- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02988401
Intranasal Insulin for Improving Cognitive Function in Multiple Sclerosis
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Maryland
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Baltimore, Maryland, United States, 21287
- Johns Hopkins University School of Medicine
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / 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.
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All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.
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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.
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All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.
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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.
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All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT)
Time Frame: Up to week 24 visit
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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).
Higher scores reflect a better outcome (range 0 to 110).
In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the SDMTs acquired within the active treatment phase (from baseline to week 24 visit).
We then calculated and report the average change per week in the SDMT.
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Up to week 24 visit
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Adverse Events Leading to Study Discontinuation
Time Frame: Up to week 24 visit
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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.
We report overall adverse events in the relevant section.
Here, we report adverse events that led to study discontinuation.
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Up to week 24 visit
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Fingerstick Blood Glucose (Subset)
Time Frame: At the baseline visit, monitored twice within the 90 minutes following the first dose administration of study drug
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Fingerstick blood glucose levels were monitored twice within the 90 minutes following the first dose administration of study drug for the first 15 participants.
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At the baseline visit, monitored twice within the 90 minutes following the first dose administration of study drug
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Change From Baseline in Cognitive Function as Assessed by the Controlled Oral Word Association Test (COWAT)
Time Frame: Up to week 24 visit
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This test measures phonemic fluency.
The test scores the number of words a participant can provide that begin with a specified letter within one minute, such that scores range from zero (worst) to an infinite number (better).
Total score is sum of three 60-second trials.
In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the COWAT scores acquired within the active treatment phase (from baseline to week 24 visit).
We then calculated and report the average change per week in the score.
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Up to week 24 visit
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Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test, Second Edition (CVLT-II)
Time Frame: Up to week 24 visit
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This is a verbal learning and memory test.
Scores range from zero to 16; a higher number is better.
In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the CVLT-II scores acquired within the active treatment phase (from baseline to week 24 visit).
We then calculated and report the average change per week in the score.
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Up to week 24 visit
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Change From Baseline in Cognitive Function as Assessed by the Brief Visuospatial Memory Test - Revised (BVMT-R) Delayed Recall
Time Frame: Up to week 24 visit
|
This is a visual, nonverbal test of learning and memory.
Scores range from zero to 12; higher is better.
In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the BVMT-R delayed recall scores acquired within the active treatment phase (from baseline to week 24 visit).
We then calculated and report the average change per week in the score.
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Up to week 24 visit
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Change in Cognitive Function as Assessed by the Rao-version of the Paced Auditory Serial Addition Test (PASAT)
Time Frame: Up to week 24 visit
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The Rao-version of the PASAT evaluates processing speed, working memory, and basic addition skills.
Scores range from zero to 60; higher is better.
Herein we present 3-second PASAT results ("PASAT-3").
In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include PASAT-3 scores acquired within the active treatment phase (from baseline to week 24 visit).
We then calculated and report the average change per week in the SDMT.
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Up to week 24 visit
|
Change From Baseline in Cognitive Function as Assessed by the Judgement of Line Orientation Test (JLO)
Time Frame: Up to week 24 visit
|
Judgment of Line Orientation Test measures a person's ability to match the angle and orientation of lines in space.
Scores range from zero to 30; higher is better.
In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include JLO data acquired within the active treatment phase (from baseline to week 24 visit).
We then calculated and report the average change per week in the score.
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Up to week 24 visit
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Change From Baseline in Cognitive Function as Assessed by the Delis-Kaplan Executive Function System Sorting Test
Time Frame: Up to week 24 visit
|
This test measures executive functioning, concept formation, and cognitive flexibility.
Scores range from zero to 16; higher is better.
In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include DKEFS correct sort scores acquired within the active treatment phase (from baseline to week 24 visit).
We then calculated and report the average change per week in the score.
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Up to week 24 visit
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Assess Depression Severity, as Measured by the Beck Depression Inventory-II (BDI-II)
Time Frame: Up to week 24 visit
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The BDI-II is a 21-question multiple-choice self-report inventory test for measuring the severity of depression.
Scores range from zero to 63; higher scores indicate greater depression.
In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the BDI-II scores acquired within the active treatment phase (from baseline to week 24 visit).
We then calculated and report the average change per week in the scores.
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Up to week 24 visit
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Evaluation of Impact of Study Products on Health Related Quality of Life Using the Functional Assessment of Multiple Sclerosis Questionnaire (FAMS)
Time Frame: Up to week 24 visit
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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.
Scores range from zero to 176; higher scores indicate better health-related quality of life.
In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the FAMS scores acquired within the active treatment phase (from baseline to week 24 visit).
We then calculated and report the average change per week in the score.
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Up to week 24 visit
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Evaluation of How Overall Sleep Quality Impacts People With MS Using a Sleep Questionnaire (Pittsburgh Sleep Quality Index)
Time Frame: Up to week 24 visit
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The sleep questionnaire asks subjects to report various aspects related to their sleep routine.
Scores range from zero to 21; higher score indicates worse sleep quality.
In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the PSQIs acquired within the active treatment phase (from baseline to week 24 visit).
We then calculated and report the average change per week in the score.
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Up to week 24 visit
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Ellen Mowry, MD, MCR, Johns Hopkins University
- Principal Investigator: Scott Newsome, DO, Johns Hopkins University
Publications and helpful links
General Publications
- Mitolo M, Venneri A, Wilkinson ID, Sharrack B. Cognitive rehabilitation in multiple sclerosis: A systematic review. J Neurol Sci. 2015 Jul 15;354(1-2):1-9. doi: 10.1016/j.jns.2015.05.004. Epub 2015 May 9.
- Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. doi: 10.1001/archneurol.2011.233. Epub 2011 Sep 12.
- Benedict RH, Cookfair D, Gavett R, Gunther M, Munschauer F, Garg N, Weinstock-Guttman B. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc. 2006 Jul;12(4):549-58. doi: 10.1017/s1355617706060723.
- Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology. 1991 May;41(5):692-6. doi: 10.1212/wnl.41.5.692.
- Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C. Aminopyridines for symptomatic treatment in multiple sclerosis. Cochrane Database Syst Rev. 2001;(4):CD001330. doi: 10.1002/14651858.CD001330.
- DeLuca J, Barbieri-Berger S, Johnson SK. The nature of memory impairments in multiple sclerosis: acquisition versus retrieval. J Clin Exp Neuropsychol. 1994 Apr;16(2):183-9. doi: 10.1080/01688639408402629.
- Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol. 2001 Oct;58(10):1602-6. doi: 10.1001/archneur.58.10.1602.
- DeLuca J. What we know about cognitive changes in multiple sclerosis. In: LaRocca N, Kalb R, eds. Multiple Sclerosis: Understanding the Cognitive Challenges. New York: Demos Health; 2006: 17-40.
- Rao S. Cognitive Function in Patients with Multiple Sclerosis: Impairment and Treatment. IJMSC 2004;1:9-22.
- Ruet A, Deloire M, Hamel D, Ouallet JC, Petry K, Brochet B. Cognitive impairment, health-related quality of life and vocational status at early stages of multiple sclerosis: a 7-year longitudinal study. J Neurol. 2013 Mar;260(3):776-84. doi: 10.1007/s00415-012-6705-1. Epub 2012 Oct 19.
- Strober LB, Christodoulou C, Benedict RH, Westervelt HJ, Melville P, Scherl WF, Weinstock-Guttman B, Rizvi S, Goodman AD, Krupp LB. Unemployment in multiple sclerosis: the contribution of personality and disease. Mult Scler. 2012 May;18(5):647-53. doi: 10.1177/1352458511426735. Epub 2011 Dec 19.
- Morrow SA, Drake A, Zivadinov R, Munschauer F, Weinstock-Guttman B, Benedict RH. Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline. Clin Neuropsychol. 2010 Oct;24(7):1131-45. doi: 10.1080/13854046.2010.511272. Epub 2010 Sep 8.
- Schultheis MT, Weisser V, Ang J, Elovic E, Nead R, Sestito N, Fleksher C, Millis SR. Examining the relationship between cognition and driving performance in multiple sclerosis. Arch Phys Med Rehabil. 2010 Mar;91(3):465-73. doi: 10.1016/j.apmr.2009.09.026.
- Patti F. Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. Patient Prefer Adherence. 2010 Feb 4;4:1-9. doi: 10.2147/ppa.s8230.
- Amato MP, Razzolini L, Goretti B, Stromillo ML, Rossi F, Giorgio A, Hakiki B, Giannini M, Pasto L, Portaccio E, De Stefano N. Cognitive reserve and cortical atrophy in multiple sclerosis: a longitudinal study. Neurology. 2013 May 7;80(19):1728-33. doi: 10.1212/WNL.0b013e3182918c6f. Epub 2013 Apr 10.
- Lacy M, Hauser M, Pliskin N, Assuras S, Valentine MO, Reder A. The effects of long-term interferon-beta-1b treatment on cognitive functioning in multiple sclerosis: a 16-year longitudinal study. Mult Scler. 2013 Nov;19(13):1765-72. doi: 10.1177/1352458513485981. Epub 2013 May 7.
- DeLuca J, Gaudino EA, Diamond BJ, Christodoulou C, Engel RA. Acquisition and storage deficits in multiple sclerosis. J Clin Exp Neuropsychol. 1998 Jun;20(3):376-90. doi: 10.1076/jcen.20.3.376.819.
- Thornton AE, Raz N, Tucke KA. Memory in multiple sclerosis: contextual encoding deficits. J Int Neuropsychol Soc. 2002 Mar;8(3):395-409. doi: 10.1017/s1355617702813200.
- DeLuca J, Chelune GJ, Tulsky DS, Lengenfelder J, Chiaravalloti ND. Is speed of processing or working memory the primary information processing deficit in multiple sclerosis? J Clin Exp Neuropsychol. 2004 Jun;26(4):550-62. doi: 10.1080/13803390490496641.
- Demaree HA, DeLuca J, Gaudino EA, Diamond BJ. Speed of information processing as a key deficit in multiple sclerosis: implications for rehabilitation. J Neurol Neurosurg Psychiatry. 1999 Nov;67(5):661-3. doi: 10.1136/jnnp.67.5.661.
- Krupp LB, Christodoulou C, Melville P, Scherl WF, Pai LY, Muenz LR, He D, Benedict RH, Goodman A, Rizvi S, Schwid SR, Weinstock-Guttman B, Westervelt HJ, Wishart H. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology. 2011 Apr 26;76(17):1500-7. doi: 10.1212/WNL.0b013e318218107a.
- Lovera JF, Kim E, Heriza E, Fitzpatrick M, Hunziker J, Turner AP, Adams J, Stover T, Sangeorzan A, Sloan A, Howieson D, Wild K, Haselkorn J, Bourdette D. Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial. Neurology. 2012 Sep 18;79(12):1278-84. doi: 10.1212/WNL.0b013e31826aac60. Epub 2012 Sep 5.
- Lovera JF, Frohman E, Brown TR, Bandari D, Nguyen L, Yadav V, Stuve O, Karman J, Bogardus K, Heimburger G, Cua L, Remingon G, Fowler J, Monahan T, Kilcup S, Courtney Y, McAleenan J, Butler K, Wild K, Whitham R, Bourdette D. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010 Jun;16(6):715-23. doi: 10.1177/1352458510367662. Epub 2010 May 18.
- Morrow SA, Kaushik T, Zarevics P, Erlanger D, Bear MF, Munschauer FE, Benedict RH. The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial. J Neurol. 2009 Jul;256(7):1095-102. doi: 10.1007/s00415-009-5074-x. Epub 2009 Mar 5.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Immune System Diseases
- Demyelinating Autoimmune Diseases, CNS
- Autoimmune Diseases of the Nervous System
- Demyelinating Diseases
- Autoimmune Diseases
- Multiple Sclerosis
- Multiple Sclerosis, Chronic Progressive
- Sclerosis
- Multiple Sclerosis, Relapsing-Remitting
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Insulin
Other Study ID Numbers
- IRB00095554
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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