Clinical Trial to Explore the the Amyloid Beta Draining Effect of Thiethylperazine (TEP) in Subjects With Newly Diagnosed Early-to-mild Dementia Due to Alzheimer's Disease (AD) in Comparison to Healthy Volunteers

NCT03417986 | Completed Phase 2

• 1 other identifier: IMU-AD-001
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

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.

Conditions

Alzheimer Disease

Keywords

Thiethylperazine; Alzheimer Disease

Outcome Measures

Primary Outcomes (1)

• Efflux of Amyloid beta peptides (Group mean changes from baseline)

  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.

  Gr. 1a: up to 10 days; Gr.1b / 2: up tp 84 days

Secondary Outcomes (3)

• 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).

• Incidence of Treatment-Emergent Adverse Events [Safety and tolerability]

  Gr. 1a: up to 10 days; Gr.1b / 2: up tp 84 days

• Cerebrospinal fluid (CSF) levels of Tau

  Gr. 1a: up to 10 days; Gr.1b / 2: up tp 84 days

Study Arms (3)

Group 1a: TEP 26 mg daily for 4d

EXPERIMENTAL

Drug: TEP

Group 1b: TEP 52 mg daily for 4d

EXPERIMENTAL

Drug: TEP

Group 2: TEP 26 mg daily for 54d

EXPERIMENTAL

Drug: TEP

Interventions

TEP DRUG

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.

Also known as: Thiethylperazine

Group 1a: TEP 26 mg daily for 4d; Group 1b: TEP 52 mg daily for 4d; Group 2: TEP 26 mg daily for 54d

Eligibility Criteria

• Age: 55 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For AD subject
• 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
• 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)
• AD subject has full legal competence according to investigator opinion
• Ability to comply with requirements or cognitive and other testing for the entire length of the trial available
• For healthy volunteer
• 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
• Age \> 55 - \< 75 years
• Written informed consent to participate within this trial
• 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)
• 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.

You may not qualify if:

• CSF cut-off values identified during routine Neurochemical Dementia Diagnostics
• History or evidence of other significant neurological disease of the Central Nervous System (such as Parkinson's disease, multi-infarct dementia, fronto-temporal dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supra nuclear palsy, epilepsy, myasthenia gravis, subdural hematoma or multiple sclerosis)
• History of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities
• Significant neuroimaging abnormalities, previously known or discovered on the MRI scan, including evidence of infection, infarction (\> 3 mm in size), brain tumors (other than small meningiomas), or other focal lesions, multiple lacunas or lacunas in a critical memory structure or severe confluent microvascular disease (but not mild white matter changes, which are frequent with aging)
• History or evidence of moderate congestive heart failure defined by the New York Heart Association criteria (class I-IV)
• Clinical relevant ECG findings, abnormalities, e.g. pro-arrhythmic potential/effects on QT interval (QTc \>450 msec for males, \>470 msec for females, confirmed by manual assessment of ECG parameters)
• History of new cardiovascular event within the last 6 months
• Resting sitting vital signs: Systolic blood pressure ≤ 100 mmHg or ≥ 165 mmHg, Diastolic blood pressure ≤ 60 mmHg or ≥ 100 mmHg, heart rate ≤ 50 beats/min or ≥ 90 beats/min9. Clinically significant renal disease or insufficiency, including but not limited to creatinine value of \>1.5 mg/dl
• Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), total bilirubin, or alkaline phosphatase \>2.5 times the upper limit of normal laboratory range, or history of severe hepatobiliary disease (e.g. hepatitis B or C, or cirrhosis) without enzyme elevation
• Positive tested for hepatitis B surface antigen (HBsAG) or hepatitis C virus/antibodies (anti-HCV) for the first time within the last 6 months prior to the Screening Visit
• Positive tested for human immunodeficiency virus (HIV) at Screening Visit
• Fasting triglycerides \>2.5 times of the upper limit of normal
• Uncontrolled diabetes (FBG \> 150 mg/dl)
• Coagulopathy or any kind of anti-coagulant therapy
• Extrapyramidal syndrome

Sponsors & Collaborators

• Immungenetics AG: lead

Study Sites (2)

Klinik für Psychiatrie und Psychotherapie Universitätsmedizin Göttingen

Göttingen, 37075, Germany

Location

Zentralinstitut für seelische Gesundheit, Medizinische Fakultät Mannheim, Universität Heidelberg,

Mannheim, 68159, Germany

Location

MeSH Terms

Conditions

Alzheimer Disease

Interventions

tetraethylpyrazine; Thiethylperazine

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Phenothiazines; Sulfur Compounds; Organic Chemicals; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Lutz Frölich, Prof. Dr.

  Zentralinstitut für seelische Gesundheit, Medizinische Fakultät Mannheim, Universität Heidelberg,

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 29, 2017
• First Posted: January 31, 2018
• Study Start: November 24, 2017
• Primary Completion: July 12, 2021
• Study Completion: October 22, 2021
• Last Updated: February 22, 2023

Record last verified: 2023-02

Locations

DE (2)