Clinical trial NCT04044131: Metabolic Cofactor Supplementation in Alzheimer's Disease (AD) and Parkinson's Disease (PD) Patients
Official title: A Phase 2, Randomized, Placebo Controlled Study to Evaluate the Efficacy, Tolerability and Safety of Metabolic Cofactor Supplementation in Alzheimer's Disease (AD) And Parkinson's Disease (PD) Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer Disease
Parkinson Disease
Lead sponsor: Istanbul Medipol University Hospital
Sponsor class: OTHER
Collaborators: name: ScandiBio Therapeutics AB
name: Alanya Alaaddin Keykubat University
name: Sahlgrenska University Hospital
name: KTH Royal Institute of Technology
First posted: 2019-08-05
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A total of 60 Alzheimer's and 60 Parkinson's disease patients will be randomized on a 2:1 basis to the cofactor mixture or placebo.
Primary purpose: TREATMENT

Brief summary: This double-blind, randomized, placebo-controlled, investigator-initiated, multi-centre trial aims to establish metabolic improvements in AD and PD subjects by dietary supplementation with cofactors N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside and serine. Concomitant use of pivotal metabolic cofactors via simultaneous dietary supplementation will stimulate to enhance hepatic β-oxidation and this study's hypothesis is that this will result in increased mitochondrial activity in human brain cell-types.

Detailed description: In this study, investigators aim to activate mitochondria of brain cell-types in AD and PD patients by increasing the hepatic, plasma and brain levels of pivotal metabolic cofactors via simultaneous dietary supplementation of serine, L-carnitine, N-acetylcysteine (NAC) and nicotinamide riboside (NR).

The study is based on a three-step strategy to activate the mitochondria in human brain cells: (1) The investigators will use L-carnitine tartrate to enhance the transport of fatty acids across the mitochondrial membrane (by forming a long chain acetylcarnitine ester and being transported by carnitine palmitoyltransferase \[CPT\] I and CPT II) and to stabilize acetyl-CoA and coenzyme A levels. (2) Nicotinamide riboside, precursor of NAD+ will be included to boost the level of hepatic β-oxidation of fatty acids in mitochondria. Decreased electron transport chain function combined with impaired rates of fatty acid β-oxidation leads to the accumulation of incomplete products of β-oxidation, which combined with increased levels of reactive oxygen species (ROS), contribute to insulin resistance. Nicotinamide riboside stimulates the transfer of fatty acids from cytosol to mitochondria, similar to L-carnitine tartrate. (3) Two glutathione precursors, serine and N-acetylcysteine, will be included to increase glutathione levels in the hepatocytes. Increased glutathione levels will also protect against free radical-mediated oxidative stress generated by the increased β-oxidation of fatty acids in mitochondria.

Previous studies showed that each agent is able to activate mitochondria separately and a proof-of-concept study using serine supplementation, and a phase I study using this three-step approach resulted in a significant decrease in plasma metabolites associated with mitochondrial dysfunction without significant side effect. The novel design with this study is to give the L-carnitine, NR, serine and NAC as a cocktail. Based on investigators' earlier results, that this will improve the efficacy of the intervention.

The study population will consist of 60 Alzheimer's and 60 Parkinson's disease patients. Eligible subjects must have signed an informed consent, meet all inclusion criteria and have none of the exclusion criteria listed below. Patients will be randomized on a 2:1 basis to the cofactor mixture or placebo in two different centres.

The subjects will take a mixture of cofactors or matching placebo as powder dissolved in water by mouth. Subjects in active treatment will receive dietary supplementation with N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside, and serine, administered as a mixture. Half dosage of the co-factors will be given for two weeks (one dose taken just after dinner), and full dosage for 8 weeks (two equal doses taken just after breakfast and dinner). Patients who cannot tolerate taking full dose may continue the study with half dose (i.e. one dose taken just after dinner). Patients who cannot tolerate the study agents will be withdrawn from the study.

Active treatment duration will be 12 weeks for each subject and the total study duration is estimated as 6 months. Study comprises four clinical visits; (1) a screening visit, (2) randomization visit, (3) treatment visit and (4) end of treatment visit. At visit 1 and visit 4, all procedures including clinical and physical examination, adverse events recording, MRI volumetric and rest-state fMRI, determination of the motor, cognitive and behavioral functions using clinical scales, biochemical, omic and oral/gut microbiota analysis will be done. At visit 2, eligible study subjects will be randomized to active therapy or placebo groups and study agents will be dispensed. At visit 3, clinical and physical examination, determination of the motor, cognitive and behavioural functions using clinical scales, laboratory safety parameters, omic and oral/gut microbiota analysis will be repeated as in Visit 1. After the visit 4, participants will stop taking study agents.

