Efficacy Potential of Goal Management Training to Improve Cognitive Function in Older People Living With HIV
Phase: NA
Conditions: Hiv
Sponsor: McGill University

Efficacy potential of goal management training to improve cognitive function in older people living with HIV Protocol_Version 
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Full Title: 
 
 
Abbreviated title:  
 
Efficacy potential of goal management training to improve cognitive 
function in older people living with HIV  
 
Goal Management training in people living with HIV 
Version Number: 
V1.0 
 
Date of Protocol:  
April 8, 2016 
 
Funding: 
Canadian Foundation for AIDS Research (CANFAR) 
 
Principal Investigators: 
Dr. Lesley Fellows & Dr. Marie-Josée Brouillette 
Chronic Viral Illness Service of the Royal Victoria Hospital 
McGill University Health Centre 
Glen site 
D 02.4110 – 1001 Decarie 
Montreal, Quebec H4A 3J1 
 
Associate investigators: 
 
 
 
 
Data Management Group: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr. Brian Levine 
Neuropsychologist 
Professor in the Department of Psychology and Medicine  
University of Toronto  
 
Dr. Nancy Mayo 
Royal Victoria Hospital, Room 4.29 
687 Pine Avenue West  
Montreal, Quebec H3A 1A1 
The Rotman Research Institute 
Baycrest Centre for Geriatric Care 
3560 Bathurst Street 
Toronto, Ontario 
M6A 2E1 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SUMMARY 
 
 
 
Full Title 
Efficacy potential of goal management training to improve cognitive function in 
older people living with HIV  
 
Short title 
Goal Management training  in people living with HIV 
Sponsor  
McGill University Health Centre 
Funding 
Canadian Foundation for AIDS Research (CANFAR) 
Principal Investigators 
Dr. Marie-Josée Brouillette & Dr. Lesley Fellows  
Associate investigators 
Dr. Brian Levine & Dr. Nancy Mayo 
Primary Objectives 
1. 
Determine the feasibility and acceptability of GMT in people with stable 
HIV infection who report cognitive concerns 
 
2. 
Provide preliminary evidence of the effect of GMT on cognitive 
performance, compared to a waitlist control group, as measured by (i) 
cognitive performance tests and (ii) self-report questionnaires 
 
Study Population 
Inclusion Criteria 
 
Age ≥ 45  
 
HIV infection for at least 1 year 
 
Able to communicate in English or French 
 
Capable of providing informed consent 
 
Subjective complaints of cognitive difficulties 
 
Evidence of cognitive deficit (B-CAM score ≤ 24) 
  
Exclusion Criteria 
 
Dementia (MSK-rating stage 3 or more-cognitive component only)  
 
Concern about capacity to consent  
 
Life expectancy of < 3 years or other personal factor limiting the ability 
to participate in follow-up 
 
Non-HIV-related neurological disorder likely to affect cognition 
 
Known active CNS opportunistic infection or hepatitis C requiring IFN 
treatment during the follow-up period 
 
Known psychotic disorder 
 
Current substance dependence or abuse within the past 12 months.  
 
Study Design 
Observational 
Sample Size 
60 
Study Duration 
1 year  
 
 

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Contents 
PROTOCOL SUMMARY ...................................................................................................................... 2 
EFFICACY POTENTIAL OF GOAL MANAGEMENT TRAINING TO IMPROVE COGNITIVE FUNCTION IN 
OLDER PEOPLE LIVING WITH HIV ....................................................................................................... 4 
Background information ..................................................................................................................... 4 
Clinical Significance ........................................................................................................................... 5 
Study Hypothesis .............................................................................................................................. 56 
Study Objectives ................................................................................................................................. 6 
STUDY DESIGN .................................................................................................................................. 6 
Procedure ............................................................................................................................................ 6 
Intervention ....................................................................................................................................... 67 
TREATMENTS .................................................................................................................................... 7 
STUDY EVALUATIONS/PROCEDURES ................................................................................................. 7 
Informed Consent................................................................................................................................ 7 
Subject Identification Number Assignment ........................................................................................ 7 
DETAILS OF STATISTICAL ANALYSIS .................................................................................................... 7 
Analysis and Sample Size ................................................................................................................... 7 
REFERENCES ...................................................................................................................................... 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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EFFICACY POTENTIAL OF GOAL MANAGEMENT TRAINING TO IMPROVE COGNITIVE 
FUNCTION IN OLDER PEOPLE LIVING WITH HIV 
 
Background information 
People living with HIV worry about their memory, and with good reason.  It is now clear that this chronic 
illness can have disabling effects on cognition, even with excellent systemic viral control (1).  Although 
the burden of cognitive impairment in HIV in Canada is unknown, it is likely to be high.  Recent studies 
in other developed countries, using comprehensive neuropsychological assessment, report a prevalence of 
(primarily mild) cognitive impairment of 30-50% (1, 2).  Even higher rates have been documented in those 
over the age of 50, a rapidly expanding group at the frontier of existing knowledge about the combined 
effects of aging and longstanding HIV infection (3).  Impaired cognition can affect medication adherence 
(in turn posing a public health risk for the spread of HIV), occupational and social function, quality of life, 
and even accelerate mortality (4, 5).  We are only beginning to understand this emerging co-morbidity, 
which is likely the result of multiple interacting processes, including chronic neuroinflammation, 
premature cerebrovascular disease, neurotoxic effects of drug treatment, and co-existing mental health 
issues (1).   
Given these hypotheses, the field has assumed that cognitive impairment in HIV is likely to be progressive, 
in fact our own work using the CHARTER data shows this is not generally the case. Although 246/701 in 
the longitudinal cohort were classified as cognitively impaired at baseline, only 16% (N=111) showed 
decline at 3 years, most of the time on a single neuropsychological test.  This observation suggests that 
for the majority of people, mild cognitive impairment may be a relatively static condition.  On-going work 
in several countries aims to better understand the factors contributing to cognitive impairment in older 
people with HIV, including a CIHR-funded project we are currently leading [Positive Brain Health Now 
(+BHN), http://brainhealthnow.mcgill.ca].  However, we need not wait for a full understanding of the 
determinants of cognitive impairment to take action; patients with these difficulties need solutions now.  
Testing the impact of available interventions can establish what works, and can also help us understand 
whether the impact of brain injury in HIV can be mitigated to preserve function and quality of life. 
Rehabilitation is a well-established approach to maintain function in the face of chronic disease, and holds 
promise for addressing the health challenges faced by older people with HIV (6). A Canadian-led 
knowledge synthesis review published in 2014 identified cognitive rehabilitation as a promising approach 
in HIV, but highlighted the absence of high quality, HIV-specific evidence in this area (7).  A recent 
focused review also highlights the dearth of evidence on this topic (8). Very few studies have been 
published, and to date all have been restricted to computerized training programs only (8).  While there is 
limited evidence for computerized cognitive rehabilitation in any context, there is better evidence for more 
conventional, in-person rehabilitation approaches, at least in other neurological disorders.  Although 
computerized training is appealing because it is more feasible to deliver on a wide scale than conventional 
cognitive rehabilitation, we propose that the first step should be to establish an evidence base regarding 
the efficacy of any form of cognitive rehabilitation in HIV.  Evidence of efficacy of a ‘high dose’ 
established rehabilitation method could be followed by work to define the key elements, and to study how 
those elements could be delivered most cost-effectively, but there is no point in pursuing these secondary 
steps if the most well-established cognitive rehabilitation approaches do not show efficacy.  Thus, we 
propose to test conventional rehabilitation as a crucial first step is a research program focused on evidence-
based interventions for improving brain health in HIV. 
There is no gold standard conventional cognitive rehabilitation program, but most existing approaches 
combine face-to-face therapy with at home practice over a period of at least several weeks. In the absence 
of a gold standard, we have selected one such program:  Goal Management Training (GMT).  This 

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program targets executive dysfunction, which is a central problem in HIV-associated neurocognitive 
disorder (8, 9).  GMT is grounded in a neurobiological framework and was developed based on nearly 
two decades of research on practical approaches to minimizing the impact of executive dysfunction, 
aiming to help people with brain injury manage real life tasks.  The program teaches self-management 
principles, stress management and mindfulness, and trains participants in the use of several explicit 
strategies to reduce cognitive load in everyday tasks, and methods to cue attention to maintain focus on 
specific tasks.  GMT is now a manualized protocol with set content conveyed through a combination of 
slides and a workbook. Two-hour small group sessions are led, in person, by a trained therapist either once 
twice a week, for seven weeks.  The small group sessions allow participants to learn from each other, 
enhancing engagement.  GMT has been shown to improve cognitive function in a variety of neurological 
conditions, as well as in healthy older people with cognitive concerns (10-13).  Evidence from randomized 
trials shows that this intervention leads to (i) significant improvements in performance on cognitive tests, 
including naturalistic tests of real life tasks, (ii) reduced self-reported cognitive concerns (10, 11, 14), and 
(iii) significant improvements in everyday function (11-13, 15) compared to either a wait-list condition or 
a general brain health education control.  Positive effects have been found in older people with cognitive 
concerns, and neurological populations with mild cognitive impairment including mild traumatic brain 
injury (10), stroke (11) and spina bifida (14, 15).  These improvements have been shown to last at least 6 
months in some studies (13-15) and are accompanied by changes in the brain networks underlying 
executive function (16).  GMT is thus a well-validated, high yield intervention with which to test the 
potential of cognitive rehabilitation in older HIV+ people with cognitive concerns. 
 
Clinical Significance 
The proposed project brings together a high profile multidisciplinary team to perform the first randomized 
controlled study of in-person cognitive training in the HIV population.  The core platform is a low burden 
observational study that aims to understand and address the heterogeneous, multi-factorial nature of 
compromised brain health in people living with HIV.  The pilot project is cost- and time-effective, nested 
within this ongoing observational cohort study. A standardized intervention will be used, supported by 
good evidence of efficacy in studies involving other neurological disorders with similar profiles of 
cognitive impairment.  Dr. Levine (co-I) had a pivotal role in the validation of the GMT intervention and 
is an expert in the area of cognitive training. Our team also has extensive experience with all of the project 
requirements, including HIV clinical trials, large-scale health outcomes research, data management, and 
advanced statistical methodologies.  Addressing or preventing cognitive impairment is a pressing concern 
for people living with HIV, and those who care for them.  Cognitive training is resource consuming and 
not the standard of care in HIV. High quality evidence is needed to justify committing resources to such 
training. We propose work that directly addresses this need, taking advantage of the ‘window of 
opportunity’ provided by the on-going +BHN project. Regardless of the outcome, this study will provide 
important information to orient future work aiming to improve cognition in people living with HIV. The 
results of this pilot study will inform the development of a full randomized controlled trial. 
 
 
 
Study Hypothesis 
We hypothesize that GMT, a cognitive rehabilitation intervention, will lead to improved cognitive 
function as assessed by better performance on cognitive tests and reduced cognitive concerns in people 
with stable HIV infection who report cognitive concerns at baseline, compared to a wait-list group. 

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Study Objectives 
The specific objectives of this study are to: 
1. Determine the feasibility and acceptability of GMT in people with stable HIV infection who report 
cognitive concerns 
2. Provide preliminary evidence of the effect of GMT on cognitive ability, as measured by changes 
in (i) cognitive performance tests and (ii) self-report questionnaires. 
 
STUDY DESIGN  
This is a concurrently controlled trial. Study participants will be randomly selected from those 
participating in the ongoing, longitudinal +BHN study at 2 sites in Montreal (The Montreal Chest Institute 
and L'Actuel Medical Clinic).  This CIHR Team Grant-supported observational, prospective cohort study 
is enrolling consecutive patients attending 5 HIV clinics across Canada for a total sample of 900, followed 
every 9 months for 27 months.  Inclusion criteria are: age 35 y or older, HIV infection for at least 1 year, 
able to communicate in English or French and capable of providing informed consent.  Exclusions are 
presence of dementia, life expectancy < 3 y, other neurological disorder including active opportunistic 
CNS infection, psychotic disorder, current substance dependence or abuse, and Hepatitis C requiring 
interferon therapy during the study period. Montreal sites will enroll 350 participants, which should 
provide an adequate pool for recruitment to this sub-study.   
The GMT intervention will be tested in a randomly selected sub-group (N=30) of this cohort who meet 
the following additional criteria: over age 45, subjective complaints of cognitive difficulties, and 
performance on objective computerized cognitive tests that falls at or below the 50th percentile of 
performance in the cohort as a whole (as measured by the cohort study’s primary outcome, a combination 
of self-report and performance items called the Brief Cognitive Ability Measure [B-CAM] (17)).  The 
concurrent control group will be comprised of those eligible for GMT but not randomly selected. 
 
Procedure 
Participants will be recruited at the time of their routine +BHN study visit, at which comprehensive 
information about their current health status, function, quality of life, cognitive concerns, and cognitive 
performance is already being gathered.  Following informed consent, all participants will complete a short 
set of neuropsychological tests and questionnaires that have been shown to be sensitive to the effects of 
GMT [Sustained Attention to Response Task-SART (18),Tower of London (19), and Dysexecutive 
Questionnaire-DEX (20)] immediately, or at a visit arranged for this purpose, separate from the +BHN 
main study. Participants will then begin GMT, as described below. Within 4 weeks of completing the 
GMT program, they will be asked to repeat the neuropsychological testing and complete additional tests 
which form part of the standard +BHN visit at a second study visit, coincident with the +BHN study visit 
if timing permits.  
 
Intervention 
The standard GMT program lasts 9 weeks and involves 9 weekly 2-hour small group sessions led by a 
trained therapist.  It follows a manualized program that teaches participants a series of techniques to build 
attention and executive function, and shows them how to implement these techniques in their everyday 
life.  The small group sessions allow individualization of the training to show how it can be applied to 

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meet the particular challenges reported by participants, and explicitly encourage participants to share their 
challenges and successes with others in the group to promote learning and engagement with the program.  
The sessions are reinforced with homework, in which participants practice what they have learned. 
Sessions will be audiotaped for later review by the trainer and/or study investigators to ensure adherence 
to the intervention manual. The material, including homework, is provided in a workbook that participants 
use throughout the training, and keep for later reference. 
 
TREATMENTS 
There are no pharmacological treatments involved in the current study. 
 
STUDY EVALUATIONS/PROCEDURES 
 
Informed Consent 
The subject will be asked to read and sign the approved informed consent form prior to any assessments 
being performed. Sufficient opportunity will be given to discuss the study and consider the information in 
the consent process prior to agreeing to participate. The original signed informed consent form will be 
retained in the subject’s study files and a copy will be provided to the subject. 
 
Subject Identification Number Assignment 
Subject Identification (ID) numbers assigned for the core platform will be used for this sub-study. 
 
DETAILS OF STATISTICAL ANALYSIS 
 
Analysis and Sample Size 
The feasibility and acceptability of the GMT will be evaluated in the whole group (N=30) based on the 
proportion of GMT sessions attended, the proportion of the homework completed, and the overall level of 
satisfaction with the program, as determined by an anonymous questionnaire filled out by the participants 
at the end of the intervention.   
The potential impact on cognition of GMT will be evaluated in two ways: (i) a within-person analysis of 
change in cognitive outcomes after all persons have completed the GMT program; and, for exploratory 
purposes, (ii) a between group comparison contrasting change in cognitive outcomes between the GMT 
group and the concurrent control group assessed in the main study.   
For all analyses, the B-CAM (performance measure) will be the primary cognitive outcome and a global 
outcome response will be based on changes in the B-CAM and on four secondary cognitive outcome 
measures: SART, Tower of London, Dysexecutive Questionnaire-DEX and PDQ.    
For the within-person analysis, change from pre-to post will be calculated for each person and a 95% 
confidence interval (CI) around the mean change will be calculated.  A 95% CI that excludes 0 indicates 
statistically significant change. A sample size of 30 will provide 80% power to detect an average 
standardized response mean (effect size for change) of 0.38, within the reported range for GMT in other 
conditions.  However, average change is not very interpretable as this average change can occur in many 
ways including no change for a lot of people and large change for a few, or even deterioration for some.  
To provide a more interpretable estimate of treatment impact, an overall effect will also be reported, based 

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on the proportion of individuals who improved at least 0.5 SD on one of the cognitive outcome measures. 
A change of 0.5 SD is considered clinically relevant (21).  For this analysis, generalized estimating 
equations (GEE) will be utilized to adjust for a possible correlation between the different measures.  The 
outcome will be the binary response for each of the five cognitive outcomes, and the analysis yields an 
estimated charge proportion adjusted for non-independence.  Having five outcome measures increases the 
number of observations available for analysis by a factor of 1.8, termed the design effect.  The design 
effect (22) is a function of the number of measures (here m-1) and the correlation between measures 
(estimated at 0.2).  Hence the number of observations effectively available for analysis is 30 x 1.8 or 54.  
With this sample size, the 95% CI will exclude a low responder proportion (20%) as long as the responder 
proportion is greater than 28% (www.vassarstats.net).    
For the between-group analysis, 30 people in the intervention group and a concurrent control group of 100 
(with five outcome measures, the effective sample size is inflated by the design effect of 1.8).  Thus, using 
all measures, the sample would provide 80% power to detect an effect size of 0.4 (0.4 of a SD).  For this 
analysis, generalized estimating equations (GEE) for a continuous outcome will be utilized to adjust for a 
possible correlation between the different measures.  Each measure will be transformed onto a 0 to 100 
scale for permit a global intervention effect to be estimated.   
 
 
 
 
 

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REFERENCES 
 
1. 
Clifford DB, Ances BM. HIV-associated neurocognitive disorder. The Lancet Infectious diseases. 
2013;13(11):976-86. 
2. 
Robertson KR, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans S, et al. Neurocognitive 
effects of treatment interruption in stable HIV-positive patients in an observational cohort. 
Neurology. 2010;74(16):1260-6. 
3. 
Cysique LA, Brew BJ. Prevalence of non-confounded HIV-associated neurocognitive impairment 
in the context of plasma HIV RNA suppression. Journal of neurovirology. 2011;17(2):176-83. 
4. 
Au A, Cheng C, Chan I, Leung P, Li P, Heaton RK. Subjective memory complaints, mood, and 
memory deficits among HIV/AIDS patients in Hong Kong. Journal of clinical and experimental 
neuropsychology. 2008;30(3):338-48. 
5. 
Power C, Boisse L, Rourke S, Gill MJ. NeuroAIDS: an evolving epidemic. The Canadian journal 
of neurological sciences Le journal canadien des sciences neurologiques. 2009;36(3):285-95. 
6. 
Worthington C, Myers T, O'Brien K, Nixon S, Cockerill R. Rehabilitation in HIV/AIDS: 
development of an expanded conceptual framework. AIDS patient care and STDs. 
2005;19(4):258-71. 
7. 
O'Brien KK, Solomon P, Trentham B, MacLachlan D, MacDermid J, Tynan AM, et al. Evidence-
informed recommendations for rehabilitation with older adults living with HIV: a knowledge 
synthesis. BMJ open. 2014;4(5):e004692. 
8. 
Weber E, Blackstone K, Woods SP. Cognitive neurorehabilitation of HIV-associated 
neurocognitive disorders: a qualitative review and call to action. Neuropsychology review. 
2013;23(1):81-98. 
9. 
Woods SP, Moore DJ, Weber E, Grant I. Cognitive neuropsychology of HIV-associated 
neurocognitive disorders. Neuropsychology review. 2009;19(2):152-68. 
10. 
Levine B, Robertson IH, Clare L, Carter G, Hong J, Wilson BA, et al. Rehabilitation of executive 
functioning: an experimental-clinical validation of goal management training. Journal of the 
International Neuropsychological Society : JINS. 2000;6(3):299-312. 
11. 
Levine B, Schweizer TA, O'Connor C, Turner G, Gillingham S, Stuss DT, et al. Rehabilitation of 
executive functioning in patients with frontal lobe brain damage with goal management training. 
Frontiers in human neuroscience. 2011;5:9. 
12. 
Levine B, Stuss DT, Winocur G, Binns MA, Fahy L, Mandic M, et al. Cognitive rehabilitation in 
the elderly: effects on strategic behavior in relation to goal management. Journal of the 
International Neuropsychological Society : JINS. 2007;13(1):143-52. 
13. 
Spikman JM, Boelen DH, Lamberts KF, Brouwer WH, Fasotti L. Effects of a multifaceted 
treatment program for executive dysfunction after acquired brain injury on indications of executive 

Efficacy potential of goal management training to improve cognitive function in older people living with HIV Protocol_Version 
1.0 
 
Page 10 
 
functioning in daily life. Journal of the International Neuropsychological Society : JINS. 
2010;16(1):118-29. 
14. 
Stubberud J, Langenbahn D, Levine B, Stanghelle J, Schanke AK. Goal management training of 
executive functions in patients with spina bifida: a randomized controlled trial. Journal of the 
International Neuropsychological Society : JINS. 2013;19(6):672-85. 
15. 
Stubberud J, Langenbahn D, Levine B, Stanghelle J, Schanke AK. Goal Management Training 
improves everyday executive functioning for persons with spina bifida: self-and informant reports 
six months post-training. Neuropsychological rehabilitation. 2014;24(1):26-60. 
16. 
Chen AJ, Novakovic-Agopian T, Nycum TJ, Song S, Turner GR, Hills NK, et al. Training of goal-
directed attention regulation enhances control over neural processing for individuals with brain 
injury. Brain : a journal of neurology. 2011;134(Pt 5):1541-54. 
17. 
Koski L, Brouillette MJ, Lalonde R, Hello B, Wong E, Tsuchida A, et al. Computerized testing 
augments pencil-and-paper tasks in measuring HIV-associated mild cognitive impairment(*). HIV 
medicine. 2011;12(8):472-80. 
18. 
Fronczek R, Middelkoop HA, van Dijk JG, Lammers GJ. Focusing on vigilance instead of 
sleepiness in the assessment of narcolepsy: high sensitivity of the Sustained Attention to Response 
Task (SART). Sleep. 2006;29(2):187-91. 
19. 
Shallice T. Specific impairments of planning. Philosophical transactions of the Royal Society of 
London Series B, Biological sciences. 1982;298(1089):199-209. 
20. 
Burgess PW, Alderman N, Wilson BA, Evans JJ, Emslie H. Validity of the battery: Relationship 
between performance on the BADS and ratings of executive problems. UK: Thames Valley Test 
Company; 1996. 
21. 
Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: 
the remarkable universality of half a standard deviation. Medical care. 2003;41(5):582-92. 
22. 
Campbell MJ. Challenges of cluster randomized trials. Journal of comparative effectiveness 
research. 2014;3(3):271-81.