Peer-Educator-coordinated vs Nurse-coordinated ART Refill for Adolescents and Young Adults Living With HIV in Lesotho - a Cluster Randomized Clinical Trial (PEBRA Trial)
Phase: NA
Conditions: HIV/AIDS
Sponsor: Amstutz Alain

THIS DOCUMENT IS CONFIDENTIAL 
Clinical Study Protocol
-
Peer-Educator-coordinated vs nurse-coordinated ART 
refill for adolescents and young adults living with HIV 
in Lesotho – a cluster randomized clinical trial
abbreviated title:
PEBRA study („Peer-Educator Based Refill of ART”)
This study is embedded in a research project called GET ON IT (“GETing tOwards Ninety 
In Teens”)
Protocol Version Num-
ber
3
Document Date
24.05.2019
Principal Investigator 
(PI)
Alain Amstutz
Swiss Tropical and Public Health Institute,
University Hospital Basel (Division of Infectious Diseases 
and Hospital Epidemiology),
University of Basel
Protocol authors
AA, JAB, MK, NB, NDL, TIL, TRG
The information contained in this document is confidential. It is intended solely for the
Investigators, potential Investigators, consultants, or applicable independent ethics committees. It is under-
stood that this information will not be disclosed to others without prior written authorization from the spon-
sor, except where required by applicable local laws.
Signature PI:  
Date: 24.05.2019
     
 
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I. List of investigators
Status in the study
Name
Institutional/organizational affiliations
Principal Investigator;
study physician 
Alain Amstutz, MD
Swiss Tropical and Public Health Institute; 
alain.amstutz@swisstph.ch; +41 79 489 94 48 (CH); 
+266 5860 4300 (LS)
Co-Investigators 
-
Coordinator of study 
implementation
Josephine Muhairwe, 
MD, MPH
SolidarMed Lesotho; Country Director; j.muhairwe@soli­
darmed.ch; +26628325172
-
Deputy coordinator 
of study 
implementation
Palesa Mphohle
Sentebale Lesotho; Country Director; pales­
amphohle@sentebale.org.ls; +26658882275
-
Local Principal 
Investigator; 
Research Manager
Thabo Ishmael Le­
jone, RN, MIH
SolidarMed Lesotho; Research Manager;  t.lejone@solid­
armed.ch; +266 62000584
-
Local study 
coordinator
Mathebe Kopo
SolidarMed Lesotho; mathebe.mathyk.kopo@gmail.com; 
+266 58456861
-
Statistician
Tracy Renée Glass, 
PhD
Swiss Tropical and Public Health Institute;
 tracy.glass@swisstph.ch 
-
Study chair
Prof. Niklaus Daniel 
Labhardt, MD, MIH, 
DTM&H
Swiss Tropical and Public Health Institute; University 
Hospital Basel (Division of Infectious Diseases and Hos­
pital Epidemiology); University of Basel; 
n.labhardt@swisstph.ch; +41 79 870 18 59
-
Overall laboratory 
expertise
Jennifer Anne 
Brown, MSc
Department of Biomedicine – Haus Petersplatz, Univer­
sity of Basel, Switzerland;                    
jennifer.brown@unibas.ch 
-
Focal person cost-
effectiveness 
analysis
Nadine Bachmann, 
MSc
Swiss Tropical and Public Health Institute; 
nadine.bachmann2@usz.ch 
II. List of collaborators involved and acknowledged
III.Contact person Ministry of Health
NH-REC Chairperson, Research Coordination Unit, Ministry of Health of Lesotho; +266 22226317
2 of 26
Name
Institutional/organizational affiliations
Role in the study
Lebohang Sao, MD
District Health Management Team Butha-Buthe; lebo­
hangchere@gmail.com; 
+266 58847542
Coordinator of study implementa­
tion in Butha-Buthe district
Kabelo Matjeane, MD
District Health Management Team Mokhotlong; +266 
63688788
Coordinator of study implementa­
tion in Mokhotlong district
Katleho Tlali, MLS
SolidarMed, District Laboratory Services Butha-Buthe, 
Lesotho; k.tlali@solidarmed.ch
Contact person for local laboratory 
analyses
Bienvenu Lengo 
Nsakala, MD
SolidarMed Lesotho; b.nsakala@solidarmed.ch; +266 
59355461
Study physician
Mpho Kao
SolidarMed Lesotho; mphojk4@gmail.com; +266 
58479072
Research Assistant
Lefu Khesa, PN
SolidarMed Lesotho; khesalefu@yahoo.com
 
 ;   +266 
56425205
Study nurse
Christoph Schwizer, 
BSc
eHealth application developer; University of Zurich, 
Switzerland; christoph.schwizer@gmail.com; +41 
797669804
PEBRApp developer
Thato Rammoko
eHealth application developer; Managing Director Tech­
nify Lesotho; www.technifyls.com; +266 53094658; that­
orammoko@gmail.com
PEBRApp developer
Prof. Thomas 
Klimkait, PhD
Department of Biomedicine – Haus Petersplatz, Univer­
sity of Basel, Switzerland; thomas.klimkait@unibas.ch
Guidance on laboratory analyses

PEBRA study / study protocol 
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IV. Remarks
1)
A list of all other involved staff (i.e. peer-educators) will only be available at the start of the study and is not feasible 
to include at this stage. They will all receive a specific training and those who enrol patients will get an introduction 
into GCP (without certificates).
2)
This is an investigator-initiated trial. The Principal Investigator, the Swiss TPH respectively, acts as Sponsor.
3)
This study protocol will be prospectively registered on clinicaltrials.gov, before the first study participant is included, 
the registration number will be provided at a later stage.
4)
According to Swiss lab (ClinO, Art. 19, 20, App 3, 1.1) this is a Category A trial, study type “other clinical trial”.
5)
Conflict of Interest: All authors declare that they have no competing interests.
V.  Signatures
­
-
­
-
tion of Helsinki and the principles of Good Clinical Practice (GCP).
Co-investigators in Switzerland
Signature
(electronically signed)
12.03.2019
Name 
Tracy Renée Glass
Date of Signature 
Title
PhD
Institution
Swiss Tropical and Public Health Institute
Address
Socinstrasse 57; 4002 Basel
Phone
+41 612848714
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Signature
(electronically signed)
12.03.2019
Name 
Niklaus Daniel Labhardt
Date of Signature 
Title
MD, MIH
Institution
Swiss Tropical and Public Health Institute
Address
Socinstrasse 57; 4002 Basel
Phone
+41 612848255

PEBRA study / study protocol 
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Phone
Co-Investigators in Lesotho
Signature
(electronically signed)
14.03.2019
Name 
Josephine Muhairwe
Date of Signature 
Title
MD, MPH
Institution
SolidarMed Lesotho (Country Director)
Address
Premium House #224, Kingsway, Maseru West
P.O.Box 0254, Maseru West 105, Lesotho
Phone
+266 28325172
Signature
(electronically signed)
13.03.2019
Name 
Palesa Mphohle
Date of Signature 
Title
Ms 
Institution
Sentebale Lesotho (Country Director)
Address
Thaba Bosiu - Ha Ramarame (Lihaseng), Maseru
PO Box 644, Maseru 100, Lesotho
Phone
+266 58882275
VI.Table of Contents
1.
GENERAL INFORMATION.....................................................................................................................7
1.1
ABBREVIATIONS / GLOSSARY OF TERMS.............................................................................................7
1.2
SYNOPSIS.........................................................................................................................................8
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2
BACKGROUND....................................................................................................................................10
2.1
THE HIV/AIDS EPIDEMIC AMONG ADOLESCENTS AND YOUNG PEOPLE IN SUB-SAHARAN AFRICA..........10
2.2
THE HIV/AIDS EPIDEMIC IN LESOTHO..............................................................................................10
2.3
DIFFERENTIATED SERVICE DELIVERY AND THE RATIONAL OF THE PEBRA MODEL..............................10
3
STUDY OBJECTIVES..........................................................................................................................11
3.1
OVERALL OBJECTIVE........................................................................................................................11
3.2
PRIMARY OBJECTIVE........................................................................................................................11
3.3
SECONDARY OBJECTIVES.................................................................................................................11
3.4
OTHER OBJECTIVES.........................................................................................................................11
4
STUDY SETTING, DESIGN, AND METHODS.....................................................................................11
4.1
SETTING.........................................................................................................................................11
4.2
DESIGN OF PEBRA STUDY..............................................................................................................11
4.3
METHODS.......................................................................................................................................11
4.3.1
Cluster sampling and randomization.........................................................................................11
4.3.2
Eligibility – clusters....................................................................................................................12
4.3.3
Eligibility – individuals................................................................................................................12
4.3.4
Procedures in all study clusters.................................................................................................12
4.3.5
Intervention clusters: PEBRA model.........................................................................................12
4.3.6
Control clusters: Standard of Care............................................................................................16
4.3.7
Peer-Educators – training and responsibility.............................................................................16
4.3.8
Blinding.....................................................................................................................................16
5
ENDPOINTS AND DEFINITIONS.........................................................................................................16
5.1
PRIMARY ENDPOINT.........................................................................................................................16
5.2
SECONDARY ENDPOINTS..................................................................................................................16
5.3
SAFETY ENDPOINT...........................................................................................................................17
6
BIOMOLECULAR RESEARCH............................................................................................................18
7
QUALITATIVE RESEARCH.................................................................................................................18
8
COST-EFFECTIVENESS ANALYSIS AND SYSTEM IMPACT EVALUATION...................................18
9
PREFERENCE AND FEASIBILITY ASSESSMENT.............................................................................19
10
PILOT TRIAL....................................................................................................................................19
11
SAMPLE SIZE AND ANALYSIS PLAN............................................................................................19
11.1
SAMPLE SIZE CALCULATION..............................................................................................................19
11.2
ANALYSES.......................................................................................................................................19
11.2.1
Primary analysis....................................................................................................................19
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11.2.2
Baseline characteristics; secondary, exploratory, subgroup and sensitivity analyses...........20
12
DATA MANAGEMENT, BIOLOGIC MATERIAL, MONITORING, SAE............................................20
12.1
DATA ENTRY, DATA MONITORING, DATA STORAGE, DATA CONFIDENTIALITY..........................................20
12.2
MANAGEMENT OF BIOLOGIC MATERIAL..............................................................................................20
12.3
MONITORING AND DATA SAFETY MONITORING BOARD (DSMB).........................................................21
12.4
ADVERSE EVENTS (AES) AND SERIOUS ADVERSE EVENTS (SAES)...................................................21
13
ETHICAL CONSIDERATIONS.........................................................................................................21
13.1
RESEARCH ETHICS APPROVAL / INFORMED CONSENT / AMENDMENTS.................................................21
13.2
PUBLICATION AND DISSEMINATION POLICY........................................................................................22
13.3
COMPENSATION...............................................................................................................................22
13.3.1
Study participants..................................................................................................................22
13.3.2
Study personel......................................................................................................................22
14
WITHDRAWAL OF PARTICIPANTS AND DISCONTINUATION OF TRIAL...................................22
14.1
WITHDRAWAL..................................................................................................................................22
14.2
DISCONTINUATION OF THE ENTIRE STUDY.........................................................................................22
15
FUNDING SOURCES AND ROLE OF THE FUNDING SOURCES..................................................23
16
STUDY TIMELINE............................................................................................................................23
17
REFERENCES..................................................................................................................................24
18
APPENDIX........................................................................................................................................26
18.1
STAFF LIST (INCL. CVS, DIPLOMA, GCP)..........................................................................................26
18.2
INFORMED CONSENT FORMS............................................................................................................26
18.3
CASE REPORT FORM.......................................................................................................................26
18.4
MATERIAL TRANSFER AGREEMENT...................................................................................................26
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1.
GENERAL INFORMATION
1.1
Abbreviations / Glossary of Terms
AYPLHIV
Adolescent & Young People Living with HIV
CAC
Community Adherence Clubs
CI
Confidence Interval
CYC
Community Youth Club
CPP
Cluster Per Protocol
CRF
Case Report Forms
DHMT
District Health Management Team
DSD
Differentiated Service Delivery
DSMB
Data Safety Monitoring Board
EAC
Enhanced Adherence Counseling
FGD
Focus Group Discussion
HIV
Human Immunodeficiency Virus
ICC
Intra-cluster Correlation Coefficient
ICF
Informed Consent Form
ITT
Intention To Treat
KII
Key Informant Interviews
LIS
Laboratory Information System
LTFU
Loss-To-Follow-Up
PE
Peer-Educator
PEBRA
Peer-Educator-Based Refill of ART
PHC
Primary Health Care
PI
Principal Investigator
PP
Per Protocol
QoC
Quality of Care
QoL
Quality of Life
(S) AE
(Serious) Adverse Events
SCC
Saturday Clinic Club
SSA
Sub-Saharan Africa
Swiss TPH
Swiss Tropical and Public Health Institute
UNAIDS
United Nations Programme on HIV/AIDS
VHW
Village Health Worker
VL
Viral Load (Plasma HIV-1 RNA)
VS
Viral Suppression
WHO
World Health Organization
1.2
Synopsis
study title
Peer-Educator-coordinated vs nurse-coordinated ART refill for adolescents and young adults 
living with HIV in Lesotho – a cluster randomized clinical trial
abbreviated 
title
PEBRA study (Peer-Educator-Based Refill of ART)
background & 
rational
Sub-Saharan Africa (SSA) is home to 85% of the adolescents and young people living with HIV 
(AYPLHIV) globally. AYPLHIV in SSA are the only population group for whom HIV-related mor­
tality continues to increase, and they have overall poorer outcomes than all other age groups. 
Lesotho has the second-highest HIV prevalence and shows a viral suppression rate among 
AYPLHIV of only 49%. 
In order to address the multiple barriers in the adolescent HIV care cascade and their unique 
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needs, multicomponent packages of differentiated service delivery (DSD) are a promising ap-
proach. 
In close collaboration with different local stakeholders, we designed a DSD model specifically 
for AYPLHIV, called the PEBRA model. In the PEBRA model the peer-educator (PE) plays a 
pivotal role, by coordinating the ART refill/care according to the patients’ preferences using a 
tablet-based application, called PEBRApp. The PEBRApp helps the PE to assess each partici-
pants’ preference, to adapt the ART refill according to these preferences in a feasible manner, 
to keep track of the ART refill, and to ensure regular contact between the PE and the partici-
pant. The model includes key innovative options such as individualized automatic SMS notifi-
cations and decentralized ART delivery.
primary aim
This study aims to evaluate the feasibility and effectiveness of a DSD model (“PEBRA model”) 
among AYPLHIV.
study design
PEBRA study is a cluster randomized, open-label, superiority trial in a resource-limited setting. 
The rational for a cluster randomized design with health facilities as clusters, is the high risk of 
cross-contamination between the study arms if randomization would be done at individual 
level. The clusters (health facilities) will be randomized (randomly-varying block sizes, 1:1 al­
location) into the 2 groups using a computer-generated randomization list, stratified by district. 
The study will be conducted at 20 health facilities in three districts of Lesotho (Leribe, Butha-
Buthe, Mokhotlong).
major 
eligibility 
criteria
Eligibility – clusters
Inclusion criteria: 
1)
the cluster is a public or missionary health center from the study districts, that offers ART 
services
2)
the cluster has at least one PE who is willing to participate and fulfills the following criteria:
a)
underwent the Sentebale Peer-Educator two-weeks training
b)
attended and successfully passed the training assessment
Exclusion criteria: 
1)
health facility authority opposed to trial participation (verbal assent)
2)
the health facility is a hospital
3)
the health facility is situated in an area without cellphone signal
Eligibility – individuals
1)
Individual is living with HIV and in care in a participating cluster
2)
Individual is 15-24 years old (AYPLHIV)
3)
Informed consent given
4)
Declares to seek the next follow-up visit at the same health facility
intervention 
and control
V
Participants in the intervention clusters are offered the PEBRA model. In the PEBRA model the 
ART visit/refill is coordinated by the PE according to the participants’ preferences, using a tab­
let-based application, called PEBRApp. The preference assessment entails the following three 
domains of DSD:
1)
ART Refill
2)
SMS notifications
3)
Support
In each of the domains, the participants’ preferences will be assessed and the most feasible 
option will be selected. The PEBRApp not only helps the PE to assess each participants’ pref-
erence, but also to keep track of the ART refill, and to ensure regular contact between the PE 
and the participant. The model includes key innovative options such as individualized auto-
matic SMS notifications and decentralized ART delivery
Participants in the control clusters are offered standard of care: ART visit/refill is coordinated 
by the nurse, is mostly clinic-based, not adapted to youth, and differentiated according to clin-
ical values (i.e. if VL suppressed then option of ART Refill in a Community Adherence Club).
primary 
endpoint
In care with documented viral suppression at 12 months, defined as the proportion of parti­
cipants in care with a documented VL <20 copies/mL 12 months (range: 9 – 15 months) after 
enrolment out of all participants enrolled.
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secondary 
endpoints
a)
Adherence to ART at 3 months, 6 months and 12 months after enrolment
b)
Quality of Life at 6 months and 12 months after enrolment
c)
Perceived quality of ART Care / patient service satisfaction at 6 months and 12 months 
after enrolment
d)
Engagement in care at 6 months
e)
Alternative viral suppression level at 12 months
f)
Engagement in care at 12 months
g)
All-cause mortality at 6 and 12 months
h)
LTFU at 6 and 12 months
i)
Transfer out at 6 and 12 months
sample size & 
statistical 
considerations
An overall target sample size of 300 AYPLHIV in 20 clusters (10 per arm) will provide us 90% 
power (design effect of 1.7) to detect a 20% increase of viral suppression in the intervention 
group, assuming a type 1 error of 0.05, and an intra-cluster correlation coefficient (ICC) of 
0.05.
Clusters, i.e. clinics, will be set as unit of randomization (stratified by district), whereas individu­
als are set as unit of analysis. The primary analysis will use multi-level logistic regression mod­
els (on the intention-to-treat set) including clinic as random effect to assess the difference 
between viral suppression rate in the intervention versus control arm, adjusted for the pre-spe­
cified randomization stratification factor, baseline VL, and relevant baseline factors that may be 
randomly unbalanced between intervention and control clusters. All results will primarily be 
presented as odds ratios and their respective 95% confidence intervals.
recruitment & 
study duration
We expect recruitment to start August/September 2019 and a total study duration of approxim­
ately 18 months. We anticipate a recruitment period of 4-5 months. A pilot trial, assessing 
PEBRA model at one health facility, will form the basis for the main trial.
GCP 
statement
This study will be conducted in compliance with the protocol, the current version of the 
Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) as well as all 
national legal and regulatory requirements.
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2
BACKGROUND
2.1
The HIV/AIDS epidemic among adolescents and young people in sub-Saharan Africa
The latest UNAIDS report showed encouraging progress towards an AIDS-free generation by 2030. This 
progress is, however, counterbalanced by persistent challenges among young people in sub-Saharan Africa 
(SSA). SSA accounts for 85% of the adolescents and young people living with HIV (AYPLHIV) globally and 
they represent one of the population groups most affected by the HIV/AIDS epidemic: Almost a third of new 
HIV-infections are among individuals aged 15–25 years, mostly female.1,2 AYPLHIV are more likely to drop 
out of HIV-care, both before and after starting antiretroviral therapy (ART), are the only population group for 
whom HIV-related mortality continues to increase, and have overall poorer outcomes than all other age 
groups. AIDS remains the leading cause of death among young people in SSA.3–6
AYPLHIV face particular challenges in accessing and adhering to ART. The distinct rapid physical, 
psychological and emotional changes that occur during adolescence impact on how AYPLHIV view their 
health, make decisions, perceive risk and interact with health and related services.7 Thus, barriers of the 
adolescent HIV care cascade are multifactorial:  Psychological and social barriers such as heightened 
stigma both within the community and health system, structural barriers such as time-consuming expensive 
ART visits (especially in remote rural areas of SSA), individual behavioral barriers such as non-disclosure, 
as well as policy barriers such as the requirement for parental consent to access HIV and broader sexual 
and reproductive health services.8–12
2.2
The HIV/AIDS epidemic in Lesotho
Lesotho, a small land-locked country surrounded by South Africa, has the second-highest adult HIV preval­
ence in the world with 25.6%.1,13 Compared to the other Southern African countries, Lesotho presents one of 
the highest HIV-incidence among adolescent girls and young women.14 According to the recent household-
based national survey (LePHIA) overall  viral suppression (VS), the final target in the HIV care cascade, 
among people living with HIV is 67.7%. VS is highest among people living with HIV aged 45 to 59 years 
(80.9%), and significantly lower among AYPLHIV (50.9% among female and 46.1% among male).13
The geographic characteristics of Lesotho impose an extra impediment on the HIV/AIDS epidemic. 
About 70% of Lesotho’s population lives in rural mountainous areas (>1500m) characterized by widespread 
poverty, poor transport infrastructure and hard-to-reach villages. Thus, access to the health care facilities re­
mains a major barrier for engagement in care. 
2.3
Differentiated Service Delivery and the Rational of the PEBRA model
In order to address the multiple barriers in the adolescent HIV care cascade, multicomponent packages of 
differentiated service delivery (DSD) are a promising approach.15,16 Unlike service delivery models that apply 
standardized care for all people living with HIV, the idea of DSD models is to consider the specific needs of 
different groups of people living with HIV, while facilitating service scale-up by reducing the burden on 
health systems and increasing efficiency. Among AYPLHIV with their unique and heterogenous needs, DSD 
models may provide an opportunity to ensure better outcomes. 
In 2018, Paediatric-Adolescent Treatment Africa, in collaboration with other key stakeholders, un­
dertook a situational analysis of DSD for AYPLHIV in neighboring South Africa. They report a lack of pub­
lished literature documenting adolescent-specific DSD models in the Southern African region, including 
Lesotho. Moreover, the analysis shows that most adolescents are not accessing DSD models even where 
they exist, an indicator that the few existing DSD models are not tailored according to adolescent-specific 
preferences. DSD models usually include stable patients. However, differentiated care should not only be 
designed for stable patients, but include patients who would otherwise not engage in care. The definition of 
a “stable patient” bears challenges itself, leading to late inclusion in these models.17
The South African situation analysis identified key principles to make DSD work for AYPLHIV: a) to 
remove structural barriers (decentralized community-based and fast-track ART refills), b) to develop and de­
liver DSD models with young people using youth-friendly communication (i.e. social media, cellphone), c) to 
include psychosocial support as an essential component in any DSD model, and d) to make the surrounding 
health framework more youth-friendly. Overall, there is a strong emphasis on the diverse needs and prefer­
ences of AYPLHIV while planning DSD models.18
In close collaboration with different local stakeholders, especially Sentebale and their existing Peer-Edu­
cator program, we designed a DSD model specifically for AYPLHIV, called the PEBRA (Peer-Educator 
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Based Refill of ART) model. In the PEBRA model the peer-educator (PE) plays a pivotal role, by coordinat-
ing the ART refill/care according to the patients preferences using a tablet-based application, called PEB-
RApp. The PEBRApp helps the PE to assess each participants’ preference, to adapt the ART refill accord-
ing to these preferences in a feasible manner, to keep track of the ART refill, and to ensure regular contact 
between the PE and the participant. The model includes key innovative options such as individualized auto-
matic SMS notifications and the option of decentralized ART delivery.
3
STUDY OBJECTIVES
3.1
Overall objective
This study aims to evaluate the feasibility and effectiveness of a DSD model (“PEBRA model”) among 
AYPLHIV.
3.2
Primary objective
As primary objective this study seeks to assess the rate of viral suppression among AYPLHIV 12 months 
after enrolment between the intervention clusters, where AYPLHIV were offered the PEBRA model, and the 
control clusters, where AYPLHIV were offered standard of care.
3.3
Secondary objectives
Secondary objectives include a comparison of adherence to ART, the level of perceived quality of ART care 
and patient service satisfaction, engagement in care, viral suppression, lost-to-follow-up (LTFU), mortality, 
and transfer out between the intervention and control clusters.
3.4
Other objectives
Further objectives include a cost-effectiveness evaluation and qualitative research regarding acceptance, 
scalability and feasibility of the DSD model.
4
STUDY SETTING, DESIGN, AND METHODS
4.1
Setting
The study will be conducted in northern Lesotho, in the districts of Leribe, Butha-Buthe and Mokhotlong. 
Butha-Buthe and Mokhotlong districts are both characterized by mostly rural settings with an estimated pop­
ulation of 220,000, mainly subsistence farmers and mine workers as well as construction or domestic la­
bourers who work in neighbouring South Africa. Each district has only one single mid-size town: Buthe-
Buthe with ca. 25,000 inhabitants, and Mokhotlong with ca. 10,000 inhabitants. The remaining population 
lives in villages scattered over a mountainous area of 5,842 km2. Leribe has an estimated population of ap­
proximately 330,000 inhabitants and two bigger cities: Maputsoe with 55,000 and Hlotse with 40,000 inhab­
itants. Butha-Buthe district comprises 12 public/missionary health facilities (10 health centers, 2 hospitals), 
Leribe district 26 public/missionary health facilities (24 health centers, 2 hospitals) and Mokhotlong district 
10 public health facilities (9 health centers, 1 hospital), that offer ART services. The HIV prevalence among 
individuals 15 to 59 years old ranges from 17.8% (Butha-Buthe), 23.7% (Leribe) to 26.1% (Mokhotlong).13
4.2
Design of PEBRA study
The PEBRA study is embedded in an overarching research project, called GET ON IT (“GETing tOwards 
Ninety In Teens”). The abbreviated title of this study is “PEBRA study” and stands for “Peer-Educator Based 
Refill of ART”. The PEBRA study is a cluster randomized, open-label, superiority trial in a resource-limited 
setting.  The rational for a cluster randomized design with health facilities as clusters, is the high risk of 
cross-contamination between the study arms if randomization would be done at individual level.
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4.3
Methods
4.3.1
Cluster sampling and randomization
The clusters (health facilities) will be randomized (randomly-varying block sizes, 1:1 allocation) into interven­
tion and control clusters using a computer-generated randomization list, stratified by district (Leribe vs 
Butha-Buthe vs Mokhotlong). The randomization list will be prepared by a statistician not involved in the 
study.
4.3.2
Eligibility – clusters
Inclusion criteria: 
1)
the cluster is a public or missionary health center from the study districts, serving a rural population and 
offering ART services
2)
the cluster has at least one PE who is willing to participate and fulfills the following criteria:
a)
underwent the Sentebale Peer-Educator training
b)
attended and successfully passed the study training assessment
Exclusion criteria: 
1)
health facility authority opposed to trial participation (verbal assent)
2)
the health facility is situated in an area without cellphone signal
4.3.3
Eligibility – individuals
1)
Individual is living with HIV and in care in a participating cluster
2)
Individual is 15-24 years old (AYPLHIV)
3)
Informed consent given
4)
Declares to seek the next follow-up visit at the same health facility
4.3.4
Procedures in all study clusters
A trained PE per cluster will actively screen all AYPLHIV for eligibility. If eligible, the PE will continue with 
the baseline assessment, using a tablet-based application. The following data will be collected (from med­
ical records and patient interview):
-
Consent documentation (and if not consenting, then reason for refusal and stop data collection)

Details about consent process see in section 13.1
-
ART number
-
Clinic/Cluster
-
Year of birth
-
Gender
-
Village
-
Cellphone number
-
Date of ART initiation
-
WHO-stage at ART initiation
-
Laboratory information: CD4 at ART initiation, last CD4, VL history and baseline VL*
-
Co-morbidities
-
TB history
-
Co-medication
-
ART regimen history
-
Socio-demographic data including age, gender, level of education, employment status, marital 
status, pregnancy
-
Structural data incl. distance and time and costs (incl. opportunity costs) to visit the health facility
-
HIV/AIDS knowledge and stigma19
-
Adherence: Pill count and setting- & age-validated treatment adherence questions20–22
-
Quality of Life (QoL): WHO HIV QoL questionnaire (whoqol_hiv_bref questionnaire)23–25 
-
Quality of Care (QoC): a setting-validated perceived QoC & patient satisfaction questionnaire26
*Note: Baseline VL is defined as the last VL within the previous 12 months, taken from the medical records 
(bukana, patient file, laboratory databases). If no VL within previous 12 months available, then the parti­
cipant will be sent to the nurse for blood draw for routine VL measurement. This is not a study-specific pro­
cedure, but standard of care. If the patient is new in care and due for 6 months VL, then the 6m routine VL  
will be taken as baseline VL.
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4.3.5
Intervention clusters: PEBRA model
The participants in the intervention clusters are offered the PEBRA model. In the PEBRA model the ART 
visit/refill is coordinated by the PE, as much as feasible according to the participants’ preferences. Thus, the 
preferences of each participant are captured at enrolment and after a strict schedule thereafter. The PE 
conducts the preference assessment using a tablet-based application, called PEBRApp. The PEBRApp will 
automatically alert the PE when the next preference assessment of each participant is due. The preference 
assessment interval is independent from the ART refill interval and can be performed via phone as well. 
Participants with a suppressed VL will get a preference assessment every 3 months and participants with 
unsuppressed VL a preference assessment every month. As a strict part of the preference assessment, the 
PE asks two psychosocial questions (“Is there anything you would like to share with me today?” / “How do 
you think you are doing today?”) and for those patients with unsuppressed VL an additional third question 
(“Do you have a safe environment to take your medication?”).
The preference assessment works as a two-step approach: First, the participant will be asked his/
her preference regarding different domains of DSD (see below) and this will be entered into the PEBRApp. 
Secondly, the chosen preferences are assessed regarding feasibility with specific questions, as not all pref­
erence options are available to everyone all the time, e.g. no nearby Village Health Worker (VHW) available 
who could dispense ART, or no Community Youth Club (CYC) established in the participants’ community, or 
home-delivery by PE not feasible.
The preference assessment entails the following three domains of DSD:
1)
ART Refill
2)
SMS notifications
3)
Support
For each domain, the following options can be chosen:
1)
ART Refill (one option possible):
a.
At the clinic
b.
Village Health Worker (VHW) in the community
c.
Home-delivery by the PE
d.
Through a Community Adherence Club (CAC)
e.
Through a Treatment Buddy
2)
SMS notifications (several options possible):
a.
Adherence reminder: Frequency (to be chosen) and pre-defined message (to be chosen)
b.
Refill visit reminder: Frequency (to be chosen) and pre-defined message (to be chosen)
c.
VL-triggered message after blood draw as soon as VL result is available: pre-defined 
message for “unsuppressed” and “suppressed” (to be chosen)
3)
Support (several options possible):
a)
By the nurse at the clinic
b)
Saturday Clinic Club (SCC)
c)
Community Youth Club (CYC)
d)
Phone Call by PE
e)
Home-visit by PE
f)
School visit and health talk by PE
g)
Pitso visit and health talk by PE
h)
Condom demonstration
i)
More information about contraceptives
j)
More information about VMMC
k)
For pregnant: Linkage to young mothers group (DREAMS or Mothers-to-Mothers)
l)
For females: Linkage to a female WORTH group (Social Asset Building Model)
m) Legal aid information
n)
Show me tuneme.org (teenage topics)
o)
Show me Ntlafatso Foundation Facebook (HIV stigma/discrimination topics)
p)
No support wished 
Every PE who delivers PEBRA model receives a tablet, that has a calling function and the PEBRApp in­
stalled. PEBRApp is protected by a password, only known to the PI and the PE, and does not entail confid ­
ential patient information, i.e. names. PEBRApp serves as a data collection tool (baselines assessment, 
preference assessment, etc.) and as a patient management tool to keep track of the ART refill of each parti­
cipants (WHERE and WHEN) and his/her chosen support. PEBRApp will keep overview of all due dates 
(next ART refill date, next preference assessment date) and automatically alert the PE for an action. 
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The PEBRApp helps the PE to assess each participants’ preference, to adapt the ART refill accord-
ing to these preferences in a feasible manner, to keep track of the ART refill, and to ensure regular contact 
between the PE and the participant. The chosen SMS notifications will be sent automatically through an ex-
ernal platform (VL platform, www.lstowards909090.org/db), and always include a call-back option to the 
PE’s number. 
The PEBRA model as well as the PEBRApp have been developed and refined in several multi-stakeholder 
workshops together with adolescents and young people (Sentebale PEs, Sentebale Youth staff, AYPLHIV, 
various youth club members from urban and rural areas, international and national App developers). 
Figures 1a and 1b illustrate the PEBRA model and Figures 2a and 2b the PEBRApp. Under the following 
link (https://bit.ly/2TA5RA5) a prototype version of PEBRApp can be accessed. 
FIGURE 1a. Schematic description of PEBRA model for AYPLHIV

PEBRA study / study protocol 
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FIGURE 2a. Screenshot of PEBRApp: Main Screen
FIGURE 2b. Screenshot of PEBRApp: Excerpt from Preference Assessment Screen
4.3.6
Control clusters: Standard of Care
Participants in the control clusters are offered standard of care: ART visit/refill is coordinated by 
the nurse, is mostly clinic-based and not specifically adapted to youth. Currently the Ministry of 
Health is piloting an SMS notification system that alerts patients once their VL result is out and 
entered into the LIS (Laboratory Information System). Thus, the standard of care at the health fa­
cilities in our study districts nowadays entails several options, however not all option are available 
at all health facilities:  
1)
ART Refill:
a.
Nurse at the clinic
b.
Through a Community Adherence Club
c.
Through a Treatment Buddy
2)
SMS notifications:
a.
VL-triggered message: “Your laboratory result is out. Please come to the health 
facility to collect it”
3)
Support:
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a.
Nurse at the clinic
b.
Community Youth Club
c.
Saturday Clinic Club
4.3.7
Peer-Educators – training and responsibility
The PEs for this research project will be recruited within the existing network of Sentebale (www.sente­
bale.org). The Sentebale PEs are young people (18-24 years) living in a community from their attached 
health facility catchment area. All Sentebale PEs received at the beginning of their volunteering work a one-
week training on general issues around HIV/AIDS and youth-related health topics with focus on psychoso­
cial support. All PEs involved in PEBRA study will receive an additional training on the PEBRApp, the use of 
the tablet, reporting & documentation system, obtaining of informed consents and other study-specific pro­
cedures.
4.3.8
Blinding
This is a pragmatic implementation trial, assessing the effectiveness of a new DSD model. Due to the 
nature of the trial it is not possible to fully blind participants nor staff to the intervention. But allocation will be 
concealed due to the design of a cluster randomization, which implies randomization before participant in­
clusion.
5
ENDPOINTS AND DEFINITIONS
Table 1 summarizes all endpoints.
5.1
Primary endpoint
In care with documented viral suppression at 12 months, defined as the proportion of participants in care 
with a documented VL <20 copies/mL 12 months (range: 9 – 15 months) after enrolment out of all parti­
cipants enrolled
i.
Rational for VL suppression level at 20 copies/mL: VL determination will be done on COBAS TaqMan® HIV-1 
Test, v2.0 (Roche Diagnostics) using plasma, and has a reliable lower limit of detection of 20 copies/mL
ii.
Definition of “in care”: at least one ART visit in the defined window
I.
Including participants who transferred out to any other health facility with known outcome (documented 
proof of follow-up visit or laboratory test)
II.
Excluding  participants  who  died  (all-cause),  were  lost  to  follow-up  (LTFU),  or  were  known 
defaulters/refusers, i.e. were more than 2 months late for ART refill with a reason available (e.g. currently  
no money for clinic-visit, busy working in South Africa, etc.)
iii.
The study will use VL results from routine VL monitoring. To synchronize routine VL monitoring and study VL 
monitoring, study staff will help ensure each site has the capacity to collect these samples and will support  
existing systems that help to provide results back to sites. VLs will only be performed on individuals who return 
for visits and no tracking will be performed by the study staff to obtain VLs.
5.2
Secondary endpoints
a)
Adherence to ART at 3 months (range 2.5 – 3.5), 6 months (range 5 – 8) and 12 months (range 9 – 15) 
after enrolment
i.
Assessed by 4 different setting- and age-validated ART adherence questions20–22: 
a.
pill count: change in percentage
b.
 “When was the last time you missed any medications?”  i) past week, ii) 1-2 weeks ago, iii) 3-4 
weeks ago, iv) never: Dichotomous outcome missed doses vs. no missed doses in the past month
c.
“ART missed at two or more consecutive days within last month?” (“drug holiday” question)
d.
“How would you rate your adherence over the last month” i) very poor, ii) poor, iii) fair, iv) good, v) 
very  good,  vi)  excellent:  Dichotomous  outcome  adherent  vs  non-adherent  (anything  less  than 
‘excellent’)
b)
Quality of Life (QoL) at 6 months (range 5 – 8) and 12 months (range 9 – 15) after enrolment
i.
Assessed by WHO QoL in PLHIV: WHO HIV QoL questionnaire (whoqol_hiv_bref questionnaire with 31 five-
point Likert Scale items with categorical outcome)23–25
c)
Perceived quality of ART Care (QoC) / patient service satisfaction at 6 months (range 5 – 8) and 12 
months (range 9 – 15) after enrolment
i.
Assessed by a setting-validated QoC and patient service satisfaction questionnaire (12 five-point Likert Scale  
items with categorical outcome)26 by an external data collector, not the PE
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d)
Engagement in care at 6 months, defined as the proportion of participants engaged in care 6 months 
(range 5 – 8) after enrolment out of all participants enrolled
i.
Definition of “in care”: at least one ART visit in the defined window
I.
Including participants who transferred out to any other health facility with known outcome (documented 
proof of follow-up visit or laboratory test)
II.
Excluding  participants  who  died  (all-cause),  were  lost  to  follow-up  (LTFU),  or  were  known 
defaulters/refusers, i.e. were more than 2 months late for ART refill with a reason available (e.g. currently  
no money for clinic-visit, busy working in South Africa, etc.)
e)
Alternative viral suppression at 12 months, defined as the proportion of participants with a documented 
VL <1000 copies/mL 12 months (range 9 – 15) after enrolment out of all participants enrolled
i.
Rational for alternative VL suppression definition at 1000 copies/mL: According to the currently used Lesotho 
national guidelines, an unsuppressed VL is defined as a 1000 copies/mL or more
f)
Engagement in care at 12 months, defined as the proportion of participants engaged in care 12 months 
(range 9 – 15) after enrolment out of all participants enrolled (definitions see above under d)
g)
All-cause mortality at 6 and 12 months, defined as the proportion of participants dead 6 months (range 5 
– 8) and 12 months (range 9 – 15) after enrolment, respectively, out of all participants enrolled
i.
Verbal autopsy to capture cause of death whenever possible. No death certificate or autopsy report required.
h)
LTFU at 6 and 12 months, defined as the proportion of participants LTFU 6 months (range 5 – 8) and 12 
months (range 9 – 15) after enrolment, respectively, out of all participants enrolled
i.
We define participants lost to follow-up if they or their treatment buddies were more than 2 months late for a  
scheduled consultation or medication pick-up and no information was found about the participant
i)
Transfer out at 6 and 12 months, defined as the proportion of participants who transferred out to any 
other health facility (than the initially attached one) with known outcome (documented proof of follow-up 
visit or laboratory test) 6 months (range 5 – 8) and 12 months (range 9 – 15) after enrolment, 
respectively, out of all participants enrolled
5.3
Safety Endpoint
We specifically assess the safety of our PEBRA model, defined as the proportion of participants experien­
cing a Serious Adverse Events (SAE) within 12 months after enrolment out of all participants enrolled. See 
chapter 12.4 for a detailed description of SAEs. 
 
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TABLE 1. Summary of PEBRA study endpoints
Following enrolment
endpoints
At 3 months 
(range: 2-5 – 3.5) 
At 6 months
(range: 5-8)
At 12 months
(range: 9-15)
In care with documented viral suppression 
<20 copies/ml
Primary
Adherence to ART
Secondary
Secondary
Secondary
QoL
Secondary
Secondary
Secondary
QoC
Secondary
Secondary
Secondary
In care with documented viral suppression 
<1000 copies/ml
Secondary
Engagement in care
Secondary
Secondary
All-cause mortality
Secondary
Secondary
LTFU
Secondary
Secondary
Transfer out
Secondary
Secondary
SAE
Safety
Note: we consider 1 month = 30 days
6
BIOMOLECULAR RESEARCH
In the frozen 12-month follow-up blood samples, we may assess ART drug levels as a marker for adher­
ence. This analysis would be done in collaboration with Department of Biomedicine at University of Basel 
that are part of this research consortium. These samples would fall under attached Material Transfer Agree­
ment, submitted together with this study protocol (see Appendix 18.4) for approval. 
7
QUALITATIVE RESEARCH
Besides above outlined qualitative research (QoL, QoC, longitudinal description of participants’ preference 
assessments) we will explore the acceptability of the PEBRA model in a) Focus Group Discussions (FGD) 
with study participants from the intervention clusters, and b) key informant interviews (KII) with the main 
stakeholders (District Health Management Team and different health center staff). We plan to conduct at 
least 2 FGD (with about 5 study participants) per district and 3 KII per district, according to the concept of 
saturation. Data will be collected by trained facilitators using piloted interview questionnaires and discussion 
guides, in the local language (Sesotho). Qualitative data will be recorded, transcribed, translated into Eng­
lish and coded and analyzed using the Framework Method.27 All participants in this qualitative research will 
be required to sign a separate consent form to participate and to be recorded. These consent forms and in­
terview questionnaires will be submitted as an amendment to the ethics committee in Lesotho at a later 
stage.
8
COST-EFFECTIVENESS ANALYSIS AND SYSTEM IMPACT EVALUATION
We will perform a system impact evaluation and cost-effectiveness analysis, in order to estimate the impact 
of the PEBRA model on health benefits and costs. First, we will assess the direct costs of the PEBRA 
model. Secondly, we will assess the cost-effectiveness of the PEBRA model. Thirdly, we will assess the 
economic burden of the PEBRA model to the study participants, i.e. including both direct costs and the op­
portunity costs of their time. The assessment of direct costs includes staff costs (PEs, clinic staff, VHWs), 
personnel training costs (especially for the PEs), the cost of equipment needed (PEBRApp, logistics), med­
ical costs to the participant (medication, laboratory tests, consumables, etc.), and non-medical costs to the 
participant (i.e. cost of transportation to ART service). Data to assess patient level costs will be collected 
from a randomly selected sub-sample of study participants from each cluster arm, using medical expendit­
ure records and interviews. Cost outcomes will include:
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i)
The average cost to the service provider per patient achieving the primary endpoint at 12 
months in each cluster arm (‘per patient suppressed provider cost’)
ii)
The average cost to the patient per patient achieving the primary endpoint at 12 months in each 
cluster arm (‘per patient suppressed patient cost’)
iii)
The annual cost per patient in each cluster arm (‘per patient year cost’)
iv)
The cost-effectiveness of the PEBRA model with respect to viral suppression and engagement 
in care
Costs will be reported as means (incl. standard deviations) and medians (incl. interquartile range) in local 
currency and US dollar and International Dollar.
9
PREFERENCE AND FEASIBILITY ASSESSMENT
We will systematically assess the following exploratory analyses regarding feasibility and youth ART service 
preference: 
1)
Youth ART service preferences: Longitudinal description of participants’ preference assessments 
2)
Feasibility of youth ART service according to preferences: Percentage of ART service delivered 
according to participants’ preferences
3)
Differentiated Impact of the different support options on key study outcomes
10 PILOT TRIAL
PEBRA model will be piloted at one representative health facility in Butha-Buthe district, that will be prag­
matically chosen in collaboration with the District Health Management Team. The pilot trial will be crucial to 
assess feasibility of the PEBRA model and the study procedures. The same procedures apply in the pilot 
trial as outlined in section 4.3.4 and 4.3.5, using the same consent process and baseline data collection. 
One PE will be specifically trained for the pilot. Recruitment for the pilot will be closed once 3-5 study parti­
cipants are enrolled and follow-up will last for 2.5 months after having enrolled the last participant. All end­
points that are mentioned in Table 1 under “At 3 months (range 2.5 – 3.5)” will be assessed and analyzed.  
The aim of the pilot trial is to give a first insight into PEBRA model and provide detailed information for the 
main trial.
11 SAMPLE SIZE AND ANALYSIS PLAN
11.1
Sample size calculation
Based on data from our database with VL results from all health facilities of Butha-Buthe and Mokhotlong 
district (VL platform, www.lstowards909090.org/db), there are on average 15 AYPLHIV per health center 
with an overall viral suppression rate of 70%, thus, we expect this proportion of viral suppression for the 
control clusters. An overall target sample size of 300 AYPLHIV in 20 clusters (10 per arm) will provide us 
90% power (design effect of 1.7) to detect a 20% increase of viral suppression in the intervention group, as­
suming a type 1 error of 0.05, and an intra-cluster correlation coefficient (ICC) of 0.05, an ICC based on 
similar studies28,29.
11.2
Analyses
All analyses will be done using R (the R Foundation for Statistical Computing) or Stata (version 14, Stata 
Corporation) in Lesotho. For all tests, we will use 2-sided p-values with alpha 0.05 level of significance. A 
detailed data analysis plan will be developed separately.
Clusters will be set as unit of randomization (stratified by district), whereas individuals are set as 
unit of analysis. Multilevel random effects models will be used to analyze the data. We will present a CON­
SORT flowchart of the participants, including screening, enrollment and follow-up. The following analysis 
sets will be used in this trial:
1.
Intention-to-treat (ITT) set: All study participants will be evaluated according to cluster assignment 
at randomization
2.
Per-protocol (PP) set: This set includes all participants who completed the study without a major 
protocol deviation
11.2.1
Primary analysis
The primary analysis will use multi-level logistic regression models (on the intention-to-treat set) including 
clinic as random effect to assess the difference between viral suppression rate in the intervention versus 
control arm, adjusted for the pre-specified randomization stratification factor, baseline VL, and relevant 
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baseline factors that may be randomly unbalanced between intervention and control clusters. All results will 
be presented as odds ratios and their respective 95% confidence intervals (CI). 
11.2.2
Baseline characteristics; secondary, exploratory, subgroup and sensitivity analyses
Baseline characteristics will be presented according to randomized groups, no formal testing will be per­
formed. Categorical variables will be described as absolute and relative frequencies and continuous vari­
ables as medians and interquartile ranges. As with the primary analysis, secondary (binary and categorical) 
endpoints will primarily be analyzed with multi-level logistic regression models and presented as odds ratios 
and their respective 95% CI. To estimate incidence of attrition (defaulting from care), a poisson regression 
will be used. We will do a quadature check of the model fit and it found to be unreliable, we will utilize gener­
alized estimating equations. The effect of sociodemographic and clinical determinants (age groups, gender, 
employment status, WHO-stage, CD4-count, HIV/ART history, HIV/AIDS knowledge, HIV/AIDS stigma) on 
key study outcomes will be assessed by including interaction terms in the model. If the interaction term is 
found to be significant, effect estimates will be summarized descriptively by subgroup. As the study is not 
powered for these pre-planned subgroup analyses, these results will be considered exploratory.
12 DATA MANAGEMENT, BIOLOGIC MATERIAL, MONITORING, SAE
12.1
Data entry, data monitoring, data storage, data confidentiality
The PEs collect data directly in two tablet-based applications: PEBRApp (patient management tool and data 
collection tool) and KoboToolbox (data collection tool, incorporated in PEBRApp). The PEBRApp is pass­
word-protected and only accessible to the peer-educator that is responsible for the participant. All data will 
be regularly uploaded into at a password-protected database. Similarly, relevant data for the SMS interven­
tion will be entered and stored in a separate encrypted and password-protected online database, that offers 
the possibility to send out SMS automatically and is connected to the district laboratory database containing 
the VL results (VL platform, www.lstowards909090.org/db). The VL platform data are stored on a dedicated 
server in a data center, which meets FINMA-RS 08/07 requirements, is ISO-27001-certified, encrypts data 
in-transit with SSL and all patient names at-rest using OpenSSL with AES-256-CTR cipher method. SMS 
are dispatched using the trusted third-party provider Twilio, certified with the Privacy Shield Framework. Ac­
cess to all data collection tools and databases are strictly limited and regulated through personal user pro­
files. 
Data for the follow-up period comes from routinely collected medical records at the health facilites, 
primarily from the patient file, if necessary also from patients health booklet (bukana), antenatal care re­
gister, postnatal care register, ART register, ART treatment card and file, TB treatment register, TB treat­
ment card, pharmacy register/dispensing logs, and the viral load monitoring platform. All the above men­
tioned documents act as source documents. For additional information that is not part of these documents, 
data is taken specifically for the study and the two data collection tools act as source document.
Following an initial period of weekly quality review, a study data manager will monitor data quality 
and completeness on a bi-monthly/monthly basis. Queries about the data will be sent to the local team for 
follow-up and correction, as needed. Data integrity checks will be written into the data collection tools to limit 
the entry of incorrect data and ensure entry of data into required fields.
Apart from the informed consent form, the study documents and data collection tools will not contain 
any names but solely the study-ID or unique ART number. There will be one confidential electronic master 
list with the subject identification code and the names. The informed consent forms will be stored in a se­
cure way in the headquarter of the study center (SolidarMed Office in Butha-Buthe, Lesotho) and the master 
list will be stored in an encrypted online cloud with password controlled access and only accessible for pre-
defined study personnel. Participant files will be maintained in storage for a period of at least 10 years after 
completion of the study. 
12.2
Management of biologic material
Additionally, collected standard-lab-ID-coded blood samples would be stored at -80°C at the laboratory of 
Butha-Buthe government hospital. All samples that are stored at Butha-Buthe Government Hospital Labor­
atory fall under the current biobanking regulation agreement (“Biobanking regulations, v2.0”), approved by 
the ethics committees in Switzerland and Lesotho, and under the attached Material Transfer Agreement, 
submitted together with this study protocol (see Appendix 18.4) for approval. Remaining sample material 
after analysis of the ART drug levels will be destroyed. 
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12.3
Monitoring and Data Safety Monitoring Board (DSMB)
At least one external monitoring visit will assess compliance with the approved trial protocol, accuracy of 
completed data entries, and the electronic dataset. The Principal Investigator agrees to allow inspectors 
from regulatory agencies to review records and will assist the inspectors in their duties, if requested.
The PEBRA study represents implementation research, safety profiles of all used drugs are well-
known, and the intervention does not include any new drugs. We do not expect major adverse effects on 
patients’ health from this intervention. Moreover, participants in the PEBRA model can opt to switch back or 
be referred to facility-based care at any time during the trial period. Therefore it is not planned to establish a 
DSMB. Nevertheless, a safety monitoring plan for (Serious) Adverse Events has been outlined (see chapter 
12.4) before the trial start.
12.4
Adverse Events (AEs) and Serious Adverse Events (SAEs)
Prescription and use of ART will follow current national guidelines of Lesotho. All ART used in Lesotho have 
a well-established safety profile. The most frequent adverse events are summarized on page 54 of the 
Lesotho national guidelines on the use of antiretroviral therapy for HIV prevention and treatment, 5th edition, 
201630 and on page 138 of the consolidated guidelines on the use of antiretroviral drugs for treating and pre­
venting HIV infection of the WHO31. AE and SAE will be graded according to the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0., November 201432 and managed 
according to study sites standard procedure following the national guidelines. SAEs are defined as follows: 
a) life-threatening event, b) hospitalization, c) persistent or significant disability or incapacity, d) congenital 
anomaly / birth defect, e) death. In case of SAEs, any study personel must inform one of the study physi­
cians within 72 hours of his/her awareness of the SAE. The study physicians must then inform the Principal 
Investigator within 24 hours of his/her awareness of the SAE. The Principal Investigator will inform the local 
ethics committee in Lesotho within 48 hours. The study physicians are responsible for all direct safety pro­
cedures among study participants. If a participant develops an AE of Grade 2 or higher at last study visit, 
he/she remains under observation by the study physicians until the AE is resolved or stabilized.
13 ETHICAL CONSIDERATIONS
13.1
Research ethics approval / Informed consent / Amendments
This trial will be conducted in compliance with the protocol, International Conference on Harmonisation 
Good Clinical Practice E6 and the current version of the Declaration of Helsinki. Ethics approval will be 
sought from the National Health Research and Ethics Committee of Lesotho and the Ethikkomission Nordw­
est- und Zentralschweiz (EKNZ) in Switzerland and the trial will only commence once both committes have 
awarded approval. This is a cluster randomized health systems implementation research trial, thus its in­
formed consent process is based on two fundamental principles that need to be balanced33,34:
First, specific ethical requirements (e.g., informed consent, confidentiality, avoidance of harm) 
should be fulfilled. Second, a generally accepted claim is that a study being methodologically sound consti­
tutes a necessary condition for its being ethically sound. Because only sound design can produce valid find­
ings, methodological demands carry moral weight. In cluster-randomized trials, if participants would be 
aware of their cluster assignment and would know that there is another cluster arm with a different interven­
tion, it would introduce the possibility of post-randomization selection bias and compromise the methodol­
ogy. Some even argue that no individual informed consent should be obtained in a cluster-randomized trial 
in order to sustain a high-quality and sound methodology.34 However, in our view we value individual con­
sent higher and hence propose the following approach:
-
Before cluster randomization, verbal consent from all health facility managers and the respective 
District Health Management Team will be obtained 
-
Before inclusion into PEBRA study we will obtain individual informed consent (for data collection 
and blood draw during follow-up), but using two different Informed Consent Forms (ICF) to keep the 
risk of selection bias as low as possible by concealing the allocation: One ICF for participants in 
PEBRA intervention clusters and one ICF for participants in PEBRA control clusters.
