A Phase III Trial of Nilvadipine to Treat Alzheimer's Disease

Study Overview
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Brief Summary
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Alzheimer's disease (AD) is an ever-increasing public health concern among the aging population and is the most common form of dementia affecting more than 15 million individuals worldwide and around 5 million Europeans. The direct and indirect costs of AD and other dementias amount to more than €440,000 million each year (www.alz.org, 2010). Even modest therapeutic advances that delay disease onset and progression could significantly reduce the global burden of the disease and the level of care required by patients. While there are symptomatic-based drug therapies available for AD, these medications do not prevent the disease process itself. There is therefore an imperative to develop new treatments for AD that have disease modifying effects. This double-blind placebo controlled study will test the efficacy and safety of nilvadipine in 500 subjects with mild to moderate AD over a treatment period of 18 months. There is a strong scientific rationale for this study: Nilvadipine, a licensed calcium channel enhances Aß clearance from brain and restores cortical perfusion in mouse models of AD. Nilvadipine is safe and well tolerated in AD patients and clinical studies with this medication have shown stabilization of cognitive decline and reduced incidence of AD, pointing to both symptomatic and disease modifying benefits. Male and female patients with mild to moderate AD aged between 50 and 90 with a range of medical morbidities and frailty will be included in the study. If this trial is successful, nilvadipine would represent an advance in the treatment of AD patients and would have a major impact on the health and social care costs incurred in Europe by this neurodegenerative disorder. Furthermore, the creation of the NILVAD network will support future clinical trials and research innovation in AD across Europe.

Detailed Description
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Please see 'Brief Summary', above

Official Title
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A European Multicentre Double-blind Placebo-controlled Phase III Trial of Nilvadipine in Mild to Moderate Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Nilvadipine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range: Adult subjects, males and females over age 50 years. Prior diagnosis of mild to moderate probable AD based on NINCDS-ADRDA criteria (see Appendix B) and Standardised Mini-Mental State Examination (SMMSE) score > 12 on stable dose (>3 months of cholinesterase inhibitor and or memantine). Subjects who are not on cholinesterase inhibitors or memantine due to poor tolerability and/or who will not require treatment with these medications during the course of the study can be included. Collateral informants such as a spouse, family member, close friend. The informant must have close contact with the subject and agree to monitor/manage study drug adherence, observe for possible adverse events, assist with psychometric measures requiring informant information, and accompany the subject to all evaluation visits. Fluency in relevant language sufficient to reliably complete all study assessments. Systolic BP > 100 mmHg but ≤ 159 mmHg, and diastolic BP > 65 mmHg but ≤ 99 mmHg on resting office based BP measurements, or a Systolic BP > 105 mmHg but ≤ 140 mmHg, and diastolic BP > 70 mmHg but ≤ 90 mmHg on ABPM measurement Exclusion Criteria: Subjects with co-morbid dementia due to other neurological disorders such as Parkinson's disease, vascular dementia, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, or multiple sclerosis, as well as subjects with HIV disease, neurosyphilis, history of significant head trauma with loss of consciousness followed by persistent neurological deficits, known structural brain abnormalities, or any other condition known to interfere with cognitive function. Subjects currently taking any calcium channel blocker or Beta-blocker Subjects who in the opinion of the investigator, have a medical condition that would preclude them from participating in the study (e.g.hemodynamically significant coronary artery disease., chronic heart failure, syncope within the past year, significant valvular heart disease i.e. severe aortic and mitral stenosis.. symptomatic orthostatic hypotension within the last year, subjects requiring more than one agent to control BP.), or subjects who in the opinion of the investigator are unlikely to complete per protocol due to care issues etc: Current Axis I diagnosis of schizophrenia, bipolar disorder, major depression. Subjects who are currently or who have within the past year met criteria for drug or alcohol abuse or dependence. Pregnant women or women who may possibly become pregnant. Subjects with a history of hypersensitivity to nilvadipine (Nivadil). Subjects who have taken an investigational or other unapproved drug during the 30 days or five half-lives, whichever is longer, prior to baseline. Subjects who are participating in other research studies. Patients with a SBP of ≤ 100 mmHg and/or a DBP of ≤ 65 mmHg on office based BP measurements, or a SBP ≤ 105 mmHg and/or a DBP of ≤ 70 mmHg on ABPM will not be included in the study.

Ages Eligible for Study
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Minimum Age: 50 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>250 patients will receive the placebo | Drug: Placebo<br>* 8mg Placebo tablet taken once a day at lunch time for 78 weeks<br>|
| Active Comparator: Nilvadipine<br>250 patient will receive the active drug Nilvadipine 8mg | Drug: Nilvadipine<br>* 8mg of Nilvadipine taken once a day at lunch time for 78 weeks<br>* Other names: Also known as Nilvadil (Brand Name);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alzheimer's Disease Assessment Scale (ADAS) Cog | The Alzheimer's Disease Assessment Scale (Cognitive) (Mohs et al. 1983) ADAS-cog 12 is a primary efficacy outcome measure, and includes 12 items of cognitive evaluation, namely immediate word recall, naming objects and fingers, commands, constructional praxis, ideational praxis, orientation, word recognition, remembering test instructions, spoken language ability, word-finding difficulty in spontaneous speech, comprehension & delayed recall. A higher ADAS-cog score indicates a poorer cognitive function. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) | Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) (Morris et al 1993) is the secondary efficacy outcome measure. This is a semi-structured interview with the caregiver and the patient. The patient's performance in the domains of memory, orientation, judgment, problem solving, community affairs, home and hobbies and personal care are assessed. The CDR-sb is scored from 0-18, with the higher score indicated greater impairment. | 18 months | 
| Disability Assessment for Dementia (DAD) | Disability Assessment for Dementia (DAD) (Gelinas et al. 1999) is a key secondary efficacy outcome measure and evaluates the basic and instrumental activities in daily activities of elderly people with dementia. This 40-item scale addresses a range of functional domains: eating, meal preparation, telephoning, hygienic, dressing, medication, corresponding, finance, leisure, and housework. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Investigator-driven clinical trial, Nilvadipine, Calcium Channel blocker, Elderly, Therapeutic Intervention