NCT04820478: KETO-ALS

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

Recruiting now NA Last updated 8 May 2024

What this trial tests

NA trial testing Beta Hydroxybutyrate Ester (KetoneAid KE4) in Amyotrophic Lateral Sclerosis in 76 participants. Currently enrolling.

Timeline

1 April 2022

Primary endpoint
1 October 2025

1 October 2025

Quick facts

Lead sponsor	University of Ulm
Phase	NA
Status	Recruiting now
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	76
Start date	1 April 2022
Primary completion	1 October 2025
Estimated completion	1 October 2025
Sites	1 location across Germany

Drugs / interventions tested

• Beta Hydroxybutyrate Ester (KetoneAid KE4)
• Placebo

Conditions studied

• Amyotrophic Lateral Sclerosis — all drugs for Amyotrophic Lateral Sclerosis →

Sponsor

University of Ulm

Who can join

18 and older, any sex, with Amyotrophic Lateral Sclerosis. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Mitochondrial dysfunction in neurodegenerative disorders.
   Klemmensen MM, Borrowman SH, Pearce C, Pyles B, et al · · 2024 · cited 201× · PMID 38241161 · DOI 10.1016/j.neurot.2023.10.002
2. The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS.
   Obrador E, Salvador-Palmer R, López-Blanch R, Jihad-Jebbar A, et al · · 2021 · cited 69× · PMID 34198557 · DOI 10.3390/ijms22126352
3. Current Insights Into Oligodendrocyte Metabolism and Its Power to Sculpt the Myelin Landscape.
   Narine M, Colognato H. · · 2022 · cited 43× · PMID 35573837 · DOI 10.3389/fncel.2022.892968
4. Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.
   Wadan AS, Shaaban AH, El-Sadek MZ, Mostafa SA, et al · · 2025 · cited 10× · PMID 40163151 · DOI 10.1007/s00210-025-04014-0
5. Immunosenescence in aging and neurodegenerative diseases: evidence, key hallmarks, and therapeutic implications.
   Chen Z, Mao Z, Tang W, Shi Y, et al · · 2025 · cited 4× · PMID 41299782 · DOI 10.1186/s40035-025-00517-1
6. Unraveling the Translational Relevance of β-Hydroxybutyrate as an Intermediate Metabolite and Signaling Molecule.
   Pali DV, Kim S, Mantik KEK, Lee JB, et al · · 2025 · cited 4× · PMID 40806491 · DOI 10.3390/ijms26157362
7. Nutraceutical Strategies for Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases.
   Davì F, Iaconis A, Cordaro M, Di Paola R, et al · · 2025 · cited 4× · PMID 40646945 · DOI 10.3390/foods14132193
8. Alterations of Fat and Ketone Body Metabolism in ALS and SMA-A Prospective Observational Study.
   Herrmann C, Uzelac Z, Michels S, Weber A, et al · · 2025 · cited 2× · PMID 40200760 · DOI 10.1111/ene.70132