Ultra-high-caloric, Fatty Diet in ALS (LIPCAL-ALS II)

Efficacy, Safety, and Tolerability of Ultra-high-caloric, Fatty Diet (UFD) in Amyotrophic Lateral Sclerosis (ALS)

This study aims at evaluating efficacy and tolerability of an ultra-high-caloric, fatty diet (UFD) compared to placebo in patients with amyotrophic lateral sclerosis (ALS).

Study Overview

• Status: Not yet recruiting
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Dietary supplement: Ultra-high-caloric fatty diet; Other: Placebo

Detailed Description

ALS is a fatal neurodegenerative disease, leading to progressive paralysis of voluntarily innervated muscles and to death caused by respiratory failure after a mean disease duration of 2-4 years.The proposed study aims at improving survival of ALS patients by targeting metabolic parameters. ALS patients feature an intrinsic hypermetabolism as signified by an increased resting energy expenditure, which significantly contributes to progressive weight loss and cachexia. The extent of weight loss is an independent prognostic factor for survival in ALS. It has been shown that survival of ALS mice can be prolonged by applying a high-caloric nutrition. Furthermore, ALS patients feature distinct alterations of lipid metabolism, and various studies suggest a protective effect of high triglyceride serum levels.

In the precursor-study LIPCAL-ALS-I, a randomized, placebo-controlled, multicenter trial, evaluating the effects of a high-caloric fatty diet (HCFD), the primary endpoint (survival in the whole study population) was missed. However, post-hoc analysis revealed showed that HCFD (1) increased survival and reduced weight loss in normal to fast-progressing patients (patients with a functional decline measured by ALS Functional Rating Scale Revised) above the median at baseline; p=0.02), (2) slowed down functional decline (measured by Amyotrophic Lateral Sclerosis Functional Rating Scale Revised) in the whole study population (p<0.0125), and (3) lowered neurofilament light chain (NfL) serum levels as a prognostic biomarker in the whole study population (p=0.0225).

Therefore, this study aims at prolonging survival in ALS patients by applying 1.5-fold dosage of the same intervention as in LIPCAL-ALS I in a larger number of patients, excluding patients with slow disease progression.

• Study Type: Interventional
• Enrollment (Estimated): 392
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Johannes Dorst, Prof. Dr.; Phone Number: +497311775285; Email: johannes.dorst@uni-ulm.de

Study Locations

• Germany
  • Aachen, Germany
    • RWTH Aachen
  • Berlin, Germany
    • Charité Universitätsmedizin Berlin
    • Contact: André Maier, Dr.
  • Bochum, Germany
    • University Clinic Bochum
  • Bonn, Germany
    • University Clinic Bonn
    • Contact: Patrick Weydt, Dr.
  • Dresden, Germany
    • Technical University Dresden
    • Contact: René Günther, Dr.
  • Erlangen, Germany
    • University Clinic Erlangen
    • Contact: Jürgen Winkler, Prof. Dr.
  • Essen, Germany
    • Alfried Krupp Krankenhaus Essen
    • Contact: Torsten Grehl, Dr.
  • Göttingen, Germany
    • University Clinic Göttingen
    • Contact: Jan C Koch, Dr.
  • Halle, Germany
    • University Clinic Halle
    • Contact: Elena Schlapakow, Dr.
  • Hannover, Germany
    • Hannover Medical School
    • Contact: Susanne Petri, Prof. Dr.
  • Jena, Germany
    • University Clinic Jena
    • Contact: Annekathrin Rödiger, Dr.
  • Kassel, Germany
    • DRK Clinic Kassel
    • Contact: Clemens Eickhoff, Dr.
  • Kempten, Germany
    • Klinikum Kempten
    • Contact: Elmar Pinkhardt, Dr.
  • Leipzig, Germany
    • University Clinic Leipzig
    • Contact: Moritz Metelmann, Dr.
  • Lübeck, Germany
    • University Clinic Lübeck
    • Contact: Julian Großkreutz, Prof. Dr.
  • Mannheim, Germany
    • University Clinic Mannheim
    • Contact: Joachim Wolf, Dr.
  • Munich, Germany
    • Technical University Munich
    • Contact: Paul Lingor, Prof. Dr.
  • Münster, Germany
    • University Clinic Münster
    • Contact: Matthias Böntert, Dr.
  • Regensburg, Germany
    • University Clinic Regensburg
    • Contact: Zacharias Kohl, Dr.
  • Rostock, Germany
    • University Clinic Rostock
    • Contact: Johannes Prudlo, Prof. Dr.
    • Principal Investigator: Andreas Herrmann
  • Ulm, Germany
    • University of Ulm
    • Contact: Johannes Dorst, Prof. Dr.
  • Wiesbaden, Germany
    • DKD HELIOS Clinic Wiesbaden
    • Contact: Bertold Schrank, Dr.
  • Würzburg, Germany
    • University Clinic Würzburg
    • Contact: Daniel Zeller, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Possible, probable (clinically or laboratory supported) or definite amyotrophic lateral sclerosis according to the revised version of the El Escorial criteria
• Disease duration (onset of first paresis or bulbar symptoms) < 24 months
• Loss of amyotrophic lateral sclerosis functional rating scale revised of ≥ 0.33 points/month based on the formula: (48 - myotrophic lateral sclerosis functional rating scale revised score at screening visit) / (months between onset and screening visit)
• Age ≥18 years.
• Either continuously treated with a stable dose of riluzole, OR not treated with riluzole for the last 4 weeks prior to inclusion
• Either continuously treated with a stable dose of edaravone, OR not treated with edaravone for the last 4 weeks prior to inclusion
• Either continuously treated with a stable dose of sodium-phenylbutyrate/taurursodiol, OR not treated with sodium-phenylbutyrate/taurursodiol for the last 4 weeks prior to inclusion
• Capable of thoroughly understanding all information given
• full written informed consent according to good clinical practice

Exclusion Criteria:

• Previous participation in another interventional study involving an active treatment within the preceding 4 weeks
• Tracheostomy or continuous permanent ventilator dependence (>22 hours per day)
• Pregnancy or breastfeeding
• Any medical condition known to have an association with motor neuron dysfunction which might confound or obscure the diagnosis of ALS
• Presence of any concomitant life-threatening disease or impairment likely to interfere with functional assessment.
• Evidence of a major psychiatric disorder or clinically evident dementia precluding evaluation of symptoms.
• Liable to be not cooperative or comply with study requirements as assessed by the investigator, or unable to be reached in the case of emergency

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ultra-high-caloric fatty diet; ultra-high-caloric, high-fat, fluid nutritional supplement oral intake of 4 times 35 ml per day in addition to normal food intake, corresponding to +630 kcal and +70g fat per day	Dietary supplement: Ultra-high-caloric fatty diet; 100% fat (70g), saturated fatty acids 7,5g, monounsaturated fatty acids 42,6g, polyunsaturated fatty acids 19,9g, long-chain fatty acids 100%, ratio omega-6 to omega-3 fatty acids 5:1, protein 0g, carbohydrates 0g, fiber 0g
Placebo Comparator: Placebo; placebo, fluid nutritional supplement oral intake of 4 times 35 ml per day in addition to normal food intake, corresponding to +50 kcal and +3,5g fat per day	Other: Placebo; <5% fat (<3,5g), protein 0g, carbohydrates 0g, fiber 0g

