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.
Similar content being viewed by others
Abbreviations
- CG:
-
caregivers
- HE:
-
hepatic encephalopathy
- HEGI:
-
HE Grading Instrument
- OHE:
-
overt HE
- SC:
-
steering committee
- WH:
-
West Haven
References
Amodio P, Montagnese S, Gatta A, Morgan MY (2004) Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 19:253–267
Bajaj JS, Cordoba J, Mullen KD, et al. Review article: the design of clinical trials in hepatic encephalopathy – an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). consensus statement (2011) Aliment Pharm Ther 33:739–747
Bajaj JS, Bass NM, Frederick RT, Coyne K, Margolis MK, Coakley DF, Mokhtarani MM, Jurek M, Scharschmidt BF. (2015) Development of a Novel Clinician Reported Outcome Tool for Assessment of Hepatic Encephalopathy. Hepatology1 (suppl): 935 A
Blei AT, Cordoba J (2001) Hepatic encephalopathy. Am J Gastroenterol 96:1968–1976
Braun V, Clark V (2006) Using thematic analysis in psychology. Qual Res Psychol 3:77–101
Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL (1977) Comparison of lactulose and neomycin in the treatment of chronic potal-systemic encephalopahty. A double blind controlled trial Gastroenterology 72:573–583
Crisp J, Pelletier D, Duffield C, Adams A, Nagy S (1977) The Delphi method. Nurs Res 46:116–118
Dalkey N, Helmer O (1963) An experimental application of the Delphi method to the use of experts. Manag Sci 9:458–467
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT (2002) Hepatic encephalopathy–definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th world congresses of gastroenterology, Vienna, 1998. Hepatology 35:716–721
Food and Drug Administration (www.fda.gov) Guidance for Industry (2009) Patient-reported outcome measures: use in medical product development to support labeling claims. Fed Regist 74:65132–65133
Frederick RT, Ghabril M, Coyne K, Margolis MK, Santoro M, Coakley DF, Mokhtarani M, Scharschmidt BF, Jurek M. Development of an Electronic Diary (E-Diary) for Caregivers (CG) of Patients with Overt Hepatic Encephalopathy (OHE). (2015) Hepatology; 1 (suppl): 926 A
Gwet KL (2008) Interrater reliability. Wiley Encyclopedia of Clinical Trials. John Wiley and Sons, Hoboken, In, pp. 1–14
Hassanein TI, Tofteng F, Brown RS Jr, McGuire B, Lynch P, Mehta R, Larsen FS, Gombein J, Stange J, Blei AT (2007) Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopahty in advanced cirrhosis. Hepatology 46:1853–1862
Hassanein TI, Hilsabeck RC, Perry W (2008) Introduction to the hepatic encephalopathy scoring algorithm (HESA). Dig Dis Sci 53:529–538
Hassanein T, Blei AT, Perry W, Hilsabeck R, Stange J, Larsen FS, Brown RS Jr, Caldwell S, McGuire B, Nevens F, Fontana R (2009) Performance of the hepatic encephalopathy scoring algorithm in a clinical trial of patients with cirrhosis and severe hepatic encephalopathy. Am J Gastroenterol 104:1392–1400
Hsu C-C, Sandford BA (2007) The Delphi technique: making sense of consensus. Practical Assessment, Research Evaluation 12:1–8
Kottner J, Audigé L, Brorson S, Donner A, Gajewski BJ, Hróbjartsson A, Roberts C, Shoukri M, Streiner DL (2011) Guidelines for reporting reliability and agreement studies (GRRAS) were proposed. J Clin Epidemiol 64:96–106
Liao SC, Hunt EA, Chen W (2010) Comparison between inter-rater reliability and inter-rater agreement in performance assessment. Ann Acad Med 39:613–618
Ortiz M, Córdoba J, Doval E, Jacas C, Pujadas F, Esteban R, Guardia J (2007) Development of a clinical hepatic encephalopathy staging scale. Aliment Pharmacol Ther 26:859–867
Parson-Smith BG, Summerskill WHJ, Dawson AM, Sherlock S (1957) The electroencephalograph in liver disease. Lancet 2:867–871
Patrick DL, Burke LB, Gwaltney CJ, Leidy NK, Martin ML, Molsen E, Ring L (2011) Content validity—establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO good research practices task force report: part 1—eliciting concepts for a new PRO instrument. Value Health 14:967–997
Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Alexeeva O, Zupanets I, Grinevich V, Baranovsky A, Dudar L, Fadieienko G, Kharchenko N, Klarytska I, Morozov V, Grewal P, McCashland T, Reddy G, Reddy R, Syplyviy V, Bass NM, Dickinson K, Norris C, Coakley D, Mokhtarani M, Scharschmidt, BF for the HALT-HE Study Group (2014) Randomized, controlled, double blind study of glycerol phenylbutyrate in patients with cirrhosis and episodic hepatic encephalopathy. Hepatology 59:1073–1083
Rowe G, Wright G, Bolger F (1991) Delphi: a reevaluation of research and theory. Technol Forecast Soc Chang 39:235–251
Salam M, Matherly S, Farooq IS, Stravitz RT, Sterling RK, Sanyal AJ, Gibson DP, Wade JB, Thacker LR, Heuman DM, Fuchs M, Puri P, Luketic V, Bickston SJ, Bajaj JS (2012) Modified-orientation log to assess hepatic encephalopathy. Aliment Pharmacol Ther 35:913–920
Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P (2014) Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the liver. Hepatology 60:715–735
Woudenberg F (1991) An evaluation of Delphi. Technol Forecast Soc Chang 40:131–150
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Electronic supplementary material
Supplemental Table 1
(DOCX 27 kb)
ESM 1
(DOCX 13 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-016-9851-9