A Phase 2 Trial Evaluating the Effects of Thiethylperazine as diagnostic tool and therapeutic agent in Patients Diagnosed with an Early Stage of Alzheimer's disease

Prior treatment

• Coagulopathy or any kind of anti-coagulant therapy (except Acetylsalicylic acid), that cannot be switched to monotherapy with Acetylsalicylic acid for one week before each CSF sampling.
• Male and female subjects with reproductive potential who refuse to use adequate means of contraception from screening and up to 3 months after stopping treatment with TEP
• 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
• Current treatment with TEP or treatment up to 24 months prior to screening
• Subject is receiving a treatment that may interact with TEP, e.g. adrenaline, tricyclic antidepressants, narcotics, bromocriptine, MAO inhibitors, CYP2D6 inhibitors, tramadol, pentetrazol, levodopa, anticonvulsants. Medication causing extrapyramidal symptoms increases the likelihood of central nervous system side effects.
• Participation in an interventional trial involving another investigational drug within 4 weeks prior to screening visit

Other illness

• For AD subjects and disease controls:
• Positive tested for human immunodeficiency virus (HIV) at Screening Visit
• Extrapyramidal syndrome
• History of significant head trauma/brain injury with persistent neurologic defect(s) OR pre-existent known structural brain defect
• Elevation of prolactin, e.g. subject with prolactin-dependent breast cancer or pituitary tumour
• History of severe psychiatric disease like psychotic disorder or anxiolytic or neuroleptic therapy (for dementia-related or other psychiatric disorder) within the last 3 months of enrolment
• Chronic depression or bipolar disorder or history of major depression within the past 2 years or history of any episode of treatment-resistant depression (requiring > 1 antidepressant, ECT etc.)
• Significant history of alcohol abuse or drug abuse within the past 6 months (according to the investigator’s assessment)
• Sensory impairment that prevents or significantly interferes with neuropsychological testing
• History or evidence of other significant neurological diseases of the Central Nervous System (such as Parkinson's disease, multi-infarct dementia, frontotemporal dementia, Huntington's disease, normal pressure hydrocephalus, brain tumour, progressive supranuclear palsy, epilepsy, myasthenia gravis, subdural hematoma or multiple sclerosis)
• Significant brain injury or abnormalities as demonstrated with neuro-imaging: pre-existent and/or diagnosed as per MRI (magnetic resonance imaging) scan(s), including evidence of cerebral infection, infarction (> 3 mm in size), brain tumours/ metastases/ leptomeningeal cancers (other than small meningiomas), or other focal lesions; the latter include multiple lacunas or lacunas in critical memory structure of the brain or severe confluent microvascular disease (but NOT mild white matter changes, which are frequent with ageing)
• History or evidence of moderate congestive heart failure defined by the New York Heart Association criteria (class I-IV)
• History of a 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/min

Lab values

• Uncontrolled diabetes (fasting blood glucose [FBG] > 150 mg/dl)
• Clinical relevant electrocardiogram (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)
• Clinically significant renal disease or insufficiency, including but not limited to creatinine value of >1.5 mg/dl
• ALT, 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

Other

• Fasting triglycerides >2.5 times the upper limit of normal
• Acute /current depression assessed by anamneses and a Geriatric Depression score > 5
• Abnormal involuntary movement scale (AIMS) ≥ 2
• Known incompatibility of TEP or phenothiazines
• Women of childbearing potential not using adequate measures of contraception and women who are pregnant or nursing

• For AD subjects only:
• Males and Females, aged ≥ 55 and ≤ 80 years
• Willing and able to sign and date an Independent Ethics Committee-approved written informed consent form in accordance with regulatory and institutional guidelines. This must be performed before the performance of any protocol-related procedures that are not part of the normal subject care
• Willing and able to comply with scheduled study visits, treatment schedule, laboratory and cognitive testing, and other requirements of the study
• Screening laboratory values must meet the following criteria and should be obtained within 6 weeks prior to entry into the trial: - Normal Full Blood Count (FBC, haematology) - Normal kidney function: serum creatinine < 1.5 X ULN - Normal hepatic function: Total bilirubin < 1.5 X ULN, Transaminases (ALT and AST) < 3 X ULN, Alk Phospatase < 2.5 X ULN - Normal prolactin - Fasting triglycerides < 2.5 X ULN
• Subjects who are on the following concomitant medications are allowed into this trial ON THE CONDITION THAT they have been on a stable dose of these drugs for at least 3 months prior to study screening (and will continue to be on this stable dose): - acetylcholinesterase inhibitors - N-Methyl D Aspartate (NMDA) receptor antagonists
• Subjects in this trial who are on the following medications/agents are obligated to comply with a wash-out period of 4 weeks prior to commencing screening for this trial: anticholinergic agents, Hypericum perforatum (St. John’s Wort) containing/derived drugs, oral corticosteroids, propranolol, metoprolol, clonidine, antihistamines other than cetirizine and EBSTEL® prior to screening must be completed
• Good general health with no additional disease states that interferes with the trial according to the investigator’s assessment
• Availability of an informant who is willing to provide information on the participant throughout the study period
• Proficient/fluent in the German language
• Florbetaben-PET no older than 12 months (at date of visit 2) with an SUVR above 1.44 (cut-off).
• Newly diagnosed (< 12 months) mild cognitive impairment (MCI) due to Alzheimer’s disease or as classified by a Mini-Mental State Examination (MMSE) Score of ≤ 30 ≥ 20 reconfirmed at screening
• Diagnosis of AD on the basis of the recommended examinations per the International Working Group (IWG) and the standard parameters/methodology of the respective clinical unit: o A Clinical Dementia Rating (global CDR) of 0.5 or 1. Memory box score must be at least 0.5. o Isolated or predominant episodic memory deficit, manifesting itself as either or both: ▪ Wechsler Memory Scale IV ≤ -1.5 SD below age-adjusted norm (Logical Memory subscale = Delayed Recall, Story A), ▪ ≤ -1.5 SD on the delayed recall trial of the CERAD word list (age-, sex- and education-adjusted performance)
• Trial subject has full legal competence according to the investigator’s opinion
• For trial subjects in disease control/reference (non-AD group) only:
• Mini-Mental State Examination (MMSE) Score of ≤ 30 and ≥ 28 at screening. In case of MMSE score of ≤ 27, do NOT present with CSF biomarker profile and/or PET SUVR indicative of Alzheimer’s disease. If both are available but inconclusive, subjects are only eligible if PET SUVR is NOT indicative of AD
• For AD subjects and disease controls:
• Trial participants agree to APOE genotyping, or have a known APOE genotype (determined within the past 24 months).