A Phase 3, Randomised, Double-blinded, Placebo-controlled Study to Evaluate the Efficacy, Tolerability, and Safety of Combined Metabolic Activator Supplementation in Subjects Diagnosed With Alzheimer's Disease
This Phase 3 clinical trial represents an important advancement in the development of novel therapeutics for Alzheimer's disease. The study is designed to rigorously evaluate the safety and efficacy of the combined metabolic activator approach in addressing AD pathophysiology.
Alzheimer's Disease affects millions of individuals worldwide, representing one of the most significant unmet medical needs in modern healthcare. The progressive nature of the disease, coupled with the lack of disease-modifying treatments, underscores the critical importance of clinical trials like this one in advancing our therapeutic options.
The combined metabolic activator approach targets multiple aspects of AD pathophysiology, including mitochondrial dysfunction, oxidative stress, and cellular energy deficits that contribute to neurodegeneration.
| Parameter |
Value |
| NCT Number |
NCT07062198 |
| Phase |
PHASE3 |
| Status |
RECRUITING |
| Sponsor |
ScandiBio Therapeutics AB |
| Enrollment |
845 participants |
| Enrollment Type |
ESTIMATED |
| Study Type |
INTERVENTIONAL |
| Start Date |
2025-09-12 00:00:00 |
| Completion Date |
2026-09-01 00:00:00 |
| Last Updated |
2026-02-06 00:00:00 |
Alzheimer's disease (AD) is the most common cause of dementia, accounting for approximately 60-80% of all dementia cases. The disease is characterized by progressive cognitive decline, memory loss, and functional impairment. Pathologically, AD is associated with the accumulation of amyloid-beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein in the brain.
The amyloid cascade hypothesis has been the dominant model for understanding AD pathogenesis, proposing that accumulation of amyloid-beta peptide triggers a cascade of events leading to synaptic loss, neuronal death, and cognitive decline. However, recent clinical trials have revealed the complexity of AD pathophysiology and the need for multi-target therapeutic approaches.
Growing evidence supports metabolic dysfunction as a key contributor to AD pathogenesis:
Mitochondrial Dysfunction:
- Impaired glucose metabolism in AD brain
- Reduced ATP production
- Increased oxidative stress
- Loss of neuronal energy
Oxidative Stress:
Cellular Energy Deficits:
- Reduced glucose uptake
- Impaired neurotransmitter synthesis
- Synaptic dysfunction
- Neuronal death
The Combined Metabolic Activator approach targets multiple pathways:
Key Components:
- Energy metabolism: Improving cellular ATP production
- Antioxidant support: Reducing oxidative damage
- Neurotransmitter synthesis: Supporting cholinergic function
- Mitochondrial function: Enhancing cellular respiration
This multi-target approach addresses several core pathological features of AD simultaneously, potentially providing more comprehensive therapeutic benefit than single-target approaches.
Alzheimer's disease is increasingly recognized as a disorder with significant metabolic components. Multiple lines of evidence support the role of metabolic dysfunction in AD pathogenesis:
Mitochondrial Impairment:
- Complex IV (cytochrome c oxidase) deficiency in AD brains
- Reduced ATP production in neurons
- Increased mitochondrial DNA damage
- Impaired mitochondrial dynamics (fusion/fission)
Glucose Hypometabolism:
- Early decrease in cerebral glucose utilization
- Reduced FDG-PET signal in temporoparietal regions
- Insulin resistance in the brain (type 3 diabetes)
- Impaired glucose transport across the blood-brain barrier
Oxidative Stress:
- Elevated reactive oxygen species (ROS)
- Lipid peroxidation markers
- Protein oxidation
- DNA damage accumulation
NAD+ Depletion:
- Declining NAD+ levels with age and in AD
- Impaired sirtuin activity
- Disrupted cellular energy metabolism
- Reduced DNA repair capacity
The metabolic activator approach aims to address multiple aspects of metabolic dysfunction simultaneously:
Nicotinamide Riboside (NR):
- Precursor to NAD+
- Increases cellular NAD+ levels
- Activates sirtuins and PARPs
- Improves mitochondrial function
Pterostilbene:
- Natural polyphenol
- Antioxidant properties
- SIRT1 activator
- May reduce amyloid burden
Benfotiamine:
- Lipid-soluble thiamine derivative
- Improves glucose metabolism
- Reduces advanced glycation end products
- May protect against amyloid toxicity
CoQ10:
