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Trial record 1 of 1 for:    T3D-959
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Feasibility Study in Subjects With Mild to Moderate Alzheimer's Disease

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ClinicalTrials.gov Identifier: NCT02560753
Recruitment Status : Unknown
Verified June 2016 by T3D Therapeutics, Inc..
Recruitment status was:  Active, not recruiting
First Posted : September 25, 2015
Last Update Posted : June 8, 2016
Sponsor:
Information provided by (Responsible Party):
T3D Therapeutics, Inc.

Brief Summary:

The study is a randomized, parallel, 4-dose design in subjects with mild-to-moderate Alzheimer's Disease. Subjects will be randomized to one of 4 doses of T3D-959. Subjects will be evaluated for changes from baseline in cerebral metabolic rate of glucose (FDG-PET imaging), functional connectivity of the hippocampus (BOLD-fMRI), and cognitive function (ADAS-Cog11 and DSST) as well as assessed for safety and tolerability to T3D-959.

An expanded access extension is planed to provide access to study medication to subjects who have completed the main study and requested continued use.


Condition or disease Intervention/treatment Phase
Alzheimer's Disease Drug: T3D-959 Phase 1 Phase 2

Detailed Description:

T3D-959 is an orally-delivered, once-a-day administered, small molecule dual nuclear receptor agonist that has been shown in animal and Phase 1 studies in normal human subjects to be safe and well tolerated. The purpose of this clinical study in AD patients is to demonstrate mechanistic proof of concept that T3D-959, can produce desired changes in cerebral glucose metabolism and functional connectivity that may indicate potential for cognitive improvement. The therapeutic approach to be tested is based on two suppositions; (A) ameliorating multiple pathologies in the disease with a single therapy may provide a superior clinical benefit than therapeutic approaches which target a single pathology and (B) correcting insulin resistance in the brain, (highly correlated with AD and potential key driver of AD pathophysiology) and peripherally may be disease remedial.

The brain requires integral insulin signaling for metabolic homeostasis and neuronal plasticity. Insulin resistance disrupts energy balance and signaling networks needed for a broad range of functions. Impaired insulin signaling in neurons enhances apoptosis, promotes oxidative cell death induced by Abeta1-42, increases secretion of Abeta1-42, blocks removal of extracellular Abeta oligomers and increases plaque loads. A growing body of evidence suggests that brain insulin resistance promotes or possibly is the trigger of key pathologies in AD and is supported by observed changes in levels of insulin signaling molecules in AD forebrains and associated changes in memory. Pre-clinical studies in animals have demonstrated the insulin sensitizing activity of T3D-959 and ability to improve multiple pathologies of AD in a rat model of disease.

This non-placebo controlled trial will be conducted in one to three clinical centers. Thirty six (36) patients with mild-to-moderate Alzheimer's disease will be randomly assigned to once daily, orally administered treatment with 3mg, 10mg, 30mg or 90mg doses of T3D-959. Participants will be treated for two weeks and will undergo at baseline and at two weeks; FDG-PET scans to measure brain glucose metabolism, BOLD fMRI scans to measure functional connectivity of the hippocampus, venous blood draws for biomarker analysis and ApoE genotyping, and ADAS-Cog11 and DSST cognitive testing. For monitoring potential toxicities of the drug subjects will undergo physical examination, neurological examination, adverse event review, blood chemistries, and pharmacokinetic (PK) analyses for T3D-959 plasma levels.

Expanded Access Extension: This is an open label 10 visit extension for up to 5 subjects who have completed the T3D959-201 protocol and whose caregivers and physician requested their continued treatment in an expanded access protocol. All subjects enrolled in this study will be treated with a 15mg q.d. dose of T3D959 for six months, regardless of their assigned dose level from the main study. A continued risk/benefit assessment by the investigator will be conducted at each visit to determine the need for treatment continuation. Subjects will be assessed for safety and tolerability to T3D-959 and evaluated for changes from baseline cognitive function via ADAS-Cog11 and DSST testing and global change via CIBIC-plus testing.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2a Feasibility Study of T3D-959 in Subjects With Mild to Moderate Alzheimer's Disease
Study Start Date : July 2015
Actual Primary Completion Date : May 2016
Estimated Study Completion Date : January 2017


Arm Intervention/treatment
Experimental: T3D-959 3mg
Nine subjects will take 3mg by mouth once daily for two weeks, with or without food.
Drug: T3D-959
The 3mg dosage is supplied as 1mg capsules (three capsules, taken once daily by mouth) The 10mg dosage is supplied as 5mg capsules (two capsules, taken once daily by mouth) The 30mg dosage is supplied as either 5mg or 15mg capsules (six 5mg capsules or two 15mg capsules taken once daily by mouth) The 90mg dosage is supplied as 15mg capsules (six capsules, taken once daily by mouth)

Experimental: T3D-959 10mg
Nine subjects will take 10mg by mouth once daily for two weeks, with or without food.
Drug: T3D-959
The 3mg dosage is supplied as 1mg capsules (three capsules, taken once daily by mouth) The 10mg dosage is supplied as 5mg capsules (two capsules, taken once daily by mouth) The 30mg dosage is supplied as either 5mg or 15mg capsules (six 5mg capsules or two 15mg capsules taken once daily by mouth) The 90mg dosage is supplied as 15mg capsules (six capsules, taken once daily by mouth)

Experimental: T3D-959 30mg
Nine subjects will take 30mg by mouth once daily for two weeks, with or without food.
Drug: T3D-959
The 3mg dosage is supplied as 1mg capsules (three capsules, taken once daily by mouth) The 10mg dosage is supplied as 5mg capsules (two capsules, taken once daily by mouth) The 30mg dosage is supplied as either 5mg or 15mg capsules (six 5mg capsules or two 15mg capsules taken once daily by mouth) The 90mg dosage is supplied as 15mg capsules (six capsules, taken once daily by mouth)

Experimental: T3D-959 90mg
Nine subjects will take 90mg by mouth once daily for two weeks, with or without food.
Drug: T3D-959
The 3mg dosage is supplied as 1mg capsules (three capsules, taken once daily by mouth) The 10mg dosage is supplied as 5mg capsules (two capsules, taken once daily by mouth) The 30mg dosage is supplied as either 5mg or 15mg capsules (six 5mg capsules or two 15mg capsules taken once daily by mouth) The 90mg dosage is supplied as 15mg capsules (six capsules, taken once daily by mouth)




Primary Outcome Measures :
  1. The effect of treatment with T3D-959 on changes in 18F-FDG-PET measurements of the cerebral metabolic rate for glucose (CMRgl) in an empirically pre-specified statistical region of interest (sROI) that is preferentially affected by AD. [ Time Frame: after 14 days of treatment ]
    Two-week potential changes in regional cerebral metabolic rate of glucose in an empirically pre-specified statistical region of interest (sROI) that is preferentially affected by AD, normalized for the absolute variation in an empirically pre-specified statistic ROI that is relatively spared. For additional exploratory purposes, we will also assess longitudinal changes in a priori regions of interest (ROI) including bilateral regions: posterior cingulate, parietal cortex (angular gyrus), lateral temporal cortex, medial temporal cortex, and anterior cingulate-medial frontal cortex, and using statistical brain maps of regional CMRgl change, with and without correction for multiple comparisons in AD-affected search regions. The imaging protocol developed for the AD Neuroimaging Initiative (ADNI2) will be used.

  2. The effect of treatment with T3D-959 on changes in resting state Blood Oxygen Level Dependent (BOLD) signal in functional Magnetic Resonance Imaging (fMRI) of the brain areas associated with cognitive tasks. [ Time Frame: after 14 days of treatment ]
    The baseline default mode network (DMN) connectivity pre-drug scan will be compared to that for the scan obtained after 2 weeks of drug therapy. The connectivity between a priori regions of interest (ROI) the precuneus/posterior cingulate and left hippocampus will be our primary interest. The resting state functional connectivity protocol developed for ADNI2 will be used.


Secondary Outcome Measures :
  1. Change from Baseline in the score of the Digit Symbol Substitution Test [ Time Frame: after 14 days of treatment ]
    The digit symbol substitution test assesses attention, psychomotor speed, complex scanning, visual tracking, and immediate memory. This test consists of 4 rows each with 25 small blank squares; above each square is a number between 1 and 9. At the top is a 'key,' which pairs each number (1 through 9) with an unfamiliar symbol. The participant has 90 seconds to work as quickly as possible (left to right across the rows) to fill in each blank square with the appropriate symbol based on the number above the square. Results are presented as total number correct; therefore, lower numbers indicate greater impairment. Scores on the DSST range from 0-93.

