Time to Diagnosis of HCV Re-infection With the Use of a Self-test: A Feasibility Study
Phase: NA
Conditions: Hepatitis C Recurrent, HIV-1-infection
Sponsor: Erasmus Medical Center

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Time to diagnosis of HCV re-infection with the 
use of a self-test. A feasibility study.  
 
RESEARCH PROTOCOL 
(v2.0 02-01-2019) 
 
 
 
 
 
 

NL67745.078.18 
 
  
 
 
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PROTOCOL TITLE ‘Time to diagnosis of HCV re-infection with the use of a self-test. A 
feasibility study’ 
 
Protocol ID 
NL67745.078.18 
Short title 
Self-testing for HCV re-infection in MSM 
Version 
2.0 
Date 
02-01-2019 
Coordinating investigator/project 
leader 
 
B. Rijnders, Erasmus MC, Rotterdam 
Erasmus MC, Room Rg-530 
Postbox 2040  
3000 CA Rotterdam, the Netherlands 
Phone No. +31107033510 
Fax No. +317035945 
b.rijnders@erasmusmc.nl 
Principal investigator at Erasmus 
MC 
Subinvestigators 
at 
Erasmus 
MC: 
 
Other study centers: 
 
 
B. Rijnders, MD PhD 
 
 
R. Verwijs, MD 
 
J. Arends, UMCU, Utrecht 
H. Ammerlaan, Catharina-Ziekenhuis, Eindhoven 
C. Delsing, Medisch Spectrum Twente, Enschede 
M. Claassen, Rijnstate, Arnhem 
J. den Hollander, Maasstad, Rotterdam 
R. Soetekouw, Spaarne Gasthuis, Haarlem 
 
 
Sponsor 
(in 
Dutch: 
verrichter/opdrachtgever) 
Erasmus MC, department of internal medicine, 
section infectious diseases 
 
 
Subsidising party 
Gilead sciences 

NL67745.078.18 
 
  
 
 
Self-testing for HCV re-infection in MSM 
 
 
 
Independent expert (s) 
Dr. R.J. de Knegt, 
Erasmus MC, Room Na-607 
Postbox 2040  
3000 CA Rotterdam, the Netherlands 
Phone No. +31107033793/35942 
r.deknegt@erasmusmc.nl 
 
 
 
 
 
 
Laboratory sites 
Laboratory of Virology,  EMC 
 
 
 
 
Erasmus MC, Room Na-420 
Postbox 2040  
3000 CA Rotterdam, the Netherlands 
Phone No. +31107035514 
 
 
 
 
 
 

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Self-testing for HCV re-infection in MSM 
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
 
Head of Department 
Dr. S.C.E. Klein Nagelvoort-Schuit, MD, 
PhD 
Erasmus MC, Room RG-536  
Postbox 2040  
3000 CA Rotterdam, the Netherlands 
Phone No. +31107037549 
s.schuit@erasmusmc.nl 
 
 
 
Coordinating 
Investigator/Project 
leader/Principal Investigator: 
Bart J.A. Rijnders, MD, PhD 
Erasmus MC, Room RG-530  
Postbox 2040  
3000 CA Rotterdam, the Netherlands 
Phone No. +31107033510 
Fax No. +317035945 
b.rijnders@erasmusmc.nl 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................11 
2. 
OBJECTIVES ................................................................................................................14 
3. 
STUDY DESIGN ...........................................................................................................15 
4. 
STUDY POPULATION ..................................................................................................19 
4.1 
Population (base) ...................................................................................................19 
4.2 
Inclusion criteria .....................................................................................................20 
4.3 
Exclusion criteria ....................................................................................................20 
4.4 
Sample size calculation ..........................................................................................21 
5. 
TREATMENT OF SUBJECTS .......................................................................................21 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................21 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................22 
8. 
METHODS ....................................................................................................................22 
8.1 
Study parameters/endpoints ...................................................................................22 
8.2 
Randomisation, blinding and treatment allocation ..................................................22 
8.3 
Study procedures ...................................................................................................22 
8.4 
Withdrawal of individual subjects ............................................................................24 
8.5 
Replacement of individual subjects after withdrawal ...............................................24 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................24 
8.7 
Premature termination of the study .........................................................................24 
9. 
SAFETY REPORTING ..................................................................................................24 
9.1 
Temporary halt for reasons of subject safety ..........................................................24 
9.2 
AEs, SAEs and SUSARs ........................................................................................25 
9.2.1 
Adverse events (AEs) ......................................................................................25 
9.2.2 
Serious adverse events (SAEs) .......................................................................25 
9.3 
Annual safety report ...............................................................................................26 
9.4 
Follow-up of adverse events ...................................................................................26 
10. 
STATISTICAL ANALYSIS ..........................................................................................26 
10.1 
Interim analysis (if applicable) ................................................................................27 
11. 
ETHICAL CONSIDERATIONS ...................................................................................27 
11.1 
Regulation statement .............................................................................................27 
11.2 
Recruitment and consent........................................................................................27 
11.3 
Objection by minors or incapacitated subjects (if applicable) ..................................28 
11.4 
Benefits and risks assessment, group relatedness .................................................28 
11.5 
Compensation for injury .........................................................................................29 
11.6 
Incentives (if applicable) .........................................................................................29 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................29 
12.1 
Handling and storage of data and documents ........................................................29 
12.2 
Monitoring and Quality Assurance ..........................................................................31 
12.3 
Amendments ..........................................................................................................31 
12.4 
Annual progress report ...........................................................................................31 
12.5 
Temporary halt and (prematurely) end of study report ............................................31 

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12.6 
Public disclosure and publication policy ..................................................................32 
13. 
STRUCTURED RISK ANALYSIS...............................................................................32 
13.1 
Potential issues of concern .....................................................................................32 
14. 
REFERENCES ..........................................................................................................32 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
ABR form, General Assessment and Registration form, is the application 
form that is required for submission to the accredited Ethics Committee (In 
Dutch, ABR = Algemene Beoordeling en Registratie) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT
European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics; in Dutch: officiële productinfomatie 
IB1-tekst 
Sponsor 
The sponsor is the party that commissions the organisation or performance 
of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party 
that provides funding for a study but does not commission it, is not 
regarded as the sponsor, but is referred to as a subsidising party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)
WMO
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY  
 
