Parkinson Disease
Conditions
Keywords
intranasal, insulin
Brief summary
This project will investigate exploratory outcomes related to the effect of intranasal insulin on cognition, mood, apathy and motor performance of subjects with Parkinson's disease over a 3 week period.
Detailed description
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's dementia and was originally described as a motor disease. The diagnosis of PD is still based on the core motor features of bradykinesia, resting tremor, and rigidity, primarily as a result of degeneration of nigrostriatal dopaminergic neurons. In addition to the classic motor symptoms, however, PD is increasingly recognized as a multisystem disorder. A variety of non-motor symptoms, including cognitive deficits and dementia, are commonly observed in patients with PD. In this study, we aim to investigate which intranasal insulin dose out of three doses and placebo, administered at three different doses or placebo over a 21-day period, is the optimum dosage based on safety and tolerability in Parkinson's disease. A similar design was used in a trial investigating intranasal oxytocin in frontotemporal dementia. Dosing for the first two groups of this study is based on previously conducted intranasal insulin studies in Alzheimer's disease (AD) and mild cognitive impairment (MCI), using daily doses on 20 and 40 IU of intranasal insulin. Higher dose have been found to be safe in healthy adults. Prior studies performed have demonstrated favorable effects of this regimen in the MCI/AD population without peripheral hypoglycemia.
Interventions
DRUGRegular Novolin R
Intranasal insulin
DRUGPlacebo
Intranasal placebo (0.9% saline)
Sponsors
HealthPartners Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
All participants, care providers, investigators, and outcomes assessors are masked.
Intervention model description
Participants will be randomly assigned to one of 3 treatment groups or the placebo group. * 20 international units twice daily (n=7) * 40 international units twice daily (n=7) * 80 international units twice daily (n=9) * placebo (n=7)
Eligibility
Sex/Gender
ALL
Age
41 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
* Subject has Idiopathic PD defined by the cardinal sign, bradykinesia, plus the presence of at least 1 of the following: resting tremor or rigidity and without any other known or suspected cause of Parkinsonism (according to Movement disorder society (MDS) clinical diagnostic criteria for Parkinson's disease confirmed by a fellowship trained movements disorder specialist * Subject is Hoehn \& Yahr stage less than or equal to 3 * Subject has a MOCA score ≥10. * Subject is \> 40 and \<90 years of age. * Female subjects are post-menopausal or have a negative pregnancy test * The subject must be proficient in speaking, reading and understanding English in order to comply with procedural testing of cognitive function, memory and physiology. * Subject has provided informed written consent prior to participation. In the event that subject is legally unable to provide informed written consent due to deterioration in cognitive abilities, fully informed written consent must be provided by a legally authorized representative. * Subject is on a stable dose (at least 1 month prior to baseline visit) of antiparkinsonian agents and is willing to remain on this dose for the duration of the study. If the subject is on a cholinesterase inhibitor, a stable dose without changes for 1 month is also required. * Subject has undergone a brain CT or MRI prior to the study as part of their previous diagnostic workup for PD to rule out underlying structural lesions, as determined clinically significant by the investigator
Exclusion criteria
* Subject has atypical Parkinson's syndrome(s) due to drugs (e.g., metoclopramide, neuroleptics), metabolic neurogenetic disorders (e.g., Wilson's Disease), encephalitis, cerebrovascular disease, or degenerative disease (e.g., Progressive Supranuclear Palsy, Multiple System Atrophy, Corticobasal Degeneration, Lewy Body dementia) * Subject has medical history and/or clinically determined disorders: chronic sinusitis, untreated thyroid disease, or significant head trauma. * Subject has history of any of the following: moderate to severe pulmonary disease, poorly controlled congestive heart failure, significant cardiovascular and/or cerebrovascular events within previous 6 months, condition known to affect absorption, distribution, metabolism, or excretion of drugs such as any hepatic, renal or gastrointestinal disease or any other clinically relevant abnormality that inclusion would pose a safety risk to the subject as determined by investigator. * Subject has had previous nasal and/or oto-pharyngeal surgery and severe deviated septum and/or other anomalies. * Subject has history of any psychiatric illness that would pose a safety risk to the subject as determined by investigator. * Subject is currently taking sedative medications that are clinically contraindicated as determined by investigator. * Subject has undergone a recent change (\<1 month) in their anti-parkinsonian medication, cholinesterase inhibitor or anti-depressant medication. * Subject has current or recent drug or alcohol abuse or dependence as defined by Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV TR). * Screening laboratory results that are medically relevant, in which inclusion would pose a safety risk to the subject as determined by investigator. * Subject has participated in a clinical trial investigation within 3 months of this study. * Subject has an insulin allergy. * Subject has Insulin-dependent diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Measured by Fasting Glucose | baseline and 3 weeks | Pre-post change in fasting glucose (mg/dL). A larger decrease in fasting glucose indicates a less safe treatment. |
| Safety Measured by Count of Safety Events | 3 weeks | Composite safety event - this is a count of either a reduction of fasting glucose to \<70 mg/dL or an unintended reduction of weight \>5%. A larger composite event count indicates a less safe treatment. |
| Safety Measured by Body Weight | baseline and 3 weeks | Pre-post change in body weight (lbs). An unintended decrease in body weight indicates a less safe treatment. |
| Safety Measured by the Number of Serious Adverse Events (SAE) and Adverse Events (AE) | 3 weeks | Total number of AEs/SAEs during the course of treatment. More AEs/SAEs indicates a less safe treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive Function Measured by the Montreal Cognitive Assessment (MoCA) | 5 weeks | Pre-post difference. Total sum of scores. Range: 0-30. Higher score indicates less memory loss |
| Cognitive Function Measured by the Weschler Adult Intelligence Scale - Fourth Edition (WAIS-IV) Digit Span | 3 weeks | Pre-post difference. Scaled score. Range: 1-19. Forward and backward. Lower score indicates more impairment. |
| Cognitive Function Measured by the Trailmaking Test Part A Time | baseline and 3 weeks | Pre-post difference. T-score. Mean: 50, Standard deviation: 10. A higher T-score indicates a better outcome/performance. Clinically, 1-1.5 standard deviations would be significant, 2 standard deviations would be considered abnormal/impaired. |
| Cognitive Function Measured by the Trailmaking Test Part B Time | baseline and 3 weeks | Pre-post difference. T-score. Mean: 50, Standard deviation: 10. A higher T-score indicates a better outcome/performance. Clinically, 1-1.5 standard deviations would be significant, 2 standard deviations would be considered abnormal/impaired. |
| Cognitive Function Measured by the Trailmaking Test Parts A & B Errors | 3 weeks | Pre-post difference. Total number of errors. No range. More errors indicate more impairment. |
| Cognitive Function Measured by the Judgement of Line Orientation | baseline and 3 weeks | Judgement of Line Orientation is an assessment of visuospatial ability. A Z-score of 0 represents the population mean. Pre-post difference. A positive difference indicates an improvement. |
| Cognitive Function Measured by the Logical Memory Scaled Scores | baseline and 3 weeks | Pre-post difference. Scaled score. Range: 1-19. Logical memory immediate and delayed. Lower score indicates more impairment. |
| Cognitive Function Measured by the Logical Memory, Recognition | baseline and 3 weeks | Pre-post difference in median category from baseline to 3 weeks on the Logical memory, recognition subscale. Scoring of this and all outcomes were based on best practices conveyed by study neuropsychologist during study design, and scoring approaches were chosen completely a priori. The recognition outcome of the LM test is derived from a series of conversions, as follows. First, the raw "process" score is converted to cumulative percentage (0-100). Because the cumulative percentage distribution is known to be skewed, best practice is to report scores as the following ordinal categorizations of cumulative percentages: \<1, 3-9, 10-16, 17-25, 26-50, 51-75, and \>75. To analyze them using simple statistics, these ordinal categories are converted to integer values (1-7), and the change in median ordinal category is presented along with 95% confidence intervals, generated by the Wilcoxon signed rank test with continuity correction. |
| Cognitive Function Measured by the Hopkins Verbal Learning Test - Revised (HVLT) | baseline and 3 weeks | Pre-post difference. T-score. Mean: 50, Standard deviation: 10. A higher T-score indicates a better outcome/performance. Clinically, 1-1.5 standard deviations would be significant, 2 standard deviations would be considered abnormal/impaired. |
| Cognitive Function Measured by the Visuospatial Memory Test - Revised (BVMT) | 3 weeks | Pre-post difference. T-score. Mean: 50, Standard deviation: 10. A higher T-score indicates a better outcome/performance. Clinically, 1-1.5 standard deviations would be significant, 2 standard deviations would be considered abnormal/impaired. |
| Cognitive Function Measured by the Stroop Color Word Test (CWT) | baseline and 3 weeks | Pre-post difference. T-score. Mean: 50, Standard deviation: 10. A higher T-score indicates a better outcome/performance. Clinically, 1-1.5 standard deviations would be significant, 2 standard deviations would be considered abnormal/impaired. |
| Cognitive Function Measured by Fluency | baseline and 3 weeks | Pre-post difference. T-score. Mean: 50, Standard deviation: 10. A higher T-score indicates a better outcome/performance. Clinically, 1-1.5 standard deviations would be significant, 2 standard deviations would be considered abnormal/impaired. |
| Mood Measured by the Beck Depression Inventory - Second Edition | baseline and 3 weeks | Pre-post difference. Raw score. Range: 0-63. Higher score indicates more symptomatic. |
| Apathy Measured by the Apathy Scale | baseline and 3 weeks | Pre-post difference. Raw score. Range: 0-42. Higher score indicates more symptomatic. |
| Mood Measured by the Columbia Suicide Severity Rating (C-SSRS) | baseline and 3 weeks | Pre-post difference. Raw score. Range:1 or 0. 1 score - more symptomatic, 0 score - no symptoms. |
| Motor Function as Measured by the United Parkinson's Disease Rating Scale (UPDRS-III) | baseline and 3 weeks | Pre-post difference. Raw score. Range: 0-72. Higher score indicates more symptomatic. |
| Cognitive Function Measured by Visuospatial Memory Test - Revised (BVMT Recognition) | baseline and 3 weeks | Pre-post difference in median category from baseline to 3 weeks on the Brief Visual Spatial Memory Test - Revised recognition. Scoring of this and all outcomes were based on best practices conveyed by study neuropsychologist during study design, and scoring approaches were chosen completely a priori. The recognition outcome of the BVMT test is derived from a series of conversions, as follows. First, the raw score is converted to cumulative percentage (0-100). Because the cumulative percentage distribution is known to be skewed, best practice is to report scores as the following ordinal categorizations of cumulative percentages: \<2, 2-5, 6-10, 11-16, \>16. To analyze them using simple statistics, these ordinal categories are converted to integer values (1-5), and the change in median ordinal category is presented along with 95% confidence intervals, generated by the Wilcoxon signed rank test with continuity correction. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJulia C Johnson, MD
HealthPartners Neurology
Participant flow
Pre-assignment details
One participant was deemed ineligible prior to randomization. One participant completed treatment but was removed before analysis following the revision of eligibility criteria around MOCA score. 28 participants who completed treatment and were eligible were included in the analysis.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 63.4 years STANDARD_DEVIATION 5.1 |
| Baseline HbA1C | 5.7 percent STANDARD_DEVIATION 0.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Montreal Cognitive Assessment (MoCA) | 24.5 units on a scale STANDARD_DEVIATION 1.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 2 Participants |
| UPDRS | 24.4 units on a scale STANDARD_DEVIATION 10.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 7 | 0 / 9 | 0 / 6 |
| other Total, other adverse events | 6 / 6 | 7 / 7 | 9 / 9 | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 7 | 0 / 9 | 0 / 6 |
Outcome results
None listed