  2. Comparison of the response to treatment of T3D-959 based on ApoE genotype [ Time Frame: after 14 days of treatment ]
    The results from the primary outcome with FDG-PET and BOLD fMRI will be segregated in this secondary analysis by ApoE genotype.

  3. Change from Baseline in the plasma metabolome profile after 2 week treatment with T3D-959 using mass spectrometry. [ Time Frame: after 14 days of treatment ]
    Analyze the plasma metabolome to assess the hypothesis that AD is associated with a unique metabolome and that subsets of this metabolome change in response to treatment with T3D-959.

  4. Change from Baseline in the total score of the 11-item Alzheimer's Disease Assessment Scale - Cognitive Subscale [ Time Frame: after 14 days of treatment ]
    The ADAScog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment and the maximum severity score is 70. A positive change indicates cognitive worsening.


Other Outcome Measures:
  1. Safety and tolerability of treatment with T3D-959 over a 2-week period in subjects with mild-to-moderate AD. [ Time Frame: during and after 14 days of treatment ]
    Number of participants with treatment related adverse events as assessed by analysis of adverse events, including symptoms, and abnormal findings on physical and neurological examinations, and standard labs.



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Ages Eligible for Study:   50 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Meets criteria for mild-to-moderate AD with Mini-Mental State Examination (MMSE) score of 14 through 26
  • Clinical Dementia Rating = 0.5 to 2.0
  • Modified Hachinski less than or equal to 4
  • A clinical diagnosis of AD per NINCDS-ADRDA criteria
  • Washout of psychoactive medication (other than anti-depressants): at least 4 weeks prior to baseline
  • Stability of all permitted medications for 4-12 weeks prior to baseline
  • Visual and auditory acuity adequate for neuropsychological testing
  • Home monitoring available for supervision of medications

Exclusion Criteria:

  • Unstable diabetes or insulin use
  • Unable to participate in FDG-PET scanning
  • Inability to undergo a clinical MRI of the brain
  • Diagnosis of significant neurological/psychiatric disease other than AD
  • History of moderate or severe congestive heart failure, NYHA class III or IV, within 12 months prior to baseline.
  • Previous cardiovascular event within the past 6 months prior to baseline
  • Subject is pregnant, or lactating.
  • ALT and/or AST levels that are twice the upper limit of normal; bilirubin levels that exceed 2 mg/dL; serum creatinine >1.5 mg/dL in men or > 1.4 mg/dL in women.
  • Current or history of severe or unstable disorder (medical or psychiatric) requiring treatment that may make the subject unlikely to complete the study.
  • Current use of fluvoxamine.
  • Current unstable use of warfarin.
  • Current use (within 30 days of baseline, visit 2) of certain highly protein-bound medications
  • Malignancy within the last 5 years (other than non-melanoma skin cancer, stable, non-progressive prostate cancer not requiring treatment or in situ cervical cancer).
  • Known history of HIV, hepatitis B, or hepatitis C.
  • Blood pressure greater than 160/100 mmHg.
  • Known or suspected intolerance or hypersensitivity to the study drugs, closely related compounds, or any of their stated ingredients.
  • History of alcohol, drug abuse or dependence (except nicotine dependence) within 2 years.
  • Investigational amyloid lowering therapies use within two months prior to baseline
  • Have participated in any other investigational study or received an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to baseline
  • Any surgical or medical condition which may significantly alter the absorption of any drug substance
  • Resides in hospital or moderate to high dependency continuous care facility.
  • Non ambulatory, or wheelchair-bound
  • History of swallowing difficulties.
  • Evidence of clinically relevant pathology that in the investigator's opinion could interfere with the study results or put the subject's safety at risk.

Expanded Access Extension :

Subjects must continue to meet the main study inclusion/exclusion criteria to insure continued safety to continue on a 6 months study extension


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02560753


Locations
United States, Florida
Brain Matters Research
Delray Beach, Florida, United States, 33445
Miami Jewish Health Systems
Miami, Florida, United States, 33137
United States, North Carolina
New Hope Clinical Research
Charlotte, North Carolina, United States, 28204
Sponsors and Collaborators
T3D Therapeutics, Inc.
Investigators
Study Chair: John Didsbury, Ph.D. T3DTherapeutics, Inc.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: T3D Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT02560753     History of Changes
Other Study ID Numbers: T3D959-201
First Posted: September 25, 2015    Key Record Dates
Last Update Posted: June 8, 2016
Last Verified: June 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders