nct05266417-nose-pd

Intranasal Insulin and Glutathione for Parkinson's Disease (NOSE-PD)

Overview

This Phase 2 clinical trial (NCT05266417), known as NOSE-PD (Nasal Insulin and Glutathione for Parkinson's Disease), investigates the safety and efficacy of intranasal insulin and glutathione as an add-on therapy for patients with Parkinson's disease. The study is sponsored by the [Gateway Institute for Brain Research](/institutions/gateway-institute-for-brain-research) and is currently recruiting participants in Florida["@clinicaltrialsgov"][@gateway].

Intranasal Insulin and Glutathione for Parkinson's Disease (NOSE-PD)

Overview

This Phase 2 clinical trial (NCT05266417), known as NOSE-PD (Nasal Insulin and Glutathione for Parkinson's Disease), investigates the safety and efficacy of intranasal insulin and glutathione as an add-on therapy for patients with Parkinson's disease. The study is sponsored by the [Gateway Institute for Brain Research](/institutions/gateway-institute-for-brain-research) and is currently recruiting participants in Florida["@clinicaltrialsgov"][@gateway].

The trial represents a novel approach combining two interventions with complementary mechanisms: intranasal insulin for its potential neuroprotective effects through insulin signaling pathways, and glutathione as a potent antioxidant to combat oxidative stress in the dopaminergic system.

Trial Identification

| 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) |
| Acronym | NOSE-PD |
| Phase | Phase 2 |
| Status | Recruiting |
| Enrollment | 56 patients (estimated) |
| Study Start Date | February 7, 2022 |
| Primary Completion | December 2026 (estimated) |
| Study Completion | January 2027 (estimated) |

Trial Design

Study Type

• Design: Randomized, double-blind, placebo-controlled
• Allocation: Randomized
• Intervention Model: Parallel
• Primary Purpose: Treatment
• Masking: Triple (Participant, Care Provider, Investigator)

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 |

Inclusion Criteria

• Documented clinical diagnosis of idiopathic Parkinson's disease
• Modified Hoehn & Yahr stage < 5
• Able to self-administer or have caregiver assistance for study drug administration
• Stable PD medications or nutraceuticals for at least 30 days prior to screening
• Stable antidepressant or anxiolytic dose for at least 90 days prior to screening (if applicable)

Exclusion Criteria

• Type 1 or Type 2 Diabetes Mellitus
• HbA1c level ≥ 6.5%
• History of hypoglycemia or documented plasma glucose ≤ 50 mg/dL
• MMSE score ≤ 24 (cognitive impairment)
• Positive COVID-19 test at screening
• Chronic inflammation of nasal cavity that may prevent absorption
• Insufficiently controlled respiratory disease (asthma, COPD)
• History of significant neurologic or psychiatric disease other than PD
• Epilepsy with recent seizures
• History of stroke
• Use of insulin, anti-hyperglycemic agents, or glutathione supplementation

Mechanism of Action

Intranasal Insulin

Insulin plays a crucial role in neuronal function and survival through multiple signaling pathways:

Insulin Signaling in the Brain

• Insulin receptors are widely expressed in the brain, including the substantia nigra and basal ganglia[@craft2018]
• Central insulin signaling modulates dopamine transmission and synaptic plasticity
• Intranasal delivery bypasses the blood-brain barrier, achieving direct CNS effects

Neuroprotective Effects

• PI3K/Akt Pathway: Activates downstream signaling that promotes neuronal survival and inhibits apoptosis
• mTOR Pathway: Regulates protein synthesis and autophagy
• MAPK/ERK Pathway: Promotes neuronal differentiation and plasticity

Relevance to Parkinson's Disease

• PD patients often show evidence of insulin resistance in the brain[@avilesolmos2013]
• Impaired insulin signaling may contribute to dopaminergic neuron vulnerability
• Restoring insulin signaling could protect remaining neurons and improve function

Glutathione

Glutathione (GSH) is the body's most important antioxidant:

Antioxidant Mechanisms

• Direct scavenging of reactive oxygen species (ROS)
• Regeneration of other antioxidants (vitamin C, vitamin E)
• Detoxification of xenobiotics and heavy metals

Role in Parkinson's Disease

• The substantia nigra in PD patients shows significantly reduced GSH levels[@dexter1992]
• Oxidative stress is a central pathological feature in PD
• GSH depletion precedes mitochondrial dysfunction and dopaminergic cell death

Intranasal Delivery

• Bypasses systemic degradation
• Direct delivery to brain regions affected in PD
• Maintains higher CNS concentrations than oral supplementation

Outcomes

Primary Outcome

| Measure | Description | Timeframe |
|---------|-------------|-----------|
| Verbal Fluency | FAS (F, A, S) words test | 24 Weeks |

Secondary Outcomes

| Measure | Description | Timeframe |
|---------|-------------|-----------|
| Verbal Fluency | Change in FAS test | 28 Weeks |
| Motor Function | Timed Up and Go (TUG) test | 24 Weeks |
| Motor Function | MDS-UPDRS Part III total score | 24 Weeks |
| Motor Function | MDS-UPDRS total score | 24 Weeks |
| Motor Function | Clinical Global Impression (CGI) score | Week 24 |
| Motor Function | Clinical Impression of Severity Index for Parkinson's Disease (CISI-PD) | Week 24 |
| Cognitive Function | Cambridge Brain Sciences (CBS) computerized neuropsychological battery | Week 24 |
| Non-Motor Function | Hamilton Rating Scale for Depression | Week 24 |
| Patient Reported Outcome | Parkinson's Disease Quality of Life Questionnaire (PDQ-39) | Week 24 |
| Patient Reported Outcome | Patient Global Impression (PGI) score | Week 24 |

Study Locations

| Facility | City | State | Status |
|----------|------|-------|--------|
| Institute for Neuroimmune Medicine | Davie | Florida | Recruiting |
| Las Mercedes Medical Research | Hialeah | Florida | Recruiting |

Principal Investigators

• Davie: Irina Rozenfeld, DPN, APRN
• Hialeah: Frank Alvarez, MD

Contact Information

• Primary Contact: Susana Restrepo, PhD (srestrepo@gifbr.com, 786-216-5334)
• Secondary Contact: Vanesa Javier (vaday@gifbr.com, 954-636-2166)

Rationale and Significance

Combination Therapy Approach

This trial uses a dual-mechanism approach:

The combination is designed to:

• Protect dopaminergic neurons from multiple insults
• Potentially improve both motor and non-motor symptoms
• Provide disease-modifying effects rather than purely symptomatic relief[@oxidative2023]

Advantages of Intranasal Delivery

• Bypasses blood-brain barrier
• Direct delivery to CNS
• Avoids systemic side effects
• Maintains therapeutic concentrations in target tissues[@nasaldelivery2023]

Clinical Implications

If successful, this trial could:

• Establish a novel therapeutic approach for PD
• Provide evidence for insulin signaling as a therapeutic target
• Validate antioxidant therapy as a disease-modifying strategy
• Open avenues for combination therapies in neurodegeneration

Oxidative Stress in Parkinson's Disease

Pathological Role

Oxidative stress is considered one of the central mechanisms of dopaminergic neuron degeneration in Parkinson's disease. The substantia nigra pars compacta (SNc) is particularly vulnerable due to several factors:

Evidence of Oxidative Damage in PD

Multiple lines of evidence support oxidative stress involvement in PD:

• Reduced GSH: The substantia nigra shows 40-50% reduction in glutathione[@dexter1992]
• Elevated lipid peroxidation: Malondialdehyde and 4-hydroxynonenal are increased
• DNA oxidation: 8-hydroxy-2'-deoxyguanosine (8-OHdG) is elevated in PD brains
• Protein oxidation: Carbonyl groups and nitrated proteins are increased

Therapeutic Implications

Given the central role of oxidative stress, antioxidant therapies have been explored:

• Coenzyme Q10: Mixed results in clinical trials
• Vitamin E: Some positive signals but not definitive
• Glutathione: Limited by poor CNS penetration until intranasal delivery

Intranasal Insulin: Comprehensive Mechanism

Brain Insulin Signaling

Insulin signaling in the brain has emerged as a critical pathway in neurodegeneration. Unlike peripheral insulin resistance, brain insulin resistance in PD involves:

Insulin Receptor Distribution

• High density in basal ganglia, hippocampus, and cerebral cortex
• Present on dopaminergic neurons
• Involved in modulating dopamine signaling

Signaling Cascade

Pathological Implications in PD

• Impaired insulin signaling in the SNc of PD patients
• Reduced IR expression and signaling
• Links between insulin resistance and alpha-synuclein toxicity[@insulinsignaling2024]

mTOR Pathway

The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and metabolism:

mTORC1 Functions

• Protein synthesis regulation
• Autophagy inhibition (via ULK1 inhibition)
• Cell growth promotion
• Metabolic reprogramming

mTOR in PD

• mTOR hyperactivity may contribute to impaired autophagy
• Alpha-synuclein accumulation may result from reduced autophagy
• mTOR inhibition promotes alpha-synuclein clearance in models[@mtor2023]

MAPK/ERK Pathway

The mitogen-activated protein kinase pathway is also modulated by insulin:

Functions

• Neuronal differentiation
• Synaptic plasticity
• Cell survival
• Memory formation

In PD

• ERK pathway may be neuroprotective
• Insulin's effects on ERK could promote neuronal resilience

Glutathione: Antioxidant Defense

Cellular Functions

Glutathione (γ-glutamyl-cysteinyl-glycine) is the most abundant cellular antioxidant:

Direct Antioxidant Actions

• Scavenging ROS directly
• Regenerating oxidized vitamin C and E
• Detoxifying xenobiotics
• Maintaining protein thiols in reduced state