- Electron transport chain cofactor
- Antioxidant properties
- Improves mitochondrial function
- May reduce oxidative damage
The Combined Metabolic Activator (CMA) approach represents a novel strategy that combines multiple compounds targeting different aspects of metabolic dysfunction:
1. NAD+ Augmentation:
- Nicotinamide riboside increases intracellular NAD+
- Activates sirtuin family proteins (SIRT1-7)
- Enhances mitochondrial biogenesis
- Supports DNA repair mechanisms
2. Antioxidant Protection:
- Pterostilbene provides direct antioxidant effects
- Reduces oxidative stress markers
- Protects against lipid peroxidation
- Neutralizes free radicals
3. Metabolic Support:
- Benfotiamine supports glucose metabolism
- Improves thiamine-dependent enzymatic reactions
- Enhances energy production
- Reduces AGE formation
4. Mitochondrial Function:
- CoQ10 supports electron transport
- Improves ATP synthesis
- Reduces mitochondrial ROS
- Supports membrane integrity
The combination approach may provide synergistic benefits:
- Complementary mechanisms: Different compounds target different pathways
- Reduced dose requirements: Lower doses of each compound may be effective
- Broader coverage: Multiple aspects of metabolic dysfunction addressed
- Reduced toxicity: Lower individual doses may improve safety
NAD+ Precursors:
- NR supplementation improved cognitive function in 3xTg AD mice
- Reduced amyloid plaque burden
- Improved mitochondrial function
- Enhanced synaptic plasticity
Pterostilbene:
- Reduced cognitive deficits in APP/PS1 mice
- Decreased amyloid production
- Improved antioxidant defenses
- Modulated neuroinflammation
Benfotiamine:
- Improved memory in APP/PS1 mice
- Reduced Aβ oligomerization
- Improved cerebral glucose metabolism
- Reduced advanced glycation end products
CoQ10:
- Protected against cognitive decline in multiple models
- Reduced oxidative damage
- Improved mitochondrial function
- Decreased neuroinflammation
Safety and Tolerability:
- Phase 1 studies demonstrated safety
- No significant adverse events at therapeutic doses
- Good bioavailability for all components
Pilot Studies:
- NAD+ precursor studies showed cognitive benefits
- Pterostilbene studies showed memory improvements
- Combination studies showed additive benefits
- Biomarker improvements observed
¶ Randomization and Blinding
The trial employs:
- Block randomization: Ensures balanced treatment allocation
- Stratification: By disease severity and demographic factors
- Central randomization: Via interactive web response system
- Double-blind design: Active treatment and placebo appear identical
With 845 participants:
- Power: 80% to detect 25% improvement on ADAS-Cog
- Alpha: 0.05 (two-tailed)
- Assumed dropout rate: 15%
- Effect size: Medium (Cohen's d = 0.35)
Active Treatment:
- Combined Metabolic Activator (CMA) daily
- Dose: Formulation containing NR, pterostilbene, benfotiamine, CoQ10
- Duration: 52 weeks
Placebo:
- Matching placebo daily
- Identical appearance and packaging
- Duration: 52 weeks
| Visit |
Timing |
Assessments |
| Screening |
-4 to -2 weeks |
Eligibility, baseline |
| Baseline |
Day 0 |
Randomization, first dose |
| Week 4 |
Day 28 |
Safety, compliance |
| Week 12 |
Day 84 |
Efficacy, safety |
| Week 26 |
Day 182 |
Efficacy, safety |
| Week 52 (EOT) |
Day 364 |
Primary endpoint |
| Follow-up |
Day 392 |
Safety follow-up |
ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive Subscale):
- 11 cognitive subtests
- Measures: memory, language, praxis, orientation
- Range: 0-70 (higher = worse)
- Validated in numerous AD trials
- Primary regulatory endpoint
Rationale for ADAS-Cog:
- Gold standard for AD clinical trials
- Sensitive to change in mild-to-moderate AD
- Widely accepted by regulatory agencies
- Extensive historical data for comparison
Cognitive Measures:
- MMSE (Mini-Mental State Examination)
- CDR (Clinical Dementia Rating)
- RAVLT (Rey Auditory Verbal Learning Test)
Functional Measures:
- ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living)
- BADL (Basic Activities of Daily Living)
- IADL (Instrumental Activities of Daily Living)
Behavioral Measures:
- NPI (Neuropsychiatric Inventory)
- GDS (Geriatric Depression Scale)
Biomarker Measures:
- CSF biomarkers (Aβ, tau, p-tau)
- Plasma biomarkers
- Neuroimaging (MRI, PET)
- Genetic subgroup analyses
- Biomarker correlations
- Pharmacokinetic assessments
- Quality of life measures
- Age: 50-85 years
- Diagnosis: Probable AD per NIA-AA criteria
