Efficacy and Safety of Talsaclidine in Patients With Mild to Moderate Dementia of Alzheimer Type

Study Overview
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Brief Summary
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The objective of this trial was to assess the dose-response relationship of symptomatic efficacy of talsaclidine base on ADAScog and to assess safety and tolerability

Official Title
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Efficacy and Safety of 6, 12, 24, and 36 mg Tid po and 36 mg Bid po Talsaclidine (Free Base) for 12 Weeks in a Double-blind, Randomised, Placebo-controlled Parallel Group Comparison in Patients With Mild to Moderate Dementia of Alzheimer Type

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Talsaclidine 6 mg
* Drug: Talsaclidine 12 mg
* Drug: Talsaclidine 24 mg
* Drug: Talsaclidine 36 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient, age: over 40 years (lower age if genetic Dementia of Alzheimer Type (DAT) is documented. Patients over 85 years need to be in a clinically stable state (investigator's judgement) Patient's educational level is > 4 years Patient is able to understand the patient information and give informed consent Patient has given written informed consent in accordance with Good Clinical Practice and local legislation Patient has a non-demented relative or care giver who is willing to support the clinical trial; his/her written informed consent is optional Body weight: within +/- 30% of normal weight (Broca index) Diagnosis of DAT by the National Institute of Neurological and communicative Disorders-Alzheimer's Disease and Related Disorder Association (NINCDS-ADRDA) criteria MMS-score 10 - 24 inclusive Rosen ischemia score is lower or equal to two Patient is able to complete the trial examinations, to hear, speak, read and write in a basic way and primary sensorial functions are intact Exclusion Criteria: Any dementia of vascular genesis (excluded by Rosen ischemia score > 2) Magnetic Resonance Imaging (MRI) or Computer Tomogram (CT) (more recent than 12 months; if a MRI of CT recording is performed more than 12 months before study entry, it must be repeated) findings make the diagnosis of DAT unlikely Any stroke history All secondary dementia (exclusion diagnosis defined by the NINCDS-ADRDA criteria) as a late complication of: Cranio-cerebral trauma Intoxication (incl. history of alcohol and drug abuse) Cerebral infections (e.g. neurosyphilis) Thyroid dysfunction Cerebral dysfunction due to metabolic disorders (e.g. unstable thyroid dysfunction, or unstable insulin-dependent diabetes mellitus with hypo-/hyper-glycemic episodes) Deficiency of vitamin B12 or folic acid as a reason of dementia Brain tumour (A patient with an incidental tumour found on CT not felt to be clinically relevant may be included, i.e.: meningioma) Down's syndrome, Parkinsonism, Huntington's chorea Multiple sclerosis Major depression defined by the Hamilton Depression Rating Scale (HAMD) 17 item scale (≥ 16) Depressive pseudo dementia Mental retardation Hydrocephalus Epilepsy Endogenous psychoses (schizophrenia) Untreated or non-compensated hypertension (Blood Pressure systolic > 180 and/or diastolic > 110 mmHg) Hypertension being treated with reserpine, clonidine or β-blockers (these cases have to be adjusted to therapy with e.g. calcium antagonists 4 weeks before start of treatment) Severe heart failure (NYHA: III and IV) Arrhythmias (Lown: II-IV, Electrocardiogram > 30 ventricular extrasystoles/hour, multifocal or multiform and repetitive forms of ventricular extrasystoles) Bronchial asthma with phases of exacerbation or inducible by aspirin or other Nonsteroidal anti-inflammatory drugs Severe diabetes mellitus: insulin dependent and not stabilised (patient with an HbA1c in normal range, clinically stable diabetes and any case of insulin dose ≤ 0.5 UI/kg/day may be included), or other metabolic diseases Renal insufficiency: calculated creatinine clearance is less than 60 ml/min Acute hepatic disorder (liver enzymes above 50 % upper normal limit) Chronic hepatitis within the last two years (positive hepatitis titer, Hepatitis A Virus, Hepatitis B Virus, Hepatitis C Virus, cytomegalovirus, Epstein-Barr virus or abnormal immunological values (positive immunoglobulin M(IgM)/IgG) are allowed if all liver enzymes are within the normal range) Recent history of liver disease (2 years) including drug intoxication (e.g. narcotics, cytostatics etc.) Patients with obvious symptoms of dehydration History of drug or alcohol abuse or dependence on other hepatotoxic agents (if a patient is permanently hospitalised and a drug screen performed at the beginning of hospitalisation, no additional drug screen is necessary) Neoplasm currently active or likely to recur (except basal cell carcinoma) Participation in another clinical trial within the last four weeks and re-entering from this or a previous talsaclidine trial Pregnant and lactating woman, woman with childbearing potential not using an approved method of contraception Insufficient compliance: in the investigator's opinion the patient or family is unable to comply with the protocol requirements

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Talsaclidine, 6 mg tid<br> | Drug: Talsaclidine 6 mg<br> <br> |
| Experimental: Talsaclidine, 12 mg tid<br> | Drug: Talsaclidine 12 mg<br> <br> |
| Experimental: Talsaclidine, 24 mg tid<br> | Drug: Talsaclidine 24 mg<br> <br> |
| Experimental: Talsaclidine, 36 mg tid<br> | Drug: Talsaclidine 36 mg<br> <br> |
| Experimental: Talsaclidine, 36 mg bid<br> | Drug: Talsaclidine 36 mg<br> <br> Drug: Placebo<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Alzheimer's Disease Assessment Scale cognitive part (ADAScog) |  | Baseline, week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ADAScog (extension) | measures cognitive capability | Baseline, week 4, 8 and 12 | 
| Change in ADAScog (Total) | Defined as ADAScog + ADAScog (Extension) | Baseline, week 4, 8 and 12 | 
| Change in mini mental state (MMS) |  | Screening, week 12 | 
| Change in neuropsychiatric inventory (NPI) | measures behavioural symptoms | Baseline, week 12 | 
| Change in Hamilton Depression Rating Scale | measures depressive mood | Screening, week 12 | 
| Change in instrumental activity of daily living (IADL) | measures functional performance | Baseline, week 12 | 
| Change in living status rated on a 6-point verbal rating scale |  | Baseline, week 12 | 
| Change in clinician's global impression rated with Alzheimer's Disease cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) |  | Baseline, week 12 | 
| Number of patients with adverse events |  | up to 12 months |