ST/ischemia surveillance where appropriate, blood pressure, vasopressors and haemodynamic instability.
Show the intended physical effect
Patient-side gas temperature, humidity, flow and thermal extraction; body/target-organ temperature surrogate selected for the study setting.
Do not stop observation when cooling stops
Repeat airway/biomarker measures after exposure to demonstrate whether acute effects normalize and to identify delayed secretion or inflammatory responses.
Sequential escalation
Safety Review Committee/DSMB reviews each cohort. Predefined hold rules should cover bronchospasm, pressure/resistance increase, gas-exchange deterioration, biomarker outliers, secretion burden and cardiovascular events.
Statistical strategy
Use the studies to estimate dose-response, not to manufacture one prevalence number.
Multilevel regression
Model objective airway endpoints against sport, training volume, cumulative years, cold/dry exposure, pollution/chloramine exposure and atopy. Site and season should be treated explicitly. Report adjusted estimates with uncertainty.
Within-person mixed models
Use participant-level random effects and interaction terms for temperature × humidity × ventilation. Predefine multiplicity handling for multiple biomarkers and distinguish exploratory from confirmatory endpoints.
Bayesian or rule-based escalation can be discussed
A model-assisted escalation design may be more efficient than rigid cohorts, but only if regulators and investigators agree on a clinically interpretable airway-toxicity definition. A simple sequential cohort design remains easier to audit.
Regulatory integration
Each study closes a different regulatory question.
| Evidence module | Regulatory question | Technical file / submission use |
|---|---|---|
| ATHLETE-AIRWAY | Which background airway phenotypes and exposure variables are biologically plausible confounders? | Clinical evaluation, state-of-the-art review, ISO 14971 hazard identification, endpoint justification. |
| COLD-DOSE | How do temperature, humidity, ventilation and duration interact in human airway response? | Dose justification, risk controls, proposed operating envelope, FDA Pre-Sub / Notified Body discussion. |
| Large-animal AIRCHILL | Does prolonged endotracheal delivery produce tissue, secretion, gas-exchange or mucociliary injury? | Preclinical safety package and justification to proceed to route-specific human testing. |
| AIRCHILL-FIRST | Can the qualified device deliver the intended respiratory thermal dose safely in humans? | MDR clinical investigation / CER, FDA IDE/Pre-Sub evidence, labeling and contraindication development. |
| Emergency feasibility | Does safety/performance remain acceptable in the real target workflow? | Intended-use validation, EMS human factors, transport performance and basis for later efficacy trial. |
Operational clinical package
The study strategy now has controlled working documents.
Full development Clinical Investigation Plans for cardiac arrest and stroke are now linked to a shared Schedule of Assessments/CRF data dictionary, DSMB Charter, Statistical Analysis Plan, screening/monitoring plan, safety-reporting plan, Investigator’s Brochure framework and EU/FDA submission map.