Noradrenergic Add-on Therapy With Guanfacine (NorAD)
Primary Purpose
Alzheimer Disease
Status
Recruiting
Phase
Phase 3
Locations
United Kingdom
Study Type
Interventional
Intervention
Guanfacine
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Alzheimer Disease
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)
Sites / Locations
- Imperial Memory Unit, Charing Cross HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Guanfacine
Placebo
Arm Description
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Tests of Attention: Trails A and B
Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD.
Digit-symbol substitution
Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD.
Test of Everyday attention
Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD.
CANTAB-RVP
Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD.
Neuropsychiatric Inventory (NPI)
Examination and scoring of behavioural domains to determine the frequency and severity of behaviour with the patient and caregiver.
Zarit Burden Interview (22 Item)
Examination and scoring of behavioural domains to determine the frequency and severity of behaviour with the patient and caregiver.
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.
Blood pressure
Measure of side effects.
Epworth Sleepiness Scale
Measure of side effects.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03116126
Brief Title
Noradrenergic Add-on Therapy With Guanfacine
Acronym
NorAD
Official Title
Randomised Clinical Trial of Noradrenergic Add-on Therapy With Extended-Release Guanfacine in Alzheimer's Disease
Study Type
Interventional
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Recruiting
Study Start Date
January 4, 2019 (Actual)
Primary Completion Date
December 31, 2022 (Anticipated)
Study Completion Date
December 31, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Imperial College London
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
160 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Guanfacine
Arm Type
Active Comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Guanfacine
Intervention Description
2mg oral daily tablet
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
inactive oral daily tablet
Primary Outcome Measure Information:
Title
Cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog)
Description
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.
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Tests of Attention: Trails A and B
Description
Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD.
Time Frame
12 weeks
Title
Digit-symbol substitution
Description
Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD.
Time Frame
12 weeks
Title
Test of Everyday attention
Description
Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD.
Time Frame
12 weeks
Title
CANTAB-RVP
Description
Neuropsychological test sensitive detecting cognitive impairment associated with dementia/AD.
Time Frame
12 weeks
Title
Neuropsychiatric Inventory (NPI)
Description
Examination and scoring of behavioural domains to determine the frequency and severity of behaviour with the patient and caregiver.
Time Frame
12 weeks
Title
Zarit Burden Interview (22 Item)
Description
Examination and scoring of behavioural domains to determine the frequency and severity of behaviour with the patient and caregiver.
Time Frame
12 weeks
Title
Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory (ADCS-ADL)
Description
Examination and scoring of behavioural domains to determine the frequency and severity of behaviour with the patient and caregiver.
Time Frame
12 weeks
Title
Blood pressure
Description
Measure of side effects.
Time Frame
12 weeks
Title
Epworth Sleepiness Scale
Description
Measure of side effects.
Time Frame
12 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paresh Malhotra, MA BMBCh PhD
Organizational Affiliation
Imperial College London
Official's Role
Principal Investigator
Facility Information:
Facility Name
Imperial Memory Unit, Charing Cross Hospital
City
London
ZIP/Postal Code
W6 8RF
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Team
Phone
020 3311 5228
Email
imperial.memory.research@nhs.net
12. IPD Sharing Statement
Citations:
PubMed Identifier
35915506
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.
Results Reference
derived
Links:
URL
https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/norad-version-10/
Description
HRA research summary
Learn more about this trial
Noradrenergic Add-on Therapy With Guanfacine
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