Effects of Glucocorticoids on Cognition in HIV-infected Women (MsSCORE)

Despite treatment with antiretroviral therapy, women living with HIV continue to experience cognitive impairment. Psychological risk factors, including stress, impair cognition more in HIV-infected women than HIV-uninfected women. This study plans to examine a novel intervention for cognitive dysfunction that targets the mechanisms by which stress negatively affects cognitive functioning.

Study Overview

• Status: Completed
• Conditions: Hiv
• Intervention / Treatment: Drug: Hydrocortisone; Drug: Placebo Oral Tablet

Detailed Description

The overall aim of this study is to contribute important foundational knowledge of the utility of targeting neuroinflammation and the hypothalamic-pituitary-adrenal (HPA) axis to improve cognition in HIV and will provide key clinical insights into the mechanisms underlying any cognitive benefit. The investigators are conducting a single-dose study of low dose hydrocortisone (LDH) followed by a 4-week study of daily LDH as a probe of the mechanisms of neuroinflammation including myeloid-lineage cells and the HPA axis in HIV-infected (HIV+) women demonstrating cognitive dysfunction and reporting high levels of stress, trauma history, and mental health risk factors which commonly occur in this population. The use of a pharmacological challenge may aid in the identification of: 1) a putative biomarker of stress- and psychiatric disorder-related neurocognitive complications in HIV-infected women and/or 2) an adjunctive, cost-effective therapy for the treatment of cognitive deficits in HIV

The design is a two-phase study of HIV+ women who: 1) first participate in a double-blind, placebo-controlled cross-over study of a single, low dose (10 mg) of hydrocortisone versus placebo on cognition; and 2) then participate in a mechanistic, randomized, double-blind, placebo controlled trial of daily LDH for 4 weeks on cognition and side effects. The clinical trial will include 100 virally suppressed HIV+ women who show elevated stress and cognitive impairment and who represent the range of psychological risk factors characteristic of this population. Next, to understand the mechanism and broader clinical significance of LDH on cognition, investigators will conduct a 4-week randomized study of the effects of daily treatment with LDH versus placebo on cognition in HIV+ women (targeted n=80).

Women meeting enrollment criteria will complete three cognitive assessments. The first and second assessments will be embedded in the double-blind, placebo-controlled, cross-over study of a single administration of LDH versus placebo (targeted n=100). Investigators will measure cognitive performance 30 minutes and 4 hours post-dosing, because an emerging literature shows that the cognitive effects of LDH depends on timing of the assessment post-dosing. The 30-minute assessment addresses how the maximal cortisol levels following LDH affect cognition. This immediate assessment is standard in studies of stress and cognition and allows for comparisons with the broader literature. More novel and clinically important is the 4-hour assessment which occurs post-peak, when cortisol levels are more steady state and typical of the broader daily cortisol profile following LDH. The third assessment will take place after 4 weeks of treatment with LDH or placebo. That assessment addresses the clinical significance and safety of longer-term LDH treatment. Lastly, the investigators will explore glucocorticoids and inflammation and immune activation as mechanisms by which LDH might affect cognition.

Objective 1 To examine immediate and delayed effects of a single administration of LDH on cognition in HIV+ women.

Objective 2 To examine the effects of a 4-week course of daily LDH on cognition in HIV+ women.

Objective 3 To investigate potential mechanisms of LDH effects on cognition in HIV+ women.

• Study Type: Interventional
• Enrollment (Actual): 136
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Leah H Rubin, PhD, MPH; Phone Number: 410-955-7311; Email: lrubin1@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Females only;
• HIV-infected;
• Able to give informed consent;
• Able to travel to study site for study participation;
• Age between 18 and 65;
• English as a first language;
• Above-average self-reported levels of perceived stress (>14 on the perceived stress scale (PSS-10)) and/or current SCID-V diagnosis of mood and/or anxiety disorder;
• Meet criteria for HIV-associated cognitive dysfunction (based on Neurocognitive test battery and instrumental activities of daily living assessment-impairment on only 1 cognitive domain is required)
• Virally suppressed and on combination antiretroviral therapy (Plasma HIV RNA<1000cp/ml and bring in medications)

Exclusion Criteria:

• Current use of hormone-based contraceptives (birth control pills or patch);
• Currently pregnant, post-partum or lactating;
• Currently regular use of steroids;
• History of closed head injury resulting in loss of consciousness greater than 1 hour;
• History of schizophrenia or schizoaffective disorder;
• Current untreated hypertension or diabetes*;
• History of dementia or any other neurologic central nervous system (CNS) or AIDS-defining disorder;
• Positive urine toxicology screen (except marijuana) or breathalyzer and/or any evidence of acute intoxication or withdrawal.
• History of substance abuse/dependence in the past six months.

Participants who present with a heretofore untreated condition (e.g., hypertension) will be excluded; however, they may be rescreened for eligibility after receiving appropriate treatment for the condition in the course of their standard medical care (at least 6 months).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydrocortisone; Low dose hydrocortisone (10mg orally)	Drug: Hydrocortisone; Low dose hydrocortisone (10mg)
Placebo Comparator: Placebo; Placebo tablets, made of starch 1500 powder	Drug: Placebo Oral Tablet; capsules of starch 1500 powder

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hopkins Verbal Learning Test-Revised assesses total learning	a 12-item list-learning task across 3 trials used to measure total learning. Outcome=total learning across trials (range 0-36). Neuropsychological measures are normed on populations and therefore the clinical significance of a score can be assessed in relation to expected levels of performance.	change between baseline and 28 days
Hopkins Verbal Learning Test-Revised assesses verbal memory	following the 3 learning trials there is a 20-25 minute delay. After the delay, participants are asked to recall as many words as they can from the initial learning list. Outcome=delayed free recall (range 0-12).Neuropsychological measures are normed on populations and therefore the clinical significance of a score can be assessed in relation to expected levels of performance.	change between baseline and 28 days
Wechsler Adult Intelligence Scale IV Letter-Number Sequencing assesses working memory condition	participants hear a series of letters and numbers, and then recite them back in ascending order, with the numbers first and then the letters. Outcome=total correct (range 0-24). Neuropsychological measures are normed on populations and therefore the clinical significance of a score can be assessed in relation to expected levels of performance.	change between baseline and 28 days
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Line Orientation Task assesses visuospatial abilities	In each of 10 trials, a visual array of 13 lines fans out from a common point of origin. Two target lines are shown beneath each array, and participants must identify the lines within the array that match each of the two target lines. Outcome=Total correct (range=0-20).	change between baseline and 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trail Making Test Part A assesses processing speed/attention	25 circles distributed over a sheet of paper. The circles are numbered 1 - 25 and the participant should draw lines to connect the numbers in ascending order. Outcome=Time to completion (range: 10 to 300 seconds). Neuropsychological measures are normed on populations and therefore the clinical significance of a score can be assessed in relation to expected levels of performance.	change between baseline and 28 days
Trail Making Test Part B assesses mental flexibility	25 circles are distributed over a sheet of paper. Circles include both numbers (1 - 13) and letters (A - L). The participant draws lines to connect the circles in an ascending pattern, but with the added task of alternating between the numbers and letters (i.e., 1-A-2-B-3-C, etc.). Outcome=time to completion (range: 18-300). Neuropsychological measures are normed on populations and therefore the clinical significance of a score can be assessed in relation to expected levels of performance.	change between baseline and 28 days
Comalli Stroop Test, Trial 1 assesses processing speed/attention	Participants identify aloud the colors of a series of squares. Outcome=time to completion (range: 30 to 240). Neuropsychological measures are normed on populations and therefore the clinical significance of a score can be assessed in relation to expected levels of performance.	change between baseline and 28 days
Comalli Stroop Test, Trial 2 assesses processing speed/attention	Participants read a series of color names printed in black ink. Outcome=time to completion (range: 30 to 240). Neuropsychological measures are normed on populations and therefore the clinical significance of a score can be assessed in relation to expected levels of performance.	change between baseline and 28 days
Comalli Stroop Test, Trial 3 assesses behavioral inhibition	Participants name the color of the ink but ignore the word. Outcome=time to completion (range: 50 to 240). Neuropsychological measures are normed on populations and therefore the clinical significance of a score can be assessed in relation to expected levels of performance.	change between baseline and 28 days
Liver function as assessed by aspartate aminotransferase (AST) levels	levels from blood. Clinical significance will be determined using the Division of AIDS (DAIDS) Table for grading the severity of adult and pediatric adverse events.	change between baseline and 28 days
Liver function as assessed by alanine transaminase (ALT) levels	levels from blood. Clinical significance will be determined using the Division of AIDS (DAIDS) Table for grading the severity of adult and pediatric adverse events.	change between baseline and 28 days
Liver function as assessed by alkaline phosphatase levels	levels from blood. Clinical significance will be determined using the Division of AIDS (DAIDS) Table for grading the severity of adult and pediatric adverse events.	change between baseline and 28 days
renal function assessed by creatinine levels	levels from blood. Clinical significance will be determined using the Division of AIDS (DAIDS) Table for grading the severity of adult and pediatric adverse events.	change between baseline and 28 days
metabolic function assessed by glucose levels	levels from blood. Clinical significance will be determined using the Division of AIDS (DAIDS) Table for grading the severity of adult and pediatric adverse events.	change between baseline and 28 days
metabolic function assessed by hemoglobin A1c (HbA1c)	levels from blood. Clinical significance will be determined using the Division of AIDS (DAIDS) Table for grading the severity of adult and pediatric adverse events.	change between baseline and 28 days

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Leah Rubin, Johns Hopkins University

Publications and helpful links

Helpful Links

• Brief Report: Low-Dose Hydrocortisone Has Acute Enhancing Effects on Verbal Learning in HIV-Infected Men
• Elevated stress is associated with prefrontal cortex dysfunction during a verbal memory task in women with HIV
• Prefrontal cortical volume loss is associated with stress-related deficits in verbal learning and memory in HIV-infected women
• Post-traumatic stress is associated with verbal learning, memory, and psychomotor speed in HIV-infected and HIV-uninfected women
• The association of perceived stress and verbal memory is greater in HIV-infected versus HIV-uninfected women

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2017
• Primary Completion (Actual): September 8, 2023
• Study Completion (Actual): September 8, 2023

Study Registration Dates

• First Submitted: July 31, 2017
• First Submitted That Met QC Criteria: July 31, 2017
• First Posted (Actual): August 2, 2017

Study Record Updates

• Last Update Posted (Actual): September 29, 2023
• Last Update Submitted That Met QC Criteria: September 27, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Inflammatory Agents; Hydrocortisone
• Other Study ID Numbers: IRB00145327; R01MH113512 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No