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Intranasal Treatment of HIV-associated Neurocognitive Disorders

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ClinicalTrials.gov Identifier: NCT03277222
Recruitment Status : Not yet recruiting
First Posted : September 8, 2017
Last Update Posted : November 21, 2017
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
University of Alberta
Epidemiology Coordinating and Research Centre, Canada
Information provided by (Responsible Party):
John Gill, University of Calgary

Brief Summary:
This study aims to see whether intranasal insulin is an effective treatment for problems with memory, concentration, slowed thinking, or any other cognitive function in people living with HIV/AIDS. This group of signs and symptoms are called 'HIV-associated neurocognitive disorders' or HAND. HAND can affect people living with HIV/AIDS even when they receive potent anti-HIV treatments. Treatment of HAND by specific medication or other means is not yet available. Intranasal insulin treatment has virtually no side-effects, and has already been tested in people with Alzheimer's disease, where it showed beneficial effects on memory, mood and quality of life

Condition or disease Intervention/treatment Phase
HIV Associated Neurocognitive Disorder (HAND) Biological: IN insulin Biological: IN saline Phase 2

Detailed Description:

This study is designed as a prospective, double-blinded, dose-ranging pilot study of intranasal (IN) insulin versus placebo in people with HAND (n = 45) on stable ART medication. Participants will be randomly assigned to one of three groups: 20 IU IN insulin R twice daily, 40 IU IN insulin R twice daily, or matched-volume saline placebo, which will be administered by dose escalation over 4 weeks (10→20 IU or 10→20→30→40 IU twice daily), taken after breakfast and again after dinner using the a nasal delivery device. Each escalated dose will be given for 1 week. Serum glucose will be tested for hypoglycemia one hour after the initial administration of each dose. If no side effects are reported, the dose will be escalated each week to a final dose of 20 or 40 IU in week 4. If a higher dose is not tolerated, dose will be de-escalated to the tolerated level.

The objectives of this study are as follows:

Primary: Determine if IN insulin treatment administered twice daily for 4 months reduces overall neurocognitive deficits (based on the global z-score in people with HAND).

Secondary: Measure effects of IN insulin on individual neuropsychological domains (e.g., memory, processing speed, executive functions, motor functions) and on HAND disease progression; Define impacts of IN insulin on quality of life and mood in people with HAND; Investigate IN insulin's effects on HAND biomarker profiles in urine and blood.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Arm 1: Drug: IN insulin Dose: Twice daily IN insulin R at 20 IU (n=15) twice daily using a nasal delivery device. IN insulin R diluted in saline will be administered by dose escalation over 4 weeks (10→20 IU). Each escalated dose will be given for 1 week.

Arm 2: Drug: IN insulin Dose: Twice daily IN insulin R at 40 IU (n=15), twice daily using a nasal delivery device. IN insulin R diluted in saline will be administered by dose escalation over 4 weeks (10→20 IU). Each escalated dose will be given for 1 week.

Arm 3: Drug: IN Saline Dose: Placebo (saline, matched volume; (n=15) twice daily using nasal delivery device.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: This is a prospective dose-ranging double-blinded pilot study over 4 months. At enrolment, participants and their physicians will be blinded to treatment.
Primary Purpose: Treatment
Official Title: HAND IN Insulin-001: Intranasal Treatment of HIV-associated Neurocognitive Disorders
Estimated Study Start Date : December 2017
Estimated Primary Completion Date : February 2019
Estimated Study Completion Date : August 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: IN insulin 20 IU
Drug: IN insulin Dosage form: intranasal Dose: 20 IU Frequency: bid Duration: 16 weeks dose escalation over 4 weeks 10→20 IU twice daily
Biological: IN insulin
IN insulin twice daily taken after breakfast and again after dinner using the a nasal delivery device. Each escalated dose will be given for 1 week.
Other Name: Intranasal Humulin R
Active Comparator: IN insulin 40 IU
Drug: IN insulin Dosage form: intranasal Dose: 40 IU Frequency: bid Duration: 16 weeks dose escalation over 4 weeks 10→20→30→40 IU twice daily
Biological: IN insulin
IN insulin twice daily taken after breakfast and again after dinner using the a nasal delivery device. Each escalated dose will be given for 1 week.
Other Name: Intranasal Humulin R
Placebo Comparator: IN saline
Drug: Saline Dosage form: intranasal Frequency: bid Duration: 16 weeks
Biological: IN saline
IN saline twice daily taken after breakfast and again after dinner using the a nasal delivery device.



Primary Outcome Measures :
  1. Change in Global Neurocognitive Performance from Baseline [ Time Frame: 18 weeks ]
    Change in overall neurocognitive function as measured by the global z score. The global z score is one measurement calculated as the average of z scores from each domain tested.


Secondary Outcome Measures :
  1. Change from Baseline in Neurocognitive Performance: Memory [ Time Frame: 18 weeks ]
    Change from baseline in the overall z score for the memory domain, calculated as the average of z scores from: Hopkins Verbal Learning Test, Logical Memory Test, and Brief Visual Memory Test (immediate and delayed recall).

  2. Change from Baseline in Neurocognitive Performance: Executive Function [ Time Frame: 18 weeks ]
    Change from baseline in the overall z score for the executive function domain, calculated as the average of z scores from: D-KEFS Trail-making Task (Letter-Switching) and Color-Word Interference (Stroop).

  3. Change from Baseline in Neurocognitive Performance: Attention [ Time Frame: 18 weeks ]
    Change from baseline in the overall z score for the attention domain, calculated as the average of z scores from: Symbol Digit Modalities Test, D-KEFS Trail-making Test (Number), and Color-Word Interference (Color and Word Reading).

  4. Change from Baseline in Neurocognitive Performance: Motor Function [ Time Frame: 18 weeks ]
    Change from baseline in the overall z score for the motor function domain, calculated as the average of z scores from: grooved pegboard completion times for dominant and non-dominant hands.

  5. Change from Baseline in Neurocognitive Performance: Language [ Time Frame: 18 weeks ]
    Change from baseline in the overall z score for the language domain, calculated as the average of z scores from: D-KEFS Letter and Category Verbal Fluency Tasks


Other Outcome Measures:
  1. Change from baseline in HQoL questionnaire score [ Time Frame: 18 weeks ]
    Change from baseline in health-related quality of life (HQoL) questionnaire score

  2. Change from baseline in the PHQ-9 Questionnaire score [ Time Frame: 18 weeks ]
    Change in the Patient Health Questionnaire-9 (PHQ-9) depressive symptoms score.

  3. Change from Baseline in the Frailty Index Score - questionnaire and clinic assessment [ Time Frame: 16 weeks ]
    Change in the overall Frailty Index score measured from baseline to Week 8.

  4. Change from Baseline HAND inflammasome biomarker laboratory result profile [ Time Frame: 16 weeks ]
    Change in inflammasome biomarker laboratory result profile between baseline and week 16.

  5. Change from Baseline HAND metabolomics biomarker laboratory result profile [ Time Frame: 16 weeks ]
    Change in metabolomics biomarker laboratory result profile between baseline and week 16.

  6. Change from Baseline plasma HIV-1 viral load laboratory result [ Time Frame: 16 weeks ]
    Change in plasma HIV-1 viral load between baseline and week 16.

  7. Change from Baseline blood CD4 T-cell count laboratory result [ Time Frame: 16 weeks ]
    Change in blood CD4 T-cell count between baseline and week 16.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Documented HIV-1 infection
  • Maintained on stable ART for ≥6 months (defined as undetectable viral load)
  • HAND-MND or -ANI diagnosis with evidence of clinical onset or progression within the prior 2 years, based on established criteria
  • Currently followed at the Southern Alberta Clinic (SAC; Calgary, AB, Canada)

Exclusion Criteria:

  • HAND with a) changed dose of any medication for HIV-1 infection with a corresponding increase in viral load (e.g., ART), or b) secondary therapies for HAND (e.g., memantine, amphetamines).
  • Advanced liver, renal or lung disease, cancer or diabetes requiring insulin
  • Secondary diagnosis of neurocognitive impairment or other major neuropsychiatric illness such as epilepsy, Alzheimer's or Parkinson's diseases, major depression (PHQ-9 score >10), or schizophrenia
  • Central nervous system lesion (diagnosed by neuroimaging) that may impair cognition
  • Previous allergic reaction to insulin or any of the carrier components.
  • Education < 9 years or inability to read and write English fluently
  • Uncontrolled HIV-1 or hepatitis C co-infection
  • Inability to perform NP or questionnaire measures, functional illiteracy
  • Past or current substance abuse that could interfere with the study assessments as determined by the PI
  • Marijuana use on the day of NP testing
  • Uncontrolled cardiovascular disease (hypertension, coronary or peripheral artery disease)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03277222


Contacts
Contact: Brenda Beckthold 403-955-6309 Brenda.Beckthold@ahs.ca
Contact: Noshin Koenig 403-955-6320 Noshin.Koenig@ahs.ca

Locations
Canada, Alberta
Southern Alberta Clinic Not yet recruiting
Calgary, Alberta, Canada, T2R 0X7
Contact: Brenda Beckthold    403-955-6309    Brenda.Beckthold@ahs.ca   
Contact: Noshin Koenig    403-955-6320    Noshin.Koenig@ahs.ca   
Principal Investigator: Michael J Gill, MBChB FACP         
Principal Investigator: Christopher Power, MD FRCPC         
Sub-Investigator: Sean Rourke, FCAHS PhD         
Sub-Investigator: Ross Tsuyuki, PharmD,FCSHP         
Sub-Investigator: Esther Fujiwara, PhD         
Sponsors and Collaborators
University of Calgary
Canadian Institutes of Health Research (CIHR)
University of Alberta
Epidemiology Coordinating and Research Centre, Canada
Investigators
Principal Investigator: Christopher Power, MD, FRCPC University of Alberta
Principal Investigator: Michael J Gill, MBChB FACP University of Calgary

Additional Information:
Publications:
Fujiwara, E., Gill, J.M. & Power, C. Risk Factors for HIV-Associated Neurocognitive Disorders (HAND) in a Canadian Cohort (P1.321). Neurology 86 P1.321 (2016).
Sacktor, N., et al. Paroxetine and Fluconazole Therapy for HAND: A Double-Blind, Placebo-Controlled Trial. Conference on retroviruses and opportunistic infections. 2016 Boston MA USA Sesssion O-12 Abstract 146(2016).

Responsible Party: John Gill, Medical Director, Southern Alberta Clinic, University of Calgary
ClinicalTrials.gov Identifier: NCT03277222     History of Changes
Other Study ID Numbers: REB17-0104
Control# 204512 ( Other Identifier: Health Canada )
First Posted: September 8, 2017    Key Record Dates
Last Update Posted: November 21, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by John Gill, University of Calgary:
Neurocognitive impairment
HIV-1
Intranasal insulin
Neurocognitive Disorder
Cognition
Memory

Additional relevant MeSH terms:
Disease
Neurocognitive Disorders
Pathologic Processes
Mental Disorders
Insulin, Globin Zinc
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs