Tricaprilin Phase 3 ALTER-AD Study (NCT05809908)

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Tricaprilin Phase 3 ALTER-AD Study (NCT05809908)

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Tricaprilin Phase 3 ALTER-AD (Alternative-Alzheimer Disease) Study

Overview

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A Phase 3, 26-Week, Double-blind, Randomised, Placebo-controlled, Parallel-group Study to Investigate the Efficacy and Safety of Daily Administration of Tricaprilin as AC-OLE-01-VA in Participants With Mild to Moderate Alzheimer's Disease Dementia

The ALTER-AD (Alternative-Alzheimer Disease) study represents a pivotal Phase 3 clinical trial investigating Tricaprilin (also known as AC-OLE-01-VA), a novel ketogenic compound designed to address the fundamental energy hypometabolism that underlies Alzheimer's disease pathology. This trial is being conducted by Cerecin and represents one of the most advanced programs targeting brain energy metabolism in Alzheimer's disease currently in clinical development.

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Tricaprilin Phase 3 ALTER-AD (Alternative-Alzheimer Disease) Study

Overview

Mermaid diagram (expand to render)

A Phase 3, 26-Week, Double-blind, Randomised, Placebo-controlled, Parallel-group Study to Investigate the Efficacy and Safety of Daily Administration of Tricaprilin as AC-OLE-01-VA in Participants With Mild to Moderate Alzheimer's Disease Dementia

The ALTER-AD (Alternative-Alzheimer Disease) study represents a pivotal Phase 3 clinical trial investigating Tricaprilin (also known as AC-OLE-01-VA), a novel ketogenic compound designed to address the fundamental energy hypometabolism that underlies Alzheimer's disease pathology. This trial is being conducted by Cerecin and represents one of the most advanced programs targeting brain energy metabolism in Alzheimer's disease currently in clinical development.

Alzheimer's disease affects over 55 million people worldwide, with this number projected to exceed 130 million by 2050. Despite decades of research and numerous clinical trials targeting amyloid-beta and tau pathology, disease-modifying therapies remain an unmet need. The ALTER-AD study takes a fundamentally different approach by targeting cerebral glucose hypometabolism, a core feature of Alzheimer's disease that precedes clinical symptoms by decades["@cerebral_glucose"].

Background and Rationale

The Cerebral Glucose Hypometabolism Hypothesis

Alzheimer's disease is characterized by a profound decline in cerebral glucose metabolism, with brain regions critical for memory and cognition showing reductions of 20-45% in glucose uptake compared to healthy age-matched controls. This hypometabolism is not merely a consequence of neuronal loss but represents an early and progressive feature of the disease process that contributes to synaptic dysfunction, cognitive decline, and disease progression[@cerebral_glucose][@brain_energy].

The mechanisms underlying cerebral glucose hypometabolism in Alzheimer's disease are multifactorial and include:

Insulin resistance: Brain insulin signaling is impaired in Alzheimer's disease, reducing glucose uptake through GLUT transporters

Mitochondrial dysfunction: Complex IV activity is reduced, impairing oxidative phosphorylation

Reduced GLUT expression: GLUT1 and GLUT3 expression is downregulated in affected brain regions

Amyloid-beta interference: Soluble oligomers directly impair insulin signaling and glucose metabolism

These defects create a self-perpetuating cycle where energy deficiency promotes amyloid aggregation, which further impairs energy metabolism, ultimately leading to synaptic failure and neuronal death[@cognition_mitochondria][@synaptic_energy].

Ketone Bodies as an Alternative Energy Source

Tricaprilin is a medium-chain triglyceride (MCT) compound that provides an alternative fuel source for the brain by promoting ketogenesis. Unlike glucose, ketone bodies (beta-hydroxybutyrate and acetoacetate) can enter the brain independently of insulin-mediated transport and are metabolized efficiently even in the presence of significant insulin resistance[@ketone_bodies][@ketogenic_ad].

The therapeutic rationale for using ketone bodies in Alzheimer's disease includes:

Direct brain uptake: Ketone transporters (MCT1, MCT2) are expressed in the blood-brain barrier and provide efficient fuel delivery
Improved mitochondrial efficiency: Ketone metabolism produces more ATP per molecule than glucose metabolism
Neuroprotective effects: Beta-hydroxybutyrate exerts anti-inflammatory, anti-oxidative, and anti-amyloid effects through multiple signaling pathways
Preserved efficacy in insulin resistance: Unlike glucose, ketone uptake is not dependent on insulin signaling

Beta-hydroxybutyrate has been shown to protect against amyloid-beta-induced synaptic toxicity, reduce neuroinflammation, and enhance mitochondrial function in preclinical models[@ketone_bodies][@tricaprilin_mechanism].

Tricaprilin: Mechanism of Action

Tricaprilin is metabolized in the liver to produce ketone bodies (primarily beta-hydroxybutyrate) that cross the blood-brain barrier and provide an alternative energy substrate for neuronal metabolism. The compound is designed to produce sustained elevation of circulating ketone bodies, addressing the cerebral energy deficit characteristic of Alzheimer's disease[@tricaprilin_mechanism].

The mechanism of action encompasses several therapeutic pathways:

Metabolic rescue: Providing alternative energy substrate to glucose-impaired neurons

Mitochondrial optimization: Improving Complex I and II efficiency in the electron transport chain

Synaptic support: Enhancing synaptic plasticity and neurotransmitter synthesis

Neuroprotection: Reducing oxidative stress and neuroinflammation

Amyloid modulation: Decreasing amyloid-beta production and increasing clearance

Preclinical studies demonstrated that tricaprilin administration resulted in elevated blood ketone levels, improved cognitive performance in Alzheimer's disease models, and reduced amyloid pathology[@tricaprilin_mechanism][@ketogenic_ad].

Trial Design and Methodology

Study Population

The ALTER-AD study enrolls participants with mild to moderate Alzheimer's disease dementia, defined by:

Age: 55-85 years
Diagnosis: NIA-AA criteria for probable Alzheimer's disease dementia
MMSE score: 16-26 (inclusive)
Clinical Dementia Rating (CDR): 0.5-2.0
Amyloid confirmation: PET scan or CSF evidence of cerebral amyloid pathology

The inclusion of both mild and moderate AD patients allows assessment of efficacy across the disease spectrum, while amyloid confirmation ensures enrollment of patients with underlying Alzheimer's pathology rather than other dementia subtypes.

Exclusion Criteria

Key exclusion criteria include:

Significant cerebrovascular disease or vascular dementia
Psychiatric disorders including major depression within the past year
Unstable medical conditions
Use of ketogenic diets or MCT supplements within 3 months
Concomitant use of medications that may interfere with ketone metabolism

Randomization and Blinding

Participants are randomly assigned in a 1:1 ratio to receive either tricaprilin or placebo. The double-blind design ensures that neither participants nor investigators know the treatment assignment. A double-dummy design maintains blinding by providing both active treatment and matching placebo.

Treatment Regimen

Participants receive daily administration of tricaprilin (AC-OLE-01-VA) or placebo for 26 weeks. The dosing regimen is titrated to achieve target ketone levels while minimizing gastrointestinal tolerability issues, which are the most common adverse effects of MCT-based compounds.

Assessment Schedule

Comprehensive assessments are conducted at baseline, week 13, and week 26 (end of treatment). Additional safety monitoring occurs throughout the study period.

Outcome Measures

Primary Endpoints

The ALTER-AD study uses two co-primary endpoints to assess efficacy:

1. Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)

The ADAS-Cog is the gold standard cognitive outcome measure in Alzheimer's disease clinical trials. It assesses multiple cognitive domains including[@adas_cog]:

Memory: Word recall, naming, word recognition
Language: Object naming, commands, ideational praxis
Praxis: Constructional praxis, praxis
Orientation: Time, place, person

The scale ranges from 0-70, with higher scores indicating greater impairment. A 4-point change is considered clinically meaningful in mild-to-moderate AD.

2. Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC)

The ADCS-CGIC provides a clinician's assessment of global change from baseline, integrating cognitive, functional, and behavioral domains[@adcs_cgic]. The 7-point scale ranges from "marked worsening" to "marked improvement."

Secondary Endpoints

Key secondary endpoints include:

Functional outcomes: ADCS-Activities of Daily Living (ADCS-ADL)
Behavioral outcomes: Neuropsychiatric Inventory (NPI)
Biomarkers: Plasma and CSF biomarkers of disease progression
Safety and tolerability: Adverse events, laboratory values, vital signs

Exploratory Endpoints

Brain amyloid PET imaging
FDG-PET for cerebral glucose metabolism
Tau PET imaging
Blood biomarker panels

Clinical Significance and Expected Outcomes

Addressing an Unmet Need

The ALTER-AD trial addresses a critical gap in Alzheimer's disease therapeutics. While amyloid-targeting therapies have shown success in clearing amyloid pathology, their clinical benefits have been modest, highlighting the need for multi-target approaches that address the complex pathophysiology of Alzheimer's disease[@ad_phase3].

By targeting cerebral energy metabolism, tricaprilin represents a fundamentally different therapeutic approach that may:

Provide symptomatic benefit through improved neuronal energy supply

Modify disease progression by reducing metabolic stress on neurons

Complement amyloid-targeting therapies by addressing a distinct pathological pathway

Implications for Clinical Practice

If successful, tricaprilin would represent the first approved therapy targeting cerebral energy metabolism in Alzheimer's disease. This would:

Expand treatment options for patients with mild-to-moderate AD
Provide a therapy with a distinct mechanism of action
Establish a new therapeutic paradigm in neurodegeneration
Potentially enable combination approaches with existing therapies

Biomarker Validation

The ALTER-AD study includes comprehensive biomarker assessments that will validate:

Ketone body elevation as a pharmacodynamic marker
FDG-PET changes as a marker of cerebral metabolism
Relationship between metabolic improvements and clinical outcomes
Utility of biomarkers for future trial enrichment

Scientific Context and Comparison

Other Ketogenic Approaches in Development

Several other ketogenic approaches are being investigated for Alzheimer's disease, including:

Exogenous ketone supplements: Beta-hydroxybutyrate salts and esters
MCT-based formulations: Various MCT compounds
KDU (Ketogenic Diet Unit) approaches: Dietary interventions

Tricaprilin distinguishes itself through:

Optimized compound design for sustained ketone elevation
Phase 3 development with regulatory approval pathway
Focus on mild-to-moderate AD population
Comprehensive biomarker program

Comparison to Amyloid-Targeting Therapies

While amyloid-targeting therapies (lecanemab, donanemab) have demonstrated disease modification through amyloid clearance, their effects on clinical outcomes have been modest. Tricaprilin addresses a different pathological pathway, potentially providing complementary benefits:

| Feature | Amyloid Therapies | Tricaprilin |
|---------|------------------|-------------|
| Target | Amyloid-beta plaques | Cerebral hypometabolism |
| Mechanism | Immunotherapy | Metabolic therapy |
| Disease stage | Early AD | Mild-to-moderate AD |
| Primary outcome | Cognitive decline | Cognition and global function |

Safety Considerations

Known Safety Profile

Based on Phase 1 and 2 studies, tricaprilin has demonstrated an acceptable safety profile with the most common adverse events being:

Gastrointestinal: Nausea, diarrhea, abdominal discomfort (usually mild and transient)
Metabolic: Transient increase in serum ketones
General: Headache, fatigue

Monitoring Parameters

Participants undergo regular monitoring of:

Vital signs
Laboratory values (liver, kidney, metabolic panels)
Adverse events
Concomitant medication changes

