Intranasal Insulin and Glutathione for PD (NOSE-PD)

Overview

The NOSE-PD trial (NCT05266417) is a Phase 2 randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and efficacy of intranasal insulin and glutathione (INS-GSH) as an add-on therapy for patients with Parkinson's Disease["@nct"]. This trial represents a novel approach targeting both insulin signaling dysfunction and oxidative stress — two key mechanisms implicated in dopaminergic neuron degeneration.

The study is sponsored by the [Gateway Institute for Brain Research](/institutions/gateway-institute-brain-research) and is currently recruiting participants at sites in Florida.

Trial Details

Overview

The NOSE-PD trial (NCT05266417) is a Phase 2 randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and efficacy of intranasal insulin and glutathione (INS-GSH) as an add-on therapy for patients with Parkinson's Disease["@nct"]. This trial represents a novel approach targeting both insulin signaling dysfunction and oxidative stress — two key mechanisms implicated in dopaminergic neuron degeneration.

The study is sponsored by the [Gateway Institute for Brain Research](/institutions/gateway-institute-brain-research) and is currently recruiting participants at sites in Florida.

Trial Details

| Attribute | Value |
|-----------|-------|
| NCT Number | NCT05266417 |
| Official Title | A Randomized, Double-Blind, Placebo-Controlled, Phase II Study to Evaluate the Safety, Tolerability, and Efficacy of Intranasal Insulin and Glutathione as an Add-On Therapy in Subjects With Parkinson's Disease (NOSE-PD) |
| Phase | Phase 2 |
| Status | Recruiting |
| Enrollment | 56 participants (estimated) |
| Start Date | February 7, 2022 |
| Primary Completion | December 2026 |
| Completion | January 2027 |
| Sponsor | Gateway Institute for Brain Research |
| Design | Randomized, Triple-Blind, Placebo-Controlled, Parallel Assignment |

Study Arms

| Arm | Type | Intervention |
|-----|------|--------------|
| Active | Experimental | Intranasal Insulin (Novolin R) and Glutathione (INS-GSH) twice daily |
| Control | Placebo Comparator | Intranasal matched placebos (insulin placebo + glutathione placebo) twice daily |

Study Locations

• Institute for Neuroimmune Medicine — Davie, Florida, 33314
• Contact: Rafael Iglesias, PhD — 954-262-2876 — ri73@nova.edu
• Principal Investigator: Irina Rozenfeld, DPN, APRN
• Las Mercedes Medical Research — Hialeah, Florida, 33012
• Contact: Ariadna Zarzuela, RN, BSN — 786-577-5977 ext. 5005
• Principal Investigator: Frank Alvarez, MD

Mechanism of Action

This trial targets two complementary pathological pathways in Parkinson's disease:

Intranasal Insulin

Insulin signaling dysfunction in the brain is increasingly recognized as a key contributor to neurodegeneration — a concept formalized as [Type 3 Diabetes](/mechanisms/type-3-diabetes)[@type]. In PD, brain insulin resistance contributes to:

• Impaired mitochondrial function: Reduced PI3K/Akt signaling leads to decreased mitochondrial biogenesis and increased susceptibility to oxidative stress
• Accelerated alpha-synuclein aggregation: Insulin signaling normally promotes autophagy; dysfunction impairs clearance of misfolded proteins
• Synaptic dysfunction: Insulin supports synaptic plasticity and dopamine release in the striatum
• Neuroinflammation: Insulin has anti-inflammatory effects in the brain; resistance exacerbates microglial activation

Glutathione

[Glutathione](/mechanisms/glutathione-metabolism) is the brain's primary endogenous antioxidant. PD patients show significantly reduced glutathione levels in the substantia nigra[@glutathione], making this a rational therapeutic target:

• Direct ROS scavenging: Glutathione neutralizes hydrogen peroxide and lipid peroxides
• Mitochondrial protection: Maintains mitochondrial redox balance
• Neuroinflammation modulation: Reduces oxidative stress-induced inflammatory responses
• Alpha-synuclein oxidation prevention: Reduces oxidative modification of alpha-synuclein that promotes aggregation

Synergistic Potential

The combination of insulin and glutathione addresses both sides of the oxidative stress equation:

This dual approach may provide more comprehensive neuroprotection than targeting either pathway alone.

