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

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ClinicalTrials.gov Identifier: NCT03237689
Recruitment Status : Recruiting
First Posted : August 2, 2017
Last Update Posted : August 16, 2018
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Johns Hopkins University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hiv Drug: Hydrocortisone Drug: Placebo Oral Tablet Early Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 148 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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.

Below includes the number of arms for the second study phase and is the phase of the study being considered a Phase 0 clinical trial. All information to follow will pertain to this phase of the study.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The only entity knowledgeable of randomization is the Johns Hopkins University Investigational Drug Service Pharmacy. They are responsible for randomizing and encapsulating the drug and placebo tablets
Primary Purpose: Basic Science
Official Title: Effects of Glucocorticoids on Cognition in HIV-infected Women
Actual Study Start Date : November 20, 2017
Estimated Primary Completion Date : May 31, 2022
Estimated Study Completion Date : August 31, 2022


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




Primary Outcome Measures :
  1. Hopkins Verbal Learning Test-Revised assesses total learning [ Time Frame: change between baseline and 28 days ]
    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.

  2. Hopkins Verbal Learning Test-Revised assesses verbal memory [ Time Frame: change between baseline and 28 days ]
    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.

  3. Wechsler Adult Intelligence Scale IV Letter-Number Sequencing assesses working memory condition [ Time Frame: change between baseline and 28 days ]
    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.

  4. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Line Orientation Task assesses visuospatial abilities [ Time Frame: change between baseline and 28 days ]
    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).


Secondary Outcome Measures :
  1. Trail Making Test Part A assesses processing speed/attention [ Time Frame: change between baseline and 28 days ]
    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.

  2. Trail Making Test Part B assesses mental flexibility [ Time Frame: change between baseline and 28 days ]
    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.

  3. Comalli Stroop Test, Trial 1 assesses processing speed/attention [ Time Frame: change between baseline and 28 days ]
    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.

  4. Comalli Stroop Test, Trial 2 assesses processing speed/attention [ Time Frame: change between baseline and 28 days ]
    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.

  5. Comalli Stroop Test, Trial 3 assesses behavioral inhibition [ Time Frame: change between baseline and 28 days ]
    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.

  6. Liver function as assessed by aspartate aminotransferase (AST) levels [ Time Frame: change between baseline and 28 days ]
    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.

  7. Liver function as assessed by alanine transaminase (ALT) levels [ Time Frame: change between baseline and 28 days ]
    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.

  8. Liver function as assessed by alkaline phosphatase levels [ Time Frame: change between baseline and 28 days ]
    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.

  9. renal function assessed by creatinine levels [ Time Frame: change between baseline and 28 days ]
    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.

  10. metabolic function assessed by glucose levels [ Time Frame: change between baseline and 28 days ]
    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.

  11. metabolic function assessed by hemoglobin A1c (HbA1c) [ Time Frame: change between baseline and 28 days ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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).


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): NCT03237689


Contacts
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Contact: Leah H Rubin, PhD, MPH 410-955-7311 lrubin1@jhmi.edu

Locations
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United States, Maryland
Johns Hopkins University School of Medicine Recruiting
Baltimore, Maryland, United States, 21224
Contact: Leah Rubin       lrubin1@jhu.edu   
Sponsors and Collaborators
Johns Hopkins University
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Leah Rubin Johns Hopkins University

Additional Information:
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Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT03237689     History of Changes
Other Study ID Numbers: IRB00145327
R01MH113512 ( U.S. NIH Grant/Contract )
First Posted: August 2, 2017    Key Record Dates
Last Update Posted: August 16, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
Glucocorticoids
Anti-Inflammatory Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs