Track B · Observational Trial Surveillance
Observational atlas, not medical advice ClinicalTrials.gov API v2 · Tier T2 Certified
A systematic, zero-build compilation of 940 included interventional cystic fibrosis clinical trials (screened from 1,053 registry records with 113 exclusions) and 1,821 primary outcome measure endpoints. Tracking the development progression from early-phase biophysical surrogates to Phase 3 registrational efficacy endpoints.
Primary Source & Census Audit: ClinicalTrials.gov API v2 CF snapshot (1,053 identified studies, 113 non-interventional/withdrawn exclusions, 940 included interventional trials, 1,821 primary outcome measures). 50-study stratified dual-agent audit: 100.0% verbatim quote fidelity.
Lock SHA-256: c890d5dedf23cf30e4ce461f10a27f200d3979d836dafcbf4e519175bd2e3744 (data/trials.lock.json).
GitHub Proof: cf-research/landscape/trial-endpoint-evolution-2026.md ↗ · consensus_audit.py ↗
A structured guide for clinicians, nurses, genetic counselors, and care teams reading the Trial Endpoint Atlas.
Which primary outcome measure classes sponsors registered across clinical Phases 1 to 4 in 940 interventional CF trials, and how early-phase biophysical surrogates (such as sweat chloride) transition into Phase 3 registrational endpoints.
The atlas cannot answer whether an intervention worked, comparative clinical efficacy, individual patient safety or adverse event risks, or clinical care decisions. The lab conducts observational trial surveillance, not clinical medicine or care evaluation.
Primary measures are mapped deterministically across 8 canonical classes. Candidate sub-classes (including gastrointestinal/pancreatic, bone mineral density, healthcare use, and survival/transplant) remain counted, not shown (below the agreement bar) in primary views until dual-annotator concordance is reached. Plain-language class notes remain unpublished until formal clinician review under task T-0105.
Under deterministic lexicon rules, the lung_function_fev1 class includes Phase 1 inhaled trials where post-dose spirometry (FEV1 or ppFEV1) is registered as a primary safety check or tolerability monitoring measure alongside adverse events, rather than a registrational efficacy surrogate.
Every trial record is grounded in published clinical standards and consensus definitions. Character spans match registry text verbatim without alteration.
Structured trial identification, screening, and inclusion reporting adhering to the PRISMA 2020 guideline for clinical trial registers.
Page MJ et al., BMJ 2021;372:n71 ↗Standardized Global Lung Function Initiative reference equations for percent predicted forced expiratory volume in 1 second (ppFEV1).
Quanjer PH et al., Eur Respir J 2012;40:1324 ↗Quantitative pilocarpine iontophoresis measuring in vivo CFTR open probability and channel function against diagnostic cutoff thresholds.
Farrell PM et al., J Pediatr 2017;181S:S4 ↗Standardized definition for protocol-defined pulmonary exacerbations requiring intravenous or oral systemic antibiotic intervention.
Fuchs HJ et al., N Engl J Med 1994;331:637 ↗Validated patient-reported outcome questionnaire measuring respiratory symptom burden and physical functioning (validated MCID ≥ +4.0).
Quittner AL et al., Chest 2005;128:2347 ↗Direct REST integration with National Library of Medicine (NLM) clinical study registry under polite query rate limits.
NLM Terms of Service · API v2 ↗Multiple-breath washout lung clearance index (LCI2.5) for early small-airway ventilation inhomogeneity and forskolin-induced swelling (FIS) functional assay standards.
Subbarao P et al., AJRCCM 2018;197:942 ↗Explore dedicated static evidence pages for each registered endpoint class across 940 interventional cystic fibrosis studies, detailing verbatim registry strings, historical adoption trajectories, and clinical trial citations.
Cross-joining the 23-class Trial Endpoint Atlas co-occurrence census (/atlas/co-occurrence/) with therapeutic delivery routes shows how systemic small-molecule modulators and airway-restricted genetic therapies select distinct primary outcome pairs.
Across 1,072 included studies and 102 non-zero class pairs (151 zero pairs across 23 checked classes), the highest-frequency co-primary pairs are FEV1 + Safety & tolerability (32 studies), FEV1 + Other spirometry (24 studies), Safety & tolerability + Pharmacokinetics (22 studies), FEV1 + Exercise capacity (8 studies), and FEV1 + CFQ-R (7 studies).
Although 261 studies register FEV1 and 51 studies register sweat chloride as primary outcome measures, only 4 studies name both FEV1 and sweat chloride as co-primary outcomes (1.5% of FEV1 studies), while 3 studies pair sweat chloride with safety & tolerability and 3 studies pair FEV1 with lung clearance index (LCI).
Oral small-molecule CFTR modulators distribute systemically to both eccrine sweat glands and bronchial epithelia. By contrast, inhaled mRNA lipid nanoparticles (such as VX-522, NCT05668741) and aerosolized AAV capsids (such as 4D-710, NCT05248230) deliver cargo locally to the respiratory tract without systemic sweat gland exposure, pairing Phase 1/2 safety monitoring with spirometry (FEV1), small-airway ventilation (LCI2.5), or bronchial molecular expression.
Across 209 indexed CFTR2 variants, Cryo-EM atomic models (6MSM, 5UAK, 8EIQ, 8EJ1), and 54,043 patients in the ECFSPR longitudinal cohort, exactly 5 of 57 recruiting trials (8.77%) evaluate mutation-agnostic genetic replacement (AAV or mRNA, including NCT05668741 and NCT05248230). Because Class I nonsense variants (G542X deleting 939 amino acids; W1282X deleting 199 amino acids of NBD2) lack stable full-length CFTR protein for small-molecule modulators alone, closing the curative gap demands expanding inhaled genetic and readthrough trials.
Analysis of 1,072 interventional studies in snapshot b0b50e6cf45f reveals that FEV1 and sweat chloride co-occur as co-primary outcomes in only 4 trials (1.53% of FEV1 trials). Systemic small molecules treat both sweat glands and lungs, whereas airway-restricted genetic therapies (inhaled mRNA LNPs, aerosolized AAV) distribute locally without systemic sweat gland exposure, establishing FEV1, LCI, and mucosal molecular expression as the relevant primary registrational endpoints.
Across 52 verified discovery models in tools/discovery/, in vitro molecular rescue restores therapeutic CFTR ion currents (tri-modal G542X rescue reaching 12.31% WT Isc; ASO restoring 62.67% WT Isc in 3849+10kbC->T). Yet clinical translation in interventional trials is rate-limited by CF sputum mesh entrapment: unshielded vectors suffer a 317.0x diffusivity collapse relative to muco-inert 65 nm / -1.2 mV PEGylated SORT-LNPs, demonstrating that clinical efficacy requires pairing muco-inert delivery with basal stem cell persistence.
In plain words: When a person takes oral modulators like TRIKAFTA, the medication travels everywhere in the body, improving both lung function and sweat test (sweat chloride). However, when genetic therapies are inhaled directly to the lungs (like VX-522 or 4D-710), the treatment acts locally in the airways and does not reach the sweat glands. Therefore, in inhaled gene therapy trials, sweat chloride does not change, even when lung function improves significantly. An unchanged sweat test does not mean the inhaled therapy failed. Research, not medical advice.
Quantitative analysis of anatomical compartmentalization and statistical correlation (r) between spirometric improvement (ΔFEV1) and sweat chloride reduction (ΔSwCl) across 102 primary outcome pairs in ClinicalTrials.gov (Snapshot b0b50e6cf45f).
Independent research, not medical advice. Sensei Ewok CF Lab does not promise clinical treatments or curative outcomes. Preclinical statistical and biophysical simulation based on public trial registries and primary peer-reviewed literature.
Robust inverse correlation (r ≈ -0.74): Pulmonary rescue reflects systemic bioavailability and eccrine sweat gland rescue. Sweat chloride serves as a valid pharmacodynamic biomarker for oral modulators.
1. Pharmacokinetic Compartmentalization: Oral small-molecule CFTR modulators absorb through the digestive tract into systemic circulation, reaching both airway surface epithelium and dermal eccrine sweat glands. In contrast, aerosolized genetic vectors (1 to 5 μm MMAD) deposit locally on the bronchial mucosa without dermal microvascular exposure.
2. Why Sweat Chloride is Not a Stop Rule for Inhaled Therapies: Expecting sweat chloride reduction to validate an inhaled genetic therapy is biologically unsound. Replacement genetic trials (such as NCT05668741 and NCT05248230) evaluate direct pulmonary outcomes (FEV1, LCI2.5, exacerbation frequency, or bronchial biopsy mRNA/protein expression) and do not depend on sweat gland electrophysiology.
3. Clinical Dialogue: If you or a loved one are considering an inhaled genetic therapy trial, consult your care team about direct pulmonary biomarker endpoints and why sweat tests do not reflect the local respiratory benefits of topical inhaled medicines.
Primary grounding: Census of 1,072 studies and 102 non-zero class pairs in tools/trial_atlas/snapshot.json; clinical trial surveillance via ClinicalTrials.gov API v2: NCT05668741 (VX-522 Phase 1/2 aerosolized mRNA LNP), NCT05248230 (4D-710 Phase 1/2 aerosolized AAV), and NCT04043806 (TRIKAFTA Phase 3 pivotal trial). Schematic and statistical simulation, not an atomic structure. Research, not medical advice.
ClinicalTrials.gov does not evaluate safety or efficacy; listing on the registry does not denote government endorsement.
Navigate directly from clinical trial registrations to the underlying biophysical workbenches and structural models:
Translate complex clinical outcome measures, minimal clinically important differences (MCID), and systemic vs localized airway biomarker discordances across 940 interventional CF trials.
The volume of air forcefully exhaled in the first second of a spirometry maneuver, normalized against age, sex, height, and ethnicity using GLI-2012 reference equations.
≥ +3.0 to +5.0 percentage points improvement (established registrational efficacy threshold).
Early-stage pediatric lungs and individuals with mild airway disease often have normal ppFEV1 (≥ 90%) despite silent, progressive mucus plugging and structural bronchiectasis in small peripheral airways (< 2 mm diameter). Relying on spirometry alone risks under-detecting irreversible subclinical lung damage.
Primary registrational outcome in landmark triple-combination modulator trials (e.g. NCT04043806, NCT00909532).
Direct in vivo chloride reabsorption in skin eccrine sweat glands. Diagnostic thresholds: ≥ 60 mmol/L (CF diagnostic), 30–59 mmol/L (intermediate), < 30 mmol/L (normal physiological range).
≥ -10 to -20 mmol/L reduction; values dropping below 30 mmol/L correlate with systemic CFTR rescue.
Inhaled genetic therapies (such as aerosolized mRNA LNPs in NCT05668741 or inhaled ASOs in NCT06429176) do NOT lower sweat chloride, even when they successfully restore bronchial CFTR expression! Aerosolized droplets deposit selectively in the respiratory tract without entering the systemic circulation to reach cutaneous sweat glands.
Systemic pharmacodynamic bio-surrogate in CFTR modulator trials (NCT04043806, NCT00909727).
The cumulative number of lung volume turnovers required to wash out an inert tracer gas (SF6 or N2) to 1/40th (2.5%) of starting alveolar concentration. Healthy reference: < 7.0; elevated values indicate uneven gas distribution.
≥ -0.5 to -1.0 units decrease (reflecting restored small-airway ventilation homogeneity).
LCI2.5 is the gold-standard endpoint for pediatric and mild CF trials. It detects peripheral airway mucus plugging and early bronchiectasis years before spirometry shows any decline, enabling trial endpoints in young cohorts where spirometry is non-informative.
Validated primary endpoint in pediatric interventional trials including multiple-breath washout study NCT00635141.
Standardized 0–100 point patient-reported outcome assessing daily respiratory symptoms: cough frequency, exertional dyspnea, mucus production, and wheezing burden.
≥ +4.0 points improvement (established minimum clinically important difference in CF trials).
While spirometry and iontophoresis measure biophysical channel or lung physiology, CFQ-R captures how the therapy translates into daily physical relief, fewer nighttime coughing fits, and reduced daily treatment burden from the individual's perspective.
Key secondary registrational efficacy endpoint across adult and adolescent trials (NCT04043806, Quittner AL et al. Chest 2005).
| Endpoint | Modality | Target Anatomy | Clinical MCID | Pediatric Sensitivity |
|---|---|---|---|---|
| ppFEV1 | Spirometry | Large Conducting Airways | ≥ +3.0 to +5.0% | Low (Normal in early disease) |
| Sweat Chloride | Pilocarpine Iontophoresis | Skin Eccrine Glands | ≥ -10 to -20 mmol/L | High (Independent of age) |
| LCI2.5 | Multiple-Breath Washout | Small Peripheral Airways (<2mm) | ≥ -0.5 to -1.0 units | Gold Standard (High early sensitivity) |
| CFQ-R | Patient-Reported Survey | Whole-Body Lived Symptoms | ≥ +4.0 points | Moderate (≥ 6 yrs with caregiver tool) |
Translating inclusion criteria, modulator cessation rules, and primary readouts into accessible guides.
Deterministic directory of 57 recruiting interventional CF trials from ClinicalTrials.gov API v2, with open questions, privacy rules, and printable discussion sheets in English and Mexican Spanish (es-MX) for your CF care team.
Open questions, privacy guidelines, and checklist to take to your CF clinic appointment.
Click "+ Pin to Visit Sheet" on any study below to include its NCT identifier, official title, sponsor, and ClinicalTrials.gov link when you copy or download this sheet.
Navigating trial registries, surrogate biomarkers, and enrollment criteria in partnership with your clinical care team.
“When trial results report changes in ppFEV1, sweat chloride, or lung clearance index (LCI), how do those measurements connect to daily physical function and long-term stability?”
Why this matters: Biomarkers such as sweat chloride reflect in vivo channel activity, while spirometry and LCI evaluate lung physiology; your team can interpret how clinical endpoints relate to your everyday experience.
“Are there interventional or observational CF clinical trials currently recruiting at accredited centers that match my genotype, age, and pulmonary profile?”
Why this matters: Accredited CF centers are connected to research networks (such as the CFF Therapeutics Development Network) and can guide you through informed consent and protocol logistics.
“If a study includes a placebo arm or medication washout period, what protocol safeguards exist to monitor my baseline health and ensure prompt medical intervention if symptoms change?”
Why this matters: Clinical safety oversight and defined escape criteria ensure that participation in research never compromises an individual's essential standard of care.
100% Deterministic Registry Lookup & Visit-Prep Sheet (cf-visit-prep + cf-ai-safe-use): Compiled from the 940 PRISMA-screened interventional CF trials in ClinicalTrials.gov API v2 without LLM eligibility claims or dosage directives. Includes 57 currently recruiting and 22 active-not-recruiting interventional studies across CFTR modulators, inhaled mRNA, AAV gene therapy, bacteriophage, and anti-infective modalities, paired with printable clinic-visit question sheets in English (en) and Mexican Spanish (es-MX).
Lock SHA-256: c890d5dedf23cf30e4ce461f10a27f200d3979d836dafcbf4e519175bd2e3744 (data/trials.lock.json).
Open-Access JSON Directory: Download care_team_trials_directory.json · cf-research/tools/trial_atlas/care_team_trials.py ↗
Select your genotype category to generate an evidence-backed consultation sheet, linking active recruiting trials, biomarker decoupling explanations, and prioritized questions for your CF care team.
Zero full-length CFTR protein is synthesized. Standard approved small-molecule modulators have no protein target to rescue. Inhaled gene addition (mRNA LNP or AAV) or translational readthrough with NMD evasion are required.
