Noradrenergic Add-on Therapy With Guanfacine

Study Overview
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Brief Summary
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NorAD is a clinical trial funded by the UK National Institute of Health Research. In this trial the investigators will assess whether a long-acting preparation of guanfacine, a drug used to treat Attention Deficit Hyperactivity Disorder in children, can improve thinking (particularly attention) in Alzheimer's Disease when it is added to the standard NICE-approved drugs that are normally used in this condition. This is a randomized clinical trial designed to evaluate the efficacy of extended-release guanfacine as an add-on therapy in AD, and whether it improves cognition compared to standard cholinergic therapy alone.

Detailed Description
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There is evidence suggesting that both noradrenaline and acetylcholine have key roles to play in attention. Guanfacine acts by increasing levels of noradrenaline, a substance in the brain which is closely linked with attention, both noradrenaline levels and attentional performance have been shown to be reduced in Alzheimer's Disease. In this study the investigators propose that modulation of the noradrenergic deficit that has been described in Alzheimer's Disease in addition to standard cholinergic treatment could have significant positive effects on cognition, particularly in those patients who suffer from attentional impairments. The investigators want to assess whether long-acting guanfacine should be used in addition to NICE-approved drugs that are currently being used in AD as part of combination therapy. It is a single-centre, randomised, parallel-group, double-blind controlled Phase 3 trial to compare the efficacy of standard cholinergic therapy (Donepezil, Rivastigmine or Galantamine) plus extended release guanfacine (2mg GXR) versus standard cholinergic therapy plus placebo on Cognition (as measured by the ADAS-Cog) in patients with mild to moderate Alzheimer's Disease. The trial, which will recruit 160 patients (80 randomised to GXR add-on therapy and 80 randomised to placebo), based at Imperial College London - Imperial College Healthcare NHS Trust.

Official Title
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Randomised Clinical Trial of Noradrenergic Add-on Therapy With Extended-Release Guanfacine in Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Guanfacine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatients NINCDS/ADRDA criteria for probable AD MMSE at assessment = 10-30 Identified informant to accompany patient at all visits Stable dose of donepezil, galantamine or rivastigmine for preceding 12 weeks Exclusion Criteria: Labile blood pressure or new antihypertensive medication started within 3 weeks Severe coronary insufficiency or myocardial infarction in previous 6 months History of unexplained syncope within the preceding 12 months Cardiac Conduction Block Severe Hepatic Impairment (ALT > 120 (Upper Limit of Normal (ULN) is 40) OR Alkaline Phosphatase > 390 (ULN 130)) OR Both ALT and total bilirubin > ULN OR Total bilirubin > 60 (ULN 30) Severe Renal Impairment (eGFR < 40) Treatment with other medications known to potentiate guanfacine's hypotensive effects or cause arrhythmia (specifically antipsychotics (including sultopride, chlorpromazine, thioridazine, amisulpiride, sulpiride, haloperidol), and moxifloxacin, baclofen, verapamil, quinidine, hydroquinidine, dispyramide, amiodarone, dofetilide, ibutilide, sotalol, pimazide, bepridil, cisapride, diphemanil, erythromycin, halofantrine, pentamidine, sparfloxacin, vincamine, alfuzosin, prazosin, terazosin, tamsulosin, amifostine Weight less than 45kg Pregnancy (Pre-menopausal women will only be entered into the study of they are surgically sterile or using effective birth control methods: These are abstinence for the period of the study, intrauterine contraception/device, male sexual partners with vasectomy)

Ages Eligible for Study
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Minimum Age: 45 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Guanfacine<br> | Drug: Guanfacine<br>* 2mg oral daily tablet<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* inactive oral daily tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) | The ADAS-Cog is used to determine the extent of cognitive decline in AD. It is a common cognitive testing instrument in clinical trials consisting of 11 tasks measuring disturbances in memory, language, praxis, attention and other cognitive abilities that are core symptoms of AD. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tests of Attention: Trails A and B | Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD. | 12 weeks | 
| Digit-symbol substitution | Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD. | 12 weeks | 
| Test of Everyday attention | Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD. | 12 weeks | 
| CANTAB-RVP | Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD. | 12 weeks | 
| Neuropsychiatric Inventory (NPI) | Examination and scoring of behavioural domains to determine the frequency and severity of behaviour with the patient and caregiver. | 12 weeks | 
| Zarit Burden Interview (22 Item) | Examination and scoring of behavioural domains to determine the frequency and severity of behaviour with the patient and caregiver. | 12 weeks | 
| Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory (ADCS-ADL) | Examination and scoring of behavioural domains to determine the frequency and severity of behaviour with the patient and caregiver. | 12 weeks | 
| Blood pressure | Measure of side effects. | 12 weeks | 
| Epworth Sleepiness Scale | Measure of side effects. | 12 weeks |