A subject will be considered as having completed the study if he/she has completed all assessments at the End of Treatment Visit (Visit 4) and has been followed up until 12 weeks after initiation of the study drugs.

Statistics for the primary outcome parameter will be analysed by Mann-Whitney U test or t-test depending on the results of the normality test. For the secondary outcome parameters, one-way repeated measures ANOVA will be performed.

Eligibility criteria: Inclusion Criteria:

* Men and women diagnosed with Parkinson's Disease (Hoehn Yahr 2-4, age \>18 years) or men and women diagnosed with Alzheimer's Disease. Include patients older than 50 years with mild to moderate Alzheimer's disease according to ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale; ADAS≥12) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB; CDR≤2).
* Patients with stable treatments and clinical course

Exclusion Criteria:

* Inability or unwillingness to give written informed consent
* History of stroke, severe brain trauma, toxic drug exposure
* Neurological examination which indicate to Parkinson-Plus syndrome (i.e., pyramidal, cerebellar and autonomic dysfunction findings and gaze paralysis) for PD
* Uncontrolled Type 1 or type 2 diabetes
* Diarrhea (defined as more than 2 stool per day) within 7 days before enrolment
* Chronic kidney disease with an estimated glomerular filtration rate \<60 ml/min/1.73m2
* Significant cardiovascular co-morbidity (i.e. heart failure, documented coronary artery disease, valvular heart disease)
* Patients with active bronchial asthma
* Patients with phenylketonuria (contraindicated for NAC)
* Patients with histamine intolerance
* Clinically significant TSH level outside the normal range (0.04-6 mU/L)
* Known allergy for substances used in the study
* Concomitant medication use: Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month; Use of an antimicrobial agent in the 4 weeks preceding randomization
* Active smokers consuming \>10 cigarettes/day
* Alcohol consumption over 192 grams for men and 128 grams for women per week
* Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.)
* Active participation in another clinical study

Primary outcomes:
measure: Mini Mental State Examination (MMSE)
timeFrame: 4 weeks and 12 weeks
measure: Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)
timeFrame: 4 weeks and 12 weeks
measure: Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
timeFrame: 4 weeks and 12 weeks
measure: Unified Parkinson's Disease Rating Scale (UPDRS)
timeFrame: 4 weeks and 12 weeks
Secondary outcomes:
measure: Volumetric Magnetic resonance Imaging (MRI) and resting state functional magnetic resonance imaging (rest-fMRI)
timeFrame: 12 weeks
measure: Neuropsychiatric Inventory (NPI)
timeFrame: 4 weeks and 12 weeks
measure: Montreal Cognitive Assessment (MoCA)
timeFrame: 4 weeks and 12 weeks
measure: Changes in serum omic profile from baseline
timeFrame: 4 weeks and 12 weeks
measure: Microbiota analysis
timeFrame: 4 weeks and 12 weeks
measure: Monitoring of adverse events
timeFrame: 1 week, 4 weeks and 12 weeks
measure: Change in heart rate from baseline
timeFrame: 1 week, 4 weeks and 12 weeks
measure: Change in blood pressure from baseline
timeFrame: 1 week, 4 weeks and 12 weeks
measure: Change in waist and hip circumference from baseline
timeFrame: 1 week, 4 weeks and 12 weeks
measure: Change in body weight from baseline
timeFrame: 1 week, 4 weeks and 12 weeks
measure: Change of complete blood count from baseline
timeFrame: 4 weeks and 12 weeks
measure: Changes in liver function tests (alkaline phosphatase (ALP), alanine aminotransferase (ALT), Aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total and direct Bilirubin, Albumin) from baseline
timeFrame: 4 weeks and 12 weeks
measure: Changes in blood lipid levels (total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C)) from baseline
timeFrame: 4 weeks and 12 weeks
measure: Changes in kidney function tests (creatinine, urea, urate, sodium, potassium) from baseline
timeFrame: 4 weeks and 12 weeks
measure: Changes in creatinine kinase (CK) level from baseline
timeFrame: 4 weeks and 12 weeks
measure: Change in thyroid-stimulating hormone (TSH) level from baseline
timeFrame: 4 weeks and 12 weeks
measure: Change in blood insulin level from baseline
timeFrame: 4 weeks and 12 weeks
measure: Change in glycated haemoglobin (HbA1c) level from baseline
timeFrame: 4 weeks and 12 weeks
measure: Changes in blood glucose levels from baseline
timeFrame: 4 weeks and 12 weeks
Other outcomes:
Locations:
city: Antalya
country: Turkey
facility: Alanya Alaaddin Keykubat University Hospital
city: Istanbul
country: Turkey
facility: Medipol University Hospital
Study officials:
affiliation: Medipol University
name: Lutfu Hanoglu, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Alanya Alaaddin Keykubat University
name: Burak Yulug, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: