Proof-of-Concept Protocol: STORM Prospective Validation

Authors

Erick Adrián Zamora Tehozol MD (CryptoReuMd.eth), DNAI

Study Design

Two-phase, single-center observational study with prospective genotype-guided intervention arm.

Phase 1: Retrospective Validation (n=200)

• Chart review of patients with known drug response outcomes
• Genotyping of 30-gene panel from stored samples
• STORM prediction vs actual clinical outcome concordance
• Primary endpoint: AUC >0.75 for adverse event prediction

Phase 2: Prospective Intervention (n=407)

• New patients genotyped at enrollment
• STORM-guided prescribing recommendations provided to treating rheumatologist
• 12-month follow-up for drug response, adverse events, and dose adjustments
• Comparison with historical controls (pre-STORM prescribing)

30-Gene Panel

Core 18 (STORM v3.1)

CYP2C19, CYP2D6, CYP2C9, CYP3A5, HLA-B, HLA-A, NAT2, TPMT, NUDT15, UGT1A1, MTHFR, ABCB1, SLCO1B1, CYP2B6, DPYD, G6PD, VKORC1, CYP1A2

Expansion Panel (+12)

IRF5, TLR7, DEFB1, NLRP3, ABCG2, XDH, NRAMP1, STAT4, PTPN22, IL6R, TNFAIP3, BLK

Regulatory Requirements

• SIRELCIS registration (Mexican clinical research registry)
• IMSS Ethics Committee approval (Comité Local de Investigación)
• Written informed consent per NOM-012-SSA3-2012
• Data protection per LFPDPPP
• ClinicalTrials.gov registration

Sample Size Justification

607 patients calculated for 80% power to detect AUC difference of 0.10 from null (0.65) with two-sided alpha=0.05, accounting for 15% dropout.

Primary Endpoints

1. Genotype-phenotype concordance (AUC for adverse event prediction)
2. Rate of dose modifications concordant with STORM recommendations
3. Adverse event incidence: STORM-guided vs historical controls

Secondary Endpoints

1. Cost per QALY of genotype-guided prescribing
2. Time to therapeutic response
3. Patient satisfaction with pharmacogenomic counseling

Setting

Hospital General Regional No. 1 "Ignacio García Téllez", IMSS, Mérida, Yucatán, Mexico

Timeline

• Month 1-3: Ethics approval, SIRELCIS registration
• Month 3-9: Phase 1 (retrospective)
• Month 9-21: Phase 2 (prospective enrollment)
• Month 21-24: Analysis and publication

Conclusion

This protocol enables the first prospective validation of ancestry-adjusted pharmacogenomic prescribing in Mexican rheumatology patients, with the potential to establish a new standard of care for the IMSS system serving 60+ million beneficiaries.