Enzymatic Functions

• Glutathione peroxidase (GPx): Reduces H2O2 and lipid peroxides
• Glutathione S-transferase (GST): Conjugates detoxified compounds
• Glutathione reductase (GR): Regenerates GSH from GSSG

GSH Depletion in PD

The dramatic reduction in brain GSH in PD is multifactorial:

• Reduced synthesis: GCL (glutamate-cysteine ligase) activity may be reduced
• Increased consumption: Oxidative stress consumes GSH more rapidly
• Impaired recycling: GSSG reduction may be compromised

Intranasal Glutathione Delivery

The intranasal route offers significant advantages:

• Bypasses first-pass metabolism
• Directly enters CSF
• Achieves higher CNS concentrations than oral
• Reduces systemic exposure and side effects

Clinical Trial Design Details

Dose Selection Rationale

Insulin Dosing

• Novolin R (regular insulin) is used
• Dose selected based on prior intranasal insulin studies
• Twice-daily administration maintains stable CNS exposure
• Glucose monitoring ensures safety

Glutathione Dosing

• Standard therapeutic dose of glutathione
• Optimized for nasal absorption
• Combined with insulin for synergistic effect

Assessment Schedule

| Visit | Week | Assessments |
|-------|------|-------------|
| Screening | -4 to -2 | Eligibility, baseline |
| Baseline | 0 | Full battery |
| Treatment | 4, 12, 24 | Primary/secondary endpoints |
| Follow-up | 28 | Extended observation |

Response Biomarkers

The trial assesses multiple biomarkers:

Motor Function

• MDS-UPDRS Part III (gold standard)
• Timed Up and Go (functional mobility)
• Gait analysis

Cognitive Function

• Cambridge Brain Sciences computerized battery
• Verbal fluency (FAS test)
• Executive function tests

Non-Motor Symptoms

• Depression (HAMD)
• Quality of Life (PDQ-39)
• Sleep assessments

Comparative Analysis with Other PD Trials

Similar Intranasal Trials

| Trial | Intervention | Phase | Status |
|-------|--------------|-------|--------|
| NCT02064114 | Intranasal insulin | Phase 2 | Completed[@intranasalpd2022] |
| NCT05446938 | Intranasal insulin + GSH | Phase 2 | Recruiting (this trial) |

Antioxidant Trials in PD

| Agent | Route | Results |
|-------|-------|---------|
| Coenzyme Q10 | Oral | Mixed results |
| Glutathione (IV) | Intravenous | Short-lived effects |
| N-acetylcysteine | Oral | Some benefits |
| GSH (intranasal) | Intranasal | Under investigation |

Future Implications

Precision Medicine Approaches

Results may identify:

• Subgroups who respond best to combination therapy
• Biomarkers predicting treatment response
• Optimal timing for intervention

Combination Strategies

Success would support:

• Triple combinations (insulin + GSH + dopaminergic)
• Sequential therapy approaches
• Personalized treatment selection

Related Pages

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Insulin Signaling Pathway](/mechanisms/insulin-signaling-pathway)
• [Oxidative Stress in Neurodegeneration](/mechanisms/oxidative-stress-neurodegeneration)
• [Alpha-Synuclein](/proteins/alpha-synuclein)
• [Substantia Nigra](/cell-types/substantia-nigra-dopaminergic-neurons)
• [Dopaminergic Neurons](/cell-types/dopaminergic-neurons)
• [Intranasal Drug Delivery](/mechanisms/intranasal-drug-delivery)

Extended Safety Considerations

Hypoglycemia Risk

Intranasal insulin carries minimal hypoglycemia risk because:

• Does not significantly enter systemic circulation
• No effect on peripheral glucose
• However, diabetic patients are excluded

Nasal Irritation

Potential local effects:

• Nasal irritation or congestion
• Rare epistaxis
• Usually mild and transient

Long-term Safety

With extended use:

• Effect on nasal mucosa
• Potential impact on olfaction
• Immunogenicity considerations

Pharmacokinetic Considerations

Intranasal Delivery Kinetics

The olfactory region provides direct nose-to-brain transport:

• Olfactory neuroepithelium covers ~5 cm²
• Direct axonal transport to olfactory bulb
• Perivascular pathways to broader brain regions

Drug Distribution

Both insulin and glutathione distribute to:

• Cerebrospinal fluid
• Olfactory bulb
• Basal ganglia
• Other CNS regions

Study Sites and Enrollment

Florida Sites

The trial is being conducted at specialized PD centers:

Davie, Florida

• Institute for Neuroimmune Medicine
• Focus on neuroinflammatory conditions
• PI: Irina Rozenfeld, DPN, APRN

Hialeah, Florida

• Las Mercedes Medical Research
• Community-based research site
• PI: Frank Alvarez, MD

Enrollment Projections

• Target: 56 participants
• Randomization: 1:1 active:placebo
• Duration: 28 weeks total

References

Pathway Diagram

The following diagram shows the key molecular relationships involving nct05266417-nose-pd discovered through SciDEX knowledge graph analysis: