Clinical trial NCT03116126: Noradrenergic Add-on Therapy With Guanfacine
Official title: Randomised Clinical Trial of Noradrenergic Add-on Therapy With Extended-Release Guanfacine in Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Alzheimer Disease
Lead sponsor: Imperial College London
Sponsor class: OTHER
First posted: 2017-04-14
Enrollment: 148
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog)
timeFrame: 12 weeks
Secondary outcomes:
measure: Tests of Attention: Trails A and B
timeFrame: 12 weeks
measure: Digit-symbol substitution
timeFrame: 12 weeks
measure: Test of Everyday attention
timeFrame: 12 weeks
measure: CANTAB-RVP
timeFrame: 12 weeks
measure: Neuropsychiatric Inventory (NPI)
timeFrame: 12 weeks
measure: Zarit Burden Interview (22 Item)
timeFrame: 12 weeks
measure: Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory (ADCS-ADL)
timeFrame: 12 weeks
measure: Blood pressure
timeFrame: 12 weeks
measure: Epworth Sleepiness Scale
timeFrame: 12 weeks
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Imperial Memory Unit, Charing Cross Hospital
Study officials:
affiliation: Imperial College London
name: Paresh Malhotra, MA BMBCh PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hoang K, Watt H, Golemme M, Perry RJ, Ritchie C, Wilson D, Pickett J, Fox C, Howard R, Malhotra PA. Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer's Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments. Trials. 2022 Aug 1;23(1):623. doi: 10.1186/s13063-022-06190-3.