Guanfacine NorAD - Phase 3 Trial for Alzheimer's Disease

Overview

Guanfacine NorAD (NCT03116126) is a Phase 3 clinical trial evaluating extended-release guanfacine as a noradrenergic add-on therapy for Alzheimer’s disease (AD). The trial, conducted at Imperial College London, investigates whether adding guanfacine to standard cholinergic therapy (donepezil, rivastigmine, or galantamine) can improve cognitive function, particularly attention, in patients with mild to moderate AD.[1]

The trial is named NorAD (Noradrenergic Add-on Therapy) and represents a novel approach to AD treatment by targeting the noradrenergic system, which is known to be compromised in Alzheimer’s disease and plays a critical role in attention and executive function.[2]

Scientific Rationale

Noradrenergic Dysfunction in AD

Both noradrenaline (norepinephrine) levels and attentional performance have been shown to be reduced in Alzheimer’s disease. The locus coeruleus, the primary source of noradrenergic innervation in the brain, undergoes significant degeneration in AD, contributing to:

• Impaired attention and executive function

• Reduced arousal and vigilance

• Dysregulated stress response

• Accelerated disease progression

Guanfacine Mechanism

Guanfacine is an alpha-2A adrenergic receptor agonist that:

• Increases noradrenaline levels in the prefrontal cortex

• Improves attention and working memory

• Reduces impulsivity

• Has been used successfully in Attention Deficit Hyperactivity Disorder (ADHD) treatment

The rationale for using guanfacine in AD is that modulating the noradrenergic deficit, in addition to standard cholinergic treatment, could have significant positive effects on cognition, particularly in patients with attentional impairments.[1]

Trial Design

Study Characteristics

Arms and Interventions

Randomization

• Allocation: Randomized

• Intervention Model: Parallel group

• Masking: Triple-blind (Participant, Care Provider, Investigator)

• Primary Purpose: Treatment

Eligibility Criteria

Inclusion Criteria

• Outpatients

• NINCDS/ADRDA criteria for probable Alzheimer’s disease

• MMSE score 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, Alkaline Phosphatase > 390, or total bilirubin > 60)

• Severe renal impairment (eGFR < 40)

• Treatment with medications known to potentiate guanfacine’s hypotensive effects or cause arrhythmia

• Weight less than 45 kg

• Pregnancy

Age and Population

• Minimum Age: 45 years

• Sex: All

• Healthy Volunteers: No

Outcome Measures

Primary Outcome

The ADAS-Cog is the gold standard cognitive testing instrument in AD clinical trials, consisting of 11 tasks measuring disturbances in core symptoms of AD.[1]

Secondary Outcomes

Trial Locations

Principal Investigator

• Paresh Malhotra, MA BMBCh PhD

• Affiliation: Imperial College London

Lead Sponsor

• Imperial College London

Mechanism of Action Summary

graph TD
    A["Locus Coeruleus Degeneration"] --> B["Noradrenergic Deficit"]
    B --> C["Attention Impairment"]
    C --> D["Cognitive Dysfunction in AD"]

    E["Guanfacine"] --> F["Alpha-2A Adrenergic Receptor Agonist"]
    F --> G["Increased Noradrenaline in PFC"]
    G --> H["Improved Attention"]
    H --> I["Enhanced Cognitive Function"]

    J["Standard Cholinergic Therapy"] --> K["Acetylcholinesterase Inhibition"]
    K --> L["Improved Cholinergic Signaling"]

    F -.-> M["Combination Therapy"]
    L -.-> M
    M --> N["Potential Synergistic Benefit"]

Rationale for Combination Therapy

This trial investigates whether the combination of guanfacine (noradrenergic enhancement) with standard cholinergic therapy (donepezil, rivastigmine, or galantamine) provides superior cognitive benefits compared to cholinergic therapy alone. The rationale is:

1. Complementary mechanisms: Noradrenaline and acetylcholine both play key roles in attention

2. Dual deficit targeting: AD involves both cholinergic and noradrenergic degeneration

3. Potential synergy: Combined modulation may produce additive or synergistic effects

Related Mechanisms and Targets

Noradrenergic System

• Locus coeruleus - primary noradrenergic nucleus

• Alpha-2A adrenergic receptor (ADRA2A) - guanfacine target

• Norepinephrine - key neurotransmitter

• Locus coeruleus neurons - cell type

Related Proteins and Genes

• ADRA2A gene - alpha-2A adrenergic receptor

• ADRA2B gene - alpha-2B adrenergic receptor

• Alpha-2C adrenergic receptor

Cholinergic System (Standard Therapy)

• Acetylcholinesterase

• Choline acetyltransferase (ChAT)