The trained PEs will obtain the individual informed consent from the participant before inclusion into PEBRA 
study. The investigator will explain to each participant the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits and any discomfort it may entail. All parti­
cipants will receive an information sheet and a consent form describing the study and providing sufficient in­
formation for participant to make an informed decision about their participation in the study before signing 
the consent form. Iliterate study participants will provide a thumb-print and a literate witness (independent to 
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the trial and chosen by the participant) will co-sign the form. The informed consent is provided in the local 
language, Sesotho, and the participant will receive a copy of the consent form. The participant has the right 
to withdraw consent at any time without giving reasons. In case of withdrawal, only data collected until the 
time of withdrawal will be used for research purposes (fully anonymized, identifyer removed) and the parti­
cipant will be managed according to standard of care.
This research includes adolescents and young people from the age of 15 years and older, a key 
group that is often neglected in research projects. One reason is that the consent process for people below 
18 years is more complicated and usually requires a caregiver. This leads to decreased feasibility (e.g. most 
AYPLHIV do not come with their caregivers to the health facility) and to a negative bias in the study (e.g. 
caregivers not consenting although the AYPLHIV would agree). This is an operational research project, that 
does not test any new medication or experimental substances, but tries to tailor the services more according 
to the preferences of the AYPLHIV with the help of peer-educators and an electronic application. We 
strongly feel that it is feasible, justifiable and very important that these young people living with HIV give 
consent without parental consent, as it is being discussed in other research projects. 35–39 Hence, we apply 
for a waiver of the parental consent for this specific research project.
Any modifications to the protocol which may impact on the conduct of the study, potential benefit to 
the patient or patient safety, including substantial changes of the study protocol, will require a formal 
amendment to the protocol and will be submitted to the Ethics Committee of Lesotho and the trial register 
(clinicaltrials.gov) will be updated accordingly. 
13.2
Publication and Dissemination policy
Results of this research project will be shared at three levels. At the district and community level, during 
meetings headed by the District Health Management Team, such as at the PHC (primary health care) meet­
ing where - in addition to the District Health Management Team - also representatives from all health 
centres are present. At the national level, at the national research symposium of the Ministry of Health, and 
at the international level through presentations at conferences (especially at the conferences of the Interna­
tional AIDS Society) and publications in peer-reviewed journals. The current version of the ICMJE recom­
mendations40 is applicable regarding authorship eligibility and the use of professional writers is not intended. 
Before trial start, PEBRA study will be registered in the trial register ‘clinicaltrials.gov’.
13.3
Compensation
13.3.1
Study participants
Participation in this study is not anticipated to cause any substantial additional risk or cost to the participant. 
Therefore, we will not pay compensation to the participants.
13.3.2
Study personel
As the incentive for PEs currently differs, we will ensure that all involved PEs receive a minimum stipend per 
month. They will receive an android-based tablet with the two applications (PEBRApp & KoboToolbox) in­
stalled, a simcard, and regular AirTime (prepaid money for calling and for data usage) for the duties of the 
study.
14 WITHDRAWAL OF PARTICIPANTS AND DISCONTINUATION OF TRIAL
14.1
Withdrawal
The study participant has the right to withdraw from the study at any time without giving reasons. In case of 
withdrawal, only data collected until the time of withdrawal will be used for research purposes (fully anonym­
ized, identifyer removed). Discontinued participants will not be replaced. A participant or cluster (if applic­
able) can be withdrawn from the study by the Principal Investigator for the following reasons:
1.
withdrawal of informed consent
2.
ethical concerns
3.
major violation of the study protocol
4.
intolerable side-effects, adverse events
5.
any conditions that might jeopardize the patient’s health if they were to continue in the study 
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14.2
Discontinuation of the entire study
The Sponsor/Principal Investigator may terminate the study prematurely according to certain circumstances, 
for example:
1.
ethical concerns
2.
insufficient participant recruitment
3.
when the safety of the participants is doubtful or at risk
4.
alterations in accepted clinical practice that make the continuation of a clinical trial unwise
The Sponsor/Prinicipal Investigator would provide written notice and instructions for study termination sub­
mitted at a reasonable time to all involved stakeholders.
15 FUNDING SOURCES AND ROLE OF THE FUNDING SOURCES
This trial is predominantly funded by a CIPHER grant from the International AIDS Society, obtained by AA. 
AA receives his salary through a grant from the MD-PhD programme of the Swiss National Science Founda­
tion (Grant number 323530_177576). Further funding came from a grant of the Stiftung für Infektiologie 
beider Basel and two grants from the Swiss National Science Foundation (Grant Number IZ07Z0_160876/1 
and Grant Number PCEFP3_181355), all obtained by NDL. The Swiss TPH acts as sponsor of the study. 
The study is embedded in the SolidarMed country programme and thus benefits from logistics and human 
resources from SolidarMed Lesotho. The same applies for Sentebale Lesotho.
All funding sources have no role in the design of the study, and will not be involved in data collec­
tion, data analysis, interpretation of the results and writing of the manuscript. 
16 STUDY TIMELINE
We expect recruitment to start August/September 2019 and a total study duration of approximately 18 
months. Figure 3 illustrates the time-line of PEBRA study, incl. preparation and pilot phase. We anticipate a 
recruitment period of 4-5 months.
FIGURE 3. Time-line of PEBRA study incl. preparation and pilot phase
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March&2019
15.03.19:(Submission(of(study(protocol(to(ethics(committees
30.03.19:(PEBRA(Workshop(1
31.03.19:(PEBRA(Workshop(2
Registration(on(clinicaltrials.gov
April&2019&
Finalizing(PEBRApp(and(KoboToolbox
Setting(up(PEBRA(form(on(VL(platform
Acquisition(and(setting(up(of(1(study(tablet
Training(of(1(peerNeducator(for(pilot(trial
May&2019
After(feedback(from(ethics(committees:(
Start%pilot%trial
June&2019
Training(of(all(other(peerNeducators
Training/Information(at(all(involved(health(centers(at(DHMTs
July&2019
End%pilot%trial
Analysis(of(pilot(trial(outcomes
If(needed:(Submission(of(study(protocol(amendment(for(main(trial
August&2019
Start%PEBRA%trial
October&2020
End%PEBRA%trial
Analysis,(writing(of(report,(dissemination(of(results

PEBRA study / study protocol 
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18 APPENDIX
18.1
Staff List (incl. CVs, diploma, GCP)
We refer to attached document, called “PEBRA study_staff list”. All necessary and available CVs, diploma 
and GCP certificates are attached.
18.2
Informed Consent Forms
We refer to attached documents, called “PEBRA study_ICF-Intervention” and “PEBRA study_ICF-Control”, 
both in english and sesotho.
18.3
Case Report Form
We refer to attached document, called “PEBRA study_CRF/Codebook”
18.4
Material Transfer Agreement
We refer to attached document, called “PEBRA study_MTA”
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