Investigation of the Safety of Intranasal Glulisine in Down Syndrome

Study Overview
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Brief Summary
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This study is a single center, randomized, double-blind, placebo-controlled, cross-over pilot study designed to assess the safety of intranasally (IN) delivered glulisine versus placebo in patients with DS. Subjects will be randomized into this cross-over study and within subject comparisons conducted between single treatment of intranasal insulin glulisine and single treatment of intranasal placebo. All subjects will also receive a single treatment of placebo prior to randomization to ensure adherence to study procedures.

Official Title
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A Double-Blind, Placebo-Controlled Pilot Investigation of the Safety of Intranasal Glulisine in Down Syndrome

Conditions
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Down Syndrome

Intervention / Treatment
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* Drug: Insulin glulisine
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 35-80 years with a Down syndrome diagnosis that is confirmed by karyotype. Vital signs must be within normal limits for their age. (Medically treated hypertension will be allowed). Must have an electrocardiogram free of clinically significant findings. Must have an authorized representative to provide written informed consent. Level of speech and comprehension of verbal commands are sufficient to understand and to answer simple requests. Must have a reliable caregiver or family member who agrees to accompany the subject to all visits, provide information about the subject as required by this protocol. Must be independent for activities of daily living. Must tolerate the initial IN treatment of placebo and adhere to study procedures. Exclusion Criteria: Any current psychiatric or neurologic diagnosis other than Down syndrome or Down syndrome with dementia that is judged to impact cognition. Subjects who currently meet or have within the past five years met DSM-IV (Diagnostic and Statistical Manual) criteria for drug or alcohol abuse or dependence. Subjects residing in a skilled nursing facility or subjects who are anticipated to enter a nursing home within the next 6 months. (Subjects may reside in group homes, assisted living, or other residential settings where they do not require 24 hour skilled nursing.) Subjects receiving any experimental drug for Down syndrome within the past 30 days of screening visit. Subjects with significant allergies to or other significant intolerance insulin. Presence of active seizure disorder. Presence of significant aggression or agitation that may impact participation with testing and IN administration. All subjects must have NPI-C aggression and agitation subscore ≤ 4 (severity ≤ 2; frequency ≤ 2). Significant cerebrovascular disease with Modified Hachinski Score>4. Subjects who may not be able to comply with the protocol or perform the outcomes measures due to significant hearing or visual impairment or other issues judged relevant by the investigators. Subject has been diagnosed with any form of diabetes mellitus, actively takes insulin, or has HbA1c > 6.1% at screening.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin (glulisine), then Placebo<br>Participants first receive one dose of Glulisine 20 IU/IN (.1ml/10 units intranasal in each nostril). After a washout period of 2 weeks, they then received one dose of placebo, Sterile Normal Saline 20 IU/IN (.1ml intransal in each nostril). | Drug: Insulin glulisine<br>* Insulin (glulisine) Glulisine 20 IU/IN (.1ml/10 units intranasal in each nostril), once per study<br>* Other names: insulin, glulisine, Apidra;Drug: Saline<br>* Placebo Comparator: Placebo Sterile Normal Saline 20 IU/IN (.1ml intransal in each nostril), once per study<br>* Other names: Placebo;|
| Experimental: Placebo, then Insulin (glulisine)<br>Participants first receive one dose of placebo, Sterile Normal Saline 20 IU/IN (.1ml intransal in each nostril). After a washout period of 2 weeks, they then received one dose of Glulisine 20 IU/IN (.1ml/10 units intranasal in each nostril). | Drug: Insulin glulisine<br>* Insulin (glulisine) Glulisine 20 IU/IN (.1ml/10 units intranasal in each nostril), once per study<br>* Other names: insulin, glulisine, Apidra;Drug: Saline<br>* Placebo Comparator: Placebo Sterile Normal Saline 20 IU/IN (.1ml intransal in each nostril), once per study<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Measured by Adverse Events | Number of adverse and/or serious events | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Change Measured by Fuld Object-Memory Evaluation (FOME) | During the examination, a patient is presented with ten common objects they are asked to identify by touch. The test uses distraction to test recall. For all, a higher score indicates a better outcome. Learning curve is the number of objects the difference in the number of items they are able to correctly identify from the greater of trials 4 or 5 compared to trial 1. Range: 0-10 Total immediate recall is the number of objects recalled over all of the trials. Range: 0-50 Total delayed recall is the number of objects recalled after 5 minutes. Range: 0-10 Recognition memory is the number of items correct from a multiple choice list of three when unable to correctly identify items from delayed recall. Range: 0-10 Retention estimate is the number of items recalled after 5 minutes or being reminded with multiple choice. Range: 0-10 | 20 minutes | 
| Memory Retention Measured by Fuld Object-Memory Evaluation (FOME) | Memory retention is the percentage of items correctly identify during the delayed recall trial compared storage trial 5. Range: 0-100 percent. A higher percentage indicates a better outcome. | 20 minutes | 
| Cognitive Change Measured by Rivermead Behavioral Memory Test (RBMT-C) | The RBMT-C provides an objective measure of everyday memory problems reported and observed in subjects with memory difficulties. The test is standardized for use with children ranging in age from 5 to 10 years. Here, we used it for evaluation of Down Syndrome subjects. The story recall subtests involves immediate free recall, cued recall, and delayed recall of short story material which is presented orally to subjects by the examiner. The RBMT-C is appealing for use in this population because the task is engaging, simple, and has been shown in other studies to be an effective measure of memory functions. For all, a higher score means a better outcome. Immediate Recall is the number of story elements recalled right after the story is complete. Range: 0-31 Delayed Recall is the number of story elements recalled after a delay. Range: 0-31 | 20 minutes | 
| Memory Retention Measured by Rivermead Behavioral Memory Test (RBMT-C). | The RBMT-C provides an objective measure of everyday memory problems reported and observed in subjects with memory difficulties. The test is standardized for use with children ranging in age from 5 to 10 years. Here, we used it for evaluation of Down Syndrome subjects. The story recall subtests involves immediate free recall, cued recall, and delayed recall of short story material which is presented orally to subjects by the examiner. The RBMT-C is appealing for use in this population because the task is engaging, simple, and has been shown in other studies to be an effective measure of memory functions. Memory retention is the percentage of story elements recalled after a delay compared to right after the story is complete. Range: 0-100. A higher score means a better outcome. | 20 minutes |