Collection of Comparison Neurocognitive Data in Resource-Limited Settings

A5271

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CONTENTS (Cont’d)

Page

A5271

Collection of Comparison Neurocognitive Data in Resource-Limited Settings

A Limited-Center Trial of the AIDS Clinical Trials Group (ACTG)

SITES PARTICIPATINGINTHE STUDY

The following non-U.S. ACTG clinical research sites may participate inA5271:

Rio de Janeiro, Brazil (12101)

Chennai, India (11701)

Pune, India (11601)

Blantyre, Malawi (30301)

Lilongwe, Malawi (12001)

Lima, Peru(11301 and 11302, enrolling as one site)

Johannesburg, South Africa (11101)

Durban, South Africa (11201)

Chiang Mai, Thailand (11501)

Harare, Zimbabwe (30313)

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PROTOCOL TEAM ROSTER

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PROTOCOL TEAM ROSTER (Cont'd)

Chair

Kevin Robertson, Ph.D.

Neurology, School of Medicine

University of North Carolina at Chapel Hill

2127 Physicians Office Bldg, CB7025

170 Manning Drive

Chapel Hill, NC27599-7025

Phone:(919) 966-5522

Fax: (919) 966-2922

E-mail:

Vice Chair

Jeffrey T. Schouten, M.D., J.D.

University of Washington

1100 Fairview Avenue N., LE-500

Seattle, WA98109-1024

Phone:(206) 667-5980

Fax: (206) 667-6366

E-Mail:

DAIDS Clinical Representative

Elizabeth Smith, M.D.

HIV Research Branch

DAIDS, NIAID, NIH

6700-B Rockledge Drive, MSC 7624

Bethesda, MD 20892-7624

Phone:(301) 402-3226

Fax:(301) 480-4563

E-mail:

Clinical Trials Specialist

Sean McCarthy, R.N., M.S.

ACTGOperationsCenter

Social & Scientific Systems

8757 Georgia Avenue, 12th Floor

Silver Spring, MD20910-3714

Phone:(301) 628-3394

Fax:(301) 628-3302

E-Mail:

Statisticians

Scott Evans, Ph.D.

Statistical & DataAnalysisCenter

HarvardSchool of Public Health

Complications of HIV, Adult Division

FXBBuilding, Room 513

651 Huntington Avenue

Boston, MA 02115-6017

Phone:(617) 432-2998

Fax: (617) 432-3163

E-mail:

Jeanne Jiang, M.S.

SDAC/Harvard School of Public Health

Center for Biostatistics in AIDS Research

FXB 549, 651 Huntington Avenue

Boston, MA 02115

Phone:(617) 432-6685

Fax: (617) 432-3163

E-mail:

Data Managers

Ann Walawander, M.A.

Frontier Science & Technology Research

Foundation

4033 Maple Road

Amherst, NY14226-1056

Phone:(716) 834-0900 x7290

Fax: (716) 834-8432

E-mail:

Apsara Nair, M.S.

Frontier Science & Technology Research

Foundation

4033 Maple Road

Amherst, NY14226-1056

Phone: (716) 834-0900 X7293

Fax: (716) 834-8432

E-mail:

Investigators

Thomas B. Campbell, M.D.

University of ColoradoDenver

Mail Stop B-168, Room P15-11001

12700 E. 19th Avenue

Aurora, CO 80045

Phone:(303)724-4929

Fax: (303) 724-4926

E-mail:

James G. Hakim, M.D.

University of Zimbabwe - Parirenyatwa

10 Routeledge

Milton Park

Harare
ZIMBABWE

Phone: 011 263 4 705986

Fax: 011 263 470-4897

E-mail:

Christina M. Marra, M.D.

University of Washington

HarborviewMedicalCenter

Department of Neurology

Box 359775

325 9th Avenue

Seattle, WA 98104-2499

Phone:(206) 897-5400

Fax: (206) 341-5401

E-mail:

Ned Sacktor, M.D.

JohnsHopkinsUniversity

JohnsHopkinsBayviewMedicalCenter

Department of Neurology

4940 Eastern Avenue

B Building, Room 123

Baltimore, MD 21224-2780

Phone:(410) 550-0978

Fax:(410) 550-0539

E-mail:

Investigators (cont’d)

Marcus Tulius TSilva, M.D., Ph.D.
Instituto de Pesquisa Clinica Evandro Chagas - IPEC
Fundação Oswaldo Cruz - FIOCRUZ
Avenida Brasil 4365
Manguinhos
Rio de Janeiro 21040- 900
BRAZIL
Phone:011 55 21 3865 9595
Fax: 011 55 21 25644933
E-mail:

Field Representatives

Baiba Berzins, M.P.H.

Division of Infectious Diseases

Northwestern UniversityMedicalSchool

676 North St. Clair, Suite 200

Chicago, IL60611-3015

Phone:(312) 695-5012

Fax: (312) 695-5048

E-mail:

Beverly Putnam, R.N., M.S.N

University of ColoradoDenver

Colorado ACTU

Academic Office 1, MS8205

Room L15-7519

12631 E. 17th Avenue

Aurora, CO80045

Phone:(303) 724-0762

Fax: (303) 724-0802

E-mail:

Laboratory Technologist

Daniel Eggers

Massachusetts GeneralHospital

AIDS Clinical Trials Group Lab 1

65 Landsdowne Street

4th floor, Room 435

Cambridge, MA 02139

Phone:(617) 768-8374

Fax:(617) 768-8299

E-mail:

CSS Representative

Martha Tholanah Mensah-King

CAB Member

912 Ringwood Drive

Strathven

Harare

ZIMBABWE

E-mail:

International Program Specialist

Christina Blanchard-Horan, Ph.D

ACTGOperationsCenter

Social & Scientific Systems, Inc.

8757 Georgia Avenue

Silver Spring, MD 20910

Phone:(301) 628-3339

Fax: (301) 628-3302

E-mail:

NIMH Representative

Pim Brouwers, Ph.D.

NIMH Extramural

Center for Mental Health on AIDS

6001 Executive Boulevard,

NSC Room 6216

Rockville, MD 20892-9619

Phone:(301) 443-4526

Fax: (301) 443-9719

E-mail:

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PROTOCOL TEAM ROSTER (Cont'd)

STUDY MANAGEMENT

All questions concerning this protocol should be sent to via e-mail. The appropriate team member will respond with a "cc" to . A response should generally be received within 24 hours (Monday-Friday).

Protocol E-mail Group

Sites registering to this study must contact the Computer Support Group at the Data Management Center (DMC) to have the relevant personnel at the site added to the actg.protA5271 email group. Include the protocol number in the email subject line.

Send an e-mail message to

Clinical Management

For questions concerning entry criteria and coenrollment, contact the protocol chair via an e-mail message to (ATTN: Kevin Robertson, Ph.D.). Include the protocol number, patient identification number (PID), and a brief relevant history

Data Management

For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRF), the CRF schedule of events,registration, and other data management issues, contact the data managers.

For transfers, reference the Patient Transfer from Site to Site SOP 119, and contact the protocol data managers: Ann Walawander and Apsara Nair directly( and ).
For other questions, send an e-mail message to (ATTN: Ann Walawander and Apsara Nair).
Include the protocol number, PID, and a detailed question.

Participant Registration

For questions or problems and study identification number (SID) lists:

Send an e-mail message to or

call the Statistical and Data Analysis Center (SDAC)/DMC Randomization Desk at (716) 898-7301.

Computer and Screen Problems

Contact the SDAC/DMC programmers.

Send an e-mail message or call (716) 834-0900 x7302.

Protocol Document Questions

For questions concerning the protocol document, contact the clinical trials specialist. Send an e-mail message to (ATTN: Sean McCarthy).

Copies of the Protocol

To request hard copies of the protocol, send a message to .(ATTN: Diane Delgado) via e-mail. Electronic copies can be downloaded from the ACTG Web site (

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PROTOCOL TEAM ROSTER (Cont'd)

Protocol Registration

For protocol registration questions:

Send an e-mail message to r call (301) 897-1707.

Phone Calls

Any phone calls must be documented by e-mail to . This will be the site’s responsibility.

Protocol-Specific Web Page

Additional information concerning study management of ACTG studies can be found on the ACTG Web page.

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GLOSSARY OF TERMS

AIDSAcquired immunodeficiency syndrome

ADLActivities of daily living

BMIBody mass index

CNSCentral nervous system

CRFCase report form

CRSClinical research sites

DAIDSDivision of AIDS

DMCDataManagementCenter

ECEthics committee

EIA Enzyme immunoassay

ELISAEnzyme-linked immunosorbent assay

HAARTHighly active antiretroviral therapy

HADHIV-associated dementia

HANDHIV-Associated Neurological Disorders

HIV-1Human immunodeficiency virus type 1

HIV-1 RNAHIV Viral load

HVTL-RHopkins Verbal Learning Test – Revised

IATAInternational Air Transport Association

IRBInstitutional review board

IHDSInternational HIV Dementia Scale

MOPSManual of Operations

MNDMinor neurocognitive disorder

NIAIDNational Institute of Allergy and Infectious Diseases

NIHNational Institutes of Health

NIMHNational Institute of Mental Health

OHRPOffice for Human Research Protections

PIDPatient/participant identifier (number)

PNSPeripheral nervous system

RSCRegulatory SupportCenter

SDStandard deviation

SDACStatistical and DataAnalysisCenter

SIDStudy identification number

SIPSite Implementation Plan

SOESchedule of Events

VCTVoluntary counseling and testing

SCHEMA

A5271

Collection of Comparison Neurocognitive Datain Resource-Limited Settings

DESIGNA two-step prospective, observational, multinational study to collect comparative neurocognitive data for application to other studies. Neurologically healthy HIV-seronegative individuals from resource-limited settings will be enrolled. Participants will have a baseline neuropsychological assessment performed, and a subset of participants will have a second visit in 6 months.

