TY - JOUR
T1 - Design and rationale of a multicenter defeat alcoholic steatohepatitis trial
T2 - (DASH) randomized clinical trial to treat alcohol-associated hepatitis
AU - Dasarathy, Srinivasan
AU - Mitchell, Mack C.
AU - Barton, Bruce
AU - McClain, Craig J.
AU - Szabo, Gyongyi
AU - Nagy, Laura E.
AU - Radaeva, Svetlana
AU - McCullough, Arthur J.
N1 - Funding Information:
Dr. Szabo receives grant funding from Allergan Pharmaceutical, Gilead, and NIH for Liver Disease Research. Dr. Szabo is also a consultant for multiple organizations including Allergan Pharmaceuticals, Alnylam Pharmaceuticals, Arrow Diagnostics, Inc., Durect Corporation, Generon, Glympse Bio, Inc., Mayday Foundation, NIH National Center for Advancing Training, Novartis Pharmaceuticals Corporation, Zomagen, Pandion Therapeutics, Inc., Quest Diagnostics, Surrozen, Terra Firma, University of Pennsylvania, Virginia Commonwealth University and Yale University School of Medicine.
Funding Information:
This trial is the first multicenter treatment study in the United States since the Veteran Administration trials that evaluated the role of corticosteroids and nutrition in AH [ 57 ]. The protocols were developed by the site principal investigators in consultation with the NIAAA program staff. The efforts and teams at each site were supported by grant support from the NIAAA awarded by a competitive peer review process. The DASH consortium goals were developed based on the resources available, recognizing the challenges in recruiting a well characterized population and development of robust, uniform diagnostic criteria. Since this was a treatment trial aimed toward improving outcome in severe AH, a disease state for which there are no approved treatments, an investigational new drug application was obtained from the FDA.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/9
Y1 - 2020/9
N2 - Background/aims: Despite high mortality of alcohol-associated hepatitis, there has been limited advancement in treatment strategies. Defeat Alcoholic Steatohepatitis (DASH) is a multicenter, randomized, double-blind controlled trial whose primary objective was to evaluate the safety and efficacy of a novel combination of 3 drugs targeting different perturbations in AH. Methods: Severe AH was diagnosed by liver biopsy or clinical and biochemical criteria and model for end stage liver disease (MELD) score ≥ 20 stratified by MELD scores (20–25 and ≥ 26) and randomized to a combination of an interleukin receptor 1 antagonist, Anakinra(100 mg daily for 14 days) to suppress acute inflammation, pentoxifylline (400 mg three times a day for 28 days) to prevent hepatorenal syndrome, and zinc sulfate (220 mg orally once daily for 6 months) or the standard of care therapy including methylprednisolone 32 mg orally once daily for 28 days. The primary efficacy outcome was the unadjusted log-rank test of the Kaplan-Meier survival estimates for the two treatment groups at 180 days. Results: Between July 2012 to March 2018, 500 subjects with severe AH were screened of which 104 subjects were enrolled with MELD score of 25.6 ± 3.2 (20.0–35.0) in the investigational arm and 25.8 ± 4.5 (20.0–40.0) in the standard of care arm. Causes of screen failures included not meeting eligibility criteria (n = 347), declining to participate (n = 39), and other reasons (n = 10). Conclusions: Data from the DASH consortium studies will determine if a combination of drugs targeting multiple mechanisms of injury in the severe AH will improve clinical outcomes.
AB - Background/aims: Despite high mortality of alcohol-associated hepatitis, there has been limited advancement in treatment strategies. Defeat Alcoholic Steatohepatitis (DASH) is a multicenter, randomized, double-blind controlled trial whose primary objective was to evaluate the safety and efficacy of a novel combination of 3 drugs targeting different perturbations in AH. Methods: Severe AH was diagnosed by liver biopsy or clinical and biochemical criteria and model for end stage liver disease (MELD) score ≥ 20 stratified by MELD scores (20–25 and ≥ 26) and randomized to a combination of an interleukin receptor 1 antagonist, Anakinra(100 mg daily for 14 days) to suppress acute inflammation, pentoxifylline (400 mg three times a day for 28 days) to prevent hepatorenal syndrome, and zinc sulfate (220 mg orally once daily for 6 months) or the standard of care therapy including methylprednisolone 32 mg orally once daily for 28 days. The primary efficacy outcome was the unadjusted log-rank test of the Kaplan-Meier survival estimates for the two treatment groups at 180 days. Results: Between July 2012 to March 2018, 500 subjects with severe AH were screened of which 104 subjects were enrolled with MELD score of 25.6 ± 3.2 (20.0–35.0) in the investigational arm and 25.8 ± 4.5 (20.0–40.0) in the standard of care arm. Causes of screen failures included not meeting eligibility criteria (n = 347), declining to participate (n = 39), and other reasons (n = 10). Conclusions: Data from the DASH consortium studies will determine if a combination of drugs targeting multiple mechanisms of injury in the severe AH will improve clinical outcomes.
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U2 - 10.1016/j.cct.2020.106094
DO - 10.1016/j.cct.2020.106094
M3 - Article
C2 - 32739495
AN - SCOPUS:85089065478
SN - 1551-7144
VL - 96
JO - Contemporary Clinical Trials
JF - Contemporary Clinical Trials
M1 - 106094
ER -