¶ Intranasal Insulin and Glutathione for Parkinson's Disease (NOSE-PD)
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 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.
| 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) |
- Design: Randomized, double-blind, placebo-controlled
- Allocation: Randomized
- Intervention Model: Parallel
- Primary Purpose: Treatment
- Masking: Triple (Participant, Care Provider, Investigator)
| 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 |
- 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)
- 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
Insulin plays a crucial role in neuronal function and survival through multiple signaling pathways:
- 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
- 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
- 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 (GSH) is the body's most important antioxidant:
- Direct scavenging of reactive oxygen species (ROS)
- Regeneration of other antioxidants (vitamin C, vitamin E)
- Detoxification of xenobiotics and heavy metals
- 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
- Bypasses systemic degradation
- Direct delivery to brain regions affected in PD
- Maintains higher CNS concentrations than oral supplementation
| Measure |
Description |
Timeframe |
| Verbal Fluency |
FAS (F, A, S) words test |
24 Weeks |
| 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 |
| Facility |
City |
State |
Status |
| Institute for Neuroimmune Medicine |
Davie |
Florida |
Recruiting |
| Las Mercedes Medical Research |
Hialeah |
Florida |
Recruiting |
- Davie: Irina Rozenfeld, DPN, APRN
- Hialeah: Frank Alvarez, MD
¶ Rationale and Significance
This trial uses a dual-mechanism approach:
- Insulin: Targets neuroprotection through insulin signaling pathways
- Glutathione: Addresses oxidative stress, a key pathological feature in PD
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]
- Bypasses blood-brain barrier
- Direct delivery to CNS
- Avoids systemic side effects
- Maintains therapeutic concentrations in target tissues[@nasaldelivery2023]
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 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:
- High metabolic demand: Dopaminergic neurons have high energy requirements for dopamine synthesis, packaging, and release
- Iron accumulation: Iron is concentrated in the SNc and can catalyze free radical formation
- Dopamine metabolism: Enzymatic and auto-oxidation of dopamine produces reactive oxygen species (ROS)
- Limited antioxidant capacity: The SNc has relatively low levels of antioxidant defenses
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
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
Insulin signaling in the brain has emerged as a critical pathway in neurodegeneration. Unlike peripheral insulin resistance, brain insulin resistance in PD involves:
- High density in basal ganglia, hippocampus, and cerebral cortex
- Present on dopaminergic neurons
- Involved in modulating dopamine signaling
Insulin → IR → IRS → PI3K → Akt → mTOR/GSK3β
↓
GLUT4 translocation
Autophagy regulation
Synaptic plasticity
- Impaired insulin signaling in the SNc of PD patients
- Reduced IR expression and signaling
- Links between insulin resistance and alpha-synuclein toxicity[@insulinsignaling2024]
The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and metabolism:
- Protein synthesis regulation
- Autophagy inhibition (via ULK1 inhibition)
- Cell growth promotion
- Metabolic reprogramming
- mTOR hyperactivity may contribute to impaired autophagy
- Alpha-synuclein accumulation may result from reduced autophagy
- mTOR inhibition promotes alpha-synuclein clearance in models[@mtor2023]
The balance between insulin signaling and mTOR activity is crucial for neuronal health.
The mitogen-activated protein kinase pathway is also modulated by insulin:
- Neuronal differentiation
- Synaptic plasticity
- Cell survival
- Memory formation
- ERK pathway may be neuroprotective
- Insulin's effects on ERK could promote neuronal resilience
Glutathione (γ-glutamyl-cysteinyl-glycine) is the most abundant cellular antioxidant:
- Scavenging ROS directly
- Regenerating oxidized vitamin C and E
- Detoxifying xenobiotics
- Maintaining protein thiols in reduced state
- Glutathione peroxidase (GPx): Reduces H2O2 and lipid peroxides
- Glutathione S-transferase (GST): Conjugates detoxified compounds
- Glutathione reductase (GR): Regenerates GSH from GSSG
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
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
- 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
- Standard therapeutic dose of glutathione
- Optimized for nasal absorption
- Combined with insulin for synergistic effect
| 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 |
The trial assesses multiple biomarkers:
- MDS-UPDRS Part III (gold standard)
- Timed Up and Go (functional mobility)
- Gait analysis
- Cambridge Brain Sciences computerized battery
- Verbal fluency (FAS test)
- Executive function tests
- Depression (HAMD)
- Quality of Life (PDQ-39)
- Sleep assessments
| Trial |
Intervention |
Phase |
Status |
| NCT02064114 |
Intranasal insulin |
Phase 2 |
Completed[@intranasalpd2022] |
| NCT05446938 |
Intranasal insulin + GSH |
Phase 2 |
Recruiting (this trial) |
| Agent |
Route |
Results |
| Coenzyme Q10 |
Oral |
Mixed results |
| Glutathione (IV) |
Intravenous |
Short-lived effects |
| N-acetylcysteine |
Oral |
Some benefits |
| GSH (intranasal) |
Intranasal |
Under investigation |
Results may identify:
- Subgroups who respond best to combination therapy
- Biomarkers predicting treatment response
- Optimal timing for intervention
Success would support:
- Triple combinations (insulin + GSH + dopaminergic)
- Sequential therapy approaches
- Personalized treatment selection
Intranasal insulin carries minimal hypoglycemia risk because:
- Does not significantly enter systemic circulation
- No effect on peripheral glucose
- However, diabetic patients are excluded
Potential local effects:
- Nasal irritation or congestion
- Rare epistaxis
- Usually mild and transient
With extended use:
- Effect on nasal mucosa
- Potential impact on olfaction
- Immunogenicity considerations
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
Both insulin and glutathione distribute to:
- Cerebrospinal fluid
- Olfactory bulb
- Basal ganglia
- Other CNS regions
¶ Study Sites and Enrollment
The trial is being conducted at specialized PD centers:
- Institute for Neuroimmune Medicine
- Focus on neuroinflammatory conditions
- PI: Irina Rozenfeld, DPN, APRN
- Las Mercedes Medical Research
- Community-based research site
- PI: Frank Alvarez, MD
- Target: 56 participants
- Randomization: 1:1 active:placebo
- Duration: 28 weeks total
- Unknown, ClinicalTrials.gov. NCT05266417: Intranasal Insulin and Glutathione as an Add-On Therapy in Parkinson's Disease (NOSE-PD) (n.d.)
- Unknown, Gateway Institute for Brain Research. NOSE-PD Study Information (n.d.)
- Craft S et al, Intranasal insulin therapy for Alzheimer's disease and Parkinson's disease (2018)
- Aviles-Olmos I et al, Parkinson's disease, insulin resistance and novel dopamine agonists (2013)
- Dexter DT et al, Glutathione depletion in the substantia nigra in Parkinson's disease (1992)
- Intranasal insulin for Parkinson's disease: Safety and efficacy results from a randomized controlled trial (2022)
- Oxidative stress mechanisms in Parkinson's disease: Novel therapeutic targets (2023)
- Brain insulin signaling in neurodegeneration: Implications for Alzheimer's and Parkinson's disease (2024)
- Intranasal drug delivery to the brain: Mechanisms and clinical applications (2023)
- Glutathione therapy for Parkinson's disease: Current status and future perspectives (2023)
- Gut microbiome alterations in Parkinson's disease: Implications for pathogenesis and treatment (2022)
- mTOR signaling in Parkinson's disease: Therapeutic implications (2023)