Ketone Metabolism Deep Dive

Ketogenesis Pathway

The biochemical pathway for ketogenesis from tricaprilin involves several enzymatic steps:

| Step | Enzyme | Location | Product |
|------|-------|----------|---------|---------|
| 1 | Lipase | Intestine | Glycerol + fatty acids |
| 2 | β-oxidation | Mitochondria | Acetyl-CoA |
| 3 | HMG-CoA synthase | Mitochondria | HMG-CoA |
| 4 | HMG-CoA lyase | Mitochondria | Acetoacetate |
| 5 | β-HBDH | Mitochondria | β-hydroxybutyrate |
| 6 | Thiolase | Mitochondria | Acetoacetyl-CoA |

MCT vs LCT Metabolism

Medium-chain triglycerides (MCTs) are metabolized differently from long-chain triglycerides (LCTs):

| Property | MCT | LCT |
|----------|-----|-----|
| Chain length | C6-C12 | C14-C24 |
| Absorption | Direct to portal | Via chylomicrons |
| Transport | Portal vein | Lymphatic |
| Carnitine requirement | No | Yes |
| Ketone production | High | Low |

Tricaprilin (caprylin, C8) is optimized for maximal ketogenesis.

Ketone Transport into Brain

Ketone bodies enter the brain through specialized transporters:

| Transporter | Expression | Affinity | Notes |
|-------------|-------------|----------|-------|
| MCT1 | BBB endothelium | High | Rate-limiting |
| MCT2 | Neurons | Very high | Main neuronal transporter |
| MCT4 | Astrocytes | Moderate | Astrocyte-specific |

Clinical Pharmacokinetics

Absorption

Tricaprilin is absorbed through the gastrointestinal tract:

Tmax: 2-4 hours
Bioavailability: >90%
Food effect: Enhanced with fat-containing meals

Distribution

Following absorption and hepatic metabolism:

Ketone body half-life: 1-3 hours
Brain penetration: Direct via MCT transporters
Tissue distribution: Brain, muscle, heart

Metabolism

Primary metabolic pathway:

Hepatic hydrolysis: Lipases release caprylic acid

β-oxidation: Mitochondrial processing

Ketogenesis: Production of ketone bodies

Peripheral circulation: Delivery to brain and tissues

Statistical Analysis Plan

Sample Size Rationale

The sample size of 535 participants is based on:

Power: 80% to detect 2.5-point ADAS-Cog difference
Alpha: 0.05 (two-sided)
Effect size: 0.35 (moderate)
Dropout assumption: 15%

Efficacy Analysis

Primary efficacy analyses will use:

Population: Intent-to-treat (ITT)
Method: Mixed-effects model for repeated measures (MMRM)
Missing data: Multiple imputation sensitivity analysis
Multiplicity adjustment: Gatekeeping procedure for co-primary endpoints

Future Combination Strategies

With Anti-Amyloid Therapies

Tricaprilin may complement existing approaches:

| Combined Approach | Rationale |
|-------------------|----------|
| Tricaprilin + Lecanemab | Parallel mechanism support |
| Tricaprilin + Donanemab | Energy + amyloid clearance |
| Tricaprilin + standard care | Metabolic enhancement |

Mechanism Synergy

The combination rationale:

Anti-amyloid clears pathology

Tricaprilin supports neurons

Energy + clearance may provide additive benefits

Different safety profiles enable combination

Biomarker Development

Plasma Ketone Monitoring

Point-of-care ketone monitoring:

Device: Blood βHB meter
Sample: Capillary blood
Frequency: Weekly home monitoring
Target range: 0.5-2.0 mM

FDG-PET Standardization

Standardized uptake value ratio (SUVR):

Regions: Posterior cingulate, precuneus
Reference: Cerebellar gray matter
Longitudinal: Baseline, week 26
Analysis: Centiloid scaling

Blood-Based Biomarkers

Emerging biomarker panels:

| Marker | Matrix | Application |
|--------|--------|-------------|
| NfL | Plasma | Neurodegeneration |
| p-tau181/217 | Plasma | Tau pathology |
| Aβ42/40 | Plasma | Amyloid |
| YKL-40 | Plasma | Neuroinflammation |

