Efficacy and Tolerability of Beta Hydroxybutyrate Ester in Patients With Amyotrophic Lateral Sclerosis (ALS)

NCT04820478 | Completed

• 1 other identifier: KETO-ALS V 1.41
• Study Type: interventional
• Target: 81
• Locations: 1 country
• Sites: 1

Brief Summary

Weight loss is a known negative prognostic factor in amyotrophic lateral sclerosis (ALS). One potential mechanism of weight loss in ALS is a disturbance of the mitochondrial complex I which causes an energy deficit in affected cells. Over the last years, various interventional studies targeting the energy deficit in ALS yielded promising results; however,it is still unclear which kind of nutrition or nutritional supplement is most beneficial. Ketone bodies represent a logical therapeutic option in ALS as ketone bodies are an extremely high-energetic substrate which yields the double amount of adenosine triphosphate (ATP) per mole compared to glucose. The human liver is able to synthesize ketone bodies (beta-hydroxybutyrate, acetone, and aceto-acetate) from fat in times of glucose shortage, for example after a prolonged period of fasting. This metabolic shift is the underlying principle of the ketogenic diet, a carbohydrate-free, fat-rich diet which has been successfully tested in other neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In the ALS mouse model, a ketogenic diet was associated with a slower decline of motor function. However, a ketogenic diet is difficult to implement in ALS as it requires a long-term change of eating habits, which is difficult to achieve due to progressive dysphagia, fast worsening of general condition, and limited survival. Therefore, the direct administration of ketone bodies yields a more realistic alternative in ALS as it is easy to apply and allows to maintain the usual eating habits. In this study, we hypothesize that the administration of 3 x 10 g beta hydroxybutyrate ester per day (in addition to normal food intake and the standard medication of 2 x 50 mg riluzole) slows down disease progression as measured by neurofilament light chains (NfL) in serum after 6 months compared to placebo. Power calculation relies on the results of the lipids and calories for ALS (LIPCAL-ALS) study which tested the effect of a high-caloric fatty nutritional supplement in ALS. The study revealed that NfL serum values declined significantly in the intervention group while remaining stable in the placebo group over the course of the study. Assuming a similar effect size for ketone bodies, we calculated that 76 patients had to be included in the current trial.

Conditions

Amyotrophic Lateral Sclerosis

Keywords

nutrition; beta hydroxybutyrate ester; high-caloric; ketone ester; ketone monoester

Outcome Measures

Primary Outcomes (1)

• Neurofilament Light Chain

  Neurofilament Light Chain (NfL) serum levels

  6 months

Secondary Outcomes (19)

• Survival

  6 months

• Amyotrophic Lateral Sclerosis Functional Rating Scale Revised

  6 months

• Body Mass Index

  6 months

• Slow Vital Capacity

  6 months

• Resting Energy Expenditure

  6 months

Study Arms (2)

Beta Hydroxybutyrate Ester

EXPERIMENTAL

3 x 10 g beta hydroxybutyrate ester per day, in addition to normal food intake and standard therapy (2 x 50 mg riluzole per day)

Dietary Supplement: Beta Hydroxybutyrate Ester (KetoneAid KE4)

Placebo

PLACEBO COMPARATOR

matching placebo, in addition to normal food intake and standard therapy (2 x 50 mg riluzole per day)

Dietary Supplement: Placebo

Interventions

Beta Hydroxybutyrate Ester (KetoneAid KE4) DIETARY_SUPPLEMENT

see arm/group description

Beta Hydroxybutyrate Ester

Placebo DIETARY_SUPPLEMENT

see arm/group description

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Probable (clinically or laboratory) or definite ALS according to the revised version of the El Escorial World Federation of Neurology criteria
• loss of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) of ≥ 0.33 points per month since onset (first paresis), based on the formula: (48 - score at screening visit) / (months between onset and screening visit)
• age ≥ 18 years
• continuously treated with 100 mg riluzole per day for at least 4 weeks
• capable of thoroughly understanding all information given and giving full informed consent according to good clinical practice (GCP)

You may not qualify if:

• hyperinsulinism
• pyruvate decarboxylase deficit
• disturbance of fatty acid oxidation
• disturbance of gluconeogenesis
• acute porphyria
• metabolism disorders which prevent utilization or degradation of ketone bodies
• severe gastro-esophageal reflux
• renal insufficiency (medical history and/or elevated serum creatinine levels and/or glomerular filtration rate (GFR) \<90 ml/min
• previous participation in another interventional study within the preceding 4 weeks
• tracheostomy
• pregnancy or breast-feeding females
• evidence of a major psychiatric disorder or clinically evident dementia
• intake of diuretics
• severe dysphagia
• nutrition via percutaneous endoscopic gastrostomy (PEG)

Sponsors & Collaborators

• University of Ulm: lead

Study Sites (1)

University of Ulm

Ulm, Baden-Wurttemberg, 89081, Germany

Location

Related Publications (15)

• Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9. doi: 10.1080/146608200300079536. No abstract available.

