Intranasal Treatment of HIV-associated Neurocognitive Disorders

NCT03277222 | Terminated Phase 2 DMC

• 2 other identifiers: REB17-0104Control# 204512
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

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

Conditions

HIV Associated Neurocognitive Disorder (HAND)

Keywords

Neurocognitive impairment; HIV-1; Intranasal insulin; Neurocognitive Disorder; Cognition; Memory

Outcome Measures

Primary Outcomes (1)

• Change in Global Neurocognitive Performance from Baseline

  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.

  18 weeks

Secondary Outcomes (5)

• Change from Baseline in Neurocognitive Performance: Memory

  18 weeks

• Change from Baseline in Neurocognitive Performance: Executive Function

  18 weeks

• Change from Baseline in Neurocognitive Performance: Attention

  18 weeks

• Change from Baseline in Neurocognitive Performance: Motor Function

  18 weeks

• Change from Baseline in Neurocognitive Performance: Language

  18 weeks

Other Outcomes (7)

• Change from baseline in HQoL questionnaire score

  18 weeks

• Change from baseline in the PHQ-9 Questionnaire score

  18 weeks

• Change from Baseline in the Frailty Index Score - questionnaire and clinic assessment

  16 weeks

Study Arms (2)

IN insulin 40 IU

ACTIVE COMPARATOR

Drug: IN insulin Dosage form: intranasal Dose: 40 IU Frequency: bid Duration: 16 weeks

Biological: IN insulin

IN Sterile Saline

PLACEBO COMPARATOR

Drug: Sterile Saline Dosage form: intranasal Frequency: bid Duration: 16 weeks

Biological: Sterile Saline placebo

Interventions

IN insulin BIOLOGICAL

IN insulin twice daily taken after breakfast and again after dinner using the nasal delivery device.

Also known as: Intranasal Humulin R

IN insulin 40 IU

Sterile Saline placebo BIOLOGICAL

Sterile Saline placebo twice daily taken after breakfast and again after dinner using the nasal delivery device.

IN Sterile Saline

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Calgary: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• University of Alberta: collaborator
• Epidemiology Coordinating and Research Centre, Canada: collaborator

Study Sites (1)

Southern Alberta Clinic

Calgary, Alberta, T2R 0X7, Canada

Location

Related Publications (34)

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• Yeung H, Krentz HB, Gill MJ, Power C. Neuropsychiatric disorders in HIV infection: impact of diagnosis on economic costs of care. AIDS. 2006 Oct 24;20(16):2005-9. doi: 10.1097/01.aids.0000247565.80633.d2.

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• Mamik MK, Asahchop EL, Chan WF, Zhu Y, Branton WG, McKenzie BA, Cohen EA, Power C. Insulin Treatment Prevents Neuroinflammation and Neuronal Injury with Restored Neurobehavioral Function in Models of HIV/AIDS Neurodegeneration. J Neurosci. 2016 Oct 12;36(41):10683-10695. doi: 10.1523/JNEUROSCI.1287-16.2016.

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• 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).

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• Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Morgello S, Simpson D, Grant I, Ellis RJ; CHARTER Group. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008 Jan;65(1):65-70. doi: 10.1001/archneurol.2007.31.

  PMID: 18195140 BACKGROUND

• Hyun E, Ramachandran R, Hollenberg MD, Vergnolle N. Mechanisms behind the anti-inflammatory actions of insulin. Crit Rev Immunol. 2011;31(4):307-40. doi: 10.1615/critrevimmunol.v31.i4.30.

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• Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004 Nov;29(10):1326-34. doi: 10.1016/j.psyneuen.2004.04.003.

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• 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.

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• Rosenbloom MH, Barclay TR, Pyle M, Owens BL, Cagan AB, Anderson CP, Frey WH 2nd, Hanson LR. A single-dose pilot trial of intranasal rapid-acting insulin in apolipoprotein E4 carriers with mild-moderate Alzheimer's disease. CNS Drugs. 2014 Dec;28(12):1185-9. doi: 10.1007/s40263-014-0214-y.

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• Claxton A, Baker LD, Wilkinson CW, Trittschuh EH, Chapman D, Watson GS, Cholerton B, Plymate SR, Arbuckle M, Craft S. Sex and ApoE genotype differences in treatment response to two doses of intranasal insulin in adults with mild cognitive impairment or Alzheimer's disease. J Alzheimers Dis. 2013;35(4):789-97. doi: 10.3233/JAD-122308.

  PMID: 23507773 BACKGROUND

• Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, Callaghan M, Arbuckle M, Behl C, Craft S. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis. 2015;44(3):897-906. doi: 10.3233/JAD-141791.

  PMID: 25374101 BACKGROUND

• Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JC, DeGroodt W, Mehta P, Craft S. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008 Feb 5;70(6):440-8. doi: 10.1212/01.WNL.0000265401.62434.36. Epub 2007 Oct 17.

  PMID: 17942819 BACKGROUND

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  PMID: 22162476 BACKGROUND

• Asahchop EL, Akinwumi SM, Branton WG, Fujiwara E, Gill MJ, Power C. Plasma microRNA profiling predicts HIV-associated neurocognitive disorder. AIDS. 2016 Aug 24;30(13):2021-31. doi: 10.1097/QAD.0000000000001160.

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• Lenart N, Brough D, Denes A. Inflammasomes link vascular disease with neuroinflammation and brain disorders. J Cereb Blood Flow Metab. 2016 Oct;36(10):1668-1685. doi: 10.1177/0271678X16662043. Epub 2016 Aug 2.

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• Walsh JG, Muruve DA, Power C. Inflammasomes in the CNS. Nat Rev Neurosci. 2014 Feb;15(2):84-97. doi: 10.1038/nrn3638. Epub 2014 Jan 8.

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• Kim DH, Jewison DL, Milner GR, Rourke SB, Gill MJ, Power C. Neurocognitive symptoms and impairment in an HIV community clinic. Can J Neurol Sci. 2001 Aug;28(3):228-31. doi: 10.1017/s0317167100001372.

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• Koenig N, Fujiwara E, Gill MJ, Power C. Montreal Cognitive Assessment Performance in HIV/AIDS: Impact of Systemic Factors. Can J Neurol Sci. 2016 Jan;43(1):157-62. doi: 10.1017/cjn.2015.306. Epub 2015 Dec 4.

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• Fujiwara E, Tomlinson SE, Purdon SE, Gill MJ, Power C. Decision making under explicit risk is impaired in individuals with human immunodeficiency virus (HIV). J Clin Exp Neuropsychol. 2015;37(7):733-50. doi: 10.1080/13803395.2015.1057481. Epub 2015 Jul 24.

  PMID: 26207583 BACKGROUND

• Justice AC, McGinnis KA, Atkinson JH, Heaton RK, Young C, Sadek J, Madenwald T, Becker JT, Conigliaro J, Brown ST, Rimland D, Crystal S, Simberkoff M; Veterans Aging Cohort 5-Site Study Project Team. Psychiatric and neurocognitive disorders among HIV-positive and negative veterans in care: Veterans Aging Cohort Five-Site Study. AIDS. 2004 Jan 1;18 Suppl 1:S49-59.

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• Crane HM, Van Rompaey SE, Dillingham PW, Herman E, Diehr P, Kitahata MM. A single-item measure of health-related quality-of-life for HIV-infected patients in routine clinical care. AIDS Patient Care STDS. 2006 Mar;20(3):161-74. doi: 10.1089/apc.2006.20.161.

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• Power C, Gill MJ, Johnson RT. Progress in clinical neurosciences: The neuropathogenesis of HIV infection: host-virus interaction and the impact of therapy. Can J Neurol Sci. 2002 Feb;29(1):19-32. doi: 10.1017/s0317167100001682.

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• Van Marle G, Rourke SB, Zhang K, Silva C, Ethier J, Gill MJ, Power C. HIV dementia patients exhibit reduced viral neutralization and increased envelope sequence diversity in blood and brain. AIDS. 2002 Sep 27;16(14):1905-14. doi: 10.1097/00002030-200209270-00007.

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• Skinner S, Adewale AJ, DeBlock L, Gill MJ, Power C. Neurocognitive screening tools in HIV/AIDS: comparative performance among patients exposed to antiretroviral therapy. HIV Med. 2009 Apr;10(4):246-52. doi: 10.1111/j.1468-1293.2008.00679.x. Epub 2009 Jan 23.

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• McCombe JA, Auer RN, Maingat FG, Houston S, Gill MJ, Power C. Neurologic immune reconstitution inflammatory syndrome in HIV/AIDS: outcome and epidemiology. Neurology. 2009 Mar 3;72(9):835-41. doi: 10.1212/01.wnl.0000343854.80344.69.

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• 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).

  BACKGROUND

• Power C, Boisse L, Rourke S, Gill MJ. NeuroAIDS: an evolving epidemic. Can J Neurol Sci. 2009 May;36(3):285-95. doi: 10.1017/s0317167100007009.

  PMID: 19534327 BACKGROUND

Related Links

• The Brain Power Lab

MeSH Terms

Conditions

Neurocognitive Disorders

Interventions

Insulin

Condition Hierarchy (Ancestors)

Mental Disorders

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Christopher Power, MD, FRCPC

  University of Alberta

  PRINCIPAL INVESTIGATOR

• Michael J Gill, MBChB FACP

  University of Calgary

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This is a prospective dose-ranging double-blinded pilot study over 4 months. At enrolment, participants and their physicians will be blinded to treatment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Director, Southern Alberta Clinic

Model Details: Arm 1: Drug: IN insulin Dose: Twice daily IN insulin R at 40 IU (n=10) twice daily using a nasal delivery device. IN insulin R will be administered twice daily. Arm 2: Drug: Sterile Saline placebo Dose: Placebo (Sterile Saline placebo, matched volume; (n=10) twice daily using nasal delivery device.

Study Record Dates

• First Submitted: August 28, 2017
• First Posted: September 8, 2017
• Study Start: November 1, 2018
• Primary Completion: April 21, 2019
• Study Completion: April 21, 2019
• Last Updated: June 11, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)