A Phase 2 Theranostic Trial Evaluating the Effects of Thiethylperazine in Patients Diagnosed with an Early Stage of Alzheimer's disease
- Trial ID
- 2022-501137-23-00
- Protocol
- IG-TEP-001
- Sponsor
- Immungenetics AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 trial is to test the hypothesis that **thiethylperazine** (TEP) treatment over a duration of 12 months enhances amyloid-beta (Aβ) clearance from the brain compared to placebo in patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or early dementia due to AD. This is clinically relevant as improved Aβ clearance could potentially slow the progression of Alzheimer's disease, offering a therapeutic benefit to patients in the early stages of the condition.
Secondary objectives include:
- Evaluating the diagnostic accuracy of TEP to differentiate Alzheimer's disease patients from disease controls.
- Assessing the effect of TEP treatment versus placebo on blood biomarkers of neurodegeneration.
- Evaluating the effect of TEP treatment versus placebo on the clinical progression of Alzheimer's disease.
- Assessing the effect of TEP treatment versus placebo on cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease.
Participants
The clinical trial involves participants diagnosed with **early-to-mild dementia due to Alzheimer's Disease**. The study population includes both male and female subjects aged between 55 and 80 years. Participants are required to be in good general health, with no additional disease states that could interfere with the trial, as assessed by the investigator. The trial population was selected based on specific inclusion criteria, including the ability to provide informed consent and comply with study requirements. Participants must have a newly diagnosed mild cognitive impairment due to Alzheimer's disease, confirmed by a Mini-Mental State Examination (MMSE) score between 20 and 30. Additionally, subjects must have a Florbetaben-PET scan with an SUVR above 1.44, conducted within 12 months prior to the study. The trial also requires participants to be proficient in the German language and have an informant available to provide information throughout the study period. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the effects of **thiethylperazine** in patients diagnosed with early-stage Alzheimer's disease. This is a Phase 2, randomized, double-blind, placebo-controlled trial. The primary objective is to assess the improvement in Aβ clearance from the brain over a 12-month period. The trial will compare two arms: the treatment group receiving thiethylperazine and the placebo group. The trial is expected to commence recruitment in December 2025 and conclude by December 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, health status, and cognitive assessments. Following successful screening, participants will be randomized into one of the two study arms. Regular follow-up visits will be scheduled to monitor the participants' health, adherence to the treatment regimen, and to conduct necessary laboratory and cognitive tests. The end-of-study visit will occur at the 12-month mark, where final assessments will be conducted to evaluate the primary and secondary endpoints, including changes in Florbetaben-PET SUVR and various biomarkers.
The expected length of participant involvement is approximately 12 months. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. Participants are required to maintain stable doses of certain medications and adhere to a wash-out period for others prior to screening. The trial aims to provide valuable insights into the therapeutic potential of thiethylperazine in Alzheimer's disease management.
Treatment
The clinical trial involves the administration of **Torecan** 6.5 mg coated tablets, which contain the active ingredient **thiethylperazine**. This medication is provided in the form of a coated tablet and is administered orally. The dosage regimen for Torecan is set at a maximum daily dose of 13 mg, with a total treatment period extending up to 12 months. The trial aims to evaluate the effects of thiethylperazine in patients diagnosed with an early stage of Alzheimer's disease. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.
Additionally, the trial includes the use of **Neuraceq** 300 MBq/mL solution for injection, which contains the active substance **florbetaben (18F)**. This investigational product is administered intravenously and is utilized as an auxiliary treatment in the study. The maximum daily dose for Neuraceq is 360 MBq, with a total allowable dose of 720 MBq over the course of the trial. The administration of Neuraceq is limited to a single treatment period, and its role is to assist in the evaluation of the primary treatment's efficacy.
The study also incorporates a placebo, which consists of a combination of inactive ingredients including lactose monohydrate, corn starch, magnesium stearate, talc, polyglycol 6000, sucrose, calcium carbonate, titanium dioxide (E171), povidone 90 F, glycerol 85%, and montanglycol wax. The placebo is designed to match the appearance and administration route of the active treatment, ensuring blinding of the study. The placebo is administered orally, and its use is critical for comparing the effects of the active treatment against a non-active control.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint involves comparing the two arms of the study, TEP-THX versus PBO-THX, in terms of the mean change in Florbetaben-PET **SUVR** at month 12, adjusted for baseline. This measurement will help determine the effect of Thiethylperazine on amyloid-beta clearance in patients with early-stage Alzheimer's disease.
Secondary endpoints will include the evaluation of various biomarkers and cognitive assessments. These will involve measuring differences between the groups in terms of GFAP, p-Tau181, Aβ42/40 ratio, and NfL biomarkers in plasma at month 12, adjusted for baseline. Additionally, the study will assess differences in the Aβ42/40 ratio, p-Tau181/total Tau ratio, and NfL at the same time point. Cognitive and functional outcomes will be evaluated using scales such as iADRS, ADCS-Cog 13, FCSRT, ADCS-iADL, QoL-AD, NPI-Q, and GDS levels, all adjusted for baseline at month 12.
Inclusion and Exclusion Criteria
Inclusion Criteria
- For AD subjects only:
- 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).
- 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
Exclusion Criteria
- For AD subjects and disease controls:
- History of significant head trauma/brain injury with persistent neurologic defect(s) OR pre-existent known structural brain defect
- 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
- 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
- Fasting triglycerides >2.5 times the upper limit of normal
- Uncontrolled diabetes (fasting blood glucose [FBG] > 150 mg/dl)
- Acute /current depression assessed by anamneses and a Geriatric Depression score > 5
- 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
- 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)
- 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
- Extrapyramidal syndrome
- Abnormal involuntary movement scale (AIMS) ≥ 2
- 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)
- Current treatment with TEP or treatment up to 24 months prior to screening
- Known incompatibility of TEP or phenothiazines
- 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
- Women of childbearing potential not using adequate measures of contraception and women who are pregnant or nursing
- Sensory impairment that prevents or significantly interferes with neuropsychological testing
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Yet Recruiting | 01 Dec 2025 | 228 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
lactose monohydrate (67.66 mg), corn starch (11.94 mg), magnesium stearate, talc, polyglycol 6000, sucrose (33.7 mg), calcium carbonate, titanium dioxide (E171), povidone 90 F, glycerol 85%, and montanglycol wax | Placebo | N/A | — | — | — | N/A |
Neuraceq 300 MBq/mL solution for injection | Other | SOLUTION FOR INJECTION | INTRAVENOUS | 360 | 1 | PRD6020031 |
Torecan 6,5 mg obalené tablety | Test | OBALENÉ TABLETY | ORAL | 13 | 12 | PRD759296 |