  PMID: 11464847 BACKGROUND

• Dupuis L, Oudart H, Rene F, Gonzalez de Aguilar JL, Loeffler JP. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11159-64. doi: 10.1073/pnas.0402026101. Epub 2004 Jul 19.

  PMID: 15263088 BACKGROUND

• Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D, Couratier P. Nutritional status is a prognostic factor for survival in ALS patients. Neurology. 1999 Sep 22;53(5):1059-63. doi: 10.1212/wnl.53.5.1059.

  PMID: 10496266 BACKGROUND

• Desport JC, Preux PM, Magy L, Boirie Y, Vallat JM, Beaufrere B, Couratier P. Factors correlated with hypermetabolism in patients with amyotrophic lateral sclerosis. Am J Clin Nutr. 2001 Sep;74(3):328-34. doi: 10.1093/ajcn/74.3.328.

  PMID: 11522556 BACKGROUND

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  PMID: 23944684 BACKGROUND

• Wills AM, Hubbard J, Macklin EA, Glass J, Tandan R, Simpson EP, Brooks B, Gelinas D, Mitsumoto H, Mozaffar T, Hanes GP, Ladha SS, Heiman-Patterson T, Katz J, Lou JS, Mahoney K, Grasso D, Lawson R, Yu H, Cudkowicz M; MDA Clinical Research Network. Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2014 Jun 14;383(9934):2065-2072. doi: 10.1016/S0140-6736(14)60222-1. Epub 2014 Feb 28.

  PMID: 24582471 BACKGROUND

• Dorst J, Schuster J, Dreyhaupt J, Witzel S, Weishaupt JH, Kassubek J, Weiland U, Petri S, Meyer T, Grehl T, Hermann A, Jordan B, Grosskreutz J, Zeller D, Boentert M, Schrank B, Prudlo J, Winkler AS, Gorbulev S, Roselli F, Dupuis L, Otto M, Ludolph AC. Effect of high-caloric nutrition on serum neurofilament light chain levels in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2020 Sep;91(9):1007-1009. doi: 10.1136/jnnp-2020-323372. Epub 2020 Aug 11. No abstract available.

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  PMID: 26296871 BACKGROUND

• Grammatikopoulou MG, Goulis DG, Gkiouras K, Theodoridis X, Gkouskou KK, Evangeliou A, Dardiotis E, Bogdanos DP. To Keto or Not to Keto? A Systematic Review of Randomized Controlled Trials Assessing the Effects of Ketogenic Therapy on Alzheimer Disease. Adv Nutr. 2020 Nov 16;11(6):1583-1602. doi: 10.1093/advances/nmaa073.

  PMID: 32597927 BACKGROUND

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  PMID: 30098269 BACKGROUND

• Zhao Z, Lange DJ, Voustianiouk A, MacGrogan D, Ho L, Suh J, Humala N, Thiyagarajan M, Wang J, Pasinetti GM. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci. 2006 Apr 3;7:29. doi: 10.1186/1471-2202-7-29.

  PMID: 16584562 BACKGROUND

• Clarke K, Tchabanenko K, Pawlosky R, Carter E, Todd King M, Musa-Veloso K, Ho M, Roberts A, Robertson J, Vanitallie TB, Veech RL. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012 Aug;63(3):401-8. doi: 10.1016/j.yrtph.2012.04.008. Epub 2012 May 3.

  PMID: 22561291 BACKGROUND

• Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, Stirling M, Clarke K. On the Metabolism of Exogenous Ketones in Humans. Front Physiol. 2017 Oct 30;8:848. doi: 10.3389/fphys.2017.00848. eCollection 2017.

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• Poffe C, Ramaekers M, Van Thienen R, Hespel P. Ketone ester supplementation blunts overreaching symptoms during endurance training overload. J Physiol. 2019 Jun;597(12):3009-3027. doi: 10.1113/JP277831. Epub 2019 May 22.

  PMID: 31039280 BACKGROUND

• Hashim SA, VanItallie TB. Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester. J Lipid Res. 2014 Sep;55(9):1818-26. doi: 10.1194/jlr.R046599. Epub 2014 Mar 5.

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MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: placebo-controlled study, using a placebo with similar look and taste in similar bottles; the study is double-blinded, i.e. patients and study personnel are masked
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: March 24, 2021
• First Posted: March 29, 2021
• Study Start: April 1, 2022
• Primary Completion: February 12, 2025
• Study Completion: February 12, 2025
• Last Updated: May 1, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: 3 months to 5 years following article publication
• Access Criteria: Data will be shard for analyses to achieve the aims provided in the approved proposal. Proposals should be directed to johannes.dorst@uni-ulm.de; to gain access, data requestors will need to sign a data access agreement.

Locations

DE (1)