Overview
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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
Mermaid diagram (expand to render)
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
The intranasal route bypasses the blood-brain barrier, delivering insulin directly to the brain via the olfactory and trigeminal pathways[@intranasal]. This approach avoids systemic hypoglycemia and peripheral insulin side effects while achieving therapeutic concentrations in the CNS.
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:
Insulin improves mitochondrial function and reduces ROS generation
Glutathione scavenges residual ROS that do accumulateThis 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
Unknown, NCT05266417 — Intranasal Insulin and Glutathione as an Add-On Therapy in Parkinson's Disease (n.d.)
Unknown, Type 3 Diabetes Hypothesis — Brain Insulin Resistance in Neurodegeneration (n.d.)
Unknown, Intranasal Drug Delivery Mechanisms (n.d.)
Unknown, Glutathione Metabolism in Neurodegeneration (n.d.)
Unknown, Exenatide Parkinson's Disease Trial (n.d.)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:
Mermaid diagram (expand to render)