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

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ClinicalTrials.gov Identifier: NCT04820478
Recruitment Status : Not yet recruiting
First Posted : March 29, 2021
Last Update Posted : March 29, 2021
Sponsor:
Information provided by (Responsible Party):
Albert Christian Ludolph, Prof., University of Ulm

Tracking Information
First Submitted Date  ICMJE March 24, 2021
First Posted Date  ICMJE March 29, 2021
Last Update Posted Date March 29, 2021
Estimated Study Start Date  ICMJE July 1, 2021
Estimated Primary Completion Date January 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 26, 2021)
Neurofilament Light Chain [ Time Frame: 6 months ]
Neurofilament Light Chain (NfL) serum levels
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: March 26, 2021)
  • Survival [ Time Frame: 6 months ]
    Survival (time to death or tracheostomy)
  • Amyotrophic Lateral Sclerosis Functional Rating Scale Revised [ Time Frame: 6 months ]
    Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) score, measured as individual slope (loss of points per month)
  • Body Mass Index [ Time Frame: 6 months ]
    Body Mass Index (BMI), weight (in kg) and height (in m) will be combined to report BMI in kg/m^2
  • Slow Vital Capacity [ Time Frame: 6 months ]
    Slow Vital Capacity (sVC)
  • Resting Energy Expenditure [ Time Frame: 6 months ]
    Resting Energy Expenditure (REE), measured by indirect calorimetry
  • Fatt mass [ Time Frame: 6 months ]
    Fat mass (% of total body mass), measured by bioelectrical impedance analysis (BIA)
  • Total Body Water [ Time Frame: 6 months ]
    total body water (% of total body mass), measured by bioelectrical impedance analysis (BIA)
  • Muscle Mass [ Time Frame: 6 months ]
    muscle mass (% of total body mass) measured by bioelectrical impedance analysis (BIA)
  • Fat Free Mass [ Time Frame: 6 months ]
    fat free mass (% of total body mass), measured by bioelectrical impedance analysis (BIA)
  • Body Cell Mass [ Time Frame: 6 months ]
    body cell mass (% of total body mass), measured by bioelectrical impedance analysis (BIA)
  • Extracellular Mass [ Time Frame: 6 months ]
    extracellular mass (% of total body mass), measured by bioelectrical impedance analysis (BIA)
  • Lean Body Mass [ Time Frame: 6 months ]
    lean body mass (% of total body mass), measured by bioelectrical impedance analysis (BIA)
  • Individual Quality of Life [ Time Frame: 6 months ]
    Individual Quality of Life, measured by The Schedule for the Evaluation of Individual Quality of Life questionnaire (SEIQoL-Q) index
  • Neurofilament Phosphorylated Heavy Chain [ Time Frame: 6 months ]
    Neurofilament Phosphorylated Heavy Chain (pNfH) in cerebrospinal fluid (CSF)
  • Beta Hydroxybutyrate [ Time Frame: 6 months ]
    Beta Hydroxybutyrate serum levels
  • Acetone [ Time Frame: 6 months ]
    Acetone concentration in urine
  • Appetite [ Time Frame: 6 months ]
    Appetite, measured by the Council of Appetite Questionnaire (CNAQ)
  • Eating Habits [ Time Frame: 6 months ]
    Eating Habits, evaluated by the Ulm Nutrition Questionnaire (UNQ; see LIPCAL study)
  • Adverse Events [ Time Frame: 6 months ]
    Terms and frequencies of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Tolerability of Beta Hydroxybutyrate in Patients With Amyotrophic Lateral Sclerosis (ALS)
Official Title  ICMJE Efficacy and Tolerability of Beta Hydroxybutyrate in Patients With Amyotrophic Lateral Sclerosis (ALS)
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 15.6 g beta hydroxybutyrate 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
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
Primary Purpose: Treatment
Condition  ICMJE Amyotrophic Lateral Sclerosis
Intervention  ICMJE Dietary Supplement: Beta Hydroxybutyrate
see arm/group description
Study Arms  ICMJE
  • Experimental: Beta Hydroxybutyrate
    3 x 40 ml (= 3 x 15.6 g) beta hydroxybutyrate per day, mixed with acidic juice (e.g. orange juice), in addition to normal food intake and standard therapy (2 x 50 mg riluzole per day)
    Intervention: Dietary Supplement: Beta Hydroxybutyrate
  • Placebo Comparator: Placebo
    3 x 40 ml placebo per day, mixed with acidic juice (e.g. orange juice), in addition to normal food intake and standard therapy (2 x 50 mg riluzole per day)
    Intervention: Dietary Supplement: Beta Hydroxybutyrate
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: March 26, 2021)
76
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 1, 2023
Estimated Primary Completion Date January 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • severe renal insufficiency
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Johannes Dorst, Prof +49 731 177 5285 johannes.dorst@uni-ulm.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04820478
Other Study ID Numbers  ICMJE KETO-ALS V 1.41
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Individual participant data after de-identification as well as the study protocol will be available. Data will be available beginning 3 months and ending 5 years following article publication. Data will be shared with researchers who provide a methodologically sound proposal. Data will be shared 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.
Supporting Materials: 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.
URL: https://www.uniklinik-ulm.de/neurologie.html
Responsible Party Albert Christian Ludolph, Prof., University of Ulm
Study Sponsor  ICMJE University of Ulm
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University of Ulm
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP