E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild to Moderate Alzheimer's Disease |
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E.1.1.1 | Medical condition in easily understood language |
Mild to Moderate Alzheimer's Disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the efficacy of Nilvadipine as a disease course modifying treatment for mild to moderate AD in a phase III double-blind placebo-controlled study.
To investigate the safety profile of Nilvadipine in patients with mild to moderate AD. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There are four sub studies associated with the NILVAD study.
1. Blood and Genetic Biomarker Sub study (Protocol v1 051112)
The objectives of the sub study are to: a- Determine whether there are genetic influences over the effect of Nilvadipine in AD b-To better understand the biological effects of nilvadipine in humans by measuring changes in amyloid, t tau and p tau and inflammatory markers in the peripheral blood from baseline to study endpoint.
2. Fraility Sub study (Protocol v1 051112)
The objectives of the fraility study are to: a - measure the fraility of all subjects that consent to participate cia fraility assessment schedule. b- To determine if fraility measures at baseline influence treatment response to Nilvadipine c- To determine if treatment with Nilvadipine alters the trajectory towards increased fraility over time
Please note that there are two other substudies the UK will not participate in: CSF and Blood Flow studies |
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E.3 | Principal inclusion criteria |
1. Age range: Adult subjects, males and females over age 50 years. 2.Subjects with a diagnosis of probable Alzheimer’s disease based on the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s disease and Related Disorders Association, Inc (NINCDS-ADRDA) criteria (McKhann et al, 1984) 3. Subjects with a Standardised Mini-Mental State Examination (SMMSE) (Standish & Molloy, 1991) score of greater than or equal to 12 and less than 27. 4.Subjects on a stable dose (>3 months) of cholinesterase inhibitor or memantine. The dose must be stabilised prior to randomisation. Patients due to begin these medications must not be enrolled until the dose is stabilised. 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 . 5. Subjects who retain capacity will provide written informed consent for participation. The procedure for obtaining informed consent when the subject has reduced decision making capacity will follow national law and will be assessed by the relevant bodies in each of the participating countries. 6.Fluency in relevant language sufficient to reliably complete all study assessments. 7. Subjects with blood pressure values greater than 100/65 mmHg but less than 159/99 mmHg (Grade 1 hypertension, ECS guidelines 2007; escardio.org/guidelines) using an office based BP measurement will be included. Subjects with blood pressure values greater than 105/70mmHg but less than 140/90 mmHg using an Ambulatory BP measurement will be included.
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E.4 | Principal exclusion criteria |
1. 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 tumour, 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. 2. Subjects currently taking any calcium channel blocker or -blocker. 3. 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. 4.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. 5.Pregnant women or women who may possibly become pregnant. 6.Female subjects who are breastfeeding will be excluded from the study 7.Subjects with a history of hypersensitivity to nilvadipine (Nivadil). 8.Subjects who have taken an investigational or other unapproved drug during the 30 days or five half-lives, whichever is longer, prior to baseline. 9. Subjects who are taking any medication listed in the list of exclusion medication for the study. 10. Subjects with abnormal ECG results which prevent participation in the study. 11. Standardised Mini-Mental State Examination (SMMSE) score of less than 12 or greater than 26. 12. Subjects who are participating in other clinical research studies. 13.Subjects with any clinically significant laboratory blood test abnormality on his/her screening test. 14.Subjects with blood pressure values less than 100/65 mmHg but greater than 159/99 mmHg (Grade 1 hypertension, ECS guidelines 2007; escardio.org/guidelines) using an office based BP measurement will be excluded. Subjects with blood pressure values less than 105/70mmHg but greater than 140/90 mmHg using an Ambulatory BP measurement will be excluded. 15.Subjects with clinically significant abnormalities in their CT/MRI results which would prevent inclusion in the study. 16. Patients with sigificant renal insuffiency (estimated glomerular filtration rate : eGFR <30ml/min) will be excluded . 17.Subjects with severly impaired hepatic function (liver cirrhosis)will be excluded. 18. The medical food stuff Souvenaid® is under exclusion from the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The Alzheimer's Disease Assessment Scale (Cognitive) (ADAS-Cog) is the primary efficacy end point 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 lanuage ability, word finding difficulty in spontaneous speech, comprehension and delayed recall. A higher ADAS-cog score indicates poorer cognitive function. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary end point (ADAS-Cog) will be evaluated at Week 0, Week 13, Week 52 and Week 78. |
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E.5.2 | Secondary end point(s) |
The Clinical Dementia rating sum of boxes (CDR-sb) and the Disability Assessment for Dementia (DAD) are the secondary end points for the study. The CDR-sb 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. The DAD 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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary end points (CDR-sb and DAD) will be evaluated at Week 0, Week 13, Week 52 and Week 78. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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When the last patient completes the last follow up visit which is scheduled to take place four weeks after the patient stops taking the study medication. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |