Intranasal Treatment of HIV-associated Neurocognitive Disorders

HIV Associated Neurocognitive Disorder (HAND) Clinical Trial

Official title:

HAND IN Insulin-001: Intranasal Treatment of HIV-associated Neurocognitive Disorders

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03277222
• Other study ID #: REB17-0104
• Secondary ID: Control# 204512
• Status: Terminated
• Phase: Phase 2
• Start date: November 1, 2018
• Est. completion date: April 21, 2019

Study information

• Verified date: June 2020
• Source: University of Calgary
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Description:

This study is designed as a prospective, double-blinded pilot study of intranasal (IN) insulin versus placebo in people with HAND (n = 20) on stable ART medication. Participants will be randomly assigned to one of two groups: 40 IU IN insulin R twice daily, or matched-volume placebo, which will be administered twice daily, taken after breakfast and again after dinner using a nasal delivery device. Serum glucose will be tested for hypoglycemia one hour after the initial administration of IN insulin or placebo and after administration at Weeks 1, 2, and 3. If the dose is tolerated and no side effects are reported the participant will continue in the study. If the dose is not tolerated due to hypoglycemia then the participant will be withdrawn from the study.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: April 21, 2019
• Est. primary completion date: April 21, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Disease
• HIV Associated Neurocognitive Disorder (HAND)
• Neurocognitive Disorders

Intervention

Biological:
• IN insulin
IN insulin twice daily taken after breakfast and again after dinner using the nasal delivery device.
• Sterile Saline placebo
Sterile Saline placebo twice daily taken after breakfast and again after dinner using the nasal delivery device.

Locations

Country	Name	City	State
Canada	Southern Alberta Clinic	Calgary	Alberta

Sponsors (4)

Lead Sponsor	Collaborator
University of Calgary	Canadian Institutes of Health Research (CIHR), Epidemiology Coordinating and Research Centre, Canada, University of Alberta

Country where clinical trial is conducted

Canada, 

References & Publications (34)

Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007 Oct 30;69(18):1789-99. Epub 2007 Oct 3. — View Citation

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. — View Citation

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. — View Citation

Boissé L, Gill MJ, Power C. HIV infection of the central nervous system: clinical features and neuropathogenesis. Neurol Clin. 2008 Aug;26(3):799-819, x. doi: 10.1016/j.ncl.2008.04.002. Review. — View Citation

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. Erratum in: J Alzheimers Dis. 2015;45(4):1269-70. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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).

Grant I, Franklin DR Jr, Deutsch R, Woods SP, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Collier AC, Marra CM, Clifford DB, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Smith DM, Heaton RK; CHARTER Group. Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology. 2014 Jun 10;82(23):2055-62. doi: 10.1212/WNL.0000000000000492. Epub 2014 May 9. — View Citation

Hyun E, Ramachandran R, Hollenberg MD, Vergnolle N. Mechanisms behind the anti-inflammatory actions of insulin. Crit Rev Immunol. 2011;31(4):307-40. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Lénárt N, Brough D, Dénes Á. Inflammasomes link vascular disease with neuroinflammation and brain disorders. J Cereb Blood Flow Metab. 2016 Oct;36(10):1668-1685. Epub 2016 Aug 2. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

McCombe JA, Vivithanaporn P, Gill MJ, Power C. Predictors of symptomatic HIV-associated neurocognitive disorders in universal health care. HIV Med. 2013 Feb;14(2):99-107. doi: 10.1111/j.1468-1293.2012.01043.x. Epub 2012 Sep 20. — View Citation

Nightingale S, Winston A, Letendre S, Michael BD, McArthur JC, Khoo S, Solomon T. Controversies in HIV-associated neurocognitive disorders. Lancet Neurol. 2014 Nov;13(11):1139-1151. doi: 10.1016/S1474-4422(14)70137-1. Review. — View Citation

Pandya R, Krentz HB, Gill MJ, Power C. HIV-related neurological syndromes reduce health-related quality of life. Can J Neurol Sci. 2005 May;32(2):201-4. — View Citation

Power C, Boissé L, Rourke S, Gill MJ. NeuroAIDS: an evolving epidemic. Can J Neurol Sci. 2009 May;36(3):285-95. Review. — View Citation

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. Review. — View Citation

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. Epub 2007 Oct 17. Erratum in: Neurology. 2008 Sep 9;71(11):866. — View Citation

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. — View Citation

Sacktor N, Skolasky RL, Seaberg E, Munro C, Becker JT, Martin E, Ragin A, Levine A, Miller E. Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study. Neurology. 2016 Jan 26;86(4):334-40. doi: 10.1212/WNL.0000000000002277. Epub 2015 Dec 30. — View Citation

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).

Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T. Effect of intranasal insulin on cognitive function: a systematic review. J Clin Endocrinol Metab. 2012 Feb;97(2):366-76. doi: 10.1210/jc.2011-1802. Epub 2011 Dec 7. Review. — View Citation

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. — View Citation

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. — View Citation

Vivithanaporn P, Heo G, Gamble J, Krentz HB, Hoke A, Gill MJ, Power C. Neurologic disease burden in treated HIV/AIDS predicts survival: a population-based study. Neurology. 2010 Sep 28;75(13):1150-8. doi: 10.1212/WNL.0b013e3181f4d5bb. Epub 2010 Aug 25. — View Citation

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. Review. — View Citation

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. — View Citation

* Note: There are 34 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change from baseline in HQoL questionnaire score	Change from baseline in health-related quality of life (HQoL) questionnaire score	18 weeks
Other	Change from baseline in the PHQ-9 Questionnaire score	Change in the Patient Health Questionnaire-9 (PHQ-9) depressive symptoms score.	18 weeks
Other	Change from Baseline in the Frailty Index Score - questionnaire and clinic assessment	Change in the overall Frailty Index score measured from baseline to Week 8.	16 weeks
Other	Change from Baseline HAND inflammasome biomarker laboratory result profile	Change in inflammasome biomarker laboratory result profile between baseline and week 16.	16 weeks
Other	Change from Baseline HAND metabolomics biomarker laboratory result profile	Change in metabolomics biomarker laboratory result profile between baseline and week 16.	16 weeks
Other	Change from Baseline plasma HIV-1 viral load laboratory result	Change in plasma HIV-1 viral load between baseline and week 16.	16 weeks
Other	Change from Baseline blood CD4 T-cell count laboratory result	Change in blood CD4 T-cell count between baseline and week 16.	16 weeks
Primary	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	Change from Baseline in Neurocognitive Performance: Memory	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).	18 weeks
Secondary	Change from Baseline in Neurocognitive Performance: Executive Function	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).	18 weeks
Secondary	Change from Baseline in Neurocognitive Performance: Attention	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).	18 weeks
Secondary	Change from Baseline in Neurocognitive Performance: Motor Function	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.	18 weeks
Secondary	Change from Baseline in Neurocognitive Performance: Language	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	18 weeks

External Links

•   The Brain Power Lab