Rationale: 
Elimination of HCV was recently formulated as a WHO target and was set for the year 2030. 
Globally, approximately 6.2% of HIV-infected patients are co-infected with HCV. Of the 
patients living with HIV, people who inject drugs (PWID) and men who have sex with men 
(MSM) are at particularly high risk of HCV co-infection. However, as a result of the early 
adaptation of opioid substitution and needle exchange programs in the Netherlands, the 
number of PWID co-infected with HIV and HCV is limited. This is unfortunately not the case 
for HIV-infected MSM. Until recently, the prevalence of chronic HCV in Dutch HIV+MSM was 
very high at 4,8% (compared with 0.2% in the Dutch population in general). However, after 
the restrictions on the use of direct-acting antivirals against HCV (DAA) were lifted in 2015, 
the prevalence of chronic HCV in HIV+MSM decreased rapidly. With this decreasing 
prevalence of chronic HCV a decrease in the incidence of acute HCV infections in Dutch 
HIV+MSM was observed as well. Indeed, while the incidence of acute HCV in HIV+MSM in 
care in the Netherlands was 1.1% in 2014, this decreased by 51% in 2016. However, no 
further decline in the number of acute HCV infections was observed in 2017. Also, the 
incidence of HCV re-infections in HIV+MSM that were cured of a previous HCV infection 
continues to be very high in the DAA era with reported rates varying between 5-10% per 
year.  
 
The continuously high re-infection risk and the lack of a further decline in the HCV incidence 
after 2016 illustrates that universal DAA therapy for all patients diagnosed with a chronic 
HCV infection on its own will not result in HCV elimination. Other interventions are needed to 
reach the WHO goal of HCV elimination by 2030. One of these additional interventions may 
be decreasing the time to diagnosis of HCV re-infections in order to decrease the duration 
that these re-infected patients may transmit their HCV to sex partners. Indeed, if the 
diagnosis of HCV re-infection is made earlier, counseling on transmission risk in combination 
with the prompt initiation of HCV therapy will prevent transmission to sex partners and 
prevent new HCV infections on the population level.  
 
The study we describe here was designed to evaluate the effect and feasibility of more 
frequent and home-based testing for HCV on the time to diagnosis and treatment of HCV re-
infections.  
 
 
 

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Objective:  
To assess the effectivity of HCV RNA self-testing in reducing the time to diagnosis of HCV 
re-infection in MSM previously cured of an HCV infection, compared to the current diagnostic 
standard of care.  
To evaluate whether the uptake of self-testing is sufficient and warrants the use of HCV RNA 
self-testing in clinical practice. 
  
Study design:  
Prospective controlled intervention trial. MSM cured of an HCV infection who are at 
continued risk for an HCV re-infection (based on the results of a short questionnaire, 
APPENDIX B) are offered HCV RNA self-testing and asked to use the test every 6 months 
for 2 consecutive years.  
 
Study population:  
225 to 250 adult MSM cured of HCV from 10-15 HIV and PREP clinics in the Netherlands 
and Belgium.  
 
Intervention:  
Eligible patients are instructed on the use of a capillary blood self-collection kit. They receive 
2 kits per year for 2 consecutive years to allow them to send plasma to the virology lab of the 
Erasmus MC every 6 months by regular post mail.  
 
Primary endpoints: 
Comparison of the time to HCV re-infection diagnosis in patients using the HCV RNA self-
test (intervention) with the time to HCV re-infection diagnosis with the standard diagnostic 
approach (control) in the modified intention to treat population. 
 
Secondary endpoints:  
1. Comparison of the time to HCV re-infection diagnosis in patients using the HCV RNA self-
test (intervention) with the time to HCV re-infection diagnosis with the standard diagnostic 
approach (control) in the subpopulation that has sent in all planned self-tests during their 
entire follow-up (per protocol analysis). 
 
2. Of the HIV+MSM that were offered to participate in the study, the percentage that 
accepted to participate and eventually self-collected and sent in at least one plasma sample 
in each 12-month period of study participation. 
 

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3. Overall incidence of HCV re-infection in the entire study population regardless of the type 
HCV diagnostic test that was used. 
 
4. Number of screen failures as a result of a positive HCV-RNA test at the screening visit. 
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
The burden associated with participation in the study consists of taking a finger prick blood 
sample for the self-test 4 times in 2years and sending the sample to the laboratory by regular 
post mail. No costs will have to be made for mailing the sample. Capillary finger-prick blood 
sampling is used as a standard diagnostic test for many diseases (e.g. glucose monitoring in 
diabetes) and is associated with a negligible risk. The study may potentially be beneficial for 
those participants in which an HCV re-infection is diagnosed as they will be referred for 
counselling and HCV therapy which has the potential to prevent transmission to sex partners.  

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1. INTRODUCTION AND RATIONALE 
 
Viral hepatitis was the seventh leading cause of death worldwide in 2013, increasing from the 
tenth leading cause in 2010 (1). The vast majority of morbidity and mortality attributable to 
viral hepatitis is due to hepatitis C virus (HCV) and hepatitis B Virus (HBV). In response to 
this increasing public health challenge, the World Health Organization recently released 
targets for HBV and HCV elimination by 2030 (2). Elimination is traditionally defined as a 
reduction to zero in the incidence of disease in a specific population or geographical location, 
with continued prevention efforts required to prevent the re-establishment of transmission (3).  
 
