Clinical trial NCT04820478: Efficacy and Tolerability of Beta Hydroxybutyrate Ester in Patients With Amyotrophic Lateral Sclerosis (ALS)
Official title: Efficacy and Tolerability of Beta Hydroxybutyrate Ester in Patients With Amyotrophic Lateral Sclerosis (ALS)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Amyotrophic Lateral Sclerosis
Keywords: nutrition
beta hydroxybutyrate ester
high-caloric
ketone ester
ketone monoester
Lead sponsor: University of Ulm
Sponsor class: OTHER
First posted: 2021-03-29
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Neurofilament Light Chain
timeFrame: 6 months
Secondary outcomes:
measure: Survival
timeFrame: 6 months
measure: Amyotrophic Lateral Sclerosis Functional Rating Scale Revised
timeFrame: 6 months
measure: Body Mass Index
timeFrame: 6 months
measure: Slow Vital Capacity
timeFrame: 6 months
measure: Resting Energy Expenditure
timeFrame: 6 months
measure: Fatt mass
timeFrame: 6 months
measure: Total Body Water
timeFrame: 6 months
measure: Muscle Mass
timeFrame: 6 months
measure: Fat Free Mass
timeFrame: 6 months
measure: Body Cell Mass
timeFrame: 6 months
measure: Extracellular Mass
timeFrame: 6 months
measure: Lean Body Mass
timeFrame: 6 months
measure: Individual Quality of Life
timeFrame: 6 months
measure: Neurofilament Phosphorylated Heavy Chain
timeFrame: 6 months
measure: Beta Hydroxybutyrate
timeFrame: 6 months
measure: Acetone
timeFrame: 6 months
measure: Appetite
timeFrame: 6 months
measure: Eating Habits
timeFrame: 6 months
measure: Adverse Events
timeFrame: 6 months
Other outcomes:
Locations:
city: Ulm
country: Germany
facility: University of Ulm
state: Baden-Wurttemberg
Study officials:
References:
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