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Time from date of randomization until date of death, tracheostomy, or permanent continous ventilation (>22 hours per day)	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amyotrophic Lateral Sclerosis Functional Rating Scale Revised	Change per month of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised	18 months
Rasch Overall Amyotrophic Lateral Sclerosis Disability Scale	Change per month of Rasch Overall Amyotrophic Lateral Sclerosis Disability Scale	18 months
Individual Quality of Life	Change of Euro Quality of Life 5D 5L (EQ-5D-5L) compared to baseline	18 months
Slow vital capacity	Change of slow vital capacity compared to baseline	18 months
Survival	Time from date of randomization until date of death, tracheostomy, or permanent continous ventilation (>22 hours per day)	6 months
Survival	Time from date of randomization until date of death, tracheostomy, or permanent continous ventilation (>22 hours per day)	12 months
Time to death	Time from date of randomization until date of death	18 months
Time to tracheostomy	Time from date of randomization until date of tracheostomy	18 months
Time to permanent continous ventilator dependence	Time from date of randomization to permanent continous ventilator dependence (>22 hours per day)	18 month
Ventilation assistance-free survival	Time from date of randomization until implementation of mechanical ventilation	18 months
Body Mass Index	Change of body mass index compared to baseline	18 months
Council of Nutrition Appetite Questionnaire	Change of Council of Nutrition Appetite Questionnaire sum score compared to baseline	18 months
Neurofilament light chain	Change of neurofilament light chain serum levels compared to baseline	18 months
Eating Habits	Change of Ulm Nutrition Questionnaire compared to baseline; qualitative changes on a descriptional level (the questionnaire has no sum score); the score is meant to detect changes of eating habits and has been used in the precursor study LIPCAL-ALS I (see doi: 10.1002/ana.25661).	18 months
Amyotrophic Lateral Sclerosis Functional Rating Scale Revised Prediction Model	Difference between observed and predicted decrease of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (measured as points lost per month), based on the a prediction model, which estimates disease progression based on neurofilament light chain serum baseline levels	18 months
Neurofilament Assess Score	Difference between observed and predicted survival based on the Neurofilament Assess Score, a score estimating survival based on the neurofilament light chain serum baseline levels	18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microtubule-associated protein 2 in serum	change of Microtubule-associated protein 2 levels in serum compared to baseline	18 months
Microtubule-associated protein 2 in cerebrospinal fluid	change of microtubule-associated protein 2 levels in cerebrospinal fluid compared to baseline	18 months
Ubiquitin carboxy-terminal hydrolase L1 in serum	change of ubiquitin carboxy-terminal hydrolase L1 levels in serum compared to baseline	18 months
Ubiquitin carboxy-terminal hydrolase L1 in cerebrospinal fluid	change of ubiquitin carboxy-terminal hydrolase L1 levels in cerebrospinal fluid compared to baseline	18 months
Transmembrane glycoprotein NMB in serum	change of transmembrane glycoprotein NMB levels in serum compared to baseline	18 months
Transmembrane glycoprotein NMB in cerebrospinal fluid	change of transmembrane glycoprotein NMB levels in cerebrospinal fluid compared to baseline	18 months
Human cartilage glycoprotein 39 in serum	change of human cartilage glycoprotein 39 levels in serum compared to baseline	18 months
Human cartilage glycoprotein 39 in cerebrospinal fluid	change of human cartilage glycoprotein 39 levels in cerebrospinal fluid compared to baseline	18 months
SNAP-25 in serum	change of SNAP-25 levels in serum compared to baseline	18 months
SNAP-25 in cerebrospinal fluid	change of SNAP-25 levels in cerebrospinal fluid compared to baseline	18 months
Beta-synuclein in serum	change of beta-synuclein levels in serum compared to baseline	18 months
Beta-synuclein in cerebrospinal fluid	change of beta-synuclein levels in cerebrospinal fluid compared to baseline	18 months
Aquaporin-4 in serum	change of aquaporin-4 levels in serum compared to baseline	18 months
Aquaporin-4 in cerebrospinal fluid	change of aquaporin-4 levels in cerebrospinal fluid compared to baseline	18 months
Glial fibrillary acidic protein in serum	change of glial fibrillary acidic protein levels in serum compared to baseline	12 months
Glial fibrillary acidic protein in cerebrospinal fluid	change of glial fibrillary acidic protein levels in cerebrospinal fluid compared to baseline	12 months
Soluble triggering receptor expressed on myeloid cell-1 in serum	change of soluble triggering receptor expressed on myeloid cell-1 levels in serum compared to baseline	12 months
Soluble triggering receptor expressed on myeloid cell-1 in cerebrospinal fluid	change of soluble triggering receptor expressed on myeloid cell-1 levels in cerebrospinal fluid compared to baseline	12 months
CC-chemokine ligand 2 in serum	change of CC-chemokine ligand 2 levels in serum compared to baseline	12 months
CC-chemokine ligand 2 in cerebrospinal fluid	change of CC-chemokine ligand 2 levels in cerebrospinal fluid compared to baseline	12 months
interleukin-1b in serum	change of interleukin-1b levels in serum compared to baseline	12 months
interleukin-1b in cerebrospinal fluid	change of interleukin-1b levels in cerebrospinal fluid compared to baseline	12 months
interleukin-2 in serum	change of interleukin-2 levels in serum compared to baseline	12 months
interleukin-2 in cerebrospinal fluid	change of interleukin-2 levels in cerebrospinal fluid compared to baseline	12 months
interleukin-4 in serum	change of interleukin-4 levels in serum compared to baseline	12 months
interleukin-4 in cerebrospinal fluid	change of interleukin-4 levels in cerebrospinal fluid compared to baseline	12 months
interleukin-6 in serum	change of interleukin-6 levels in serum compared to baseline	12 months
interleukin-6 in cerebrospinal fluid	change of interleukin-6 levels in cerebrospinal fluid compared to baseline	12 months
interleukin-10 in serum	change of interleukin-10 levels in serum compared to baseline	12 months
interleukin-10 in cerebrospinal fluid	change of interleukin-10 levels in cerebrospinal fluid compared to baseline	12 months
interleukin-12p70 in serum	change of interleukin-12p70 levels in serum compared to baseline	12 months
interleukin-12p70 in cerebrospinal fluid	change of interleukin-12p70 levels in cerebrospinal fluid compared to baseline	12 months
interleukin-17 in serum	change of interleukin-17 levels in serum compared to baseline	12 months
interleukin-17 in cerebrospinal fluid	change of interleukin-17 levels in cerebrospinal fluid compared to baseline	12 months
Tumor necrosis factor alpha in serum	change of tumor necrosis factor alpha levels in serum compared to baseline	12 months
Tumor necrosis factor alpha in cerebrospinal fluid	change of tumor necrosis factor alpha levels in cerebrospinal fluid compared to baseline	12 months

Collaborators and Investigators

• Sponsor: University of Ulm
• Investigators: Principal Investigator: Johannes Dorst, Prof. Dr., University of Ulm

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: February 19, 2024
• First Submitted That Met QC Criteria: February 19, 2024
• First Posted (Actual): February 28, 2024

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Survival; Amyotrophic Lateral Sclerosis; Randomized controlled trial; High-caloric, high-fat nutrition
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: LIPCAL-ALS II 1.1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after de-identification (text, tables, and figures) as well as the study protocol will be available.
• IPD Sharing Time Frame: Data will be available beginning 3 months and ending 5 years following article publication.
• IPD Sharing Access Criteria: Data will be shared with researchers who provide a methodologically sound proposal. Data will be shared for analyses to achieve the aims in the approved proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No