Amyotrophic Lateral Sclerosis
Conditions
Keywords
Amyotrophic Lateral Sclerosis, High-caloric, high-fat nutrition, Survival, Randomized controlled trial
Brief summary
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).
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.
Interventions
DIETARY_SUPPLEMENTUltra-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
OTHERPlacebo
\<5% fat (\<3,5g), protein 0g, carbohydrates 0g, fiber 0g
Sponsors
University of Ulm
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival | 18 months | Time from date of randomization until date of death, tracheostomy, or permanent continous ventilation (\>22 hours per day) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Amyotrophic Lateral Sclerosis Functional Rating Scale Revised | 18 months | Change per month of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised |
| Rasch Overall Amyotrophic Lateral Sclerosis Disability Scale | 18 months | Change per month of Rasch Overall Amyotrophic Lateral Sclerosis Disability Scale |
| Individual Quality of Life | 18 months | Change of Euro Quality of Life 5D 5L (EQ-5D-5L) compared to baseline |
| Slow vital capacity | 18 months | Change of slow vital capacity compared to baseline |
| Survival | 6 months | Time from date of randomization until date of death, tracheostomy, or permanent continous ventilation (\>22 hours per day) |
| Time to death | 18 months | Time from date of randomization until date of death |
| Time to tracheostomy | 18 months | Time from date of randomization until date of tracheostomy |
| Time to permanent continous ventilator dependence | 18 month | Time from date of randomization to permanent continous ventilator dependence (\>22 hours per day) |
| Ventilation assistance-free survival | 18 months | Time from date of randomization until implementation of mechanical ventilation |
| Body Mass Index | 18 months | Change of body mass index compared to baseline |
| Council of Nutrition Appetite Questionnaire | 18 months | Change of Council of Nutrition Appetite Questionnaire sum score compared to baseline |
| Eating Habits | 18 months | 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). |
| Neurofilament light chain | 18 months | Change of neurofilament light chain serum levels compared to baseline |
| Amyotrophic Lateral Sclerosis Functional Rating Scale Revised Prediction Model | 18 months | 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 |
| Neurofilament Assess Score | 18 months | 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 |
Countries
Germany
Contacts
CONTACTJohannes Dorst, Prof. Dr.
PRINCIPAL_INVESTIGATORJohannes Dorst, Prof. Dr.
University of Ulm
Outcome results
None listed