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The INGENIOUS trial: Impact of pharmacogenetic testing on adverse events in a pragmatic clinical trial

The Pharmacogenomics Journal volume 23, pages 169–177 (2023)Cite this article

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Abstract

Adverse drug events (ADEs) account for a significant mortality, morbidity, and cost burden. Pharmacogenetic testing has the potential to reduce ADEs and inefficacy. The objective of this INGENIOUS trial (NCT02297126) analysis was to determine whether conducting and reporting pharmacogenetic panel testing impacts ADE frequency. The trial was a pragmatic, randomized controlled clinical trial, adapted as a propensity matched analysis in individuals (N = 2612) receiving a new prescription for one or more of 26 pharmacogenetic-actionable drugs across a community safety-net and academic health system. The intervention was a pharmacogenetic testing panel for 26 drugs with dosage and selection recommendations returned to the health record. The primary outcome was occurrence of ADEs within 1 year, according to modified Common Terminology Criteria for Adverse Events (CTCAE). In the propensity-matched analysis, 16.1% of individuals experienced any ADE within 1-year. Serious ADEs (CTCAE level ≥ 3) occurred in 3.2% of individuals. When combining all 26 drugs, no significant difference was observed between the pharmacogenetic testing and control arms for any ADE (Odds ratio 0.96, 95% CI: 0.78–1.18), serious ADEs (OR: 0.91, 95% CI: 0.58–1.40), or mortality (OR: 0.60, 95% CI: 0.28–1.21). However, sub-group analyses revealed a reduction in serious ADEs and death in individuals who underwent pharmacogenotyping for aripiprazole and serotonin or serotonin-norepinephrine reuptake inhibitors (OR 0.34, 95% CI: 0.12–0.85). In conclusion, no change in overall ADEs was observed after pharmacogenetic testing. However, limitations incurred during INGENIOUS likely affected the results. Future studies may consider preemptive, rather than reactive, pharmacogenetic panel testing.

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Fig. 1: INGENIOUS trial timeline and analysis flow diagram.

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Data availability

Data is available for the INGENIOUS study in dbGaP with study accession: phs001701.v1.p1.

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Acknowledgements

The INGENIOUS trial (NCT02297126) was sponsored by an NIH/NHGRI U01-grant (HG007762). YZ, ZD, MBR, AMH, KDL, BTG, PRD, TCS are supported by the NIH-U01 HG007762 and NIH-U01 HG010245. MTE was supported by an NIH/NCCIH award (R01AT011463-02). This project was also supported by an NIH/NIGMS award entitled the Indiana University Comprehensive Training in Clinical Pharmacology (T32GM008425) which provided stipend support for BTG, RCP, and CRF. The authors thank Evgenia Teal of the Regenstrief Institute for her invaluable assistance in extracting and curating EHR data. The authors would like to remember Drs. David A. Flockhart and Brian S. Decker, who served as our collaborators, mentors, and friends while making substantial contributions to the design and conduct of this study.

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Author notes

  1. Rebecca C. Pierson

    Present address: Community Fertility Specialty Care, Indianapolis, IN, USA

  2. These authors contributed equally: Michael T. Eadon, Marc B. Rosenman.

Authors and Affiliations

  1. Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA

    Michael T. Eadon, John T. Callaghan, Kenneth D. Levy, Samir K. Gupta, Raj Vuppalanchi, Eric A. Benson, Rolf P. Kreutz, Emma M. Tillman, Tyler Shugg, Rebecca C. Pierson, Brandon T. Gufford, Zeruesenay Desta, Paul R. Dexter & Todd C. Skaar

  2. Ann & Robert H. Lurie Children’s Hospital of Chicago, and Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Marc B. Rosenman

  3. Indiana University School of Medicine, Department of Biostatistics and Heath Data Science, Indianapolis, IN, USA

    Pengyue Zhang & Yong Zang

  4. Luddy School of Informatics, Computing, and Engineering, Indianapolis, IN, 46202, USA

    Cathy R. Fulton

  5. Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, 46202, USA

    Ann M. Holmes

  6. Indiana University School of Medicine, Department of Obstetrics and Gynecology, Indianapolis, IN, USA

    David M. Haas & Rebecca C. Pierson

  7. Indiana University School of Medicine, Department of Medical and Molecular Genetics, Indianapolis, IN, USA

    Victoria M. Pratt & Todd C. Skaar

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Contributions

TCS, PRD, MBR, AMH, KDL, JTC, ZD: Conceptualization; KDL, MBR, CRF, MTE: Data curation; YZ, PZ: Formal analysis; TCS, PRD: Funding acquisition; All authors: Investigation; All authors: conduct of trial; KDL: Project administration; MTE, TCS: Writing - original draft; All authors: Review & editing.

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Correspondence to Todd C. Skaar.

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This study was approved by the Institutional Review Board (IRB # 1401206188) of Indiana University School of Medicine.

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Eadon, M.T., Rosenman, M.B., Zhang, P. et al. The INGENIOUS trial: Impact of pharmacogenetic testing on adverse events in a pragmatic clinical trial. Pharmacogenomics J 23, 169–177 (2023). https://doi.org/10.1038/s41397-023-00315-w

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