title: Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition.
  
  
  METHODS
  In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983.
  
  
  RESULTS
  Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0.06; HC/HC vs control, p=0.06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0.0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0.03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group.
  
  
  CONCLUSIONS
  Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease.
  
  
  BACKGROUND
  Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center.
authors.affiliation: Department of Neurology and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: awills@partners.org.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Wills
authors.affiliation: Harvard Catalyst/Massachusetts General Hospital Clinical Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Hubbard
authors.affiliation: Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Macklin
authors.affiliation: Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Glass
authors.affiliation: University of Vermont, Burlington, VT, USA.
authors.forename: Rup
authors.initials: R
authors.lastname: Tandan
authors.affiliation: Methodist Neurological Institute, Houston, TX, USA.
authors.forename: Ericka P
authors.initials: EP
authors.lastname: Simpson
authors.affiliation: Carolinas Medical Center Neuromuscular/ALS-MDA Center, Charlotte, NC, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brooks
authors.affiliation: Saint Mary's Health Care, Grand Rapids, MI, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Gelinas
authors.affiliation: Columbia Presbyterian Medical Center, New York, NY, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsumoto
authors.affiliation: University of California at Irvine, Irvine, CA, USA.
authors.forename: Tahseen
authors.initials: T
authors.lastname: Mozaffar
authors.affiliation: Sarasota Memorial Hospital, Sarasota, FL, USA.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Hanes
authors.affiliation: Barrow Neurological Institute/St Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Shafeeq S
authors.initials: SS
authors.lastname: Ladha
authors.affiliation: Drexel University, Philadelphia, PA, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Heiman-Patterson
authors.affiliation: California Pacific Medical Center, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Katz
authors.affiliation: Oregon Health and Science University, Portland, OR, USA.
authors.forename: Jau-Shin
authors.initials: JS
authors.lastname: Lou
authors.affiliation: Department of Neurology and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Katy
authors.initials: K
authors.lastname: Mahoney
authors.affiliation: Department of Neurology and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Grasso
authors.affiliation: Department of Neurology and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lawson
authors.affiliation: Department of Neurology and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Neurology and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Merit
authors.initials: M
authors.lastname: Cudkowicz
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000628:therapy*; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects / Q000379:methods; D004311:Double-Blind Method; D002149:Energy Intake; D004750:Enteral Nutrition / Q000009:adverse effects / Q000379:methods*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects
chemical_list: D002784:Cholesterol