Clinical trial NCT00142805: Tricaprilin in Mild to Moderate Alzheimer's Disease
Official title: Safety, Tolerability and Efficacy Study of Tricaprilin (AC-1202) Administered for Ninety Days in Subjects With Probable Alzheimer's Disease of Mild to Moderate Severity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Keywords: ketones
Apolipoprotein E
ApoE genotype
cognitive function
glucose metabolism
Lead sponsor: Cerecin
Sponsor class: INDUSTRY
First posted: 2005-09-02
Enrollment: 152
Sex: ALL
Minimum age (years): 50
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, tolerability and effectiveness of tricaprilin administered once a day for ninety days in subjects with mild to moderate, probable Alzheimer's disease.

Detailed description: Substantial scientific evidence has shown that defects in glucose metabolism occur in Alzheimer's disease. Attempts to compensate for the reduced cerebral metabolic rates in AD have met with some success. Treatment of AD patients with high doses of glucose and insulin will raise cognitive scores. However, this effect is slight, and high doses of insulin can have adverse consequences. Administration of ketone bodies or their metabolic precursors such as medium chain triglycerides (MCTs) presents an attractive alternative to glucose and insulin. In a preliminary study, tricaprilin, an MCT, demonstrated pharmacological activity and statistically significant efficacy in improving short-term memory and attention performance after a single dose.

Participants will be randomized to receive either tricaprilin or a matching placebo, administered once a day by mixing powder in a glass of liquid. The treatment period will last 90 days, followed by a 2-week washout period. Each patient will be seen 5 times: at screening, baseline, and post-baseline days 45, 90, and 104. The visits will include physical and/or neuropsychological examinations, electrocardiograms (ECGs) and laboratory tests.

Eligibility criteria: Inclusion Criteria:

* Informed Consent Form signed by patient and caregiver
* Diagnosis of probably Alzheimer's disease of mild to moderate severity
* Age 50 or older
* If female, 2 years postmenopausal or surgically sterile
* Hearing, vision, and physical abilities adequate to perform assessments (corrective aids allowed)
* Caregiver to attend all visits, perform assessments, and supervise administration of study medication
* CT or MRI within 24 months prior to screening compatible with a diagnosis of probably Alzheimer's disease
* Modified Hachinski Ischemia Scale score of 4 or less
* ADAS-Cog score between 15 and 35 inclusive at screening
* MMSE score between 14 and 24 inclusive at screening
* Stable medical condition for 3 consecutive months immediately prior to baseline
* No clinically significant abnormal findings on the physical examination, medical history, or clinical laboratory results during screening

Exclusion Criteria:

* Any condition that would, in the opinion of the Principal Investigator, render the patient or the caregiver unsuitable for the study, or place them at substantial risk of adverse outcome
* Unwillingness or inability of the patient and/or caregiver to fulfill the requirements of the study
* Resident in a skilled nursing facility
* Any significant neurological disease other than probable AD (e.g. Parkinson's disease, Huntington's disease, brain tumor, normal pressure hydrocephalus, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, history of stroke, or history of head injury requiring hospitalization)
* An alternate cause for dementia other than AD as determined by a required CT or MRI scan within 24 months prior to screening
* Current history of major psychiatric disorder
* Major depression as determined by a Cornell Scale for Depression in Dementia
* Clinically significant hypothyroidism
* Clinically significant B12 deficiency
* Unstable or clinically significant cardiovascular disease
* Diabetes of any type
* History of tertiary syphilis
* Cancer within 3 years prior to baseline, with the exception of squamous and basal cell carcinoma
* Vital sign abnormalities
* Clinically significant renal disease or insufficiency
* Clinically significant hepatic disease or insufficiency
* Alcohol consumption greater than 2 oz of spirits per day or 14 oz per week (1 oz of spirits is equal to 6 oz of wine or 12 oz of beer)
* Current history of alcohol abuse or other substance abuse within 24 months prior to baseline
* Known HIV infection
* Use of any investigational compound within 30 days prior to screening
* Use of prohibited medications (contact site for details)
* Prior or current use of medium-chain triglycerides (MCTs) for medical purposes
* Known allergies to coconut oil

Primary outcomes:
measure: Number of subjects with treatment related adverse events
timeFrame: 104 days
Secondary outcomes:
measure: Pharmacokinetics (PK) profile of tricaprilin
timeFrame: Baseline, Day 45, Day 90
measure: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)
timeFrame: 90 days
measure: Clinical Global Impression of Change
timeFrame: 90 days
measure: Mini-Mental State Exam (MMSE)
timeFrame: 90 days
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: 21st Century Neurology, a division of Xenoscience Inc.
state: Arizona
city: Cerritos
country: United States
facility: Comprehensive NeuroScience
state: California
city: Los Alamitos
country: United States
facility: Pharmacology Research Institute
state: California
city: Newport Beach
country: United States
facility: Pharmacology Research Institute
state: California
city: Northridge
country: United States
facility: Pharmacology Research Institute
state: California
city: Rancho Mirage
country: United States
facility: The Southwest Institute for Clinical Research
state: California
city: Riverside
country: United States
facility: Pharmacology Research Institute
state: California
city: Boca Raton
country: United States
facility: Baumel-Eisner Neuromedical Institute
state: Florida
city: Brooksville
country: United States
facility: Meridien Research
state: Florida
city: Fort Lauderdale
country: United States
facility: Baumel-Eisner Neuromedical Institute, Inc.
state: Florida
city: Hollywood
country: United States
facility: Sunrise Clinical Research
state: Florida
city: Melbourne
country: United States
facility: Comprehensive NeuroScience
state: Florida
city: Miami Beach
country: United States
facility: Baumel-Eisner Neuromedical Institute
state: Florida
city: Naples
country: United States
facility: Anchor Research Center
state: Florida
city: Ocala
country: United States
facility: Renstar Medical Research
state: Florida
city: Saint Petersburg
country: United States
facility: Comprehensive NeuroScience
state: Florida
city: Saint Petersburg
country: United States
facility: Meridien Research
state: Florida
city: Tampa
country: United States
facility: Meridien Research
state: Florida
city: Chicago
country: United States
facility: Radiant Research
state: Illinois
city: Raleigh
country: United States
facility: Multi-Specialty Research Associates of North Carolina
state: North Carolina
city: Portland
country: United States
facility: Radiant Research
state: Oregon
city: Dallas
country: United States
facility: Radiant Research
state: Texas
city: Dallas
country: United States
facility: Research Across America
state: Texas
city: San Antonio
country: United States
facility: Radiant Research
state: Texas
city: Wichita Falls
country: United States
facility: Grayline Clinical Drug Trials
state: Texas
Study officials:
References:
citation: Blass JP, Zemcov A. Alzheimer's disease. A metabolic systems degeneration? Neurochem Pathol. 1984 Summer;2(2):103-14. doi: 10.1007/BF02834249.
citation: Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, Thibodeau SN, Osborne D. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med. 1996 Mar 21;334(12):752-8. doi: 10.1056/NEJM199603213341202.
citation: Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY, Lavretsky H, Miller K, Siddarth P, Rasgon NL, Mazziotta JC, Saxena S, Wu HM, Mega MS, Cummings JL, Saunders AM, Pericak-Vance MA, Roses AD, Barrio JR, Phelps ME. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6037-42. doi: 10.1073/pnas.090106797.
citation: Swaab DF, Lucassen PJ, Salehi A, Scherder EJ, van Someren EJ, Verwer RW. Reduced neuronal activity and reactivation in Alzheimer's disease. Prog Brain Res. 1998;117:343-77. doi: 10.1016/s0079-6123(08)64027-3.
citation: Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999 Nov-Dec;15(6):412-26. doi: 10.1002/(sici)1520-7560(199911/12)15:63.0.co;2-8.
citation: Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-beta-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5440-4. doi: 10.1073/pnas.97.10.5440.
citation: Henderson ST, Poirier J. Pharmacogenetic analysis of the effects of polymorphisms in APOE, IDE and IL1B on a ketone body based therapeutic on cognition in mild to moderate Alzheimer's disease; a randomized, double-blind, placebo-controlled study. BMC Med Genet. 2011 Oct 12;12:137. doi: 10.1186/1471-2350-12-137.
citation: Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond). 2009 Aug 10;6:31. doi: 10.1186/1743-7075-6-31.