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

NCT ID: NCT04820478

Last Updated: 2024-05-08

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 76 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-04-01
• Study Completion Date: 2025-10-01

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Beta Hydroxybutyrate Ester

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)

Group Type: EXPERIMENTAL

Beta Hydroxybutyrate Ester (KetoneAid KE4)

Intervention Type: DIETARY_SUPPLEMENT

see arm/group description

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DIETARY_SUPPLEMENT

see arm/group description

Interventions

Beta Hydroxybutyrate Ester (KetoneAid KE4)

see arm/group description

Intervention Type: DIETARY_SUPPLEMENT

Placebo

see arm/group description

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

Inclusion Criteria

• 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)

Exclusion Criteria

• 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)
• electrolyte or acid-base imbalance
• heart failure New York Heart Association (NYHA) II or above

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Ulm

OTHER

Sponsor Role: lead

Responsible Party

Albert Christian Ludolph, Prof.

Prof.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

University of Ulm

Ulm, Baden-Wurttemberg, Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Johannes Dorst, Prof

Role: CONTACT

johannes.dorst@uni-ulm.de

+49 731 177 5285

Facility Contacts

Johannes Dorst, Prof

Role: primary

johannes.dorst@uni-ulm.de

+49 731 177 5285

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Other Identifiers

KETO-ALS V 1.41

Identifier Type: -

Identifier Source: org_study_id