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Overt hepatic encephalopathy: development of a novel clinician reported outcome tool and electronic caregiver diary

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Abstract

Clinical management and clinical trials of patients with overt hepatic encephalopathy (OHE) are compromised by lack of standardized and reproducible tools for its clinical diagnosis or for caregiver (CG) identification of OHE manifestations which merit medical evaluation. Using an iterative Delphi method, Steering Committee and international hepatologist panel, the West Haven (WH) scale was modified to develop and operationalize a clinician tool for OHE identification and grading (HE Grading Instrument, HEGI™). Major diagnostic criteria included disorientation to time, place, and person, asterixis, lethargy, and coma. Minimum HEGI requirements for OHE diagnosis included: (1) disorientation, or (2) presence of both lethargy and asterixis, or (3) coma. Inter- and intra-rater HEGI reproducibility were 97 % and 98 %, respectively. When applied to a phase II clinical trial population of 178 patients with 388 OHE episodes, HEGI demonstrated excellent concordance with investigator judgement. Additionally, a multi-stage study was conducted to develop a daily CG e-diary, based on OHE manifestations recognizable by CG including speech difficulties, unusual behavior, forgetfulness, confusion, disorientation and level of consciousness. The e-diary was designed for use on smart phone, laptop or desktop, utilized branching logic and skip patterns, incorporated automatic daily completion reminders and real time alerts to clinical sites to facilitate daily standardized CG input and was found to be user friendly and understandable. The HEGI and e-diary, which were developed using methodology accepted by regulatory authorities, are designed to facilitate the design and interpretation of clinical trials for OHE and improve outcomes for OHE patients in clinical practice.

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Abbreviations

CG:

caregivers

HE:

hepatic encephalopathy

HEGI:

HE Grading Instrument

OHE:

overt HE

SC:

steering committee

WH:

West Haven

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Acknowledgments

The authors acknowledge and thank the study coordinators caregivers involved in the development of the e-diary as well as the study team, including Amanda Landrian (Evidera); Dave DiSerafino (Exco InTouch); Carla Bello (California Pacific Medical Center); Sherri Cummings (Indiana University) and Aimee Enriquez (Horizon Therapeutics). The authors also acknowledge members of the FDA Division of Gastroenterology and Inborn Errors Products for their guidance throughout the development of the HEGI and CG e-diary.

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Authors and Affiliations

  1. Virginia Commonwealth University and McGuire VA Hospital, Richmond, VA, USA

    J. S. Bajaj

  2. California Pacific Medical Center, San Francisco, CA, USA

    R. T. Frederick

  3. University of California, San Francisco, CA, USA

    N. M. Bass

  4. Indiana University, Indianapolis, IN, USA

    M. Ghabril

  5. Evidera, Bethesda, MD, USA

    K. Coyne

  6. Patient-Centered Outcomes Research Institute, Washington, DC, USA

    M. K. Margolis

  7. Horizon Pharma, 150 S Saunders Road, Lake Forest, IL, 60045, USA

    M. Santoro, D. F. Coakley, M. Mokhtarani, M. Jurek & B. F. Scharschmidt

Authors
  1. J. S. Bajaj
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  2. R. T. Frederick
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  3. N. M. Bass
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  4. M. Ghabril
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  5. K. Coyne
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  6. M. K. Margolis
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  7. M. Santoro
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  8. D. F. Coakley
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  9. M. Mokhtarani
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  10. M. Jurek
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  11. B. F. Scharschmidt
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Corresponding author

Correspondence to B. F. Scharschmidt.

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Financial support

The study was funded by Hyperion Therapeutics, Inc.; subsequently acquired by Horizon Pharma.

Conflict of interest

M Santoro, DF Coakley, MM Mokhtarani, M Jurek and BF Scharschmidt were employees of or consultants to Horizon Pharma (formerly Hyperion Therapeutics). MM Mokhtarani, M Jurek and BF Scharschmidt are listed as inventors of a patent application pertaining to the HEGI and CG e-dairy owned by Horizon Pharma. K Coyne and MK Margolis are/were employees of Evidera, which was a paid vendor to Horizon (formerly Hyperion Therapeutics) with special expertise in Patient- and Clinician-reported outcome tools. JS Bajaj and RT Frederick were paid for their services as members of the Steering Committee for development of the HE Grading Instrument, and M Ghabril and RT Frederick were paid through their institutions as investigators in the development of the CG e-dairy.

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Bajaj, J.S., Frederick, R.T., Bass, N.M. et al. Overt hepatic encephalopathy: development of a novel clinician reported outcome tool and electronic caregiver diary. Metab Brain Dis 31, 1081–1093 (2016). https://doi.org/10.1007/s11011-016-9851-9

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  • DOI: https://doi.org/10.1007/s11011-016-9851-9

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