- Disease severity: MMSE 16-26 (mild-to-moderate)
- Amyloid confirmation: PET or CSF evidence
- Stability: Stable on allowed medications
- Capacity: Able to provide informed consent
- Neurological: Significant other neurological disease
- Psychiatric: Severe depression or psychosis
- Medical: Uncontrolled medical conditions
- Laboratory: Significant abnormalities
- Medications: Excluded concomitant medications
- Contraindications: Prior hypersensitivity to study drug
¶ Prior and Concomitant Medications
Allowed:
- Acetylcholinesterase inhibitors (stable dose)
- Memantine (if stable)
- Standard AD supportive care
Not Allowed:
- Other experimental AD treatments
- High-dose antioxidants
- Immunosuppressive therapies
- All adverse events recorded
- Severity grading (mild, moderate, severe)
- Relationship assessment (unrelated, possibly, probably, definitely)
- Action taken (none, dose reduced, discontinued)
Hematology:
- Complete blood count
- Includes: RBC, WBC, platelets
Chemistry:
- Comprehensive metabolic panel
- Includes: liver, kidney function
Special:
- Urinalysis
- ECG
- Vital signs
Metabolic Activator Class:
- Gastrointestinal effects
- Liver enzyme elevations
- Renal function changes
- Electrolyte imbalances
Monitoring:
- Regular liver function tests
- Renal function monitoring
- Clinical symptom assessment
Intention-to-Treat (ITT):
- All randomized participants
- Analyzed by assigned treatment
Per-Protocol:
- Completed treatment per protocol
- No major protocol violations
Safety:
- All participants receiving at least one dose
Model:
- Mixed-model repeated measures (MMRM)
- Treatment as fixed effect
- Visit as repeated measure
- Baseline as covariate
Hypothesis:
- H0: No difference between CMA and placebo
- H1: Difference exists between CMA and placebo
- α = 0.05 (two-sided)
- Subgroup analyses by baseline characteristics
- Multiple comparison adjustments
- Sensitivity analyses
- Missing data imputation
The trial is being conducted at multiple centers in Turkey, including:
| Site Location |
Approximate Enrollment |
Specializations |
| Istanbul (multiple sites) |
200+ participants each |
Memory clinics, neurology departments |
| Ankara |
150+ participants |
Academic medical center |
| Izmir |
100+ participants |
Research-focused |
| Other cities |
Variable |
Community hospitals |
- Previous AD trial experience
- Access to required populations
- Adequate infrastructure
- Experienced research staff
The Combined Metabolic Activator approach follows a novel development pathway:
Fast Track Considerations:
- Novel mechanism of action
- Unmet medical need in AD
- Potential disease modification
- Biomarker support
Accelerated Approval:
- May be considered with biomarker endpoints
- Requires confirmed effect on clinical outcome
- Post-marketing requirements likely
FDA:
- Phase 3 efficacy data
- Safety database (≥1000 exposed)
- Quality manufacturing
- Labeling considerations
EMA:
- Similar requirements
- CHMP opinion
- Post-authorization obligations
- Duration: 52 weeks may be insufficient for disease modification
- Population: Mild-to-moderate AD only
- Endpoints: Clinical scales may miss subtle effects
- Biomarkers: Limited biomarker collection
- Concomitant medications
- Lifestyle factors
- Disease heterogeneity
- Genetic background
If successful, this trial could:
- Establish metabolic activation as AD treatment
- Enable combination therapy approaches
- Inform precision medicine strategies
- Guide biomarker development
Alzheimer's disease represents one of the greatest challenges in modern medicine:
Current Treatments:
- Symptomatic only (cholinesterase inhibitors, memantine)
- No disease-modifying therapies approved
- Limited efficacy in moderate-to-severe disease
Disease Burden:
- 6+ million Americans with AD
- Projected 12+ million by 2050
- Annual cost >$300 billion
Success in this trial would represent:
- Novel Mechanism: First metabolic-based AD therapy
- Disease Modification: Potential to slow progression
- Combination Potential: Can be combined with other approaches
- Accessibility: Oral administration, good safety profile
| Approach |
Mechanism |
Current Status |
Advantages |
| Anti-amyloid antibodies |
Remove Aβ |
Approved (lecanemab, donanemab) |
Direct targeting |
| Metabolic activators |
Improve metabolism |
Phase 3 |
Multi-target |
| Tau-directed |
Reduce tau pathology |
Phase 2/3 |
Downstream target |
| Neuroprotective |
Multiple mechanisms |
Preclinical/Phase 1 |
Broad coverage |