INTERVAL: Varying Intervals of ART to Improve Outcomes in HIV
Phase: NA
Conditions: HIV-1-infection
Sponsor: University of California, Los Angeles

 
 
 
INTERVAL: VARYING INTERVALS OF 
ART TO IMPROVE OUTCOMES IN HIV 
Protocol ID16-001652; NCT03101592 
Risa M. Hoffman, PI 
UCLA | 10833 Le Conte Ave., Los Angeles, CA 

The INTERVAL Study: Varying Intervals of ART Dispensing to Improve Outcomes in 
HIV 
 
Version 2.4 
Page 1 of 35 
22 June 2017 
 
 
 
 
The INTERVAL Study: Varying Intervals of ART Dispensing to Improve 
Outcomes in HIV 
 
 
Sponsored by: 
USAID/PEPFAR 
 
 
 
 
 
Protocol Chair: Risa M. Hoffman 
 
Protocol Vice Chair: Thembi Xulu 
 
 
 
Version 2.4 
22 June 2017 
 
 
 
 
 
 
 

The INTERVAL Study: Varying Intervals of ART Dispensing to Improve Outcomes in 
HIV 
 
Version 2.4 
Page 2 of 35 
22 June 2017 
 
TABLE OF CONTENTS 
 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 4 
PROTOCOL TEAM ROSTER .................................................................................................... 5 
Protocol Chair: ........................................................................................................................... 5 
SCHEMA ................................................................................................................................... 1 
Figure 1 OVERVIEW OF STUDY DESIGN ................................................................................ 2 
1 
STUDY POPULATION ................................................................................................... 2 
1.1 
Inclusion Criteria ...................................................................................................................... 2 
1.2 
Exclusion Criteria ..................................................................................................................... 3 
2 
INTRODUCTION ........................................................................................................... 4 
2.1 
Background ............................................................................................................................... 4 
2.2 
Prior Research on Multi-Month Scripting/Dispensing .......................................................... 7 
2.3 
Rationale ................................................................................................................................... 7 
2.4 
Hypotheses ................................................................................................................................ 7 
3 
OBJECTIVES ................................................................................................................. 8 
4 
STUDY DESIGN ............................................................................................................. 8 
4.1 
Recruitment, Screening, and Enrollment Process .................................................................. 9 
4.2 
Co-Enrollment Considerations and Differentiated Models ................................................... 9 
4.3 
Randomization ........................................................................................................................ 10 
4.4 
Informed Consent ................................................................................................................... 10 
4.5 
Participant Retention .............................................................................................................. 11 
4.6 
Participant Withdrawal or Termination from the Study ...................................................... 11 
5 
STUDY VISITS AND PROCEDURES ........................................................................... 12 
5.1 
Screening Visit ....................................................................................................................... 12 
5.2 
Entry Visit ............................................................................................................................... 15 
5.3 
Annual Viral Load Visit (12 months, 24 months, 36 months) ............................................ 15 
5.4 
Definition of Study Endpoints ............................................................................................... 15 
5.5 
Post-Intervention Visit ........................................................................................................... 17 
5.6 
Virologic Failure .................................................................................................................... 17 
5.7 
Drug Supply ............................................................................................................................ 18 
6 
SAFETY ASSESSMENT, MONITORING, AND REPORTING ..................................... 18 
6.1 
Safety-Related Roles and Responsibilities ........................................................................... 18 
6.2 
Management of Participants Who Develop Tuberculosis or Another Opportunistic 
Infection .................................................................................................................................. 19 
6.3 
Management of Women Who Become Pregnant During Study ......................................... 19 
7 
STATISTICAL METHODS .......................................................................................... 19 
7.1 
General Design Issues ............................................................................................................ 19 
7.2 
Outcome Measures ................................................................................................................. 19 
8 
COST AND COST-EFFECTIVENESS METHODS ....................................................... 21 
8.1 
Costs to Provider .................................................................................................................... 21 
8.2 
Cost-Effectiveness .................................................................................................................. 22 
8.3 
Patient Costs ........................................................................................................................... 22 
8.4 
Clinic Resource Allocation .................................................................................................... 22 
8.5 
Sample Size and Accrual ....................................................................................................... 22 
9 
DATA HANDLING AND RECORD KEEPING ............................................................. 24 
9.1 
Data Management Responsibilities ....................................................................................... 24 
10 
SITE MONITORING .................................................................................................... 24 
11 
HUMAN SUBJECTS PROTECTIONS .......................................................................... 24 

The INTERVAL Study: Varying Intervals of ART Dispensing to Improve Outcomes in 
HIV 
 
Version 2.4 
Page 3 of 35 
22 June 2017 
11.1 
Institutional Review Board/Ethics Committee Review and Approval including Informed 
Consent ................................................................................................................................... 24 
11.2 
Potential Benefits ................................................................................................................... 25 
11.3 
Potential Risks ........................................................................................................................ 25 
11.4 
Reimbursement/Compensation ............................................................................................. 25 
11.5 
Privacy and Confidentiality ................................................................................................... 26 
11.6 
Management of New Information Pertinent to Study Participation.................................... 26 
11.7 
Post-Trial Access to Multi-Month Scripting/Dispensing .................................................... 26 
12 
ADMINISTRATIVE PROCEDURES ............................................................................ 26 
12.1 
Regulatory Oversight ............................................................................................................. 26 
12.2 
Study Implementation ............................................................................................................ 27 
12.3 
Protocol Deviation Reporting ................................................................................................ 27 
13 
PUBLICATIONS .......................................................................................................... 27 
14 
REFERENCES ............................................................................................................. 28 
 
 
 

The INTERVAL Study: Varying Intervals of ART Dispensing to Improve Outcomes in 
HIV 
 
Version 2.4 
Page 4 of 35 
22 June 2017 
 
ABBREVIATIONS AND ACRONYMS 
 
 
 
ARV: antiretrovirals 
ART: antiretroviral therapy 
CAG: community ART group 
CMC: clinical Management Committee 
DMC: differentiated model of care 
DSMB: data safety and monitoring board 
CRF: case report form 
EC: ethics committee 
IRB: Institutional Review Board 
MMS: Multi-month scripting/dispensing 
PEPFAR: President’s Emergency Plan for AIDS Relief 
PID: Patient Identification Number 
SOP: Standard Operating Procedure 
TA: Technical Assistance 
USAID: United States Agency for International Development 
 
 
 

The INTERVAL Study: Varying Intervals of ART Dispensing to Improve Outcomes in 
HIV 
 
Version 2.4 
Page 5 of 35 
22 June 2017 
 
 
 
 
 
PROTOCOL TEAM ROSTER 
 
 
Protocol Chair: 
Risa M. Hoffman MD, MPH 
Associate Professor  
UCLA School of Medicine 
10833 Le Conte Ave 37-121 CHS 
Los Angeles, CA 90095 
USA 
T: +1 310 825 7225 
Email: rhoffman@mednet.ucla.edu 
 
Protocol Vice Chair: 
Thembisile Xulu MBBS 
Chief of Party 
EQUIP 
3rd Floor Outspan Building 
1006 Lenchen North Street 
Centurion 
South Africa 
T: +27 84 555 5788 
Email: thembi.xulu@equiphealth.org 
 
Protocol Statistician 
Matthew Fox DSc, MPH 
Associate Professor 
Boston University 
801 Massachusetts Ave Crosstown Center 
Boston, MA 02118 
USA 
T: +1 617 414 1270 
Email: mfox@bu.edu 
 

The INTERVAL Study: Varying Intervals of ART Dispensing to Improve Outcomes in 
HIV 
 
Version 2.4 
Page 6 of 35 
22 June 2017 
Protocol Investigators 
Ian Sanne MBBS 
PI EQUIP RTC 
3rd Floor Outspan Building 
1006 Lenchen North Street 
Centurion 
South Africa 
T: +27 84 555 5788 
 
Sydney Rosen MPA 
Research Professor 
Boston University 
801 Massachusetts Ave Crosstown Center 
Boston, MA 02118 
USA 
T: +1 617 414 1273 
Email: brosen@bu.edu 
 
Gift Kakwesa 
Partners in Hope 
PO Box 302 
Lilongwe, Malawi 
T: +265 99 979 9200 
Email: kakwesa@pihmalawi.com  
 
Crispin Moyo 
Country Director-Zambia 
EQUIP 
5th Floor Outspan Building 
1006 Lenchen North Street 
Centurion 
South Africa 
T: +260 97 781 6438 
Email: crispin.moyo@equiphealth.org 
 
 

11-Aug-20 
Version 2.0 
0 
27 December 2016 
 
 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 1 of 35 
22 June 2017 
SCHEMA 
 
Purpose: 
To evaluate the effectiveness of two strategies for multi-month 
scripting/dispensing of antiretroviral therapy on retention and virologic 
suppression compared to standard of care 
 
Design: 
Unblinded cluster-randomized controlled trial  
 
Study Population: 
HIV-1-infected adults (18 and older) 
 
Sample Size: 
10 clusters in each of three arms representing ~8,200 patients 
 
Intervention: 
Arm 1: Standard of care scripting/dispensing 
 
Arm 2: Three-month scripting/dispensing                                                                                               
                                                                                                                                                                
Arm 3: Six-month scripting/dispensing 
 
Study Duration: 
Approximately 42 months total.  Accrual is expected to require 
approximately six months, and enrolled participants will be followed for 
36 months with the primary endpoint defined at 12 months and follow-
up through 36 months 
 
Primary Objectives  
• 
To determine, in patients stable on ART, whether scripting/dispensing of ART for intervals of three 
months is non-inferior to standard of care for the primary outcome of retention at 12 months 
• 
To determine, in patients stable on ART, whether scripting/dispensing of ART for intervals of six 
months is non-inferior to standard of care for the primary outcome of retention at 12 months 
• 
To determine, in patients stable on ART, whether scripting/dispensing of ART for intervals of six 
months is non-inferior to three months for the primary outcome of retention at 12 months 
 
Secondary Objectives  
• 
To determine whether scripting/dispensing of ART for intervals of three months is non-inferior to 
standard of care for the outcome of viral load <1,000 copies/mL at 12 months 
• 
To determine whether scripting/dispensing of ART for intervals of six months is non-inferior to 
standard of care for the outcome of viral load <1,000 copies/mL at 12 months 
• 
To determine whether scripting/dispensing of ART for intervals of six months is non-inferior to three 
months for the outcome of viral load <1,000 copies/mL at 12 months 
• 
To evaluate the impact of scripting interval on retention and virologic suppression at 24 and 36 
months 
• 
To compare cost and cost-effectiveness of all three arms 
• 
To determine whether three- and six-month scripting/dispensing is (all assessed at 12 months): 
• 
Feasible and acceptable for patients  
• 
Feasible and acceptable for providers 
• 
Feasible with regard to expanding supply chain and pharmacy storage 
• 
Non-inferior with regard to clinic resource allocation 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 2 of 35 
22 June 2017 
• 
Safe in regard to impact on the drug compound after storage for six months (based on sampling of 
any unused drug at the end of the six-month period) 
  
The INTERVAL Study: Varying Intervals of ART Dispensing to Improve Outcomes in 
HIV 
 
Figure 1 
OVERVIEW OF STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
STUDY POPULATION 
 
This study will be conducted among approximately 8,200 HIV-infected individuals 18 
years or older who are stable on antiretroviral therapy in 30 clusters who will be 
selected for the study according to the criteria outlined below.  The following countries 
are planned to participate: Malawi and Zambia. 
 
Sites will be selected based on size, ability to perform viral load determination as part 
of routine care, completeness of medical records, and ability to stock a six-month 
supply. 
 
1.1 
Inclusion Criteria 
 
All of the criteria listed below must be met in order for an individual to be included in 
this study.   
 
Randomizati
on 
3-Month Dispensing 
10 clusters 
(~271 participants per cluster) 
6-Month Dispensing 
10 clusters 
(~271 participants per cluster) 
Standard of Care 
10 clusters 
(~271 participants per cluster) 
12 months*
24
36 months
*Primary endpoint of retention will be assessed at 12 
months; all participants will continue follow-up through 
36 months; participants who reach a study endpoint will 
continue in observational follow-up 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 3 of 35 
22 June 2017 
4.1.1 
At least 18 years of age and willing and able to provide written informed consent 
for participation in this study 
 
4.1.2 
Confirmed HIV-1 infection based on country standard of care for testing 
 
4.1.3 
“Stable” on ART defined as  
(1) On ART ≥ six months  
(2) On a first-line ART regimen as defined by country specific guidelines  
(3) No drug toxicity/tolerability issues within the prior six months  
(4) No period of >one month without medication possession in the last six 
months  
(5) No active opportunistic infection suspected (including TB) and not treated 
for an opportunistic infection in the last 30 days 
(6) Undetectable viral load (as defined by country guidelines) within the last 6 
months: 
• 
Malawi: <1,000 copies/mL 
• 
Zambia: <20 copies/mL 
 
4.1.4 
Not treated for other chronic health problems or comorbidities (e.g., high 
blood pressure, diabetes) at the clinic in which they receive their ART 
 
4.1.5 
Women will be included as long as they are not currently pregnant, not 
currently breastfeeding, and ≥6 months postpartum if they have recently 
delivered a baby 
 
4.1.6 Planning to receive HIV care from the same facility for ≥1 year 
 
1.2 
Exclusion Criteria 
 
Individuals will be excluded from the study if any of the following are identified during 
screening or any other time during the study:  
 
4.2.1 
Elevated viral load (as defined by country guidelines) of standard assay within 
the prior six months: 
• 
Malawi: ³1,000 copies/mL 
• 
Zambia: ³20 copies/mL 
 
4.2.2 On alternative first-line or second-line regimen 
 
4.2.4     >One month without medication possession in the last six months 
 
4.2.5     ARV toxicity or tolerability issue within the prior six months 
 
4.2.6 Suspected or diagnosed with an opportunistic infection (including tuberculosis) 
within the prior 30 days 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 4 of 35 
22 June 2017 
 
4.2.7 
Currently receiving treatment for a comorbidity (including hypertension or 
diabetes) at the facility in which they receive their ART 
 
4.2.8     Pregnant or less than six months postpartum 
 
4.2.9 Women who are breastfeeding 
 
4.3.1     Unwilling or unable to provide informed consent 
 
4.3.2     Previously enrolled in the study 
 
4.3.3     Currently enrolled in a research study at the site that influences frequency of 
clinic visits and/or where they receive their medications 
 
4.3.4 Currently participating in an ART support group, a community ART group 
(CAG), or a group where they receive ART at a location other than the clinic 
 
4.3.5 
Not planning to receive HIV care from the same facility for ≥1 year 
 
2 
INTRODUCTION  
 
2.1 
Background 
 
The 2015 WHO Guidelines on when to start antiretroviral therapy recommend ART initiation 
regardless of CD4 count, with lifelong continuation to optimize individual health and prevent 
HIV transmission [1]. In order to realize the benefits of lifelong ART, high levels of adherence 
and retention will be needed. Barriers to adherence and retention have included long duration 
of wait times in ART clinics, cost of travel to clinics, and life events that result in interruptions in 
therapy.  Requirements for monthly dispensing and/or systems that require multiple separate 
visits for refills and clinician evaluation can raise significant challenges for individuals living 
with HIV and result in treatment interruptions or complete disengagement from care [2]. 
Extension of interval refills has been employed in many settings, with supply provided up to 
every six months for stable patients in settings where resources have been available.  This 
document will outline considerations for extending ART dispensing intervals. Given not all 
PEPFAR sites provide or have a mechanism for scripting either electronically or with paper-
based methods, this document will refer to multi-month scripting/dispensing (MMS) to 
describe the process of supplying medications for an extended interval of time.  
 
Potential benefits of multi-month dispensing/scripting include: 
§ 
Improved adherence to ART and retention in care through decreasing barriers such as time for clinic 
visits and cost of travel to clinics/dispensing sites; less risk of interruption due to unanticipated life 
events that result in missed clinical and/or pharmacy refill visits 
§ 
Reduced per-patient cost of providing ART, by reducing the number of clinic visits required 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 5 of 35 
22 June 2017 
§ 
Decongestion of clinics to allow for increased capacity to manage newly diagnosed patients, those 
with infectious complications, treatment failure, and other co-morbidities 
§ 
Decreased waiting time and improved efficiency at clinics allowing for improved quality of care and 
patient satisfaction 
 
PEPFAR has adopted the goals of 90-90-90 from UNAIDS and the new guidelines of WHO on 
when to initiate ART.  The goals of 90-90-90 are simple but ambitious – identify 90 percent of 
people living with HIV; link and initiate 90 percent of those identified on ART; and achieve viral 
suppression in 90 percent of those on ART, by 2020. This will result in 28 million people on 
treatment by 2020.  With these goals, PEPFAR also sets out to reduce new infections by 75 
percent and to attain zero discrimination and stigma for supported sites. PEPFAR funding 
changes for the upcoming year have been made to support a swift implementation of the new 
Test and Start guidelines. The goal is for implementation to occur within weeks to months, not 
years. The funding changes from the FY16 PEPFAR Technical Considerations are as follows. 
Countries that move to Test and Start are eligible for one-time commodities funds to 
immediately expand drug availability for longer follow-up intervals (Impact/Incentive Funds). 
The cost savings from adopting increased follow-up intervals and fewer laboratory tests should 
be used to dramatically expand treatment. 
 
Requirements for frequent dispensing of ART (once every one to two months) places demands 
on the health system and can lead to suboptimal adherence and disengagement in care due to 
the time and cost of frequent visits to clinic.  Keeping these considerations in mind, scaling up 
of HIV treatment must be accompanied by measures to allow stable patients to have an 
adequate supply of ART (at least three months) and should consider whether longer drug 
supply intervals are feasible (up to six months) and result in improved outcomes and/or lower 
costs. Attaining the benefits associated with 90-90-90 will require (I) support from the National 
AIDS Programs of multi-month dispensing, its incorporation in the national guidelines, and 
costing; (II) ARV forecasting and support for supply chain and pharmacy; (III) selection of 
appropriate patients for extended dispensing intervals and integration with current and 
planned differentiated models of care; (IV) support for implementation at site and community 
levels through mentorship and continuous training and support; and (V) monitoring and 
evaluation to confirm patients are adherent (ideally shown with viral suppression) and are 
retained in care.  
 
I. 
Support from the National AIDS program of the multi-month dispensing and its incorporation into 
the national guidelines including costing 
a. Support the MoH to review, adopt, and adapt policies and guidelines to include multi-
month dispensing, including costing for increased drug supply and strategies for the 
integration into both traditional clinic settings and within current and proposed 
differentiated models of care for ART.  
II. 
Preparedness and implementation for multi-month dispensing, including ARV forecasting and 
support for supply chain (including storage) and pharmacy 
a. Preparation for multi-month dispensing will require support for forecasting the necessary 
ARV supplies needed to prevent stock-outs, assessment of current medication storage 
capacity, and support for increasing storage to accommodate dispensing needs (up to 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 6 of 35 
22 June 2017 
three- to six-month supply). EQUIP will provide TA in these areas including an 
assessment of current pharmacy regulations and capacity for scripting (with consideration 
for use of an electronic national system such as a ‘cloud’, where feasible) and dispensing. 
Priority will be to support placing stable patients on a minimum three-month schedule 
and consideration of up to six-month ART supply in settings where this may be feasible.  
Countries interested in comparing provision of a three- versus six-month supply of ART 
may choose to participate in a multi-country demonstration project evaluating patient 
outcomes, cost, and impact on health system efficiencies.   
III. 
Selection of individuals for multi-month dispensing and integration with current or planned 
differentiated models of care 
a. As an initial step towards multi-month dispensing, defining ‘stable’ individuals for this 
care strategy will be required. EQUIP will provide support to define ideal scenarios and 
simple algorithms for identifying stable individuals on ART in whom extension of supply 
will be appropriate. For example, stable patients may be defined as taking ART for at 
least one year with either a suppressed viral load (in countries with immediate capacity to 
perform viral load testing) or adherence based on pill counts and appointment schedules 
(for those without immediate viral load capacity) and no other complicating health 
problems such as active infectious complication.  
b. HIV care is moving towards differentiated models where many individuals may 
participate in community-based ART delivery programs (community ART groups, 
adherence clubs, etc.) and programs that may employ alternative strategies for drug 
delivery (community drop off/distribution points), and multi-month dispensing will need 
to be integrated into these programs. Integration of multi-month dispensing may include 
consideration of utilizing lay health workers, patients, or other non-clinician health cadres 
to pick up medications from pharmacy/clinic locations, and/or utilize alternative methods 
of drug storage and dispensing that can easily be accessed by the community. These 
strategies will depend on country-specific pharmacy and drug storage regulations and 
flexibility/adaptability of systems.   
IV. 
Support for expansion/implementation of multi-month dispensing at site and community levels  
a. Based on final plans for multi-month dispensing, mentoring will be needed at all levels of 
the health system. Clinicians will require training in identification of stable patients for 
multi-month dispensing and mentoring to utilize systems that are in place to enable these 
strategies (scripting versus use of decentralized pharmacy systems or drug pick up 
points). Clinicians and community care workers will need clear, ongoing mentorship to 
be in a position to educate and support patients and continue to optimize adherence and 
retention.  With the change to viral load monitoring, care should be taken to ensure the 
patient’s understanding of the benefits of maintaining an undetectable viral load, such as 
low transmittance, decreased opportunistic infections, increased CD4 count, and 
ultimately better health outcomes. 
b. Pharmacists and related personnel will require mentoring to understand the variety of 
methods in which drug delivery may be employed in the health system and to ensure 
continuous quality improvement around drug storage and ARV forecasting.   
V. 
Monitoring and evaluation of outcomes of adherence and retention in care and resource utilization 
with multi-month dispensing 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 7 of 35 
22 June 2017 
In order to determine best practices around multi-month dispensing, programs will 
require monitoring and evaluation of systems (related to issues such as drug supply, 
adequacy of drug storage facilities, quality of pharmacy services, and resource 
utilization) and monitoring and evaluation of critical program outcomes such as viral 
suppression and retention in care. Data around improvements in these outcomes after 
switching to multi-month dispensing can be used to define best practices and to further 
scale programs within a given country and in other countries.   
 
2.2 
Prior Research on Multi-Month Scripting/Dispensing 
 
There is limited rigorous data on multi-month scripting and dispensing from resource-
limited settings. A review of the literature reveals no randomized studies of different 
dispensing intervals. An abstract from Zambia presented at CROI in February 2016 
suggests that requirements for monthly dispensing and/or systems that require 
multiple separate visits for refills and clinician evaluation can raise significant 
challenges for individuals living with HIV and result in treatment interruptions or 
complete disengagement from care [2]. 
 
2.3 
Rationale 
 
Requirements for frequent dispensing of ART (once every one to two months) places 
demands on the health system and can lead to suboptimal adherence and 
disengagement in care due to the time and cost of frequent visits to clinic.  Keeping 
these considerations in mind, scaling up of HIV treatment must be accompanied by 
measures to allow stable patients to have an adequate supply of ART (at least three 
months) and should consider whether longer drug supply intervals are feasible (up to six 
months) and result in improved outcomes. We propose a strategy trial of different 
intervals of ART dispensing with the goal of estimating any potential benefits of longer 
dispensing intervals with respect to retention, virologic suppression, and cost.   
 
2.4 
Hypotheses 
 
Among adults with HIV infection who are stable in care: 
• 
H1: Dispensing for three months will be non-inferior to SOC in regard to retention at 12 
months 
• 
H2: Dispensing for six months will be non-inferior to SOC in regard to retention at 12 
months 
• 
H3: Dispensing for six months will be non-inferior to three months in regard to retention 
at 12 months 
• 
H4: Dispensing for three or six months will be non-inferior to SOC in regard to virologic 
suppression at 12 months 
• 
H5: Dispensing for six months will be non-inferior to three months in regard to virologic 
suppression at 12 months 
• 
H6: Dispensing for three or six months will be cost-effective compared to SOC 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 8 of 35 
22 June 2017 
3 
OBJECTIVES 
 
Primary Objectives  
• 
To determine, in patients stable on ART, whether scripting/dispensing of ART for 
intervals of three months is non-inferior to standard of care for the primary outcome of 
retention at 12 months 
• 
To determine, in patients stable on ART, whether scripting/dispensing of ART for 
intervals of six months is non-inferior to standard of care for the primary outcome of 
retention at 12 months 
• 
To determine, in patients stable on ART, whether scripting/dispensing of ART for 
intervals of six months is non-inferior to three months for the primary outcome of 
retention at 12 months 
 
Secondary Objectives  
• 
To determine whether scripting/dispensing of ART for intervals of three months is non-
inferior to standard of care for the outcome of viral load <1000 copies/mL at 12 months 
• 
To determine whether scripting/dispensing of ART for intervals of six months is non-
inferior to standard of care for the outcome of viral load <1000 copies/mL at 12 months 
• 
To determine whether scripting/dispensing of ART for intervals of six months is non-
inferior to three months for the outcome of viral load <1000 copies/mL at 12 months 
• 
To evaluate the impact of scripting interval on retention and virologic suppression at 24 
and 36 months 
• 
To compare cost and cost-effectiveness of all three arms 
• 
To determine whether three- and six-month scripting/dispensing is (all assessed at 12 
months): 
o Feasible and acceptable for patients  
o Feasible and acceptable for providers 
o Feasible with regard to expanding supply chain and pharmacy storage 
o Non-inferior with regard to clinic resource allocation 
o Safe in regard to impact on the drug compound after storage for six months (based 
on sampling of any unused drug at the end of the six-month period) 
 
4 
STUDY DESIGN 
 
The study will be a cluster randomized trial comparing three different ART dispensing 
strategies. Clusters will be comprised of individual clinics in Malawi and Zambia.  
 
Individuals will be screened at routine clinic visits and enrolled if they meet inclusion 
criteria (see below). Enrolled individuals will receive standard of care at their site with 
the exception of dispensing interval based on the assigned randomization.  Outcomes 
will be assessed after 12 months but all patients will be followed for 36 months, with 
annual re-assessment of endpoints of retention and virologic suppression and 
evaluation of cost-effectiveness at those time points.  
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 9 of 35 
22 June 2017 
4.1 
Recruitment, Screening, and Enrollment Process 
 
Recruitment methods for this study may vary across sites but are expected to rely on 
active identification and referral of stable patients, as defined above, by clinic staff.  
Clinics will be randomized to a study arm, and individuals will initiate the study drug 
dispensing interval to which the clinic has been randomly assigned.  
 
Each study clinic will be asked to provide a list of potential study participants, based on 
time on ART.  Records will then be reviewed to screen out those who do not meet 
inclusion criteria, based on available information.  Upon identification of a potentially-
eligible individual, study staff will provide information about the study to the patient.  
Individuals who express interest in learning more about the study will be provided 
additional information as part of the study informed consent process.  The process will 
include detailed review of the study informed consent form, time to address any 
questions or concerns, and an assessment of the individual’s understanding before 
proceeding to an informed consent decision.  The process will be fully documented, and 
only individuals who are able to demonstrate understanding will be asked to provide 
written informed consent for study screening and enrollment.   
 
Each country will require IRB approval from their local authority, and written informed 
consent will be required. Additionally, each site must establish standard operating 
procedures (SOPs) for eligibility determination that describe where and when screening 
procedures will be performed, roles and responsibilities for performing the required 
procedures, roles and responsibilities for assessing and confirming eligibility, and 
procedures for documenting the process. These will be described in detail in IRB 
applications. Participants will be informed of the assigned drug-dispensing interval 
based on the facility randomization assignment — standard of care, three, or six 
months — and the appropriate quantity of medications will be prescribed/dispensed on 
the day of enrollment. 
 
When informed consent is obtained, a participant identification number (PID) will be 
assigned to the individual.  
 
4.2 
Co-Enrollment Considerations and Differentiated Models 
 
After enrollment in the INTERVAL study, co-enrollment in other studies will not be 
allowed given the likelihood that this will interfere with the primary study endpoint of 
retention.  
 
Differentiated models of care (DMCs) will be included as follows: if a facility utilizes 
differentiated models such as adherence clubs, CAGS, or drop off points, these facilities 
will be included in the study, though patients participating in DMCs will be excluded 
from the study.  
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 10 of 35 
22 June 2017 
4.3 
Randomization 
 
Randomization will be conducted at the level of a hospital and surrounding clinics. We 
will randomize 30 clusters evenly to one of three arms: standard of care, three-month 
dispensing, and six-month dispensing. All patients enrolled at the site will follow the 
treatment assignment for the cluster in which they are randomized. Clusters will be 
matched in groups of three on available information that might predict outcomes, 
including country, type of facility (hospital/health centre), clinic size, number retained 
on ART, location (rural/urban), etc. We will then randomly allocate one cluster in each 
group of three matched clinics to each treatment arm. This will help minimize residual 
confounding that can result in cluster randomized trials. 
 
4.3.1 Description of Study Arms 
A randomization tool in Microsoft Excel will be used to randomly assign clusters to 
study arms. Clusters will be assigned to one of three arms: 
 
1. Standard of care arm: The standard of care arm will allow dispensing based on usual 
practice at the clinic. Standard of care is anticipated to have variability in how ART is 
dispensed, although the approach should be consistent with applicable country guidelines 
at the time of study. For example, if country guidelines recommend provision of two 
months of ART to stable patients, we expect most patients will receive two months; 
however, providers may choose to deviate from this standard for some patients, and the 
study will not influence these patterns. We recognize that in countries with three-month 
dispensing as the norm, standard of care may be similar to the three-month dispensing 
arm; however, we do anticipate an increased degree of variability in prescribing practices 
at these sites, either based on provider or patient preference.  
 
2. Three month dispensing arm: Providers at facilities randomized to three-month 
dispensing will be expected to provide all enrolled patients with a 90-day supply of ART. 
All other aspects of care will be as standard of care for the enrolling clinic, though 
routine clinic visits will occur every 90 days instead of the standard of care interval. 
Information about ideal storage conditions for ART will be provided by the clinic. In a 
subset of patients, unused ART will be returned to the site and submitted to the study 
team for analysis to evaluate whether typical storage conditions have any negative impact 
on active drug compound.  
 
3. Six month dispensing arm: Providers at facilities randomized to 6-month dispensing will 
be expected to provide all enrolled patients with a 180-day supply of ART. All other 
aspects of care will be as standard of care for the enrolling clinic, though routine clinic 
visits will occur every 180 days instead of the standard of care interval. Information 
about ideal storage conditions for ART will be provided by the clinic. In a subset of 
patients, unused ART will be returned to the site and submitted to the study team for 
analysis to evaluate whether typical storage conditions have any negative impact on 
active drug compound.  
  
4.4 
Informed Consent 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 11 of 35 
22 June 2017 
Oral informed consent will be obtained prior to screening procedures. The oral consent 
process will include a brief overview of the study, information about the screening 
procedures, alternatives to participating in the screening, and a brief assessment of the 
patient’s understanding of the consent. If a patient does not have a viral load recorded 
within the prior six months but has passed all other eligibility criteria, then written 
informed consent will be obtained before a viral load test is performed.   
 
Written informed consent will be obtained prior to enrollment and any study-specific 
procedures are performed (including blood draw for a viral load test during the 
screening procedures).  The informed consent process will include information 
exchange, detailed discussion, and assessment of understanding of all required 
elements of informed consent, including the potential risks, benefits, and alternatives 
to study participation.  The process will emphasize the randomized nature of the study 
and the differences that participants may experience as part of the study relative to 
current local standards of care.    
 
4.5 
Participant Retention 
 
Because retention in care is a primary outcome for the study, once an individual is 
enrolled, there will be no additional efforts applied towards retention with the 
exception of standard of care counseling and other retention support offered by sites. 
Study interactions with participants will be minimized through use of existing medical 
records to track patient outcomes. We will obtain informed consent to contact people 
after completion of the study to perform qualitative interviews and surveys of 
acceptability, cost, and quality of life measures. 
 
4.6 
Participant Withdrawal or Termination from the Study 
 
Regardless of the participant retention procedures referenced above, individuals may 
voluntarily withdraw from the study.  Participants may also be terminated from the 
study by the site investigator or designee under the following circumstances: 
 
• 
Site investigator or designee determines that continued participation in the study would 
be unsafe or otherwise not in the best interest of the participant  
• 
The study is stopped or canceled by the sponsors, government or regulatory authorities, 
or site IRBs/ECs 
 
For any participant who is withdrawn or terminated from the study prior to scheduled 
completion of follow-up, study staff will document the reason for the withdrawal or 
termination in detail and will make every effort to complete final evaluations.  In the 
event that the circumstances that led to a participant’s withdrawal or termination 
change (e.g., he or she returns to the study site area after having re-located previously), 
the site investigator or designee should contact the study investigators to discuss 
options for resumption of follow-up. 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 12 of 35 
22 June 2017 
5 
STUDY VISITS AND PROCEDURES 
 
An overview of the schedule of study visits and evaluations is provided in Table 3 below.  
Presented in this section is additional information on visit-specific study procedures.   
 
In addition to the protocol-specified procedures listed in this section, study staff may 
complete other tasks consistent with site SOPs, including but not limited to collecting, 
reviewing, and updating demographic and locator information and reviewing elements 
of informed consent.  
 
Table 3: Schedule of Evaluations 
 
Evaluation 
Entry 
12 
months 
24 
months 
36 
months 
Administrative/Regulatory 
• 
Informed Consent 
• 
Complete final eligibility determination and 
confirmation* 
X 
 
 
 
Clinical History/Socio-demographic data 
• 
Date HIV diagnosis 
• 
Socio-demographic data 
• 
ART start date 
• 
Medications at entry (ART, CPT, IPT) 
• 
ART dispensing interval at time of entry 
• 
CD4 at ART initiation/CD4 if documented within 12 
months prior to entry 
• 
VL at entry 
X 
 
 
 
Medical Record Review for Endpoint^ 
• 
Retention in care* 
• 
Viral load 
• 
ART regimen changes 
• 
Medication review (CPT, IPT) 
• 
Current dispensing interval (if changed, date of change 
and reason for change documented) 
• 
Interval lab tests recorded, if any (CD4) 
• 
OIs if recorded 
 
X 
X 
X 
Patient Health Passport Review for Endpoint^ 
• 
Number and type of interval clinic visits (unscheduled) 
• 
General health assessment 
 
X 
X 
X 
Time and Motion Assessment 
• 
Patient wait times 
X 
X 
X 
X 
Cost Assessment 
X 
 
 
 
Clinic Resource Allocation Assessment 
X 
X 
X 
X 
Qualitative in-depth interview 
 
X 
 
X 
Qualitative in-depth interview and survey with providers 
 
X 
 
X 
^Individuals who meet an endpoint will be followed for the remainder of the study in observational follow-up; 
*Default defined as out of ART >60 days 
 
5.1 
Screening Visit 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 13 of 35 
22 June 2017 
An overview of the screening visit procedures is provided in Table 1 below. Initial 
screening will include review of participant clinical data and will be performed at the 
time of routine ART visits to clinic. If inclusion criteria are met with the exception of 
viral load (due to missing viral load information), a viral load test will be performed if 
not documented within the last six months. Viral loads should not be drawn until 
participants have met other inclusion criteria (Figure 2: Screening Algorithm). If viral 
load is savailable, the screening and entry visit procedures can be combined into the 
same visit. If no viral load is available, the viral load is performed and entry will occur at 
the time the participant comes back at the next routine appointment. Given the next 
routine appointment could be up to three months later, the screening criteria should be 
reviewed again before the entry visit procedures are performed. 
 
Table 1: Screening Visit 
 
Screening Visit Procedures  
Administrative 
and Regulatory 
• Obtain informed consent from participant before screening 
 
Screening Data from Medical 
Record 
• Review medical chart for: 
Ø ≥ 18 years of age 
Ø Confirmation of HIV+ status^  
Ø Confirmation of ART for ≥six months 
Ø No period of >one month without medication 
possession in the last six months  
Ø ART regimen is standard first-line regimen  
Ø No suspected or confirmed infectious complication 
(including tuberculosis) within the last 30 days (i.e. 
must be off treatment for other condition for >30 
days at time of entry) 
Ø Not currently pregnant or within six months of 
delivery  
  Laboratory 
• Review chart for most recent viral load (viral load must be 
<1,000 copies/mL within six months of screening for Malawi 
and must be <20 copies/mL within six months of screening 
for Zambia) 
• If no viral load available, ask clinic to draw blood sample and 
send for viral load test 
            ^based on recording of HIV status in medical record 
 
 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 14 of 35 
22 June 2017 
Figure 2: Screening Algorithm  
(Note: If screening viral load needs to be sent, participant follows up for study entry at 
next routine ART visit. At that visit, screening criteria will be re-reviewed and if still eligible 
and VL<1000, copies, study staff will proceed with entry) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial screen: 
Ø ≥ 18 years of age 
Ø HIV+ by country testing standard 
Ø On ART ≥ 6 months 
Ø On first line ART 
Ø No ART toxicity/tolerability in prior 6 months 
Ø No active OI suspected 
Ø No OI/TB treatment within the last 30 days 
Lab Screen: 
Ø Malawi: Viral Load < 1,000 
copies/mL within the prior 6 
months 
Ø Zambia: Viral Load < 20 
copies/mL within the prior 6 
months 
ELIGIBLE 
FOR STUDY 
YES 
NOT 
ELIGIBLE 
FOR STUDY 
NO
NOT 
AVAILABL
E
 
Send screening viral load 
Malawi: < 
1,000 
Malawi: ≥ 
1,000 
ELIGIBLE 
FOR STUDY 
NOT 
ELIGIBLE 
FOR STUDY 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 15 of 35 
22 June 2017 
5.2 
Entry Visit 
 
An overview of the entry visit procedures is provided in Table 2 below. All entry visit 
procedures are expected to be performed on the day of enrollment; procedures that 
may provide information relevant to eligibility for the study (e.g. viral load), should be 
performed first, prior to final eligibility determination.  
 
Additional requirements for sequencing of procedures at the entry visit are as follows: 
• 
Final eligibility determination and confirmation and provision of written informed 
consent must precede enrollment 
• 
Enrollment and entry visit procedures must precede dispensing of ART  
 
Collection of clinical history information is required at the entry visit. All history 
information will be obtained based on self-report and available medical records.  
Relevant dates will be recorded for all conditions and medications. 
 
Table 2: Entry Visit 
 
Entry Visit Procedures (Day 0) 
Administrative 
and Regulatory 
• Complete signed informed consent* 
• Complete final eligibility determination and confirmation* 
Clinical/Medical Record 
Review 
Surveys 
• HIV history, HIV-related medications, date of ART 
initiation, prior adherence/VL data  
• Socio-demographic data including age, gender, highest 
level of education, distance to travel to clinic, 
household composition (number of adults and 
children in household), employment status, 
disclosure status, marital status 
• Collection of patient cost data: travel time and costs to 
clinic, opportunity cost of time spent on medication 
pickup visits 
Dispensing 
• After enrollment, site clinician dispenses ART per cluster 
randomized assignment  
*Performed prior to entry visit procedures 
 
5.3 
Annual Viral Load Visit (12 months, 24 months, 36 months) 
 
There will be no contact with study participants during the period of follow-up. 
However, when participants are due for routine, annual viral load assessments, study 
staff will help ensure each site has capacity to collect these samples and will support 
systems that help to provide results back to sites. Viral loads will only be performed on 
individuals who return for visits, and no tracing will be performed by the study for the 
purpose of obtaining viral load. Viral loads will be considered within the window for the 
annual visit if they are performed in a window of +/- 60 days.  
  
5.4 
Definition of Study Endpoints  
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 16 of 35 
22 June 2017 
Endpoints will be determined by chart review after the primary endpoint is reached (12 
months) and will be re-assessed after the 24-month endpoint and again after the 36-
month endpoint. Endpoint data collection will include: 
 
(1) Retention in care on strategy (not lost to follow-up and not changed off dispensing 
interval; lost to follow up will be defined by being out of ART for >60 contiguous days) 
(primary) 
(2) Suppressed viral load of <1,000 copies done as part of annual viral load or performed at 
any other time during the follow-up, if ordered by clinician due to clinical concern 
(secondary) 
 
The following will be considered not retained unless otherwise noted: 
• 
Retained in care but with transitioned off assigned study arm for any reason (patient 
preference, provider preference, development of ART toxicity requiring switch and closer 
monitoring, OI, other complication) 
• 
Transferred to another clinic (if a documented transfer, will be considered retained and 
analyzed as such at the next assessment point (12, 24, or 36 months) 
• 
Death  
 
Observational Follow-Up 
All participants with loss to follow-up will be traced by existing clinic protocols (if 
present). If they are located and return to clinical care, medical records will be reviewed 
up to the 36-month time point to determine outcomes after loss to follow-up. 
Additionally, those with virologic failure will reviewed at subsequent time points for 
additional outcomes. Chart review will be performed at subsequent time points to 
determine outcomes such as: 
• 
retained and suppressed (and dispensing interval) 
• 
retained but not suppressed (and dispensing interval) 
• 
retained but dispensing interval changed for any reason 
• 
lost to follow up again (defaulted care defined by >60 days without ART) 
• 
transferred 
• 
died 
 
Health Passport Review (Malawi only) 
 
In a subset of participants (n=1,500), we will perform a review of participants’ health passports, a 
record of patient clinic visits, general health information, and medications that is possessed by 
patients in Malawi, after the 12-, 24-, and 36-month endpoint has been completed. Informed 
consent will be obtained at entry for permission to review participants’ health passports during 
their endpoint ART clinic visits. Study staff will scan the health passports and store the records in 
a secure database. Physicians who are familiar with Malawian health records will review the 
health passports to collect patient data on interim clinic visits, such as reason for visit/services 
received (sick, family planning, non-communicable disease treatment), frequency of visits, and 
location of clinic services. 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 17 of 35 
22 June 2017 
5.5 
Post-Intervention Visit 
 
In a subset of participants (~240), we will perform a post intervention study visit after the 12-
month endpoint is completed and also after the 36-month endpoint is completed. Informed 
consent will be obtained at entry for permission to contact participants after the study is over. 
Qualitative interviews will be performed with a subset of participants with the goal to include 
those that were retained in care as well as participants who reached a study endpoint. Questions 
will focus on patient experience with assigned dispensing interval, including challenges/barriers 
and facilitators towards adherence and retention. Focused questions around endpoints (if default, 
reasons; if virologic failure, reasons including adherence) will also be addressed in the post-
intervention visit.  
 
5.6 
Time and Motion Assessment 
 
In a random sample of up to 100 patients per clinic, we will perform a time and motion 
assessment at study commencement and again at each study endpoint. Participants 
already enrolled in the study will be excluded from the time and motion assessment. 
Wait times will be measured by research staff, and patients will be surveyed about clinic 
services received during their visit. Assessments will occur on randomly selected ART 
clinic days.  
 
 
Figure 3: Summary of Plan for Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.7 
Virologic Failure 
 
In the event that an elevated viral load returns (≥1,000 copies/mL for Malawi or ≥20 
copies/mL for Zambia), clinics will be expected to manage the participant as per the 
country guidelines with adherence counseling. Frequency of ART dispensing will be 
determined based on guidelines and clinician assessment. No additional study visits will 
3-Month Dispensing 
10 clusters 
(~271 participants per cluster) 
6-Month Dispensing 
10 clusters 
(~271 participants per cluster) 
Standard of Care 
10 clusters 
(~271 participants per cluster) 
^Participants who are lost to follow-up will be traced by routine clinic based protocols; individuals who return will be continued on study in 
observational follow-up 
OUTCOMES 
• Not retained (off ART for >60 
days^) 
• Viral load ≥1,000 copies/mL 
for Malawi or ≥20 copies/mL 
for Zambia 
• Transitioned off assigned study 
arm for any reason (patient 
preference, development of 
ART toxicity requiring switch 
and closer monitoring, OI, 
other complication) 
OBSERVATIONAL 
FOLLOW-UP 
• Return to care (if 
default) 
• Viral re-suppression (if 
VL elevation occurred) 
• Retention (if lost to 
follow-up) 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 18 of 35 
22 June 2017 
be performed at the time of virologic failure. Virologic failure will be captured via 
medical record review. These individuals will remain in observational follow-up.  
 
Viral load will be collected based on standard of care for the site as dictated by each 
country program and reported based on the threshold used for clinical management by 
the country program. Suppression will be defined by as <1,000 copies/mL.   
 
5.8 
Drug Supply 
 
The standard of care first line regimen will be provided by the sites. EQUIP will support supply 
chain and medication storage as needed to ensure that all participants are able to receive the 
appropriate extended interval refill and that study ART needs do not negatively impact supply 
chain needs at non-study sites or for non-study patients. 
 
In the event lost or stolen medication is reported by a participant, the clinic will proceed with 
standard of care procedures for re-dispensing of medications as defined by the country’s 
guidelines. Participants who report lost or stolen medication will remain in their assigned study 
arm and ART dispensing interval unless termination from the study has been deemed necessary 
per guidelines in section 4.6. 
 
6 
SAFETY ASSESSMENT, MONITORING, AND REPORTING 
 
Participant safety will be carefully assessed, monitored, and reported at multiple levels 
throughout this study.  Sections below describe safety-related roles, responsibilities, 
and procedures.   
 
6.1 
Safety-Related Roles and Responsibilities 
 
6.1.1 Site Investigators 
 
Site investigators are responsible for continuous monitoring of all study participants 
and for alerting the Protocol Team if unexpected concerns arise. Site investigators are 
also responsible for prompt reporting to their IRBs/ECs and other applicable review 
bodies of any unanticipated problems involving risks to participants or others. 
 
6.1.2 Clinical Management Committee (CMC) 
 
The following Protocol Team members comprise the CMC:  Protocol Chair and Vice 
Chair, selected Protocol Investigators, Statisticians, and Data Managers. The CMC will 
provide guidance as needed to site investigators regarding all aspects of participant 
management, including but not limited to questions of participant eligibility and 
management of adverse events.  
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 19 of 35 
22 June 2017 
6.1.3 Data and Safety Monitoring Board (DSMB)  
 
An independent DSMB will be assembled and will have at least three representatives 
from settings in which the study is being performed, one of whom will be a 
biostatistician. The primary purpose of the DSMB will be to perform one interim 
analysis after half of the primary study outcomes have been reached to determine 
whether the study needs to be stopped early for a positive result or whether issues such 
as slow enrollment or loss to follow-up could impact study goals. 
 
6.2 
Management of Participants Who Develop Tuberculosis or Another Opportunistic 
Infection 
 
Participants who develop TB or other opportunistic infections may require more 
frequent follow-up than required by their dispensing interval. Frequency of ART 
dispensing will be determined based on guidelines and clinician assessment. No 
additional study visits will be performed at the time of these clinical complications or 
changes in dispensing interval. These events will be captured via medical record review. 
These individuals will remain in observational follow-up. 
 
6.3 
Management of Women Who Become Pregnant During Study  
 
Women who become pregnant during the study may require more frequent clinical 
visits than required by their dispensing interval. Frequency of ART dispensing will be 
determined based on guidelines for ART in pregnancy and clinician assessment. No 
additional study visits will be performed at the time of pregnancy or change in 
dispensing interval. These events will be captured via medical record review. These 
individuals will remain in observational follow-up. 
 
7 
STATISTICAL METHODS  
 
7.1 
General Design Issues 
 
The study will be a three-arm cluster randomized trial. Accordingly, the analysis and 
sample size will need to account for statistical clustering within groups allocated to 
interventions and control arms. In addition, we will conduct one interim analysis when 
the data for 50 percent of the participants are recruited and have reached a primary 
outcome at one year of follow up. Because we may not see large differences between 
the three-month dispensing and the six-month dispensing arms, we have powered the 
trial as a cluster randomized non-inferiority trial. This was done to ensure we had 
adequate sample size to draw conclusions even if no major differences exist but also to 
be able to detect differences between each intervention arm and standard of care. 
 
7.2 
Outcome Measures 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 20 of 35 
22 June 2017 
7.2.1 Statistical Analysis for Primary Outcome Measures 
 
Our primary outcome is retention in care at one year and is the basis for our sample size 
estimates and our primary analysis. Follow up will be passive by record review and will 
not involve any patient interaction with study staff as our goal is to measure retention 
under routine conditions. 
Documented transfers will be considered retained at the next immediate time point of 
endpoint assessment and then will be censored. Deaths will be considered not retained.  
 
Our analysis will begin with descriptive measures about the study population, stratified 
by treatment arm and by clinic and presented as medians and interquartile ranges for 
continuous measures and proportions for categorical variables. These measures will be 
used to look for large variations by clinic and for imbalances between study arms. 
 
Our primary analysis will use a log linear generalized estimating equation to estimate 
the risk ratios and associated 95% confidence interval for the effect of each 
intervention arm compared to standard of care. We will specify clinic level clustering to 
account for the study design and estimate robust standard errors using an unstructured 
correlation matrix. Should we identify any baseline imbalances between study arms, we 
will adjust for these in our multivariable model and report adjusted risk ratios and 
corresponding 95% confidence intervals. 
 
7.2.2 Statistical Analysis for Secondary Outcome Measures 
 
Our study has not been powered to specifically look at secondary endpoints (described 
above), however we should have enough power to detect differences in our secondary 
endpoints if they exist. Our analytic methods for secondary outcomes will be identical 
to those for primary outcomes described above. 
 
For other secondary outcomes, analysis is defined below individually for each: 
To determine whether six-month scripting/dispensing is (all assessed at 12 months): 
(1) Feasible and acceptable for patients: In a subset of participants in all arms, qualitative 
methods (semi-structured in-depth interviews) will be used to assess feasibility and 
acceptability of scripting/dispensing interval; impact on quality of life, health, adherence, 
ability to remain in care; challenges with storage of medications; and self-perceived 
benefits or harms of different scripting/dispensing intervals (with particular focus on 
whether there is difficulty with storage of medications, risk of theft, or pressure to 
exchange medications for money or food). 
(2) Feasible and acceptable for providers: In a subset of providers in all arms, qualitative 
methods (semi-structured in-depth interviews) will be used to assess feasibility and 
acceptability of different scripting/dispensing intervals, including impact on clinic 
efficiency, systems of care around HIV, and patient outcomes.  
(3) Feasible with regard to expanding supply chain and pharmacy storage: We will describe 
infrastructure in place at each of the clusters performing six-month scripting/dispensing 
and use study site surveys to understand challenges faced with forecasting, supply chain, 
and storage of medications.  

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 21 of 35 
22 June 2017 
(4) Safe in regard to impact on the drug compound after storage for six months (based on 
sampling of any unused drug at the end of the six-month period): Providers at facilities 
randomized to six-month dispensing will be expected to give a 180-day supply to all 
participants in the study. Information about ideal storage conditions for ART will be 
provided by the clinic. In a subset of patients, unused ART will be returned to the site and 
submitted to the study team for analysis to evaluate whether typical storage conditions 
have any negative impact on active drug compound. 
 
8 
COST AND COST-EFFECTIVENESS METHODS 
  
It is expected that multi-month dispensing will reduce both facility and patient costs of 
treatment and that it will be cost-effective compared to standard of care.  For facilities, 
fewer clinic visits by patients should save the time of providers and support staff.  For 
patients, fewer clinic visits are expected to reduce the costs of travel and to save time.  
The study will estimate differences in both provider and patient costs.  Cost-
effectiveness will be estimated as the average cost per successful outcome (patient 
retained at 12 months).  We will also collect data on proxy measures of resource 
allocation within the clinic, to determine whether multi-month dispensing affects 
overall access to care. 
 
8.1 
Costs to Provider 
 
Costs will be measured from the provider perspective.  We will use micro-costing 
methods developed and published by the investigators [3-5] to estimate the cost of 
providing ART to study patients in all three arms. We will first create an inventory of all 
the resources used to achieve the observed study outcomes from study enrollment to 
the specified endpoint (e.g. 12 months).  Resources to be captured will include: 
 
• 
ARV medications (medication names and quantities dispensed) 
• 
Non-ARV medications that are prescribed in the course of HIV care (medication names 
and quantities dispensed) 
• 
Laboratory tests (number and type) 
• 
Outpatient clinic visits (number and type/purpose) 
• 
Other services provided (e.g. counseling interactions, x-rays, etc.) 
• 
Inpatient care if recorded in study clinic records (number of days admitted) 
• 
Fixed costs of patient care (building space, equipment, management staff) 
• 
Depreciated investment costs of establishing capacity for multi-month dispensing (e.g. 
drug storage capacity at the sites and clinic staff training).  
 
For each study patient, the quantity (number of units) of resources used will be 
extracted from routinely maintained medical records, which will include registers and 
logbooks kept at facilities, individual patient files (paper and/or electronic), and off-site 
sources of data, such as a centralized laboratory or medical record database. Unit costs 
of resources, which are not human subjects data, will be obtained from external 
suppliers and the site’s finance and procurement records and multiplied by the resource 
usage data to provide an average cost per study patient in each study arm. Costs will be 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 22 of 35 
22 June 2017 
reported as means (standard deviations) and medians (IQRs) in USD, using the 
exchange rate prevailing during the follow up period.  
 
8.2 
Cost-Effectiveness 
 
Using the average cost per patient as described above, we will then estimate the cost 
per outcome achieved in each arm. The main measure of effectiveness for the cost-
effectiveness analysis will be the primary study outcome of retention in care at 12 
months. We will compare average cost/patient retained in care across the three study 
arms, initially at 12 months and then again at 36 months. To provide information for 
HIV program budgets, we will also estimate the annual cost of providing ART under the 
three strategies being evaluated, independent of outcomes. 
 
8.3 
Patient Costs 
 
Costs to patients for obtaining ART will be estimated on a per-visit basis.  At study 
enrollment, patients will be asked about costs incurred per clinic visit for transport, food 
and/or accommodation during the visit, and wages lost and other time costs during the 
visit.  For each patient, the number of clinic visits made per 12-month period for any 
HIV-related reason will then be multiplied by the cost per visit.  Finally, we will estimate 
and compare the average cost per patient of obtaining care in each study arm. 
 
8.4 
Clinic Resource Allocation 
 
We will use two proxy measures to assess whether multi-month dispensing affects 
access to care, by releasing clinic resources for other purposes.  First, we will estimate 
average waiting time (minutes/patient from arrival at the clinic to seeing a clinician) 
among patients seeking HIV care at the study clinics before the start of the intervention 
and after 12 months of implementation.  Data will be collected anonymously by an 
observer stationed at each clinic, who will record the waiting times for a sequential 
sample of patients over a several-day period. Second, we will use aggregate, clinic-level 
data (e.g. DHIS) to ascertain whether the quantity or mix of services provided changes 
between the last month before Year 1 and the first month of Year 2.  None of the data 
collected for the clinic resource allocation analysis will be human subject data. 
 
8.5 
Sample Size and Accrual 
  
8.5.1 Sample Size 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 23 of 35 
22 June 2017 
Our sample size was estimated for three groups for a cluster randomized non-inferiority 
trial. We have 30 clusters available for randomization, and therefore, estimated our 
sample size assuming a fixed number of clusters (k) and an equal number of clusters per 
arm. We also assumed an equal number of participants per cluster. We estimated that 
about 5% of participants would fail to be retained in care in the intervention arms, and 
would accept up to 7.5% failure as non-inferiority. Assuming an alpha of 0.05 and power 
of 90% and an intracluster correlation coefficient of 0.004, we would need to enroll 271 
participants per cluster for a total of 2,710 participants per arm and 8,130 total 
participants in the entire study. Because our primary outcome is retention, we will 
make no adjustment for loss to follow up. We will also increase our sample size to 8,200 
as we will have one interim look at the data when 50% of the data are accrued. 
 
Sample sizes of 2,710 in each arm will be obtained by sampling 10 clusters with 271 
participants each in group to achieve 90% power to detect a non-inferiority margin 
difference between the group proportions of 0.025. We assume 
the proportion achieving our primary outcome in the control arm will be 0.05 and will 
consider 0.075 to be non-inferior in either of the other two groups (six-month or three-
month dispensing). The test statistic used is the one-sided Z test (unpooled). The 
significance level of the test is 0.05. 
  
8.5.2 Monitoring by the Protocol Team 
 
Study Progress and Quality of Study Conduct 
 
The Protocol Team is responsible for continuous monitoring of study progress, 
including timely achievement of key milestones and quality of study conduct.   
 
The team will closely monitor participant accrual based on reports that will be 
generated at least monthly. The team will monitor the timing of site-specific study 
activation, which will determine when each site will begin accruing participants, and 
actual accrual following activation. For any site that is delayed in completing the study 
activation process or that falls short of its accrual projections, the team will 
communicate with the site to identify the barriers the site has encountered and the 
operational strategies and action plans to address these.   
 
The Protocol Team will similarly review key indicators of the quality of study conduct 
(e.g. data quality, and data and specimen completeness) based on reports and take 
action with study sites as needed to ensure high quality study conduct throughout the 
period of study implementation, particularly around completion of medical records 
which will be necessary to determine study endpoints.  
 
8.5.3 Monitoring by the DSMB 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 24 of 35 
22 June 2017 
The first analysis will be performed when 50% of the patients have completed 12 
months. The DSMB will also be asked to look at whether the 30 clusters are adequately 
balanced and will provide advice regarding whether any adjustments are required to 
achieve balance (expand sites or replace sites). The study will be stopped early only if 
we find a difference between three- versus six-month dispensing with a p<0.01. 
 
Operational futility may be considered if the observed accrual patterns are exceedingly 
different than planned, and the protocol team has had a chance to address the 
shortcomings of accrual.      
 
9 
DATA HANDLING AND RECORD KEEPING 
 
9.1 Data Management Responsibilities 
 
Study sites must maintain adequate and accurate research records containing all 
information pertinent to the study for all screened and enrolled participants, including 
CRFs and supporting source data. Depending on capacity and infrastructure of 
sites/regions, data will either be collected by hand and entered into a database or 
collected electronically with data uploaded to a database.    
 
All data must be transferred to the central database within timeframes specified in the 
forms instructions; queries must also be resolved in a timely manner.  
 
10 
SITE MONITORING 
 
Site monitors under contract to EQUIP will visit study sites to inspect study facilities 
and review participant study records including consent forms and CRFs, to ensure 
protection of study participants, compliance with the IRB/EC approved protocol, and 
accuracy and completeness of records. Site investigators will make study facilities and 
documents available for inspection by the monitors.   
 
11 
HUMAN SUBJECTS PROTECTIONS 
 
11.1 Institutional Review Board/Ethics Committee Review and Approval including 
Informed Consent 
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of 
this protocol and site-specific ICFs; subsequent to initial review and approval, IRBs/ECs 
must review the study at least annually.  Site investigators must also promptly report to 
the IRB/EC any changes in the study and any unanticipated problems involving risks to 
participants or others. 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 25 of 35 
22 June 2017 
All IRB/EC policies and procedures must be followed, and complete documentation of 
all correspondence to and from the IRBs/ECs must be maintained in site essential 
document files.  Sites must submit documentation of both initial review and approval 
and continuing review to the EQUIP Protocol Team. 
 
Written informed consent will be obtained before any study-specific procedures are 
performed.  The informed consent process will include information exchange, detailed 
discussion, and assessment of understanding of all required elements of informed 
consent, including the potential risks, benefits, and alternatives to study participation.  
The process will emphasize the randomized nature of the study and the differences 
that participants may experience as part of the study relative to current local standards 
of care.    
 
11.2 Potential Benefits 
 
There may be no direct benefit to participants who take part in this study, though 
participants who are placed in study arms randomly selected to receive a larger ART 
supply may benefit from reduced visits to their ART clinic.  However, information 
learned in this study may be of benefit to participants and others in the future, 
particularly information that may lead to optimized treatment guidelines for HIV-
infected pregnant individuals.  
 
11.3 Potential Risks  
 
Most study procedures are routine clinical care associated with minimal to no risk in 
participants.  Blood collection for viral load may cause pain, bruising, swelling, and 
(rarely) infection at the site where the needle is inserted.  Participation in surveys and 
interviews may cause psychological stress or discomfort. Participants may decline to 
answer any questions that make them uncomfortable. Participants may also experience 
some added difficulties with storing and transporting their ART supply, as the study 
may require some participants to receive a larger ART supply than the standard of care. 
The increased ART supply may also make it more difficult for participants to keep their 
HIV status private if they have not disclosed their status to people in their home. 
 
Study participants who are enrolled in the three- or six-month dispensing arms may 
also experience some divergences in the timing of their clinic appointments. For 
example, participants who are enrolled in a longer dispensing arm may be required to 
return to clinic more frequently for other medical reasons (e.g., birth control injections, 
postpartum and infant care for non-breastfeeding women, other medical care).  
 
11.4 Reimbursement/Compensation 
 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 26 of 35 
22 June 2017 
Participants will not be compensated for study participation. Participants will receive 
refreshments for their time during the screening and entry visit procedures. 
Participants who are randomly selected to participate in a post-intervention interview 
will receive a reimbursement for their transportation costs to/from the clinic. 
 
11.5 Privacy and Confidentiality 
 
All study procedures will be conducted in private, and every effort will be made to 
protect participant privacy and confidentiality to the extent possible.  Participant 
information will not be released without written permission to do so except as 
necessary for review, monitoring, and/or auditing. 
 
All study-related information will be stored securely.  Participant research records will 
be stored in locked areas with access limited to study staff.  All laboratory specimens, 
CRFs, and other documents that may be transmitted off-site will be identified by PID 
only.  Likewise, communications between study staff and protocol team members 
regarding individual participants will identify participants by PID only.   
 
Study sites are encouraged to store study records that bear participant names or other 
personal identifiers separately from records identified by PID.  All local databases must 
be secured with password-protected access systems.  Lists, logbooks, appointment 
books, and any other documents that link PID numbers to personal identifying 
information should be stored in a separate, locked location in an area with limited 
access.   
 
11.6 Management of New Information Pertinent to Study Participation 
 
Study staff will provide participants with any new information learned over the course 
of the study that may affect their willingness to remain in follow-up.   
 
11.7 Post-Trial Access to Multi-Month Scripting/Dispensing 
 
After completion of the study, follow-up participants will be transitioned to country 
standard of care for stable patients. We anticipate that data from the study will be 
utilized by countries to support multi-month dispensing at three-month intervals or 
longer.   
 
12 
ADMINISTRATIVE PROCEDURES 
 
12.1 Regulatory Oversight 
 
This study is sponsored by USAID/PEPFAR.  EQUIP staff will perform monitoring visits.  
As part of these visits, monitors will inspect study-related documentation to ensure 
compliance with all applicable regulatory requirements. 

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 27 of 35 
22 June 2017 
 
Prior to implementation of this protocol, and any subsequent full version amendments, 
each site must have the protocol and the protocol ICFs approved, as appropriate, by 
their local IRBs/ECs, and any other applicable regulatory entity.  Upon receiving final 
approval, sites will submit all required protocol registration documents to EQUIP 
Protocol Team and leadership group. An EQUIP representative will review the 
submitted protocol registration packet to ensure that all of the required documents 
have been received.   
 
Site-specific ICFs will be reviewed and approved by the EQUIP key personnel, and sites 
will receive an Initial Registration Notification from EQUIP that indicates successful 
completion of the protocol registration process.  A copy of the Initial Registration 
Notification should be retained in the site's regulatory files. 
 
For any future protocol amendments, upon receiving final IRB/EC and any other 
applicable regulatory entity approvals, sites should implement the amendment 
immediately.  Sites are required to submit an amendment registration packet to the 
EQUIP Protocol Team.  EQUIP key personnel will review the submitted protocol 
registration packet to ensure that all the required documents have been received.   
 
12.2 Study Implementation 
 
Study implementation at each site will also be guided site-specific SOPs. These SOPs 
should be updated and/or supplemented as needed to describe roles, responsibilities, 
and procedures for this study. 
 
12.3 Protocol Deviation Reporting 
 
All protocol deviations must be documented in participant research records.  Reasons 
for the deviations and corrective and preventive actions taken in response to the 
deviations should also be documented.  
 
Deviations should be reported to site IRBs/ECs and other applicable review bodies in 
accordance with the policies and procedures of these review bodies.  Serious deviations 
that are associated with increased risk to one or more study participants and/or 
significant impacts on the integrity of study data must also be reported to the Protocol 
Team as soon as possible. 
 
13 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by 
EQUIP and USAID/PEPFAR policies.  

Document Upload: Study Protocol and Statistical Analysis Plan 
Version 2.4 
Page 28 of 35 
22 June 2017 
 
14 
REFERENCES 
 
1. Organization WH. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing 
HIV infection. In: HIV/AIDS, ed. Geneva, Available at http://www.who.int/hiv/pub/arv/arv-2016/en/, 
2016. 
2. Roy S, Holmes, C., Sikazwe, I., Sav, T. Evaluating appointment patterns to improve sustainability of 
HIV treatment in Zambia. In: Conference on Retroviruses and Opportunistic Infections. (Boston, 
Massachusetts). 
3. Long L, Brennan A, Fox MP, et al. Treatment outcomes and cost-effectiveness of shifting management 
of stable ART patients to nurses in South Africa: an observational cohort. PLoS Med 2011; 8:e1001055. 
4. Rosen S, Long L, Sanne I. The outcomes and outpatient costs of different models of antiretroviral 
treatment delivery in South Africa. Trop Med Int Health 2008; 13:1005-15. 
5. Scott CA, Iyer H, Bwalya DL, et al. Retention in care and outpatient costs for children receiving 
antiretroviral therapy in Zambia: a retrospective cohort analysis. PLoS One 2013; 8:e67910.