Alzheimer Disease
Conditions
Keywords
Thiethylperazine, Alzheimer Disease
Brief summary
This proof-of-mechanism clinical trial study will test the efficacy and safety of thiethylperazine (TEP) in subjects with early onset of Alzheimer's Disease (AD). There is a strong scientific rationale for this study: TEP is a very well-known substance that has been available since 1961 and approved for the prevention and treatment of nausea, vomiting as well as vertigo. Therefore, it has a well understood pharmacologic background and promising safety data. Using AD mouse models, it has been recently discovered and confirmed that TEP promotes transport of toxic Aβ from the brain into the blood. More importantly, it has also been demonstrated to improve learning deficits in mice. The striking biological effect of TEP in preclinical testing and its known safety and toxicity profile encourages the investigators to investigate this in a multicenter clinical trial in subjects with early-to-mild AD in comparison to healthy volunteers. The investigators will assess whether TEP is able to enhance the transport of Aβ peptides from the brain into the blood in subjects with early-to-mild AD and improves cognitive efficacy.
Interventions
DRUGTEP
For safety reasons the clinical trial will first enroll 14 subjects (7 patients and 7 healthy volunteers) for Group 1a receiving 26 mg TEP daily for 4 days with subsequent safety evaluation, based on adverse events and the safety parameters discussed in the protocol. A second set of patients (Group 1b), which will receive a higher dosage of 52 mg per day for 4 days will be enrolled optionally after recommendation to continue and subsequently treatment Group 2 with a treatment paradigm of 26 mg TEP daily for 54 days will start. Subjects eligible for participation are subjects with newly diagnosed (within last 12 month) early-to-mild dementia due to AD and healthy volunteers who fulfill all inclusion criteria and have none of the exclusion criteria present at screening.
Sponsors
Immungenetics AG
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
55 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
For AD subject 1. Newly diagnosed (\< 12 months) early-to-mild Alzheimer's disease as classified by a Mini-Mental State Examination (MMSE) Score of 25-18 reconfirmed at screening 2. AD diagnosis confirmed by recommended examinations in accordance with German DGN (Deutsche Gesellschaft für Neurologie)/DGPPN (Deutsche Gesellschaft für Psychiatrie und Psychotherapie,Psychosomatik und Nervenheilkunde) S3 Guideline Dementia and to standard at the clinical unit by: * psychometric and cognitive tests * lumbar puncture in subjects with uncertain AD diagnosis following central nervous system (CNS) imaging * Clinical Dementia Rating (global CDR) is 0.5 or 1. Memory box score must be at least 0.5. Isolated or predominant episodic memory deficit, manifested as memory performance in the Logical Memory subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale-III 1 below age adjusted norms, according to hospital standard) 3. AD subject has full legal competence according to investigator opinion 4. Ability to comply with requirements or cognitive and other testing for the entire length of the trial available For healthy volunteer 5. Subject is a non-demented volunteer, based on the assessment of medical history, physical examination and clinically laboratory data at screening as determined by the Investigator For AD subject and healthy volunteer 6. Age \> 55 - \< 75 years 7. Written informed consent to participate within this trial 8. Subject is on stable dose for at least 3 month prior to screening when receiving protocol-allowed concomitant medications at screening (e.g. acetylcholinesterase inhibitors, NMDA (N-methyl-D-aspartate) receptor antagonists) 9. For subject receiving anticholinergic agents, oral corticosteroids, propranolol, clonidine, antihistamines other than cetirizin and EBSTEL® a washout period of 4 weeks prior to screening must be completed. Concerning anticholinergic agents in Group 1a: only for high- to medium-potency anticholinergic agents a washout period of 4 weeks prior to screening must be completed. 10. Post-menopausal females (post menopausal amenorrhea for at least 2 years or surgically sterilized (hysterectomy), tubal ligation is not acceptable) 11. Male subjects with reproductive potential, and have not been surgically sterilized, that have been informed and agreed to that he and his partner must use a highly effective method of contraception (Pearl Index \<1%) such as implants, injectables, combined oral contraceptives, or hormonal intrauterine devices (IUDs), or refrain from sexual intercourse during the trial and until 3 months after completion of the trial 12. Good general health with no additional disease states that could interfere with the trial due to the investigator's assessment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efflux of Amyloid beta peptides (Group mean changes from baseline) | Gr. 1a: up to 10 days; Gr.1b / 2: up tp 84 days | To demonstrate a significantly increased efflux of Amyloid beta peptides from the brain into the bloodstream in subjects with newly diagnosed (within last 12 month) early-to-mild dementia due to Alzheimer's Disease vs. healthy volunteers that is expected to be caused by the ABCC1 transporter-stimulating effect of thiethylperazine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Scores obtained in psychometric tests [Cognition] | Group 1a and 1b and Group 2 on day 1, day 10 (Groups 1a/b) day 14 (Group 2) and day 84 (End of Trial-Group 1b/2). | Changes in scores obtained in psychometric tests in newly diagnosed (within last 12 month) subjects with early-to-mild dementia due to AD vs. healthy volunteers as well as the analysis of their changes from baseline will be determined after treatment with thiethylperazine. |
| Incidence of Treatment-Emergent Adverse Events [Safety and tolerability] | Gr. 1a: up to 10 days; Gr.1b / 2: up tp 84 days | To assess the safety and tolerability of thiethylperazine in newly diagnosed (within last 12 month) subjects with early-to-mild dementia due to AD and to compare this profile with the outcome of a control group of healthy volunteers Assessments: Treatment-emergent Adverse Events (AEs) Treatment-emergent Serious Adverse Events (SAEs) Adverse Events leading to premature discontinuation of trial medication |
| Cerebrospinal fluid (CSF) levels of Tau | Gr. 1a: up to 10 days; Gr.1b / 2: up tp 84 days | To investigate the effect of thiethylperazine on CSF levels of phosphoTau181 and total Tau in subjects with newly diagnosed (within last 12 month) early-to-mild dementia due to AD |
Countries
Germany
Outcome results
None listed