DURATIONOne day for the 1600participantswho do not enter Step 2;

6 months for 800 Step 2 participants.

SAMPLE SIZE2400 men and women ≥ 18 years of age.

POPULATIONAll participants will be determined as neurologically healthy HIV-seronegative individuals on the basis of a detailed medical history.

STRATIFICATIONEighty (80) strata will be utilized, defined by site (10 levels), sex (2 levels), age (2 levels), and years of education (2 levels). Each of 10 sites will enroll 30 participants in each of eight strata as defined below:

Male, age <35 years, <10 years of education
Male, age <35 years, ≥ 10 years of education
Male, age ≥35 years, <10 years of education
Male, age ≥35 years, ≥ 10 years of education
Female, age <35 years, <10 years of education
Female, age <35 years, ≥ 10 years of education
Female, age ≥35 years, <10 years of education
Female, age ≥35 years, ≥ 10 years of education

STEP 1At Step 1, study participants will be offered the option of a

single 6-month follow-up visit.

STEP 2 Participants who have elected to complete a follow-up visit (800 total participants comprising 10 from each stratum) will be registered to Step 2 and return for a second/final study visit in 6 months.

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1.0HYPOTHESIS AND STUDY OBJECTIVES

1.1Hypothesis

Data from this study will aid in the interpretation of neurocognitive data from other studies collecting neurocognitive data in these settings. No hypothesisis being tested.

1.2Primary Objective

To collect comparative neuropsychological data in healthy controls to aid in the interpretation of neuropsychological tests in resource-limited settings.

1.3Secondary Objectives

1.3.1To describethe distribution of neuropsychological scores in neurologically healthy HIV-seronegative individuals in resource-limited settings.

1.3.2To estimate practice/learning effects associated with repeated neuropsychological assessment in resource-limited settings.

2.0INTRODUCTION

2.1Background

The global burden of the HIV epidemic is staggering, but in the short term, it is largely unfelt in the developed world. Ninety-five percent of new infections occur in the developing world [1]. From the early stages of the HIV epidemic in the United States, it has been recognized that central and peripheral nervous systems (CNS and PNS) are affected by HIV. The exact mechanism of neurotoxicity is not established, as there is no compelling evidence of productive infection of neurons. There is considerable evidence to suggest that local changes in immune and inflammatory activity in the CNS and PNS are responsible for this neurotoxicity.

Initial reports indicated that as many as 40% of infected patients developed a dementing disease. This dementing illness appeared to be due to HIV infection of the CNS, and not to one of many CNS opportunistic infections. The spectrum of primary HIV neurological diseases has been given the name HIV-associated neurological disorders (HAND). HAND includes the more severe form of HIV-associated dementia (HAD). Many more patients have evidence of less severe nervous system dysfunction, which has been termed HIV-associated minor neurocognitive disorder (MND). These disorders were previously known as AIDS dementia complex and minor cognitive/motor disorder, respectively [2-6]. In the pre-highly active antiretroviral therapy(HAART) era, in the United States, as many as 80% who died from AIDS had autopsy evidence of CNS injury attributable to HIV regardless of whether there had been manifestations of HAD during life [7].

HIV-associated cognitive impairment is associated with substantial impact on even the simplest activities of daily living. Differentiation between the milder form, MND, and the more severe, HAD, depends in part on the severity of the impact on daily functioning and activities. Although not well understood and researched, there have been initial studies quantifying the relationship between HIV-related neurological disease and quality of life. The burden of neurological disease on families and communities is substantial, with an impact in terms of loss of productivity and income for the person diagnosed as well as for those who take the primary responsibility as caretakers. In resource-limited settings with high rates of HIV-infection the toll is likely devastating, but remains to be documented [8, 9].

In the developed world, cognitive impairment is relatively common in HIV-infected individuals who have not been treated with antiretroviral therapy [5]. Most HIV-infected individuals in resource-limited settings have not been on an antiretroviral regimen and are likely to be at the same or greater risk for HAD than their infected counterparts with access to HAART in the developed world. Neuropsychological assessment is sensitive and specific for HIV-1-related cognitive dysfunction [10,11].

Very little is known about the prevalence of HAD and milder neuropsychological dysfunction in HIV-infected people in resource-limited settings. Resource-limited communities in sub-Saharan Africa, Asia, and the rest of the developing world, however, represent the areas most devastated by the HIV epidemic and stand to gain the most from effective therapy.

Neuropsychological assessment is arguably the most important tool for diagnosing and categorizing HIV effects on the CNS. Especially in resource-limited settings, where sophisticated technology is often unavailable, characterization of neurocognitive functioning through neuropsychological assessments is crucial to successful diagnosis and treatment. When appropriate normative standards exist, neuropsychological assessments are sensitive to HIV-related neurocognitive disorders and provide accurate ratings of impairment.

In order to appropriately interpret and provide a standardized approach to rating neurocognitive assessments, comparison data in healthy controls is needed. The accumulation of appropriate normative data that will allow more accurate rating of neuropsychological test performance will be crucial to future efforts at identifying neurocognitive impairment directly attributable to HIV; exploring relationships between HIV-associated neurocognitive impairment, disease variables, and everyday functioning; evaluating differences in HIV-1 subtype-associated neuropathology; and determining implications for treatment.

2.2Rationale

Recent scientific discussion has resulted in recommendations to collect appropriate normative comparison data in resource-limited settings [12-15] to aid in the interpretation of neurocognitive data collected in these settings [16-18]. A recent National Institute of Mental Health (NIMH)-sponsored conference has recommended collection of normative data in studies examining neurocognitive functioning in resource-limited settings [19].

Currently, comparative data on healthy controls does not exist in resource-limited settings. This limits the ability to (1) assign individual impairment, (2) create composite scores from multiple neurocognitive tests, and (3) assess the clinical relevance of raw scores.

To address this need, we propose to enroll and collect data in healthy HIV-seronegative controls at ACTG non-U.S. sites for the neurocognitive battery implemented in A5199. These data will serve as a foundation for future normative data in these settings, and we expect this data to be utilized for many years to come. The data will also provide a foundation for the assignment of individual impairment.

3.0STUDY DESIGN

Study participants will be administered neuropsychological tests that include Timed Gait, Finger Tapping (Dominant and non-Dominant), Grooved Pegboard (Dominant and non-Dominant), Semantic Verbal Fluency, and WAIS-R Digit Symbol test. In addition, the Hopkins Verbal Learning Test-Revised (HVLT-R) with delayed recall, Color Trails, and the International HIV Dementia Scale (IHDS) will be administered. These neuropsychological tests covered the five domains stipulated in the NIMH-sponsored diagnostic criteria revision from Antinori [19]:

Fluency (Semantic Verbal Fluency)
Executive Functions (Color Trails –II)
Speed of Information Processing (Color Trails – I, WAIS-R Digit Symbol)
Verbal Learning (HVLT-R); Verbal Memory (Delayed Recall)
Motor Skills (Grooved Pegboard Test, Finger Tapping Test, Timed Gait).

An assessment of activities of daily living, quality of life, and psychosocial componentswill be also be included to assess functional deficits.

A subset of participants from each stratum will return for a follow-up visit in 6 months. These participants will be readministered the entry tests, and medical/medication assessments will be conductedto ensure continued normal neurological functioning without intervening events.

4.0SELECTION AND ENROLLMENT OF PARTICIPANTS

4.1Step 1: Inclusion Criteria

4.1.1Absence of HIV-1 infection, as documented by a negative result of any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit within 30 days of study entry.

NOTE: The term “licensed” refers to a kit that has been certified or licensed by an oversight body within that country and validated internally.

4.1.2Presented for HIV testing, at any location, within the last 30 days.

4.1.3Normal developmental history.

4.1.4Karnofsky performance score 90 within 15 days prior to study entry.

4.1.5Men and women age  18years at study entry.

4.1.6Ability to provide the number of completed years of education.

4.1.7Ability and willingness of participant to provide informed consent.

4.2Step 1: Exclusion Criteria

4.2.1Prior antiretroviral therapy.

4.2.2Current illness that in the opinion of the investigator is likely to have an impact on neurological or neurocognitive functioning.

4.2.3Current use of medication that in the opinion of the investigator is likely to alter mental status or neurocognitive functioningincluding, but not limited to, sedative hypnotics, benzodiazepines, opioid analgesics, barbiturates, antipsychotics, or anticholinergics.

4.2.4History of physical illness or neurological, psychiatric, or developmental disorder that in the opinion of the investigator is likely to have an impact on the participant’s neurocognitive functioning, including, but not limited to, dementia, neurosyphilis, CNS tuberculosis, CNS mass lesions, stroke, epilepsy, head trauma, or transient ischemic attack.

4.2.5Active drug or alcohol use or dependence that interferes with social interactions, work, or other areas of functioning.