Because a strict definition of elimination would require substantial economic and political 
resources and could be unattainable in most settings, the goal of “elimination” is often flexibly 
defined. The recent WHO elimination “as a public health threat” targets are comprised of a 
90% relative reduction in new infections and a 65% relative reduction in hepatitis-related 
mortality by 2030. Hence, to achieve the WHO incidence elimination targets, efforts must 
focus on both prevention of disease and prevention of transmission. The advent of highly 
effective HCV direct acting antiviral (DAA) therapy, with cure rates (also called sustained viral 
response, SVR) of 95% or higher has renewed optimism that substantial reductions or 
elimination of end stage liver disease and HCV-related mortality is a possibility. The WHO 
strategy does not include a discussion relating to elimination of viral hepatitis among HIV-
infected populations specifically but given the shared transmission routes many people living 
with HIV are coinfected with viral hepatitis as well. Globally, approximately 6.2% (3.4% to 
11.9%) of HIV-infected (HIV+) patients are also coinfected with HCV, equating to 
approximately 2.28 million (IQR 1.27 to 4.42) HIV/HCV coinfected individuals (4). The burden 
of HIV/HCV coinfection is particularly high in people who inject drugs (PWID) and among 
men who have sex with men (MSM). However, in the Netherlands, the early adoption of 
opioid substitution and needle exchange programs has limited the number of PWID co-
infected with HIV and HCV. 
 
Regarding the epidemiology of HCV in HIV+MSM, it has been estimated that globally 6.4% of 
them are coinfected with HCV (4). Indeed, in contrast to the lack of sexual HCV transmission 
among heterosexual couples, HCV transmission readily occurs among MSM during anal sex. 
Therefore, it comes as no surprise that before restrictions on the use of DAA therapy were 
lifted in the Netherlands, the prevalence of HCV in Dutch HIV+MSM was equally high at 
4,8% (5). Furthermore, not only the prevalence, but also the incidence of HCV in Dutch 
HIV+MSM is substantial. In 2014, 99 of the 8849 or 1.1% of HIV+MSM in care in the 19 
largest HIV centers spread across the Netherlands, were diagnosed (5). This high 

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prevalence and incidence is in sharp contrast with the very low overall prevalence of HCV in 
the Dutch population in general (0.2%), which is one of the lowest worldwide (6, 7). 
Therefore, if the Netherlands wants to achieve the WHO hepatitis elimination goals, it is 
opportune to aim for HCV elimination in population subgroups with a high HCV prevalence 
rather than the entire Dutch population. Because the large majority of the HIV infected MSM 
in the Netherlands is aware of their HIV infection and in care in one of the Dutch HIV 
treatment centers, this specific HCV risk group is already identified. Also, 98% of them 
consented to have their data used for research purposes by the Stichting HIV monitoring 
(SHM) as part of the ATHENA cohort. Therefore, reliable and up-to-date data on the number 
of HIV+MSM ever diagnosed with or treated for HCV are available, and these data are truly 
representative of the entire Dutch HIV+MSM population. The importance of the SHM data 
registry regarding the HCV epidemiology in HIV+ patients is well illustrated by several recent 
studies. In 2018, Boerekamps et al. used SHM data to measure the impact of the 
introduction of unrestricted DAA therapy in the Netherlands as of November 2015 on the 
prevalence of HCV among HIV+ patients (8). The study showed that just 15 months after the 
reimbursement restrictions on DAA therapy were lifted, already 82% of HCV coinfected 
patients were cured or receiving DAA therapy. In MSM this was even higher at 89%. 
Furthermore, because patients cured of HCV can no longer transmit HCV to their partner, it 
was anticipated that this rapid treatment uptake would result in a decrease in new (incident) 
HCV infections as well. This was indeed observed as the rapid uptake of DAA therapy in 
HIV+MSM was followed by a 51% decrease in new (=acute) HCV infections in 2016 (9). 
These interesting observations have been welcomed with enthusiasm in the HIV-HCV 
coinfection research community as an example of “HCV microelimination” and an exemplary 
first step towards HCV elimination in general (10, 11).   
 
However, not all observations regarding HCV elimination in HIV+MSM have been positive. 
Furthermore, it is uncertain to what extent the decline in the incidence of acute HCV that was 
observed is caused by the decreasing prevalence of HCV. Although we have no reasons to 
believe that risk behavior has improved, other factors may have played a role as well. Also, 
although the 51% lower HCV incidence seen in 2016 was also observed in 2017, no further 
decline in the incidence was observed (Boerekamps, personal communication). Several 
observations may explain this. First, HCV transmission among MSM doesn’t stop at the 
country borders. Indeed, cross-border HCV transmission networks have been well described 
(12). Because the DAA treatment uptake is less pronounced in some other European 
countries, cross-border transmission may become more important and may hamper HCV 
elimination. Although the reimbursement restrictions that explain this lack of treatment uptake 
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they still remain in place in others in 2018 (e.g. in the U.K. and Belgium). Another important 
hurdle that needs to be addressed is the number of HCV re-infections that is observed. 
Indeed, several studies have shown that risk of an HCV re-infection in HIV+MSM previously 
cured of an HCV infection is extremely high in the first 1 to 3 years after their infection was 
cured at 5-10% per year(13-15). Therefore, a subgroup of HIV+MSM at very high risk of HCV 
re-infection probably continues to fuel the epidemic. Last but not least, in contrast to what 
was believed previously, sexual transmission of HCV is not limited to HIV+MSM. Indeed, 
several recent publications describe a similarly high incidence of HCV in specific subgroups 
of HIV uninfected MSM (16-18). Indeed, now that it has been convincingly shown that HIV 
infected patients do not transmit HIV to their sex partner when their HIV viral load is 
undetectable as a result of combination antiretroviral therapy, the risk of acquiring HIV is no 
longer a reason to avoid sex with an HIV-infected partner. Furthermore, HIV uninfected MSM 
can protect themselves against HIV with HIV pre-exposure prophylaxis and this will increase 
mixing between HIV+ and HIV- MSM as well.  
 
For all the reasons described above, we consider it unlikely that, even in HIV+ MSM in the 
Netherlands, HCV elimination will be possible if no additional interventions are implemented. 
Therefore, we designed 3 studies of which the common goal is to provide policy makers, 
physicians and patients with data that can help in choosing the most effective interventions 
needed to eliminate HCV in men who have sex with men.  
 
The 3 studies consist of  
 
1. A phylogenetic study; By sequencing a large number of viruses from patients diagnosed 
with a prevalent or incident HCV infection, we hope to get a better picture on current 
transmission networks in order to identify the source of incident HCV infections in MSM in 
Dutch patients. This will be a study in collaboration with the Academic Medical Center in 
Amsterdam and HCV researchers from outside the Netherlands.  
 
2. An HCV prevalence study; This study will measure the prevalence of undiagnosed HCV in 
HIV negative MSM visiting the sexually transmitted diseases GGD clinic in order to evaluate 
the usefulness of systematic screening for HCV of HIV negative MSM attending STD clinics 
in the Netherlands.  
 
3. An HCV re-infection study; In this study we will evaluate if HCV RNA self-testing can 
significantly decrease the time to diagnosis of an HCV re-infection. The study will include 
MSM previously cured of an HCV. If a substantial decrease in the time to diagnosis and 

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therefore also the time to “awareness” and the time to the initiation of HCV therapy and cure 
is achievable, this will limit onward transmission and prevent new HCV infections. This study 
is described below. 
 
INTRODUCTION TO STUDY NR.3.  
 
As previously mentioned, the HCV re-infection rate in HIV+MSM is very high due to ongoing risk 
behavior. In a prospective case-control study, Vanhommerig et al. identified several risk factors 
for acquiring an HCV infection. These were receptive unprotected anal intercourse, sharing sex 
toys, unprotected fisting, injecting drugs during sex, sharing straws when snorting drugs, having 
a lower CD4 cell count and having a recent diagnosis of ulcerative sexually transmitted infection 
(19). Various studies report on re-infections following SVR in HIV+MSM, but the incidence 
estimates have a considerable range, which could be explained by differences in study 
populations regarding risk behaviors, harm reduction interventions and background viremic 
prevalence (15). In a retrospective study in 606 previously HCV infected HIV+MSM from Austria, 
France, Germany and the UK, a re-infection incidence of 7.3/100 person-years was reported 
(14). In a smaller Dutch study from the pre-DAA era, Lambers et al. found a much higher HCV 
re-infection incidence of 15.2/100 person-years in 56 HIV+MSM in the Netherlands (20). 
Consequently, it is clear that HIV+MSM with a previously cured HCV infection have an increased 
risk of acquiring a new HCV infection. At the moment, HIV+MSM with a previously cured HCV 
infection undergo ALT testing approximately twice a year during their regular HIV outpatient clinic 
visit. If an ALT elevation is observed an HCV RNA test is performed to exclude or confirm a new 
HCV infection. However, in acute and chronic HCV infections ALT is not always elevated. ALT 
levels correlate with the duration of HCV infection, the viral load and the presence of periportal 
bridging/necrosis and it has been estimated that up to 25% (range 10 to 40%) of patients with 
chronic hepatitis C infection have persistently normal aminotransferase levels (21). Given these 
factors, using an HCV RNA as well as increasing the frequency of ALT testing both have the 
potential to shorten the time to diagnosis of an HCV re-infection significantly. If this is indeed the 
case, a shorter time to diagnosis (and treatment) will also reduce the time that a patient is at risk 
of transmitting HCV to others. Therefore, it may be one of the additional steps that is needed 
towards the elimination of HCV.   
 
2. OBJECTIVES  
The main objective of this study is to demonstrate that the use of a HCV RNA self-test will be 
an effective and feasible way to decrease the time to diagnosis of an HCV re-infection. If this 
is indeed the case, interventions to prevent HCV transmission to sex partners (e.g. 
counseling, initiation of DAA treatment) can be initiated sooner after an HCV re-infection. 

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For this purpose, patients will be offered to be trained in capillary blood sampling and 
separation of plasma at home and will send the plasma sample, by regular post mail, to a 
central lab for HCV RNA testing. The HCV RNA self-test will be done twice yearly on top of 
the standard of care ALT testing policy that is also done twice a year at the HIV outpatient 
clinic. Therefore, patients in the study will undergo HCV testing 4 times a year; twice a year 
with ALT testing during their regular HIV outpatient clinic visit (followed by an HCV RNA test 
if the ALT turns out to be elevated) and twice a year with the home-based HCV RNA test. 
This self-test is done in between the HIV outpatient clinic visits (figure 1).  
 
Primary objective  
1. Measure if and to what extent HCV RNA self-testing decreases the time from HCV re-
infection to diagnosis compared with the current standard of care.  
 
Secondary objectives: 
1. Measure the uptake and acceptability of HCV RNA self-testing in MSM cured of an 
HCV. 
2. Measure the incidence of HCV re-infection in MSM in the Netherlands and Belgium in 
2018-2019-2020.  
 
3. STUDY DESIGN 
 
Single arm open label multicenter study. 
 
We consider a single arm open label multicenter study the most appropriate design, given 
the relatively small patient population at risk for HCV re-infection in the Netherlands. Indeed, 
the number of HIV+MSM that fulfill the in- and exclusion criteria (see below) in the 
participating Dutch study centers is estimated at 250-350, of which a subset will be interested 
in study participation. Three additional Belgian study centers and one Swiss center have also 
agreed to participate in the study. Even with the participation of these foreign HIV treatment 
centers, a randomized fully powered study remains unachievable. Indeed, if the time to 
diagnosis would be reduced from 4.5 to 2.5 months with the intervention and assuming a 
standard deviation of 2 and an 80% power and alfa of 5%, the study would need to include 2 
groups of patients in which a minimum of 16 re-infections would be diagnosed in each group 
(see sample size calculation below). With an incidence of HCV re-infections of ±8% during 
the 2 years of follow-up this would mean that 2x200 patients need to be included to diagnose 
2x16 re-infections. As our most optimistic inclusion scenario will allow recruitment of 250 

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patients in 2 years, this means that a single arm study with 200 patients will already take 4 
years to complete given the follow-up time of 2 years of each of the patients. Therefore, we 
consider a single arm open label multicenter study the most appropriate.  
 
For the purpose of the analysis, we will use the study population as its own “virtual” control 
group (see below for a more detailed explanation of this control group).   
 
Intervention:  
The self-test that is used to detect HCV RNA is performed every 6 months on top of standard 
of care ALT test as described above. The HCV RNA testing will be done at home by the 
patient 3 months after each HIV outpatient clinic visit and sends the plasma sample to our 
laboratory by regular post mail. If HCV RNA is detected, the treating physician will be 
informed and the patient contacted immediately and invited to visit the outpatient clinic for 
confirmation of the positive HCV RNA self-test and evaluation of liver enzymes. If the 
presence of HCV RNA is confirmed, HCV therapy can then be initiated according to the 
Dutch or Belgian HCV treatment guideline. 
 
Standard HCV diagnostic procedures in the “virtual control group”:  
The standard of care HCV re-infection diagnostic strategy used by HIV outpatient clinics is 
measuring ALT levels every 6-months. If an ALT elevation is documented, HCV RNA testing 
is performed to diagnose a potential HCV re-infection. If this HCV RNA test is positive, HCV 
therapy can then be initiated according to the Dutch HCV treatment guideline. 
 
Figure 1 illustrates the timing of the home-based HCV RNA test in the intervention group; 
The self-test is done every 6 months in between the ALT tests at the outpatient HIV clinic. 
Furthermore, the self-test is done at the screening visit as well to exclude that patients with 
an undiagnosed HCV infection are included.   
 
 
 
 
 
 
 
 
 
 

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Figure 1.  
 
 
 
Defining the time to diagnosis in the intervention and the virtual control group:  
 
Patients diagnosed with an HCV re-infection by the HCV RNA self-test are contacted 
immediately by the site investigator and invited to visit the outpatient clinic to have their liver 
enzymes tested and to confirm the HCV diagnosis with a whole blood HCV RNA PCR test. If 
at that time the ALT level is elevated, we will assume that an HCV RNA test would have 
been done by the treating physician at the next 6-monthly HIV outpatient clinic visit (in ± 3 
months) and therefore the HCV diagnosis would have been made at that time point.  
 
In patients diagnosed with an HCV re-infection in which the ALT level turns out to be normal, 
we will assume that the ALT level would not be elevated at the next planned HIV outpatient 
visit (in general ± 3 months later), but that it would be elevated at the consecutive HIV 
outpatient clinic visit (in general ± 9 months lager) and therefore the HCV diagnosis would 
have been made at that time point. This conservative approach that assumes an ALT 
elevation in all patients 9 months after the positive HCV RNA test is needed because we 
anticipate that all patients will have started HCV therapy within 6 months after diagnosis and 
this leads to prompt ALT normalization. Therefore, we cannot use the actual measured ALT 
level 9 months after the positive HCV RNA test.   
 
The date of infection is estimated as the midpoint between the date of last negative HCV test 
and the date of the first positive HCV test. The last negative HCV test can be either a 
negative ALT test or a negative HCV RNA test. The first positive HCV test can be either a 
positive HCV RNA self-test or a positive whole blood HCV RNA test performed in the 
hospital. This estimation of the date of infection will be used for the analysis of the time to 
diagnosis in both the intervention and the virtual control group.   
  

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This is illustrated by the following example and in figure 2. A study patient with a positive 
HCV RNA self-test 9 months after the start of the study had an ALT within the normal range 
at 6 months. When he is informed about the positive self-test and the positive test is 
confirmed by the local investigator his ALT is measured as well and turns out to be elevated. 
For this patient, the date of infection is estimated at 7.5 months (6+((9-6)/2)). The actual time 
to re-infection diagnosis in the intervention arm is (9-7.5) or 1.5 month. To evaluate the time 
to re-infection diagnosis as part of the “virtual” control group, we will disregard the result of 
the self-test at 9 months and assume that at 12 months an elevated ALT would have been 
detected, because his ALT was also elevated at 9 months. Therefore, the virtual time to re-
infection diagnosis for this patient is (12-7.5) or 4.5 months (scenario 1 in figure 2). However, 
if the ALT level of this patient would have been normal at 9 months, the virtual time to re-
infection diagnosis would be different. Indeed, while the actual time to re-infection diagnosis 
would still be 1.5 month, the virtual time to re-infection diagnosis would be (18-7.5) and 
therefore 10.5 months because we will assume that ALT would still be normal at the 12 
months HIV outpatient clinic visit but would have become elevated at the next consecutive 
HIV outpatient clinic visit at 18 months (scenario 2 in figure 2).  
 
Please note that all patients will undergo an HCV RNA self-test at the time of screening for 
the study. This will not only allow for the demonstration of the self-test by the trial-nurse but 
will also ascertain that patients with an undiagnosed chronic HCV are not included.  
 
Figure 2 
 
 

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4. STUDY POPULATION 
 
4.1 Population (base)  
 
Study population:  
Only patients that provide written informed consent will be included. They will first have to 
review the instruction video that explains and shows how the capillary blood collection and 
separation of plasma should be done. If the patient is still willing to participate after he has 
seen the instruction video and received all information by the research team, he will receive 
the self-testing kit with all materials needed to send in 4 plasma samples over a period of 2 
years. The patients will be offered HCV RNA self-testing for 2 consecutive years and thus 
during 400 patient years of follow-up. Recruitment will stop when at least 1 plasma sample is 
received from 200 patients. Therefore, we estimate that we will need to include 225 to 250 
patients to have an evaluable population of at least 200.  
 
We allow HIV+ as well as HIV- MSM to be included as long as they fulfill the in- and 
exclusion criteria. HIV negative MSM can only be included if they are taking PREP and if 
HCV RNA testing is not done as the standard of care HCV diagnostic strategy at the PREP 
clinic but ALT testing is done as an HCV testing policy no more often than 3x/years. Twice 
yearly testing is the standard of care in HIV+ patients in the Netherlands but the frequency 
may be higher or lower in HIV uninfected PREP users per local policy (e.g. in Belgium).  
 
