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

Study Overview
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Brief Summary
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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.

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

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Dietary Supplement: Beta Hydroxybutyrate Ester (KetoneAid KE4)
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Beta Hydroxybutyrate Ester<br>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)<br>* see arm/group description<br>|
| Placebo Comparator: Placebo<br>matching placebo, in addition to normal food intake and standard therapy (2 x 50 mg riluzole per day) | Dietary Supplement: Placebo<br>* see arm/group description<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurofilament Light Chain | Neurofilament Light Chain (NfL) serum levels | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Survival (time to death or tracheostomy) | 6 months | 
| Amyotrophic Lateral Sclerosis Functional Rating Scale Revised | Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) score, measured as individual slope (loss of points per month) | 6 months | 
| Body Mass Index | Body Mass Index (BMI), weight (in kg) and height (in m) will be combined to report BMI in kg/m^2 | 6 months | 
| Slow Vital Capacity | Slow Vital Capacity (sVC) | 6 months | 
| Resting Energy Expenditure | Resting Energy Expenditure (REE), measured by indirect calorimetry | 6 months | 
| Fatt mass | Fat mass (% of total body mass), measured by bioelectrical impedance analysis (BIA) | 6 months | 
| Total Body Water | total body water (% of total body mass), measured by bioelectrical impedance analysis (BIA) | 6 months | 
| Muscle Mass | muscle mass (% of total body mass) measured by bioelectrical impedance analysis (BIA) | 6 months | 
| Fat Free Mass | fat free mass (% of total body mass), measured by bioelectrical impedance analysis (BIA) | 6 months | 
| Body Cell Mass | body cell mass (% of total body mass), measured by bioelectrical impedance analysis (BIA) | 6 months | 
| Extracellular Mass | extracellular mass (% of total body mass), measured by bioelectrical impedance analysis (BIA) | 6 months | 
| Lean Body Mass | lean body mass (% of total body mass), measured by bioelectrical impedance analysis (BIA) | 6 months | 
| Individual Quality of Life | Individual Quality of Life, measured by the Euro Quality of Life (EQ-5D-5L) questionnaire | 6 months | 
| Neurofilament Phosphorylated Heavy Chain | Neurofilament Phosphorylated Heavy Chain (pNfH) in cerebrospinal fluid (CSF) | 6 months | 
| Beta Hydroxybutyrate | Beta Hydroxybutyrate serum levels | 6 months | 
| Acetone | Acetone concentration in urine | 6 months | 
| Appetite | Appetite, measured by the Council of Appetite Questionnaire (CNAQ) | 6 months | 
| Eating Habits | Eating Habits, evaluated by the Ulm Nutrition Questionnaire (UNQ; see LIPCAL study) | 6 months | 
| Adverse Events | Terms and frequencies of Adverse Events (AEs) and Serious Adverse Events (SAEs) | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nutrition, beta hydroxybutyrate ester, high-caloric, ketone ester, ketone monoester