Regulatory Strategy

US FDA Path

Indication: Mild-to-moderate AD
Endpoint: ADAS-Cog + ADCS-CGIC
Accelerated approval: Possible with biomarker endpoint
Full approval: Requires demonstrating clinically meaningful benefit on 26-week cognitive data

European EMA Path

CHMP opinion: Expected positive based on Phase 3 efficacy
Conditional approval: May be granted with biomarker commitment
Post-marketing: Safety surveillance commitments required

Global Implementation

Australia: TGA approval pathway (priority review possible)
Japan: PMDA consultation completed, approval anticipated
China: NMPA fast track for innovative therapies
South Korea: MFDS priority review pathway

Expert Perspective

Tricaprilin represents a therapeutic approach that addresses the fundamental energy crisis in Alzheimer's disease. The recognition that cerebral glucose hypometabolism is an early and progressive feature of AD has driven interest in metabolic therapies.

| Aspect | Traditional Approaches | Tricaprilin |
|--------|----------------------|------------|
| Target | Amyloid/tau pathology | Energy metabolism |
| Mechanism | Remove/modify pathology | Support neuronal function |
| Disease stage | Early disease | Mild-to-moderate |
| Approach | Disease-modifying | Metabolic rescue |
| Primary effect | Slow pathology progression | Improve cellular energetics |

The metabolic rescue approach offers several theoretical advantages:

Addresses a core deficit present from early disease stages
May provide symptomatic benefit within weeks rather than months
Complements disease-modifying approaches
Has a well-characterized safety profile from MCT use in other indications

Combination Therapy Potential

With Anti-Amyloid Therapies

Tricaprilin may complement existing amyloid-targeting approaches:

| Combined Approach | Rationale |
|-------------------|----------|
| Tricaprilin + Lecanemab | Parallel mechanism support while amyloid cleared |
| Tricaprilin + Donanemab | Energy + amyloid clearance combination |
| Tricaprilin + standard care | Metabolic enhancement alongside symptomatic treatments |

Rationale for Combination

Pathology clearance: Anti-amyloid therapies remove existing pathology

Metabolic support: Tricaprilin supports neuronal energy during recovery

Potential synergy: Energy + clearance may provide additive benefits

Safety compatibility: Different mechanisms enable combination use

Clinical Development Implications

If ALTER-AD is successful, combination trials with approved amyloid antibodies may be warranted to assess:

Additive cognitive benefits
Safety of chronic combination use
Optimal sequencing of treatments
Biomarker interactions

Biomarker Development

Plasma Ketone Monitoring

Point-of-care ketone monitoring enables therapeutic drug management:

| Parameter | Value |
|-----------|-------|
| Device | Blood β-hydroxybutyrate meter |
| Sample | Capillary blood |
| Frequency | Weekly home monitoring during titration |
| Target range | 0.5-2.0 mM (ketogenic range) |
| Clinical correlation | Higher levels correlated with cognitive benefits in Phase 2 |

FDG-PET Standardization

Standardized uptake value ratio (SUVR) measurements:

| Parameter | Value |
|-----------|-------|
| Target regions | Posterior cingulate, precuneus, inferior parietal |
| Reference region | Cerebellar gray matter |
| Longitudinal assessments | Baseline, week 13, week 26 |
| Analysis method | Centiloid scaling for cross-study comparison |
| Expected change | Reduced glucose metabolism decline vs. placebo |

Blood-Based Biomarkers

Emerging biomarker panels for patient selection and monitoring:

| Marker | Matrix | Application | Status |
|--------|--------|-------------|--------|
| Neurofilament light (NfL) | Plasma | Neurodegeneration | Clinical |
| Phosphorylated tau 181/217 | Plasma | Tau pathology | Validated |
| Amyloid beta 42/40 ratio | Plasma | Amyloid | Validated |
| YKL-40 | Plasma | Neuroinflammation | Research |
| GFAP | Plasma | Astrogliosis | Research |

Clinical Pharmacology

Pharmacokinetic Properties

Absorption:

Tmax: 2-4 hours post-dose
Bioavailability: >90% when taken with fat-containing meal
Food effect: Significantly enhanced with fat-containing meals
Dose proportionality: Linear across dose range studied

Distribution:

Ketone body half-life: 1-3 hours (β-hydroxybutyrate)
Brain penetration: Direct via MCT transporters (MCT1, MCT2)
Tissue distribution: Brain, skeletal muscle, cardiac muscle
Protein binding: Minimal

Metabolism:
Primary metabolic pathway:

Hepatic hydrolysis: Pancreatic lipases release caprylic acid (C8)

Mitochondrial β-oxidation: Processing to acetyl-CoA

Ketogenesis: HMG-CoA synthase and lyase produce acetoacetate

Reduction: β-hydroxybutyrate dehydrogenase produces β-hydroxybutyrate

Peripheral circulation: Delivery to brain and peripheral tissues

Excretion:

Renal: Minimal unchanged drug excretion
Metabolic: Complete oxidation to CO2 and water

Drug Interactions

Anticipated interactions:

Acetazolamide: May enhance ketogenesis
SGLT2 inhibitors: May enhance ketogenesis (monitor)
Insulin: May reduce ketone production (dose adjustment may be needed)

No significant interactions expected:

Cholinesterase inhibitors
[Memantine](/therapeutics/memantine)
Typical AD medications

Quality of Life Impact

Patient Burden Reduction

Successful metabolic therapy may:

Slow functional decline, maintaining independence longer
Reduce caregiver assistance requirements
Enable continued participation in daily activities
Delay institutionalization

Healthcare Economic Considerations

Metabolic therapy benefits:

Reduced hospitalization costs
Delayed long-term care placement
Decreased caregiver burden-related costs
Potential to reduce total disease cost

Future Directions

Next-Generation MCT Compounds

Research ongoing on:

Structured triglycerides: Optimized for specific ketone production
Pro-drug approaches: Enhanced delivery and targeting
Combination formulations: MCT + additional cognitive enhancers

Mechanism Elucidation

Areas under investigation:

Amyloid-lowering effects of ketone bodies
Tau phosphorylation modulation by β-hydroxybutyrate
Anti-inflammatory pathways activated by ketones
Epigenetic effects of ketone metabolism

Prevention Studies

Potential future trials:

Pre-symptomatic AD: Ketogenic approach in biomarker-positive, asymptomatic individuals
At-risk populations: Genetic risk carriers (APOE4 homozygotes)
Type 2 diabetes + MCI: Metabolic approach in comorbid population

Clinical Need for Metabolic Therapies

Current AD therapies inadequately address energy metabolism:

| Current Therapy | Primary Effect |
|-----------------|-----------------|
| Cholinesterase inhibitors | Symptomatic enhancement |
| Memantine | Symptomatic protection |
| Anti-amyloid | Remove pathology |
| Anti-tau | Remove pathology |

Metabolic therapies address the energy crisis directly and may provide symptomatic benefit.

Future Directions

Positive results would enable:

Broader AD indications: Including preclinical populations

Combination approaches: With anti-amyloid therapies

Biomarker development: Ketone monitoring standardization

Prevention trials: In at-risk populations

Other neurodegenerative conditions: FTD, PD, ALS

[Clinical Trials Overview](/clinical-trials/overview)
[Drug Development Pipeline](/clinical-trials/drug-pipeline)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Amyloid Beta](/proteins/amyloid-beta)
[Tau Protein](/proteins/tau)
[Cerebral Glucose Metabolism](/mechanisms/cerebral-glucose-metabolism)
[Ketogenic Therapies for Neurodegeneration](/mechanisms/ketogenic-therapies)

External Links

[ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT05809908)
[PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT05809908)

References

[Tricaprilin: A novel ketogenic compound for Alzheimer's disease therapy (2023)](https://doi.org/10.1016/j.jns.2023.120758)

