A Translational Research-Program for Compound Race Pathology: Five Framework-Distinct Trial-Design Templates

Paper 8c in the Friction Theory paper-series. The translational research-program companion to Paper 8b (compound race pathology framework). Specifies five framework-distinct intervention protocols across three pathology classes (psychiatric, post-viral, autoimmune) with full trial-design templates. Target venue: Frontiers in Medicine — Translational Medicine (primary) ; fallback Trials (BMC methodology). Abstract. Compound race pathology (Paper 8b) specifies a framework for multi-scale disease progression that exceeds any single scale's control coefficient. This translational companion paper operationalises the framework into five framework-distinct intervention protocols with full trial-design templates (Bayesian adaptive platform; substrate-vector entry criteria; per-template power calculations; framework-pivotal vs component-test stratification). Protocols span: (§3. 1) ketamine + structured CBT consolidation for treatment-resistant depression; (§3. 2) psilocybin + substrate-vector-matched integration for TRD; (§3. 3) long COVID multi-target factorial; (§3. 4) TRD upfront multi-axis substrate-vector profiling with a proposed six-axis biomarker panel (inflammation, HPA, microbiome, cognitive pattern, behavioural activation deficit, sleep substrate; target cost 400–1500; analytical validation specified as a precondition) ; and (§3. 5) CAR-T + tolerance-substrate-stabilisation for autoimmune. Trial-design contributions. Box-format trial-design templates with substrate-vector entry criteria, 4D stratification analysis (substrate-vector × demographic × clinical × outcome), framework-pivotal R-condition specification per protocol, and adaptive-modification trajectory documentation. Proposed reporting items for substrate-stratified compound-mechanism trials (§4. 6) cover substrate-vector measurement at intake, stratification-decision rules, intervention-modification trajectory, and 4D-comparison-analysis — offered as items such trials should consider rather than as a standard from a standards body. The calibrated-retrieval prediction (calibration-aware intervention preserves the recognition-commit slope; calibration-naive flattens it), distinct from Paper 8b's R1–R10 set, anchors the calibrated-retrieval-practice mechanism (Paper 1 §5. 8. 7) as a measurable clinical-substrate axis. Empirical anchors. Wilkinson 2017/2021 ketamine + CBT (Category B durability anchor) ; Carhart-Harris 2021 NEJM psilocybin-vs-escitalopram (primary p = 0. 17 NS — framework re-frames as R10 sub-population-conditional pattern) ; Müller CASTLE 2026 SLE/IIM/SSc gradient (A1/A2/A3 sub-classification empirical anchor) ; CBT-ENDURE NCT04760652 (Yale Sanacora-Wilkinson, n = 100, readout 2026–2027) ; STIMULATE-ICP and RECOVER-AUTONOMIC (long COVID factorial designs) ; Tsimberidou 2020 IMPACT precision oncology framework. The post-CAR-T relapse mechanism (Grenov 2025) is a bioRxiv preprint, disclosed as such; all other load-bearing citations are peer-reviewed. Framework-distinctness criterion. Each protocol is positioned as framework-distinct from precision-medicine biomarker-stratified single-axis stratification by virtue of the coupling-across-scales prediction operationalised in Paper 8b §4. 4: intervention at the most rate-limiting axis produces secondary modification at coupled axes within cross-scale-propagation timescales. The trial-designs incorporate cross-axis longitudinal trajectory measurement to operationalise this prediction at trial scale. Author position and invitation. The author (Pødenphant Lund) is an independent researcher without clinical credentials in the disease-domains the protocols span, without institutional affiliation, and without a clinical consortium — a venue-fit constraint the paper acknowledges explicitly, and the reason it targets a venue hospitable to research-programme papers from independent researchers. The hypothesis-and-invitation framing is the honest response, and domain-expert and consortium collaboration is explicitly invited. The paper specifies what should be tested; specific intervention-protocol development requires domain-expert engagement and standard clinical-research methodology (safety, dose-finding, regulatory pathway, ethics review). Companion papers in the Friction Theory series: Paper 8 (Psychiatric Clinical Intervention): 10. 5281/zenodo. 20059866 (reserved) Paper 8b (Compound Race Pathology — framework): 10. 5281/zenodo. 20059870 (reserved) Paper 8d (Sub-threshold Cofactor Support): 10. 5281/zenodo. 20277291 (reserved) Paper 0 (Behavioural Friction Theory): 10. 5281/zenodo. 19462499 Paper 1 (Friction Theory substrate): 10. 5281/zenodo. 20012654 Series project page: frictiontheory. org. ORCID: 0009-0000-4724-2427.