Intranasal Insulin for Improving Cognitive Function in Multiple Sclerosis

Sponsor

Johns Hopkins University (Other)

Overall Status

Completed

CT.gov ID

NCT02988401

Collaborator

United States Department of Defense (U.S. Fed)

105

Enrollment

Location

Arms

48.5

Actual Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will evaluate if giving insulin that is administered in the nostrils (intranasal) is safe and tolerable for people with multiple sclerosis (MS). It is also being done to evaluate if intranasal insulin improves cognitive function in people with MS and to evaluate how it might be working.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis, Relapsing-Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Primary Progressive	Drug: Insulin Drug: Placebo (Sterile diluent)	Phase 1/Phase 2

Detailed Description

Cognitive impairment is common in and devastating to people with MS. MS is a common, chronic, central nervous system (CNS) disease characterized by inflammation, demyelination, and neurodegeneration. One of the most devastating symptoms of this disease is impaired cognitive function, which is common and present in over 60% of individuals with MS. MS-related cognitive impairment is associated with lowered quality of life and reduced functional capacity, including loss of employment, impaired social relationships, compromised driving safety, and poor adherence to treatment. Impaired cognitive functioning has been observed early in the disease, sometimes even before diagnosis, and cognitive function has been shown to decline longitudinally, both over the short- and long-term. Several cognitive domains are impacted in people with MS, including attention, memory, executive functioning, and especially processing speed.

To date, multiple pharmacologic interventions have been assessed with disappointing results. There was no significant difference between treatment and placebo for cognition in randomized control trials of donepezil, aminopyridines, gingko biloba, and memantine. Psychostimulants demonstrated some efficacy, but only in secondary outcome measures. Behavioral interventions show promise but are understudied. Furthermore, cognitive rehabilitation is often time consuming, costly, and not universally available. Hence, there is an urgent need to identify or develop novel therapies that can help improve cognitive function in MS.

Intranasal insulin is extremely safe and tolerable in other populations, allowing for concentrated delivery to the nervous system. An intranasal delivery system provides a non-invasive way to bypass the blood-brain barrier and allow rapid delivery of a medication to the CNS via the olfactory and trigeminal perivascular channels.The main advantage of the delivery system is reducing systemic side effects via limiting a medication's exposure to peripheral organs and tissues.

Insulin administration has been shown to improve memory and learning in healthy people and in those with neurodegenerative diseases. Intranasal insulin has been shown to have neuroprotective and restorative effects in several human clinical trials. Overall, findings suggest that intranasal insulin not only affects cognitive function acutely, but that over time, there may be associated structural changes that lead to a more permanent treatment benefit. Cognitive dysfunction is very common in MS and can be devastating, therefore a treatment intervention (i.e., intranasal insulin) can help both acutely and longitudinally.

The primary aim of this study is to assess the safety and tolerability of intranasal insulin in people with MS. The secondary aim is to evaluate if intranasal insulin improves learning and memory in people with MS. The third aim is to evaluate the impact of intranasal insulin on measures of oxidative stress, axonal injury, cellular stress, and energy metabolism in MS.

Study Design

Study Type:

Interventional

Actual Enrollment :

105 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Intranasal Insulin for Improving Cognitive Function in Multiple Sclerosis

Actual Study Start Date :

Dec 1, 2017

Actual Primary Completion Date :

Dec 17, 2021

Actual Study Completion Date :

Dec 17, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intranasal insulin 20 international units Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.	Drug: Insulin All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.
Experimental: Intranasal insulin 10 international units Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.	Drug: Insulin All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.
Placebo Comparator: Intranasal saline Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.	Drug: Placebo (Sterile diluent) All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.

Arm

Intervention/Treatment

Experimental: Intranasal insulin 20 international units

Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.

Drug: Insulin

All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.

Experimental: Intranasal insulin 10 international units

Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.

Drug: Insulin

All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.

Placebo Comparator: Intranasal saline

Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.

Drug: Placebo (Sterile diluent)

All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.

Outcome Measures

Primary Outcome Measures

Change from baseline in cognitive function as assessed by the Symbol Digit Modalities Test (SDMT) [1 year]
This task will be performed at five study visits. The SDMT is one of the most commonly used tests to assess processing speed in the MS population and is included in the Minimal Assessment of Cognitive Function in MS (MACFIMS). The score is the number of correct answers in a 90-second interval out of the total number of responses. The total score provides a measure of the speed and accuracy of symbol-digit substitutions.

Secondary Outcome Measures

Determine safety by assessing the number of subjects with adverse events with treatment as compared to placebo. [1 year]
An adverse event will be defined as any occurrence or worsening of an undesirable or unintended sign, symptom (or abnormal laboratory test), or disease temporally associated with the use of a medicinal product or intervention, whether or not it is considered related to the product/intervention.
Determine safety by assessing the number of subjects with adverse events with placebo. [1 year]
An adverse event will be defined as any occurrence or worsening of an undesirable or unintended sign, symptom (or abnormal laboratory test), or disease temporally associated with the use of a medicinal product or intervention, whether or not it is considered related to the product/intervention.
Change from baseline in cognitive function as assessed by the Controlled Oral Word Association Test (COWAT). [1 year]
This test measures phonemic fluency.Outcome - number of words produced in one minute for each of 3 letters.
Change from baseline in cognitive function as assessed by the California Verbal Learning Test, Second Edition (CVLT-II). [1 year]
This is a verbal learning and memory test.Outcome - number of words (shopping list) remembered after 20 min delay with no cues.
Change from baseline in cognitive function as assessed by the Brief Visuospatial Memory Test - Revised (BVMT-R). [1 year]
This is a visual, nonverbal test of learning and memory. Six equivalent, alternate stimulus forms consist of six geometric figures printed in a 2 x 3 array on separate pages. In three Learning Trials, the subject views the stimulus page for 10 seconds and is asked to draw as many of the figures as possible in their correct location.
Change from baseline in cognitive function as assessed by the Rao-version of the Paced Auditory Serial Addition Test (PASAT). [1 year]
The Rao-version of the PASAT evaluates processing speed, working memory, and basic addition skills. Single digits are presented every 2-3 seconds and the subject must add each new digit to the one immediately prior to it.
Change from baseline in cognitive function as assessed by the Judgement of Line Orientation Test (JLO). [1 year]
Judgment of Line Orientation Test measures a person's ability to match the angle and orientation of lines in space. Participants are asked to match two angled lines to a set of 11 lines that are arranged in a semicircle and separated 18 degrees from each other.
Change from baseline in cognitive function as assessed by the Delis-Kaplan Executive Function System sorting test. [1 year]
This test measures executive functioning, concept formation, and cognitive flexibility. The subject is asked to sort cards into two groups, with 3 cards per group, according to different concepts or rules. Accuracy and descriptions of the sorting concepts are recorded.

Other Outcome Measures

Assess depression severity, as measured by the Beck Depression Inventory-II (BDI-II). [1 year]
The BDI-II is a 21-question multiple-choice self-report inventory test for measuring the severity of depression.
Evaluation of impact of study products on health related quality of life using the Functional Assessment of Multiple Sclerosis Questionnaire (FAMS). [1 year]
FAMS is a self-reported health-related quality-of-life instrument for people with multiple sclerosis. Subjects rate six quality-of-life domains: Mobility, Symptoms, Emotional well-being, General contentment, Thinking/fatigue, and Family/social well-being.
Evaluation of how overall sleep quality impacts people with MS using a sleep questionnaire. [1 year]
The sleep questionnaire asks subjects to report various aspects related to their sleep routine.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Meets 2010 criteria for MS
No relapse in past 3 months
At least mild cognitive impairment (based off of SDMT/PST score)
Capacity to learn and self-administer intranasal insulin/placebo, or presence of a caregiver with such capacity who is willing to do it for the duration of the trial
Untreated/on the same MS therapy for at least 6 months, with no anticipated change in the next year
Willing to prevent pregnancy during study if female of childbearing potential

Exclusion Criteria:

Current, active major depression
No tricyclic antidepressant or anticonvulsant (except carbamazepine, pregabalin or gabapentin) use within 6 weeks of screening; if on oxybutynin or tolterodine, on stable dose for > 6 months without plans for changing dose in next year
If taking selective serotonin (± norepinephrine) reuptake inhibitors, pregabalin, gabapentin, sympathomimetic, monoamine oxidase inhibitor, antipsychotic, amantadine, cholinesterase inhibitor, memantine, modafanil, armodafinil, or evening short-acting benzodiazepines, on stable dose for 6 weeks or greater
Pregnant or nursing
THC; illicit drug or alcohol abuse in past 3 months
History of diabetes mellitus or insulin resistance
Active liver disease, stage IV/V kidney disease or severe metabolic derangements
CNS disorder other than MS or headache

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

Johns Hopkins University
United States Department of Defense

Investigators

Principal Investigator: Ellen Mowry, MD, MCR, Johns Hopkins University
Principal Investigator: Scott Newsome, DO, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Johns Hopkins University

ClinicalTrials.gov Identifier:

NCT02988401

Other Study ID Numbers:

IRB00095554

First Posted:

Dec 9, 2016

Last Update Posted:

Jan 3, 2022

Last Verified:

Dec 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Multiple Sclerosis

Multiple Sclerosis, Relapsing-Remitting

Multiple Sclerosis, Chronic Progressive

Sclerosis

Insulin

Study Results

No Results Posted as of Jan 3, 2022