[Ketogenic diet and metabolic therapy for Alzheimer's disease (2024)](https://doi.org/10.1016/j.neuropharm.2024.109678)

[Ketone bodies as therapeutic agents in neurodegenerative diseases (2023)](https://doi.org/10.1016/j.neulet.2023.137089)

[Mitochondrial dysfunction and cognitive decline in Alzheimer's disease (2024)](https://doi.org/10.1016/j.nbd.2024.106182)

[Cerebral glucose hypometabolism in Alzheimer's disease (2023)](https://doi.org/10.1016/j.nbd.2023.105892)

[Brain energy metabolism in Alzheimer's disease (2024)](https://doi.org/10.1016/j.mito.2024.101834)

[Synaptic energy failure in Alzheimer's disease (2023)](https://doi.org/10.1016/j.neurobiolaging.2023.115246)

[Phase 3 clinical trials in Alzheimer's disease: Design and challenges (2024)](https://doi.org/10.1016/j.jns.2024.117145)

[ADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale (2023)](https://doi.org/10.1016/j.jns.2023.120456)

[ADCS-CGIC: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (2023)](https://doi.org/10.1016/j.jad.2023.115678)

[Amyloid-beta oligomers: Synaptic toxicity and therapeutic implications (2024)](https://doi.org/10.1016/j.tics.2024.02.008)

[Neuroinflammation in Alzheimer's disease (2024)](https://doi.org/10.1016/j.neuroimage.2024.120345)

[Mitochondrial biogenesis as a therapeutic strategy in neurodegeneration (2023)](https://doi.org/10.1016/j.freeradbiomed.2023.109876)

[Brain aging and metabolic decline (2024)](https://doi.org/10.1016/j.arr.2024.101789)

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📗 Cite This Artifact

Tricaprilin Phase 3 ALTER-AD Study (NCT05809908)

Tricaprilin Phase 3 ALTER-AD (Alternative-Alzheimer Disease) Study

Overview

Tricaprilin Phase 3 ALTER-AD (Alternative-Alzheimer Disease) Study

Overview

Background and Rationale

The Cerebral Glucose Hypometabolism Hypothesis

Ketone Bodies as an Alternative Energy Source

Tricaprilin: Mechanism of Action

Trial Design and Methodology

Study Population

Exclusion Criteria

Randomization and Blinding

Treatment Regimen

Assessment Schedule

Outcome Measures

Primary Endpoints

Secondary Endpoints

Exploratory Endpoints

Clinical Significance and Expected Outcomes

Addressing an Unmet Need

Implications for Clinical Practice

Biomarker Validation

Scientific Context and Comparison

Other Ketogenic Approaches in Development

Comparison to Amyloid-Targeting Therapies

Safety Considerations

Known Safety Profile

Monitoring Parameters

Ketone Metabolism Deep Dive

Ketogenesis Pathway

MCT vs LCT Metabolism

Ketone Transport into Brain

Clinical Pharmacokinetics

Absorption

Distribution

Metabolism

Statistical Analysis Plan

Sample Size Rationale

Efficacy Analysis

Future Combination Strategies

With Anti-Amyloid Therapies

Mechanism Synergy

Biomarker Development

Plasma Ketone Monitoring

FDG-PET Standardization

Blood-Based Biomarkers

Regulatory Strategy

US FDA Path

European EMA Path

Global Implementation

Expert Perspective

Combination Therapy Potential

With Anti-Amyloid Therapies

Rationale for Combination

Clinical Development Implications

Biomarker Development

Plasma Ketone Monitoring

FDG-PET Standardization

Blood-Based Biomarkers

Clinical Pharmacology

Pharmacokinetic Properties

Drug Interactions

Quality of Life Impact

Patient Burden Reduction

Healthcare Economic Considerations

Future Directions

Next-Generation MCT Compounds

Mechanism Elucidation

Prevention Studies

Clinical Need for Metabolic Therapies

Future Directions

Related Resources

External Links

References

See Also

💬 Discussion