The total number of patients that was informed about the study and the number of patients 
that reviewed the video but who never actually started using the HCV RNA self-test will be 
used to evaluate the acceptability of HCV RNA self-testing.  
 
For the statistical analysis the following populations are defined:  
 
Modified Intention to treat population (MITT):  
All patients who signed the informed consent, received the HCV RNA self-test kit and in 
which the HCV RNA test at the screening visit was negative. 
 
Per protocol population (PP):  
All patients who signed the informed consent, received the HCV RNA self-test kit and in 
which the HCV RNA test at the screening visit was negative and who collected all 6 monthly 
plasma samples during the entire follow-up. 

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4.2 Inclusion criteria 
 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
 
Cured of HCV defined as an SVR (=documented negative HCV RNA test) at least 12 
weeks after the end of DAA therapy and no new documented positive HCV RNA test 
after the date of the SVR 
 
OR 
 
Spontaneous clearance of HCV infection defined as two consecutive negative HCV 
RNA tests at least 3 months apart after a positive HCV RNA test.  
 
 
In care for an HIV infection in an HIV clinic in a study center or HIV negative and 
receiving PrEP at a PrEP clinic 
 
 
Able and willing to perform the self-test at home after viewing the instruction video 
 
 
Willing to fill out a questionnaire on risk behavior at the time of HCV self-testing  
 
 
At risk of HCV re-infection according to a short questionnaire, in other words, patients 
should have one of the following risk factors (19): 
o Receptive unprotected (condomless) anal intercourse in the last 6 months 
o Fisting or being fisted without gloves in the last 6 months 
o Sharing toys in the last 6 months 
o Syphilis or LGV in the last 12 months, 
o Slamming (injecting drug use) in the last 12 months 
o Sharing sniffing straws or other objects to sniff drugs in the last 12 months 
 
4.3 Exclusion criteria 
 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study: 
 

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 
Age < 18 
 
 
 
Patients that are tested by HCV RNA as a standard of care test (e.g. in the context of 
PREP use) > 1x/year 
 
 
Patients that are expected to be tested by ALT at their HIV or PREP clinic <1x/year 
 
4.4 Sample size calculation 
 
200 HIV+MSM with a previously cured or a spontaneously resolved HCV infection will be 
included. These patients will be offered HCV RNA self-testing for 2 years and thus during at 
least 400 patient years of follow-up.  
 
Previous reports on the incidence of HCV re-infection have observed a re-infection incidence 
of 5 to 15% per year. However, we should also consider that after the roll-out of DAA therapy 
in the Netherlands a 51% decrease in the number of acute HCV infections was observed in 
2016 compared with 2014. Therefore, we estimate that the incidence of re-infection will be 
4% rather than 5-15% per year. Therefore, we anticipate to diagnose a HCV re-infection in 
8% of the patients during the 2 years of follow-up. With the inclusion of 200 patients and an 
average follow-up of 2 years per patient, we should therefore be able to diagnose 16 re-
infections. The calculator for a continuous outcome superiority trial of the website 
sealedenvelope.com  was used for the sample size calculation because the outcome we 
measure is continuous (days).. Now assuming a time from re-infection to diagnosis of 4.5 
months or 135 days (SD of 2 months or 60 days) with the current standard of care ALT 
testing strategy (virtual control group) and a reduction to 2.5 months or 75 days with the HCV 
RNA self-testing intervention, the required sample size is 16 infections per arm. Because 
these 16 infections will be used to calculate the time to diagnosis for the intervention as well 
as for the control group, a sample size of only 16 infections will give the study 80% power to 
show a difference between the intervention and the virtual control group.  
 
 
5. TREATMENT OF SUBJECTS 
N/A 
 
6. INVESTIGATIONAL PRODUCT  
N/A 
 

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7. NON-INVESTIGATIONAL PRODUCT 
N/A 
 
8. METHODS 
8.1 Study parameters/endpoints 
 
Primary endpoints: 
1. Comparison of the time to HCV re-infection diagnosis in patients using the HCV RNA 
self-test (intervention) with the time to HCV re-infection diagnosis with the standard 
diagnostic approach (virtual control) in the modified intention to treat (MITT) 
population. 
 
Secondary endpoints:  
1. Comparison of the time to HCV re-infection diagnosis in patients using the HCV RNA 
self-test (intervention) with the time to HCV re-infection diagnosis with the standard 
diagnostic approach (control) in the subpopulation that sent in all planned self-tests 
during their entire follow-up (Per Protocol analysis). 
2. Of the HIV+MSM that were offered to participate in the study, the percentage that 
accepted to participate and eventually self-collected and sent in at least one plasma 
sample in each 12-month period of study participation. 
3. Overall incidence of HCV re-infection in the entire study population regardless of the 
type of HCV diagnostic test that was used.  
4. Number of newly diagnosed HCV infections at the time of the screening visit as a 
result of a positive HCV-RNA test at the screening visit. 
 
8.2 Randomisation, blinding and treatment allocation 
N/A 
 
8.3 Study procedures 
 
Only patients that provide written informed consent will be included. Next, they will be 
screened for the study which includes answering a 1-page questionnaire on sexual practices 
in the last 12 months (APPENDIX B) 
 
If the patient fulfills all the in- and exclusion criteria, he will have to review the instruction 
video as a next step. This video explains and shows how the capillary blood collection and 

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plasma separation should be done. If the patient is still willing to participate after he has seen 
the instruction video and received all information by the research team, he will receive the 
self-testing kit with all materials needed to send in 4 plasma samples over a period of 2 
years.  
 
HCV RNA self-test 
Patients will be instructed on how to collect capillary blood using the Demecal set, a CE-
marked and dedicated tube with an incorporated sponge, apply the filter that separates the 
plasma and send the sample to the virology lab where the plasma will be tested with the 
regular HCV PCR essay. An illustration of the procedure can be reviewed here: http://www.i-
thatsme.nl/i-my-personal-soa-check/nl/videohandleiding. 
 
The result of the HCV RNA self-test will be communicated to the investigator of the study site 
who will communicate the result to the patient. 
 
Patients will be asked to fill out a short questionnaire on sexual practices in the 6 months 
preceding the self-test (APPENDIX C) 
 
The self-testing kit will include a termination letter. The patient is asked to send this letter to 
the study coordinator when he decides to stop using the HCV RNA self-test and fill out the 
reason why he has decided to do so (appendix A).  
 
Table 12. Study procedures 
 
Procedures 
at 
time points 
Screening
Mo3 
Mo6 
Mo9  
Mo12 
Mo15 
Mo18 
Mo21 
Mo24 
Eligibility check 
x 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
Screening 
questionnaire 
x 
 
 
 
 
 
 
 
 
Instruction video 
x 
x 
 
x 
 
x 
 
x 
 
Study 
self-test 
dispensing 
x 
 
 
 
 
 
 
 
 
Self-test 
 
 
at 
hospital 
x 
 
 
 
 
 
 
 
 

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ALT 
measurement 
x 
 
x 
 
x 
 
x 
 
x 
Self-test at home 
 
x 
 
x 
 
x 
 
x 
 
Self-test 
questionnaire 
 
x 
 
x 
 
x 
 
x 
 
Whole blood HCV 
RNA PCR 
 
x* 
 
x* 
 
x* 
 
x* 
 
 
* These tests will only be performed if the result of the HCV RNA self-test is positive. The 
patient will be called and sent to the clinic for consecutive whole blood HCV RNA PCR (for 
confirmation of diagnosis) and liver enzyme testing.  
 
8.4 Withdrawal of individual subjects 
 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. Patients in which a HCV re-infection was diagnosed will leave the study. 
 
8.5 Replacement of individual subjects after withdrawal 
 
Patients who are withdrawn are not replaced by new subjects. However, the study will 
include a sufficient number of patients to have at least 200 evaluable patients (see 3.1 
above)  
 
8.6 Follow-up of subjects withdrawn from treatment 
 
The follow-up of patients withdrawn from the study will be done by their treating physician.  
 
8.7 Premature termination of the study 
N/A 
 
 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 

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health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to [the investigational product / 
trial procedure/ the experimental intervention]. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be 
recorded. 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
Because the only intervention that is performed is the HCV RNA self-test (4 capillary 
blood samples in 2 years time), we will only report SAE that are possibly directly 
related to the finger prick sampling (e.g. wound infection for which a hospital 
admission is required). 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 

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period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
 
9.3 Annual safety report 
 
NOT APPLICABLE 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol  
 
10. STATISTICAL ANALYSIS 
 
For the primary endpoint the time to HCV re-infection diagnosis will be compared between 
the intervention group (“The self-testing strategy”) and the virtual control group (“The 
standard of care ALT-based strategy”). Descriptive statistics will be used to quantify the 
difference in time to diagnosis between these groups. The focus of this study is the feasibility 
of the diagnostics and therefore to show that the amount of reduction in time to diagnose that 
the test will lead to is sufficient (i.e. at least 2 months, see paragraph 4.4) to be considered 
clinically relevant. Since the actual time to diagnosis and the virtual time to diagnosis are 
measured and estimated for the same patient, these data are dependent. Consequently, for 
inferential statistics, the Wilcoxon  signed rank test will be used in which the virtual time to 
diagnosis in considered the pre-intervention measurement and the actual time to diagnosis 
as observed with the self-test intervention will be considerd the post-intervention 
measurement. 
 
The time to diagnosis is defined as the number of days between the calculated time of 
transmission and the first positive HCV RNA test.  
 
The calculated time of transmission is defined as the midpoint between the date of the last 
negative and first positive HCV test. For this purpose, the last negative HCV test can consist 
of a normal ALT level or a negative HCV RNA test.  
 

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The analysis of the primary endpoint will be done according to the intention to treat approach 
and will therefore include the MITT population as described above.  
 
We refer to p.17 for a detailed explanation on how to define the date of the first positive HCV 
test in the virtual control group.  
 
The analysis of secondary endpoint 1 is similar to the methodology described for the primary 
endpoint. For the secondary endpoints 2 to 4 descriptive statistics will be used and 95% 
confidence intervals will be reported.  
 
For secondary endpoint 1, the follow-up time in months will be considered 24 months in all 
patients that did not send in the termination letter. In patients that confirmed that they 
stopped using the HCV RNA self-test because they no longer considered themselves at risk 
for HCV, the follow-up time ends on the termination date mentioned on the termination letter 
(or the termination date otherwise communicated by the patient as long as this date is 
documented in the patient file by the principal investigator and the reason to stop was that 
the patient considered himself no longer at risk for HCV). 
 
10.1 Interim analysis (if applicable) 
Not applicable 
 
11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be performed in accordance with the protocol, the guidelines of Good 
Clinical Practice/ICH, which underwrites the principles of the Declaration of Helsinki, as 
most recently revised by the 64th WMA General Assembly in Fortaleza, Brazil, October 
2013.  
 
11.2 Recruitment and consent 
Patients will be recruited at the study sites mentioned on page 2-3. It is the 
responsibility of the investigators or the co-investigators to obtain written informed 
consent from each subject participating in this study, after adequate explanation of the 
aims, methods, anticipated, and potential hazards of the study (patient information 
form). 
 

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Besides the specific information regarding the study, the following standard items are 
covered in the patient information form (Dutch: patiënten informatie formulier): 
 Patient’s right to withdraw from the clinical study anytime without giving reasons and 
without any consequences for further medical treatment.  
 The information that all study findings will be stored in a computer database and 
handled confidentially 
 Patient names will be kept separate from research data and patients will be 
identifiable by subject number only.   
 Information about the possibility of inspection of relevant parts of the hospital 
records by regulatory authorities. Inspection will only take place if a confidentiality 
agreement has been signed. 
 The existence of patient insurance policy in case the patient will be harmed by 
participating in the study (using the study drug) 
 All novel clinically relevant information that will become available during the study 
and is possibly important for the patient will be communicated to him/her by one of 
the investigators. 
 
The signature of an investigator or co-investigator on the form will attest that the 
information in the consent form was accurately explained and understood. Thereafter 
the patient will sign after a period of reflection. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form will be reviewed 
and updated after approval by the ethical committee. Then, all subjects (including those 
already being treated) will be informed of the new information, will be given a copy of 
the revised form and will be asked to give their consent to continue the study. 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
N/A 
 
11.4 Benefits and risks assessment, group relatedness 
Doing extra diagnostics can be a burden to the patient, for example due to anxiety or 
stress for the test results. But we believe that if a patient, after giving informed consent 
has decided to do the self-testing for HCV, this gives the patient not only more 
responsibility but also more control over his personal health and could also reduce 
anxiety. In addition, earlier diagnosis can make earlier treatment possible and can 
prevent infections to other (sexual) partners, which is of benefit to the society.  
 

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11.5 Compensation for injury 
Liability insurance sponsor/investigator 
The sponsor/investigator has a liability insurance which is in accordance with article 7, 
subsection 6 of the WMO. 
 
Insurance for study participants 
The ethics committee waived the need for a WMO insurance considering the negligible 
risk for study participants.  
 
11.6 Incentives (if applicable) 
No incentives.  
 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Data will be handled confidential and if possible anonymously. Where it is necessary to 
be able to trace data to an individual subject, a subject identification code list will be 
used to link the data to the subject. The code will not be based on the patient initials and 
birth-date. The key to the code will be safeguarded by the investigator. as the data and 
human material will be kept for a longer period of time. The handling of personal data will 
comply with the EU General Data Protection Regulation and the Dutch Act on 
Implementation of the General Data Protection Regulation (in Dutch: Uitvoeringswet 
AVG, UAVG).  
 
Case record form (CRF) 
All data of patients, including results from standard procedures during treatment, 
collected during the study will be recorded in Case Record Forms. The CRF must be 
completed fully and legibly. Corrections of possibly erroneous entries must be carried out 
in such a manner that the initial entry is not rendered illegible. Corrections should be 
written alongside or above the pertinent place with the date and initials. Correction fluid 
must not be used.  
The investigators are responsible for the quality of the data recorded in the Case Record 
Forms (CRF). Where the investigators have not been responsible for completing the 
CRF, an additional signature from the co-investigator overseeing the data entry of the 
study must be obtained. 
In the event that the investigators need to deviate from the protocol, the nature of and 
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CRF. In nearly all cases it is desirable that the patient continues the study to allow the 
most informative intention-to-treat analysis; however, the patient may be excluded from 
the per-protocol analysis. 
 
OpenClinica or another GCP compliant system that Erasmus MC supports will be used 
as the eCRF.  
 
Privacy rules 
Patients will be identified in the CRF by their identification code. The investigators will 
keep a patient identification log, including sufficient information to link the hospital record 
and CRFs.  
The subjects will be informed that the data will be stored on paper and electronically, that 
local regulations for the handling of computerized data will be followed as described in 
the written patient information / consent form and that identification of individual patient 
data will only be possible for the investigators. Furthermore, the subjects will be informed 
about the possibility of inspections of relevant parts of the hospital records by health 
authorities. These officials will be identified and have signed a confidentiality agreement. 
The data are stored and processed using a database program for personal computers.  
From this database the data will be transferred to a statistical program for further 
analysis. Only data, with coded patient identity will be transferred to the statistician for 
analysis. 
 
Data processing 
After a visual plausibility check the CRF data will be entered in the computer and 
processed using a database program. Data base print outs will be produced and 
checked by one of the principle investigators or his co-investigators. When approved, the 
data will be transferred from the database to a statistical data file, with conversion in 
uniform data and formation of a master database for further analysis. The data transfer 
to the statistician can take place during the study  
 
Data achieving  
Patient identification log, hospital records, informed consent forms, case record forms 
and databases must be kept for at least 5 years after completing the study (EU-directive 
2005/28/EG). If the investigators move or retire, they must nominate someone in writing 
to be responsible for record keeping. Archived data may be held on microfiche or 

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electronic record, provided that a backup exists and a hard copy can be obtained from it 
if required. 
 
12.2 Monitoring and Quality Assurance  
Please refer to our monitoring plan. 
 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final 

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study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority.  
 
12.6 Public disclosure and publication policy 
The sponsor is free to publically disclose and publish all research data. Please refer to the 
contract between de sponsor and the subsidising party for arrangements made 
concerning public disclose and publication of research data. 
 
13. STRUCTURED RISK ANALYSIS  
 
13.1 Potential issues of concern 
 
Capillary blood collection for HCV RNA self-test—drops of capillary whole blood collected 
from a simple prick of the finger using a tube with sponge—provide a minimally invasive 
alternative to venous blood sampling that facilitates the collection of blood samples in home-
based settings and can be done by non-medically trained personnel. It is comparable to a 
skin-prick test that patients with diabetes use. The risks are therefore negligible.  
 
 
14. REFERENCES 
 
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global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of 
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2. Organisation. WH. Global health sector strategy on viral hepatitis, 2016-2012. . 2016. 
3. Dowdle WR. The principles of disease elimination and eradication. Bull World Health 
Organ. 1998;76 Suppl 2:22-5. 
4. Platt L, Easterbrook P, Gower E, McDonald B, Sabin K, McGowan C, et al. Prevalence 
and burden of HCV co-infection in people living with HIV: a global systematic review and 
meta-analysis. Lancet Infect Dis. 2016;16(7):797-808. 
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6. Vriend HJ, Van Veen MG, Prins M, Urbanus AT, Boot HJ, Op De Coul EL. Hepatitis C 
virus prevalence in The Netherlands: migrants account for most infections. Epidemiol Infect. 
2013;141(6):1310-7. 
7. WHO. Global hepatitis report, 2017. World Health Organisation, 2017. 
8. Boerekamps A, Newsum AM, Smit C, Arends JE, Richter C, Reiss P, et al. High 
Treatment Uptake in Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Patients 
After Unrestricted Access to Direct-Acting Antivirals in the Netherlands. Clin Infect Dis. 
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