Eligibility Criteria

Key Inclusion Criteria

• Documented clinical diagnosis of idiopathic Parkinson's Disease
• Modified Hoehn & Yahr stage < 5
• Able to administer study drug or have a caregiver assist throughout the trial
• Willing to maintain stable PD medications, diet, and exercise for the study duration
• If on PD medications or nutraceuticals, stable dose for ≥30 days prior to screening
• If on chronic antidepressant or anxiolytic, stable dose for ≥90 days prior to screening

Key Exclusion Criteria

• Type 1 or Type 2 Diabetes Mellitus
• HbA1c ≥ 6.5%
• History of hypoglycemia or documented plasma glucose ≤50 mg/dL
• Mini-Mental State Exam (MMSE) score ≤24 (cognitive impairment)
• Positive COVID-19 test at screening or within 30 days
• Chronic nasal inflammation that may prevent drug absorption
• Uncontrolled respiratory disease (asthma, COPD)
• History of significant neurological or psychiatric disease other than PD
• Epilepsy or seizure history within 1 year
• History of stroke (ischemic or hemorrhagic)
• Unstable or uncontrolled cardiac disease
• Current use of insulin, anti-hyperglycemic agents, glutathione supplementation, or beta blockers

Age Range

• Minimum: 30 years
• Maximum: 85 years

Outcome Measures

Primary Outcomes

| Measure | Description | Timepoint |
|---------|-------------|-----------|
| Verbal Fluency | F, A, and S (FAS) words test | 24 weeks |

Secondary Outcomes

| Measure | Description | Timepoint |
|---------|-------------|-----------|
| Verbal Fluency | FAS test | 28 weeks |
| Motor Function | Timed Up and Go (TUG) test | 24 weeks |
| Motor Function | MDS-UPDRS Part III (motor examination) | 24 weeks |
| Motor Function | MDS-UPDRS total score | 24 weeks |
| Clinical Global Impression | CGI score | 24 weeks |
| Disease Severity | CISI-PD (Clinical Impression of Severity Index) | 24 weeks |
| Cognitive Function | Cambridge Brain Sciences computerized battery (12 tasks) | 24 weeks |
| Depression | Hamilton Rating Scale for Depression | 24 weeks |
| Quality of Life | PDQ-39 | 24 weeks |
| Patient Global Impression | PGI score | 24 weeks |

Scientific Rationale

Insulin Signaling in PD

The [insulin-IGF1 signaling pathway](/mechanisms/insulin-signaling-neurodegeneration) plays a critical role in neuronal survival. Multiple studies have demonstrated:

• Insulin receptor expression is reduced in PD substantia nigra
• Brain insulin resistance correlates with cognitive decline in PD
• GLP-1 receptor agonists (like exenatide) have shown promise in PD trials[@exenatide]
• Intranasal insulin has improved cognition in Alzheimer's disease studies

Glutathione Deficiency in PD

Post-mortem studies consistently show:

• Glutathione levels in PD substantia nigra are reduced by 40-50%
• This deficit occurs early, even in preclinical stages
• GSH deficiency makes neurons vulnerable to oxidative damage
• Antioxidant therapies have shown neuroprotective effects in preclinical models

Intranasal Delivery Advantage

The [intranasal drug delivery](/mechanisms/intranasal-drug-delivery) approach offers several advantages:

• Direct nose-to-brain transport bypassing the BBB
• Lower doses required compared to systemic administration
• Rapid onset of action
• Avoids hepatic first-pass metabolism
• Non-invasive and suitable for chronic use

Related Pages

• [Insulin Signaling in Parkinson's Disease](/mechanisms/insulin-signaling-parkinsons)
• [Glutathione Metabolism in Neurodegeneration](/mechanisms/glutathione-metabolism)
• [Oxidative Stress in Parkinson's Disease](/mechanisms/oxidative-stress-comparison)
• [Type 3 Diabetes Hypothesis](/mechanisms/type-3-diabetes)
• [Intranasal Drug Delivery for Neurodegeneration](/therapeutics/intranasal-therapy-neurodegeneration)
• [Exenatide Parkinson's Trial](/clinical-trials/exenatide-parkinsons) (similar GLP-1 approach)
• [Substantia Nigra Selective Vulnerability](/mechanisms/substantia-nigra-selective-vulnerability-parkinsons)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving Intranasal Insulin and Glutathione for PD (NOSE-PD) discovered through SciDEX knowledge graph analysis: