Clinical trial NCT04042740
Conditions: Hepatitis C Infection HIV Infection
Keywords: Acute Hepatitis C Infection Glecaprevir Pibrentasvir 4 weeks Direct-acting antivirals
Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Start date: 2019-11-20; Completion date: 2023-08-22
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to assess the efficacy of a fixed dose combination (FDC) of glecaprevir/pibrentasvir (G/P) given for 4 weeks for treatment of acute hepatitis C (HCV), with or without HIV-1 coinfection.

Detailed description:
The study was conducted in two steps. In Step 1, participants received four weeks of treatment with G/P for acute HCV infection and were then followed 24 weeks post treatment. Participants with HCV recurrence (reinfection, suspected relapse or undefined post-treatment viremia) or HCV virologic failure before or at the Step 1 Week 16 entered Step 2 and were offered HCV re-treatment. The remaining participants were followed in Step 1 for a total of 28 weeks. The study primary and secondary outcome measures pertain to Step 1.

In Step 2, participants were re-treated for up to 16 weeks (G/P or alternate regimen through standard of care), and were followed for 24 weeks post treatment. This post-treatment follow-up included a visit for the determination of HCV sustained virologic response (SVR12) after re-treatment. All summaries of data captured from Step 2 are pooled across HCV re-treatment regimens, as specified in the Statistical Analysis Plan.

In Step 1, study visits were scheduled at study entry, weeks 1 and 2 (on-treatment), week 4 (treatment discontinuation), and weeks 8, 12, 16 and 28 (post-treatment follow-up). In Step 2, participants had study visits during the re-treatment period, where the number of visits depended on the re-treatment regimen, and at weeks 12 and 24 post treatment. Study visits included physical examinations, clinical assessments, blood and urine collection, questionnaires, and HCV re-infection prevention counseling.

Arms: arm 1: Participants were assigned to receive G/P FDC tablets to be taken orally once daily for 4 weeks (Step 1).

Participants who experienced HCV re-infection, suspected relapse, virologic failure, or undefined post-treatment viremia in Step 1 were offered to enter Step 2 for re-treatment. HCV re-treatment regimens may have included G/P FDC tablets orally once daily for 8-16 weeks, or alternate regimens through clinical care.
Interventions: intervention 1: Glecaprevir/Pibrentasvir (G/P)
Intervention descriptions: intervention 1: Fixed-dose combination (FDC) tablets containing 100 mg of glecaprevir and 40 mg of pibrentasvir; administered as 3 tablets orally.

Protocol documents:
Prot_ICF_000.pdf: 
 
 
A5380 
 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose 
Combination Treatment for Acute Hepatitis C Virus 
Infection (PURGE-C) 
 
A Multicenter Trial of Advancing Clinical Therapeutics 
Globally (ACTG) 
 
NIAID CRMS # 38553 
 
This file contains the current ACTG A5380 protocol, which 
includes the following document:  
 
• Clarification Memo #3, dated 12 Apr 2022 
• Letter of Amendment #4, dated 13 Oct 2020 
• Letter of Amendment #3, dated 09 Sep 2020 
• Letter of Amendment #2, dated 14 Aug 2020 
• Clarification Memo #2, dated 20 Apr 2020 
• Letter of Amendment #1, dated 18 Dec 2019 
• Clarification Memo #1, dated 15 Oct 2019 
• Protocol Version 1.0, dated 07 June 2019  


Clarification Memo #3 
          Page 1 of 2 
12 Apr 2022 
ACTG A5380 Protocol Version 1.0 
Clarification Memo #3 for: 
A5380 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for 
Acute Hepatitis C Virus Infection (PURGE-C) 
A Multicenter Trial of Advancing Clinical Therapeutics Globally (ACTG) 
NIAID CRMS # 38553 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems, Inc., a DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3000 
CLARIFICATION MEMO 
DATE: 
April 12, 2022 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5380 Protocol Team  
SUBJECT: 
Clarification Memo #3 for Protocol A5380 
This clarification memo (CM) does not result in a change in the protocol informed 
consent document.  
The Division of AIDS does not require you to forward it to your institutional review board 
(IRB); however, you must follow your IRB's policies and procedures. If IRB review of 
clarification memos is required at your site, please submit this document for review. 
Each site should file a copy of this CM with the protocol for reference. 
The protocol clarification(s) contained in this memo should be implemented immediately. 
The following are clarifications (noted in bold and strikethrough) to Protocol A5380, Version 1.0, 
06/07/19, titled, “A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment 
for Acute Hepatitis C Virus Infection (PURGE-C).”  
Section 6.3.10 (Virologic Studies): The first paragraph of the fourth subsection has been revised 
to read: 


Clarification Memo #3 
          Page 2 of 2 
12 Apr 2022 
ACTG A5380 Protocol Version 1.0 
Plasma HCV Genotype  
At Step 1 screening, the HCV genotype sample result will be collected, and the result will 
be obtained locally (real-time) from any laboratory that has a CLIA certification or its 
equivalent. ONLY IF IT IS NOT AVAILABLE LOCALLY should it be done (real-time) at the 
designated testing laboratory (see A5380 LPC). The participant may be enrolled with the 
HCV genotype result pending. 


Letter of Amendment #4 
          Page 1 of 4 
13 Oct 2020 
ACTG A5380 Protocol Version 1.0 
Letter of Amendment #4 for: 
A5380 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for 
Acute Hepatitis C Virus Infection (PURGE-C) 
A Multicenter Trial of Advancing Clinical Therapeutics Globally (ACTG) 
NIAID CRMS # 38553 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems , a DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3000 
Fax: 301-628-3302 
LETTER OF AMENDMENT 
DATE: 
October 13, 2020 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5380 Protocol Team  
SUBJECT: 
Letter of Amendment #4 for Protocol A5380 
The following information affects the A5380 study and must be forwarded to each site’s 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) must be approved by the 
IRB/EC before implementation.  
The following information may also affect the Sample Informed Consent. The site IRB/EC 
is responsible for determining the process of informing participants of the contents of 
this LOA. 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit an 
LOA registration packet to the DAIDS Protocol Registration Office (PRO) at the 
Regulatory Support Center. Sites will receive a registration notification for the LOA once 
the DAIDS PRO verifies that all required LOA registration documents have been received 
and are complete. An LOA registration notification from the DAIDS PRO is not required 
prior to implementing the LOA. A copy of the LOA registration notification, along with 
this letter and any IRB/EC correspondence, should be retained in the site’s regulatory 


Letter of Amendment #4 
          Page 2 of 4 
13 Oct 2020 
ACTG A5380 Protocol Version 1.0 
file. 
The main reason for this LOA is to extend the upper window for Step 2 entry to 270 days to 
allow for a more flexible timeline for sites and participants, given the ongoing COVID-19 
pandemic. 
The following are changes (noted in bold or strikethrough) to A5380, Version 1.0, 06/07/19, 
titled, “A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute 
Hepatitis C Virus Infection (PURGE-C).” These changes will be included in the next version of 
the A5380 protocol if it is amended at a future date. Changes that have already been made via 
LOA #3, dated 09/09/20, have been incorporated in the excerpted text shown below (and are no 
longer presented in bold or strikethrough).  
1.
A Protocol Signature Page (PSP) is appended for submission to the DAIDS Protocol
Registration System (DPRS) as part of the LOA registration packet.
2.
Section 4.3 (Step 2 Inclusion Criteria): The following revisions have been made:
4.3.3  Detectable HCV RNA from the confirmatory sample (see section 6.2.4) collected
within 112 270 days of Step 2 entry. 
4.3.5 The following laboratory values obtained within 112 270 days prior to Step 2 entry by 
any US laboratory that has a CLIA certification or its equivalent, or at any network-
approved non-US laboratory that operates in accordance with GCLP and participates 
in appropriate external quality assurance programs.  
•
INR <1.5
NOTE: INR ≥1.5 is acceptable in participants with known hemophilia or stable on
an anticoagulant regimen affecting INR at the discretion of the site PI.
•
Albumin ≥3.0 g/dL
NOTE: For INR and albumin values, values from the virologic failure/recurrence
results in Step 1 can be used and there is no need to draw additional samples.
•
For participants receiving RBV, hemoglobin ≥12 g/dL for male, ≥11 g/dL for
female.
3.
Section 6.2.1 (Screening Evaluations): The third paragraph has been revised to read:
For Step 1, screening evaluations to determine eligibility must be completed within 28 days
prior to entry unless otherwise specified. For Step 2, participants can enter Step 2 up to 112
270 days after the confirmatory HCV RNA sample date completed as part of Step 1.
4.
Section 6.2.4 (Event-Driven Evaluations): The second paragraph of the HCV Viral
Recurrence/Virologic Failure subsection has been revised to read:
HCV Viral Recurrence/Virologic Failure 
In Step 1, all cases of confirmed HCV recurrence/virologic failure occurring before or at 
the week 16/SVR12 visit will undergo evaluation for preliminary determination of 
suspected relapse versus re-infection (see Table 6.1-1, A5380 MOPS, and A5380 LPC. 
Viral recurrence is defined as confirmed HCV RNA value >LLOQ after achieving HCV 
RNA <LLOQ (TD or TND). Virologic failure is defined as failure to achieve HCV RNA 


Letter of Amendment #4 
          Page 3 of 4 
13 Oct 2020 
ACTG A5380 Protocol Version 1.0 
<LLOQ (TD or TND) and confirmed increase in HCV RNA >1 log10 from nadir. These 
participants will enter Step 2. This confirmatory sample should be collected within 112 
270 days prior to Step 2 entry. 


Letter of Amendment #4 
          Page 4 of 4 
13 Oct 2020 
ACTG A5380 Protocol Version 1.0 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute 
Hepatitis C Virus Infection (PURGE-C) 
SIGNATURE PAGE 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
Principal Investigator: _____________________________________________________ 
Print/Type 
Signed: _______________________________________________Date: _____________ 
Name/Title 


Letter of Amendment #3 
          Page 1 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
Letter of Amendment #3 for: 
A5380 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for 
Acute Hepatitis C Virus Infection (PURGE-C) 
A Multicenter Trial of Advancing Clinical Therapeutics Globally (ACTG) 
NIAID CRMS # 38553 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems , a DLH Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3000 
Fax: 301-628-3302 
LETTER OF AMENDMENT 
DATE: 
September 09, 2020 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5380 Protocol Team  
SUBJECT: 
Letter of Amendment #3 for Protocol A5380 
The following information affects the A5380 study and must be forwarded to each site’s 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) must be approved by the 
IRB/EC before implementation.  
The following information may also affect the Sample Informed Consent. The site IRB/EC 
is responsible for determining the process of informing participants of the contents of 
this LOA. 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit an 
LOA registration packet to the DAIDS Protocol Registration Office (PRO) at the 
Regulatory Support Center. Sites will receive a registration notification for the LOA once 
the DAIDS PRO verifies that all required LOA registration documents have been received 
and are complete. An LOA registration notification from the DAIDS PRO is not required 
prior to implementing the LOA. A copy of the LOA registration notification, along with 
this letter and any IRB/EC correspondence, should be retained in the site’s regulatory 


Letter of Amendment #3 
          Page 2 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
file. 
The main reason for this LOA is to provide guidance for the resumption of study visits, in follow-
up to the COVID-19-related Clarification Memo #2 (CM #2), dated 04/20/20, as US and non-US 
sites begin to open to research visits in the presence of the ongoing COVID-19 pandemic. A 
Study Monitoring Committee (SMC) review occurred on 08/17/20 for the first 10 enrolled 
participants who were enrolled prior to the temporary closure in March 2020 due to the COVID-
19 pandemic. The outcome of the SMC review was that the study may proceed as planned. 
However, enrollment into the study (i.e., Step 1 entry) will remain paused until approval of this 
LOA #3, dated 08/26/20.   
Follow-up for these 10 enrolled participants remains ongoing with modifications to allow for a 
mix of virtual and in-person visits. Registration for Step 2 for those already enrolled in Step 1 will 
resume upon approval of LOA #2, dated 08/14/20.   
This LOA is being implemented for the following reasons, per team decision, unless otherwise 
indicated: 
•
The contact information for the Clinical Trials Specialist (CTS) needed to be updated in the
roster, and the replacement of one of the statisticians. In response, the following section has
been updated: cover page, roster, and study management section.
•
Per DAIDS directive, changes made via CM #1, dated 10/15/19, and CM #2 (with additional
revisions to reflect the current situation with the COVID-19 pandemic) have been
incorporated and remain in bold/strikethrough. In response, the following sections have
been updated: 4.1.5, 4.1.7, 4.1.8b, 6.2.3, 6.2.4, 6.3, 6.3.8, 6.3.9, 6.3.10.
•
The upper window for Step 2 entry has been extended to 112 days from the confirmation
sample. In response, the following sections have been updated: 4.3 (4.3.3, 4.3.5), 6.2.1, and
6.2.4.
•
Remote consent for Step 1 and Step 2 is permitted, per local IRB guidance. In response, the
following sections have been updated: 6.2.1 and the Sample Informed Consent (SIC).
•
The upper window for the Step 1 week 16/SVR12 in-person follow-up visit will remain
extended when the study reopens to accrual, per the COVID-19-related CM #2, dated
04/20/20 (extended upper window = +42 days). This visit remains critical for the primary
outcome of the study; thus blood sample collection is required within the study window. In
response, the following section has been updated: 6.2.3.
•
For the Step 1 week 16/SVR12 visit, a virtual visit can be scheduled to conduct all other
evaluations with a brief in-person lab visit for blood sample collection. In response, the
following sections have been updated: 6.2.3, 6.3.21, and the SIC.
•
For the Step 2 SVR12 visit (R+20, R+24, or R+28), the virtual visit should also be paired
with a brief in-person lab visit for blood sample collection. In response, the following sections
have been updated: 6.2.3, 6.3.21, and the SIC.
•
In the event of possible HCV recurrence/virologic failure in Step 1, participants should return
to the site within 2 weeks for collection of the HCV recurrence/virologic failure evaluations.
All samples should be collected per Table 6.1-1 and stored at the site. In addition, due to
COVID-19, for this visit, Liver Function Tests (LFTs), HCV RNA, HCV genotype, and HCV
RAS testing, and should be drawn locally for immediate testing. In response, the following
sections have been updated: 6.2.4 and the SIC.
•
If at any point shipment of study samples is paused due to COVID-19, for the Step 1 week
16/SVR12 visit and for the Step 2 SVR12 visit, all samples should be drawn per protocol
Table 6.1-1 or Table 6.1-2, respectively, and stored at the site. In addition, due to COVID-
19, for this visit, an HCV RNA should also be drawn locally for immediate testing. In


Letter of Amendment #3 
          Page 3 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
response, the following section has been updated: 6.3.8. 
•
If hematology, chemistries, or LFTs are drawn within 7 days prior to entry (i.e., as a part of
standard of care), these labs do not need to be repeated at entry. In response, the following
section has been updated: 6.3.8.
•
Testing required for Step 2 entry can be done at the site lab or a local commercial lab. In
response, the following section has been updated: 6.3.8.
•
Substance use testing has been changed to optional since this is not a clinical test and does
not affect study integrity. Sites would be able to conduct the respective visit without
collecting urine, given potential logistical challenges sites may face amidst the COVID-19
pandemic. In response, the following sections have been updated: 6.3.8 and the SIC.
•
The methods for substance use urine testing was revised to reflect the use of either CLIA-
waived point of care assays or laboratory-based methods. In response, the following section
has been updated: 6.3.8.
•
HCV RAS testing could be done locally. In response, the following section has been
updated: 6.3.10.
•
Virtual visits can be utilized for all follow-up visits (i.e., non-SVR12 visits for Step 1 and Step
2), due to COVID-19 and the participant’s inability to come in for an in-person visit, or their
preference not to come to the site for this visit. In response, the following sections have
been updated: 6.3.21 and SIC.
•
For participants on ribavirin (RBV), virtual visits for Step 2 should also be paired with a brief
in-person lab visit for blood sample collection and for women, pregnancy testing. In
response, the following sections have been updated: 6.3.21 and the SIC.
•
Per recent template updates, a section on Information Collected at Screening has been
added. The following section has been updated: SIC.
•
Per ACTG requirements, a separate consent form has been added for storage of samples.
In response, the following section has been added: Appendix III.


Letter of Amendment #3 
          Page 4 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
TABLE OF CONTENTS 
1.
Protocol Signature Page ................................................................................................... 5 
2.
Protocol: Cover Page, Roster, and Study Management Section ...................................... 5 
3.
Section 4.1.5 (Step 1 Inclusion Criteria) ............................................................................ 6 
4.
Section 4.1.7 (Step 1 Inclusion Criteria) ............................................................................ 6 
5.
Section 4.1.8b (Step 1 Inclusion Criteria) .......................................................................... 6 
6.
Section 4.3 (Step 2 Inclusion Criteria) ............................................................................... 6 
7.
Section 6.2.1 (Screening Evaluations) .............................................................................. 7 
8.
Section 6.2.3 (Post-Entry Evaluations) ............................................................................. 7 
9.
Section 6.2.4 (Event-Driven Evaluations) ......................................................................... 9 
10.
Section 6.3 (Instructions for Evaluations) .......................................................................... 9 
11.
Section 6.3.8 (Laboratory Evaluations) ........................................................................... 10 
12.
Section 6.3.9 (Immunologic Studies) .............................................................................. 11 
13.
Section 6.3.10 (Virologic Studies) ................................................................................... 11 
14.
Section 6.3.21 (Virtual Visits during the COVID-19 Pandemic) ....................................... 12 
15.
Appendix I: Step 1 SAMPLE INFORMED CONSENT, PART 1 SUMMARY ................... 13 
16.
APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, “WHAT DO I HAVE TO DO IF I
AM IN STEP 1 OF THIS STUDY?” ................................................................................. 13 
17.
APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, Appendix I Table 1: Part 1
Study Schedule ............................................................................................................... 13 
18.
APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, Description of Part 1 Study
Visits ................................................................................................................................ 14 
19.
APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, Description of Part 1 Study
Evaluations ...................................................................................................................... 15 
20.
APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, “CAN I CHOOSE THE TYPES
OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE USED FOR?” .......... 15 
21.
APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT, “WHAT DO I HAVE TO DO IF
I AM IN STEP 2 OF THIS STUDY?” ............................................................................... 17 
22.
APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT, Description of Part 2 Study
Visits ................................................................................................................................ 17 
23.
APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT, Description of Part 2 Study
Evaluations ...................................................................................................................... 17 
24.
APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT, “CAN I CHOOSE THE TYPES
OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE USED FOR?” .......... 18 
25.
APPENDIX III: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES ................... 19 


Letter of Amendment #3 
          Page 5 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
The following are changes (noted in bold or strikethrough) to A5380, Version 1.0, 06/07/19, 
titled "A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute 
Hepatitis C Virus Infection (PURGE-C).” These changes will be included in the next version of 
the A5380 protocol if it is amended at a future date. Changes that have already been made via 
Letter of Amendment #1, dated 12/18/19, have been incorporated in the excerpted text shown 
below (and are no longer presented in bold or strikethrough). Note: LOA#2, dated 08/14/20, did 
not have any specific protocol changes, and only provided Step 2 registration guidance. 
1.
Protocol Signature Page
A Protocol Signature Page (PSP) is appended for submission to the DAIDS Protocol
Registration System (DPRS) as part of the LOA registration packet.
2.
Protocol: Cover Page, Roster, and Study Management Section
The last name and email address of the Clinical Trials Specialist has been changed within
the following areas of the protocol: cover page, roster, and study management section,
along with a change in the ACTG’s Network Coordinating Center’s parent company name;
and Vincent Vu has been removed from the roster, and Trinh Umbleja added to the roster.
•
Clinical Trials Specialist
Chanelle Houston Wimbish, BS
ACTG Network Coordinating Center
Social & Scientific Systems, a DLH Company
8757 Georgia Avenue, 12th Floor
Silver Spring, MD  20910-3714
Phone: 301-628-3367
E-mail: chouston@s-3.com chanelle.wimbish@dlhcorp.com
•
Statisticians
Vincent Vu, MPH
ACTG Statistical & Data Analysis Center
Harvard School of Public Health
FXB Building, Room 608
Boston, MA 02115
Phone: 617-432-1352
Email: vvu@sdac.harvard.edu
Triin Umbleja, MSc
ACTG Statistical & Data Analysis Center
Harvard School of Public Health
651 Huntington Avenue
FXB Building, Room 512A
Boston, MA 02115
Phone: 617-432-0118
Email: tumbleja@sdac.harvard.edu


Letter of Amendment #3 
          Page 6 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
3.
Section 4.1.5 (Step 1 Inclusion Criteria)
The laboratory requirements have been revised to read:
HCV genotype obtained within 24 weeks prior to entry by any US laboratory that has a
Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or at any
network-approved non-US laboratory that is Virology Quality Assurance (VQA) certified.
operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in
appropriate external quality assurance programs.
4.
Section 4.1.7 (Step 1 Inclusion Criteria)
The laboratory requirements have been revised to read:
For HIV-1 co-infected participants on ART, screening HIV-1 RNA must be <50 copies/mL or
<LLOQ of local assay if LLOQ is >50 copies/mL obtained within 28 days prior to study
entry as measured by any US laboratory that has a CLIA certification or its equivalent, or at
any network-approved non-US laboratory that is VQA certified. operates in accordance
with GCLP and participates in appropriate external quality assurance programs.
5.
Section 4.1.8b (Step 1 Inclusion Criteria)
The laboratory requirements have been revised to read:
For HIV-1 co-infected participants, HIV-1 ART should meet one of the following criteria:
a) ART untreated due to (1) lack of indication per provider (CD4+ T-cell count ≥500
cells/mm3) or (2) decision by provider and participant to defer ART during the G/P dosing
period (4 weeks).
OR 
b) On a stable, protocol-defined compatible ART regimen (per sections 2.2 [Rationale for
Inclusion of Concomitant ART Regimens] and 5.4.1) for >2 weeks prior to starting G/P
with a CD4+ T-cell count >100 cells/mm3 obtained within 180 days prior to the screening
visit. Laboratory testing can be done by at any US laboratory that has a CLIA
certification or its equivalent, or at any network-approved non-US laboratory that is
Immunology Quality Assessment (IQA) certified. operates in accordance with GCLP
and participates in appropriate external quality assurance programs.
6.
Section 4.3 (Step 2 Inclusion Criteria)
The following revisions have been made:
4.3.3  Detectable HCV RNA from the confirmatory sample (see section 6.2.4) collected
within 56 112 days of Step 2 entry. 
4.3.5 The following laboratory values obtained within 56 112 days prior to Step 2 entry by 
any US laboratory that has a CLIA certification or its equivalent, or at any network-
approved non-US laboratory that operates in accordance with GCLP and participates 
in appropriate external quality assurance programs.  


Letter of Amendment #3 
          Page 7 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
•
INR <1.5
NOTE: INR ≥1.5 is acceptable in participants with known hemophilia or stable on
an anticoagulant regimen affecting INR at the discretion of the site PI.
•
Albumin ≥3.0 g/dL
NOTE: For INR and albumin values, values from the virologic failure/recurrence
results in Step 1 can be used and there is no need to draw additional samples.
•
For participants receiving RBV, hemoglobin ≥12 g/dL for male, ≥11 g/dL for
female.
7.
Section 6.2.1 (Screening Evaluations)
This section has been revised to read:
Remote consent for Step 1 entry and Step 2 registration is permitted, according to
IRB-approved site guidelines.
Screening evaluations must occur prior to the participant starting any study medications,
treatments, or interventions.
For Step 1, screening evaluations to determine eligibility must be completed within 28 days
prior to entry unless otherwise specified. For Step 2, participants can enter Step 2 up to 56
112 days after the confirmatory HCV RNA sample date completed as part of Step 1.
In addition to data being collected on participants who enroll into the study, demographic,
clinical, and laboratory data on screening failures will be captured in a Screening Failure
Results form and entered into the ACTG database.
8.
Section 6.2.3 (Post-Entry Evaluations)
This section has been revised to read:
All post-entry evaluations occur in reference to the start of study therapy.
All Step 1 study visits for the 10 participants enrolled on or before March 18, 2020 can
occur remotely (via telephone), except for the Step 1 week 16/SVR12 visit, which must
remain an in-person visit, if this visit can be conducted safely. For this visit, there is
potential for a hybrid visit in which a virtual visit can be scheduled to conduct all
other evaluations with a brief in-person lab visit for blood sample collection.
For the Step 2 SVR12 visit (R+20, R+24, or R+28), which must remain an in-person
visit, if this visit can be conducted safely. For this visit, there is potential for a hybrid
visit in which a virtual visit can be scheduled to conduct all other evaluations with a
brief in-person lab visit for blood sample collection, and conduct pregnancy testing if
the participant is a woman of child-bearing potential and is taking RBV.
The safety of participants and study staff must be taken into account when
scheduling this visits and any remote contact prior to this in-person visits, with the
consideration of delaying visits if needed. If there is a need to limit in-person
interactions at the site, the in-person component can be restricted to the blood draw,
and the remaining visit evaluations can be completed via telephone.


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ACTG A5380 Protocol Version 1.0 
If the blood draw at this visit is limited, then prioritize sample use as follows: 
•
Local testing for safety
•
HCV RNA
•
HIV-1 RNA
•
CD4+ (for participants living with HIV-1 infection)
•
Storage
Until further notice, store samples for central testing (e.g., HCV RNA and HIV-1 RNA) 
in accordance with the guidance distributed by the ACTG Lab Center on 03/17/2020. 
The team will provide further guidance on these samples as needed. 
On-Treatment Evaluations  
Study visits must be scheduled on the weeks indicated in Tables 6.1-1 and 6.1-2, within the 
visit windows described below, as appropriate for the visit.  
NOTE: Step 2 entry may be deferred until further notice. 
Step 1 (remote, via telephone, permitted):  
•
Weeks 1 and 2 have a window of ±3 days.
•
Week 4 has a window of -7 days and +14 days.
Step 2 (deferred until further notice): 
•
Week R+2 has a window of ±3 days.
•
Weeks R+4, R+8, R+12, and R+16 have a window of -7 days and +14 days.
Treatment Completion Evaluations  
Clinical assessment and laboratory evaluation, as outlined in section 6.1, will be performed 
at treatment completion (Step 1: week 4, Step 2: week R+8, R+12, or R+16).  
NOTE: Step 2 entry may be deferred until further notice. 
Post-Treatment Evaluations  
Following treatment completion, participants will undergo evaluations as outlined in Tables 
6.1-1 and 6.1-2, within the study windows, as indicated below.  
NOTE: Step 2 entry may be deferred until further notice. 
After the last dose of study drugs, the post-treatment study visits have the following 
windows:  
Step 1 (remote [via telephone] permitted, EXCEPT week 16): 
•
Study weeks 8 and 12, and 16: -5 days and +21 days
•
Study week 16: -5 days and +42 days
•
Study week 28: -7 days and +28 days
NOTE: In the midst of the COVID-19 pandemic, for study week 28, all evaluations 
should may be conducted remotely, and the week 28 specimen can be collected at a 
future date, prior to study closure, up until 36 weeks post treatment completion, as 


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ACTG A5380 Protocol Version 1.0 
long as the week 16/SVR12 visit was conducted in person. Participants should only 
have the week 28 visit in person if the week 16/SVR12 visit and sample were missed. 
If a participant has successfully attended the week 16/SVR12 visit and the blood 
sample has been collected, then that participant does not need to have an in-person 
visit at week 28. 
Step 2 (deferred until further notice): 
•
Study week R+20, R+24, or R+28 (12 weeks after re-treatment completion for those not
receiving RBV depends on Step 2 treatment duration): -5 days and +28 days
•
Study week R+32, R+36, or R+40 completion (for those receiving RBV): -14 days and +
28 days
9.
Section 6.2.4 (Event-Driven Evaluations)
•
The following revisions have been made to HCV Viral Recurrence/Virologic Failure
subsection to include a newly added first paragraph and revisions to the second
paragraph:
HCV Viral Recurrence/Virologic Failure
In the event of possible HCV recurrence/virologic failure, participants should
return to the site within 2 weeks for collection of the HCV recurrence/virologic
failure evaluations (per Table 6.1-1, A5380 MOPS, and A5380 Laboratory
Processing Chart [LPC]), and stored at the site. In addition, due to COVID-19, for
this visit, Liver Function Tests (LFTs), HCV RNA, HCV genotype, and HCV RAS
testing should be drawn for immediate local testing (i.e., at the local site lab or a
commercial lab).
In Step 1, all cases of confirmed HCV recurrence/virologic failure occurring before or at
the week 16/SVR12 visit will undergo evaluation for preliminary determination of
suspected relapse versus re-infection (see Table 6.1-1, A5380 MOPS, and A5380
Laboratory Processing Chart [LPC]). Viral recurrence is defined as confirmed HCV RNA
value >LLOQ after achieving HCV RNA <LLOQ (TD or TND). Virologic failure is defined
as failure to achieve HCV RNA <LLOQ (TD or TND) and confirmed increase in HCV
RNA >1 log10 from nadir. These participants will enter Step 2. This confirmatory sample
should be collected within 56 112 days of prior to Step 2 entry.
•
The third paragraph in the HIV-1 Virologic Breakthrough subsection has been revised to
read:
The increase in plasma HIV-1 RNA should be confirmed with repeat central or local
testing as soon as possible (not to exceed 4 weeks); see HIV-1 Virologic Breakthrough
Confirmation in Tables 6.1-1 and 6.1-2. For participants with confirmed HIV-1 viral
breakthrough (≥200 copies/mL), a plasma specimen should be sent for HIV genotyping
and sent to the designated A5380 VSL for evidence of HIV-1 drug resistance. Results
will be reported back to sites in real-time from the designated A5380 VSL. See section
6.3.10, Stored Serum and Plasma for HIV-1/HCV Studies.
10. Section 6.3 (Instructions for Evaluations)


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ACTG A5380 Protocol Version 1.0 
The following paragraph has been added as the first paragraph of this section.  
Each study site and laboratory involved in this study will comply with the DAIDS 
policy on Requirements for Laboratories Performing Testing for DAIDS-Supported 
and/or Sponsored Clinical Trials, which is available at:  
https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
11. Section 6.3.8 (Laboratory Evaluations)
The following notes have been added after the first paragraph (before the hematology
subsection):
NOTE A: 
If the following labs are drawn within 7 days prior to Step 1 entry 
(i.e., as a part of standard of care), these labs do not need to be 
repeated at entry: hematology, chemistries, and liver function tests. 
NOTE B: 
Testing for Step 2 entry can be done at the site lab or a local 
commercial lab, and not sent to the central testing lab. 
NOTE C: 
If at any point shipment of study samples is paused due to COVID-
19, for the Step 1 week 16/SVR12 visit, or the Step 2 SVR12 visit, all 
samples should be drawn per protocol Table 6.1-1 and 6.1-2, 
respectively, and stored at the site. In addition, due to COVID-19, for 
these visits, an HCV RNA should also be drawn locally for 
immediate testing. 
The following changes have been made to Urine Sample for Substance Use Screen 
subsection: 
Urine Sample for Substance Use Screen  
Urine substance use screening to be performed for must be done using a CLIA-waived 
urine drug use screening tool with these common drugs of abuse: amphetamines, 
buprenorphine, benzodiazepines, cocaine, ecstasy, methadone, methamphetamine, 
barbiturates, marijuana, opiates, oxycodone, and phencyclidine. The screening will be 
assessed by urine test and must include the following ancillary testing, pH and creatinine 
to help in confirmation of sample against adulterants. The methods used may be either 
CLIA-waived point of care assays or laboratory-based methods. The following 
results would be used as confirmation of an unadulterated human urine sample; pH of 
4.5 – 8.0 and urine creatinine ≥20 mg/dL. Urine fentanyl testing will be done using a test 
which that is not currently FDA approved or CLIA-waived.  
Testing will be done per Table 6.1-1 on each scheduled study visit, and participants with 
positive screens will be counseled before and/or at the next scheduled visit with regard 
to potential impact on medication adherence, health-related risks, as well as in 
accordance with prevailing local laws. 
NOTE: Collection of urine for substance use testing is optional given the potential 
logistical challenges sites may face amidst the COVID-19 pandemic. Sites may 
proceed with all other evaluations for the respective study visit, per Table 6.1-1, 
except for collection of urine for substance use testing.  


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ACTG A5380 Protocol Version 1.0 
The HCV Ab subsection has been revised to read: 
HCV Ab must be obtained by any FDA-approved test at any local laboratory that has a 
CLIA certification or its equivalent (US sites) or VQA certification (non-US sites). HCV 
Ab is only to be sent at screening and at a subsequent visit if the result is negative on 
the preceding visit. Once a single positive Ab is recorded, no further HCV antibody 
testing is required. 
12. Section 6.3.9 (Immunologic Studies)
The CD4+/CD8+ requirement at screening has been revised to read:
CD4+/CD8+ (For participants with HIV-1 infection only)
Screening Obtain absolute CD4+/CD8+ count and percentages must be performed within
28 days prior to study entry from at a laboratory that possesses a CLIA certification or
equivalent (US sites) or IQA certification (non-US sites).
13. Section 6.3.10 (Virologic Studies)
The first subsection has been revised to read:
Plasma HCV RNA (screening)  
The screening HCV RNA result must be obtained by any FDA-approved test for 
quantifying HCV RNA at any local laboratory that has a CLIA certification or its 
equivalent (US sites) or VQA certification (non-US sites). Screening HCV RNA must 
be obtained within 28 days prior to study entry. 
The second subsection has been revised to read: 
Plasma HCV RNA (real-time, on-study evaluations) 
At the entry and post-entry visits, HCV RNA quantification will be performed as follows: 
Plasma HCV RNA real-time testing will be collected, processed, and shipped to the 
designated testing laboratory (see A5380 LPC for directions). These results will be 
reported within 2 weeks after specimen receipt for both Steps 1 and 2. 
NOTE A: For Step 1, HCV RNA should only be done at the week 16/SVR12 visit for 
the 10 participants enrolled on or before 03/18/20. 
NOTE B For Step 2, an increase in plasma HCV RNA at any time point meeting HCV 
virologic response-based treatment stopping criteria must be confirmed with 
repeat testing within 2 weeks of receipt of results. For more information please 
see section 6.2.4. 
The third subsection has been revised to read: 
Plasma HCV RNA (real-time)  
After the treatment is completed in Step 1, for participants entering Step 2 (Viral 
Recurrence [Reinfection/Suspected Relapse/Undefined Post-Treatment Viremia] or 


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09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
virologic failure): a detectable HCV RNA after the end of treatment after achieving HCV 
RNA <LLOQ is virologic evidence of recurrence which will require confirmation and 
should be performed in real-time at the designated testing lab as soon as possible but 
no later than 2 weeks. 
The first paragraph of the fourth subsection has been revised to read: 
Plasma HCV Genotype 
At Step 1 screening, the HCV genotype result will be obtained locally (real-time) from 
any laboratory that has a CLIA certification or its equivalent (US sites) or VQA 
certification (non-US sites). ONLY IF IT IS NOT AVAILABLE LOCALLY should it be 
done (real-time) at the designated testing laboratory (see A5380 LPC). 
The first paragraph in the fifth subsection has been revised to read: 
Plasma HIV-1 RNA 
For participants with documented HIV-1 infection, a documented plasma HIV-1 RNA 
level must be noted within 28 days prior to Step 1 study entry from any laboratory that 
has a CLIA certification or its equivalent (US sites) or VQA certification (non-US 
sites). On-study HIV-1 RNA is only required for HIV-1-infected participants and should 
be performed at the ACTG central laboratory. See the A5380 LPC for processing, 
shipping, and storage information. 
The eighth subsection has been revised to read: 
HCV RAS testing  
Using stored samples for HIV-1/HCV studies above, resistance genotype near-time 
sequencing will be carried out for NS3 and NS5A genes on participants experiencing 
confirmed virologic failure or recurrence. Sequencing will be performed on baseline and 
post-treatment recurrence samples with HCV RNA >1,000 IU/mL. RAS testing related 
to the virologic failure visit described in section 6.2.4 can be done locally.  
14. Section 6.3.21 (Virtual Visits during the COVID-19 Pandemic)
The following section has been added to allow for virtual visits in the scope of COVID-19:
6.3.21 Virtual Visits during the COVID-19 Pandemic
Virtual visits by telephone or video conference will be permitted for Step 1 and 
Step 2, in the scope of COVID-19, if the participant is unable/prefers not to 
come to the site for an in-person visit due to COVID-19. In this instance, it is 
permitted that safety labs can be completed at a local commercial lab. The 
other non-safety/research labs will be completed when the participant is able 
to come back to the site for an in-person visit. See section 6.3.8. 
NOTE A: For participants on RBV, virtual visits for Step 2 should also be 
paired with a brief in-person lab visit for blood sample collection and 
for women of child bearing potential, pregnancy testing. 
NOTE B:  For the Step 2 SVR12 visit (R+20, R+24, or R+28), the virtual visit 


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          Page 13 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
should also be paired with a brief in-person lab visit for blood sample 
collection.  
These visits should be recorded as “virtual visit due to COVID-19.” 
15. Appendix I: Step 1 SAMPLE INFORMED CONSENT, PART 1 SUMMARY
The first bullet under the Blood and urine collections subsection of Required Activities has
been revised as follows:
At most visits, some blood will be collected from a vein in your arm. At a few visits, you 
will be asked to provide a urine sample. some of your urine will be collected, if you 
choose. 
16. APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, “WHAT DO I HAVE TO DO IF I AM
IN STEP 1 OF THIS STUDY?”
The following have been added as the 1st and 2nd paragraphs:
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an 
ACTG study. As part of your screening visit, some demographic (for example, age, 
gender, race), clinical (for example, disease condition, diagnosis), and laboratory 
(for example, CD4 cell count, viral load) information will be collected from you. We 
also collect information on whether you use (or have used) IV drugs. 
We will collect this information even if you do not enroll in this study. This 
information is collected so that ACTG researchers may determine whether there 
are patterns and/or common reasons why people do not join a study. 
The following has been added as the 8th paragraph: 
If the COVID-19 pandemic is still going on when you enroll into Part 1 of this 
study, you will be allowed to have some virtual visits (by telephone or video call), 
if you are unable to come to the site, or if you prefer not to come to the site for an 
in-person visit due to COVID-19. In this instance, you will be allowed to get your 
blood drawn for the safety evaluations at a lab outside of the site. The other non-
safety/research labs will be completed when you are able to come back to the site 
for an in-person visit. Site staff will discuss the details of this option with you.  
17. APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, Appendix I Table 1: Part 1 Study
Schedule
The following revisions have been made to the Blood Collection & Laboratory Testing row at
Entry, and the Urine Sample for Substance/Drug Use Test row:


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09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
Evaluation or 
Test 
Screening 
Entry 
Post-Entry Visits 
Unplanned 
Visits 
HCV 
Virologic 
Failure 
Confirmation 
HIV Virologic 
Failure 
(Breakthrough) 
Confirmation 
Early 
Discontinuation 
Weeks 
1 and 
2 
Week 
4 
Weeks 
8, 12, 
14, 16, 
28 
Blood Collection 
& Laboratory 
Testing 
 
 (see 
note in 4th 
bullet of 
Part 1 Entry 
subsection) 
 
 
 
 
 
 
 
Optional Urine 
Sample for 
Substance/Drug 
Use Test 
 
 
 
 
 
 
 
18. APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, Description of Part 1 Study Visits
The 3rd and 4th bullets in the Part 1 Entry subsection of APPENDIX I: STEP 1 SAMPLE
INFORMED CONSENT, Description of Part 1 Study Visits, has been revised to read:
•
You will may provide a urine sample to look for the use of drugs.
•
You will have blood drawn for routine lab tests for safety, virologic, immunologic (to
test how your body fights infection), and pharmacokinetic studies (to look at your
body’s response to the study medication). If you are living with HIV, blood will be
drawn to measure the amount of HIV in your blood, and to measure your CD4+ and
CD8+ cell counts. Some of the blood you provide will be stored for future protocol-
required testing. There are some safety blood tests that will not need to be done
again at entry if they were done within the last 7 days (as part of a recent
doctor’s visit).
The 5th bullet in the During Most Study Visits for Part 1 subsection of APPENDIX I: STEP 1 
SAMPLE INFORMED CONSENT, Description of Part 1 Study Visits, has been revised to 
read: 
You will may provide a urine sample to look for the use of drugs. 
The beginning of the HCV Virologic Failure Confirmation subsection of APPENDIX I: STEP 
1 SAMPLE INFORMED CONSENT, Description of Part 1 Study Visits, has been revised to 
read: 
HCV Virologic Failure Confirmation  
If laboratory tests show there is evidence of virologic failure (the amount of HCV in your 
blood is still detectable when tested), you will be asked to return to the clinic within 2 
weeks to confirm your lab results.  
The third bullet of the HCV Virologic Failure Confirmation subsection of APPENDIX I: STEP 
1 SAMPLE INFORMED CONSENT, Description of Part 1 Study Visits, has been revised to 
read: 


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09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
A urine sample will may be taken for the substance use screen. 
19. APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, Description of Part 1 Study
Evaluations
The following has been added to the Consent subsection of APPENDIX I: STEP 1 SAMPLE
INFORMED CONSENT, Description of Part 1 Study Evaluations:
Consent 
Remote consent (via email/video call) will be allowed if you are unable to come to 
the site due to the COVID-19 pandemic [Note to sites- if allowed by IRB.]. After you 
read this consent form and have had a chance to ask questions about the study, you will 
sign this consent form if you want to continue to be tested to see if you qualify for the 
study. 
The following has been added to the Sample collections and laboratory testing subsection of 
APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, Description of Part 1 Study 
Evaluations, under Urine Sample for Substance/Drug Use: 
Urine Sample for Substance/Drug Use 
Urine sample for substance use screening will may be done at study entry, and at every 
Part 1 study visit, HCV virologic failure confirmation, and early discontinuation visits. 
20. APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT, “CAN I CHOOSE THE TYPES OF
RESEARCH THAT MY SAMPLES AND INFORMATION ARE USED FOR?”
The following revisions have been made to this whole section:
Some of your blood will be stored and used for study-required pharmacologic, immunologic,
and virologic testing.
Identifiers will be removed from your samples and from any private information that
has been collected about you. This means that no one looking at the labels or at other
information will be able to know that the samples or information came from you.
The tests described above are required by this study. If you do not agree to the
storage or testing that has been described above, you should not join this study.
Please refer to APPENDIX III to consent for use of your samples in other studies.
For non-US locations, biological specimens will be shipped and/or stored outside of the
country from which they are collected.
Identifiers will be removed from your samples and from any private information that has
been collected about you. This means that no one looking at the labels or at other
information will be able to know that the samples or information came from you.
The tests described above are required by this study. If you do not agree to the storage or
testing that has been described above, you should not join this study.


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          Page 16 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
Some blood that is collected from you during the study may be left over after all required 
study testing is done. This blood will be stored and, if you give your consent below, may be 
used for ACTG-approved research. This means that researchers who are not part of the 
protocol team may use your samples without asking you again for your consent. As noted 
above, none of your samples will have any private information about you on their labels.  
You may decide whether this “extra” blood may be stored and, if so, whether additional 
testing may be performed on it. None of this testing will be used for commercial profit.  
At this time, we do not know whether any of the research will include testing of your genes 
or your DNA (your own genetic information). We do not know whether a type of testing 
called whole genome sequencing, or WGS, might be done. In WGS, researchers look at all 
of your genes and at almost all of your DNA. In “standard” genetic testing, researchers look 
at specific genes or subsets of genes, but not at all genes. Some possible genetic testing is 
described below. 
For each of the questions below, choose the response that matches what you want by 
putting your initials in the space provided. Please ask the staff any questions that you have 
before you indicate your selections. 
Research Without Human Genetic Testing – OPTIONAL (Research on leftover blood; no 
human genetic testing) 
If you agree, some of your blood that is left over after all required study testing is done may 
be stored (with usual protection of your identity) and used for ACTG-approved HIV-related 
research that does not include human genetic testing. 
____ (initials) I understand and I agree to this storage and possible use of my blood. 
OR 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 
Research With Human Genetic Testing – OPTIONAL (Human genetic research on leftover 
blood) 
If you agree, some of your blood that is left over after all required study testing is done may 
be stored (with usual protection of your identity) and used for ACTG-approved HIV-related 
research that includes human genetic testing, and may include whole genome sequencing 
(WGS).  
____ (initials) I understand and I agree to this storage and possible use of my blood. 
OR 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 


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          Page 17 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
Sharing Genetic Data - OPTIONAL  
Genetic Research Databases: If you agreed to possible genetic testing of your blood above, 
researchers may want to share genetic information (with protection of your identity) with 
other researchers around the world, so that they can learn more about the causes and 
treatment of diseases. They may store this information in dbGaP, a genetic database 
maintained by the National Institutes of Health, as well as in other protected databases. 
____ (initials) I understand and I agree to this possible sharing of my genetic data.  
OR 
____ (initials) I understand but I do not agree to this possible sharing of my genetic data. 
21. APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT, “WHAT DO I HAVE TO DO IF I
AM IN STEP 2 OF THIS STUDY?”
The following has been added as the 7th paragraph:
If the COVID-19 pandemic is still going on when you enter into Part 2 of this study,
you will be allowed to have some virtual visits (by telephone or video call), if you are
unable to come to the site, or if you prefer to not to come to the site for an in-person
visit due to COVID-19. In this instance, you will be allowed to get your blood drawn for
the safety evaluations at a lab outside of the site. The other non-safety/research labs
will be completed when you are able to come back to the site for an in-person visit.
Site staff will discuss the details of this option with you.
22. APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT, Description of Part 2 Study Visits
The following has been added as the last bullet in the During Most Study Visits for Part 2
subsection of APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT, Description of Part 2
Study Visits has been revised to read:
If you are also taking RBV as a part of your retreatment for HCV, virtual visits for 
Step 2 will be paired with a short in-person visit to have a blood sample collected 
for safety tests. If you are a woman and able to get pregnant, some of your blood 
or urine will be tested for pregnancy. 
The HCV Virologic Failure Confirmation subsection of APPENDIX I, SAMPLE INFORMED 
CONSENT, Description of Part 2 Study Visits, has been revised to read: 
HCV Virologic Failure Confirmation  
If laboratory tests show there is evidence of virologic failure (the amount of HCV in your 
blood is still detectable when tested), you will be asked to return to the clinic within 2 
weeks to confirm your lab results.  
23. APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT, Description of Part 2 Study
Evaluations
The following new subsection has been added as the first subsection to APPENDIX II,
SAMPLE INFORMED CONSENT, Description of Part 2 Study Evaluations:


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          Page 18 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
Consent 
Remote consent (via email/video call) will be allowed if you are unable to come to the 
site due to the COVID-19 pandemic [Note to sites- if allowed by IRB.]. After you read 
this consent form and have had a chance to ask questions about the study, you will 
sign this consent form if you want to continue to be tested to see if you qualify for 
Step 2 of the study. 
24. APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT, “CAN I CHOOSE THE TYPES OF
RESEARCH THAT MY SAMPLES AND INFORMATION ARE USED FOR?”
The following revisions have been made to this whole section:
Some of your blood will be stored and used for study-required pharmacologic, immunologic,
and virologic testing.
For non-US locations, biological specimens will be shipped and/or stored outside of the
country from which they are collected.
Identifiers will be removed from your samples and from any private information that has
been collected about you. This means that no one looking at the labels or at other
information will be able to know that the samples or information came from you.
The tests described above are required by this study. If you do not agree to the storage or
testing that has been described above, you should not join this study.
Please refer to APPENDIX III to consent for use of your samples in other studies.
Some blood that is collected from you during the study may be left over after all required
study testing is done. This blood will be stored and, if you give your consent below, may be
used for ACTG-approved research. This means that researchers who are not part of the
protocol team may use your samples without asking you again for your consent. As noted
above, none of your samples will have any private information about you on their labels.
You may decide whether this “extra” blood may be stored and, if so, whether additional
testing may be performed on it. None of this testing will be used for commercial profit.
At this time, we do not know whether any of the research will include testing of your genes
or your DNA (your own genetic information). We do not know whether a type of testing
called whole genome sequencing, or WGS, might be done. In WGS, researchers look at all
of your genes and at almost all of your DNA. In “standard” genetic testing, researchers look
at specific genes or subsets of genes, but not at all genes. Some possible genetic testing is
described below.
For each of the questions below, choose the response that matches what you want by
putting your initials in the space provided. Please ask the staff any questions that you have
before you indicate your selections.
Research Without Human Genetic Testing – OPTIONAL (Research on leftover blood; no
human genetic testing)
If you agree, some of your blood that is left over after all required study testing is done may


Letter of Amendment #3 
          Page 19 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
be stored (with usual protection of your identity) and used for ACTG-approved HIV-related 
research that does not include human genetic testing. 
____ (initials) I understand and I agree to this storage and possible use of my blood. 
OR 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 
Research With Human Genetic Testing – OPTIONAL (Human genetic research on leftover 
blood) 
If you agree, some of your blood that is left over after all required study testing is done may 
be stored (with usual protection of your identity) and used for ACTG-approved HIV-related 
research that includes human genetic testing, and may include whole genome sequencing 
(WGS).  
____ (initials) I understand and I agree to this storage and possible use of my blood. 
OR 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 
Sharing Genetic Data - OPTIONAL  
Genetic Research Databases: If you agreed to possible genetic testing of your blood above, 
researchers may want to share genetic information (with protection of your identity) with 
other researchers around the world, so that they can learn more about the causes and 
treatment of diseases. They may store this information in dbGaP, a genetic database 
maintained by the National Institutes of Health, as well as in other protected databases. 
____ (initials) I understand and I agree to this possible sharing of my genetic data. 
OR 
____ (initials) I understand but I do not agree to this possible sharing of my genetic data. 
25. APPENDIX III: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES
A new appendix has been added for the consent to use samples in other ACTG studies.


Letter of Amendment #3 
          Page 20 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
APPENDIX III: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES 
When samples are no longer needed for this study, the ACTG may want to use 
them in other studies and share them with other researchers. These samples are 
called “extra samples.” The ACTG will only allow your extra samples to be used in 
other studies if you agree to this. If you have any questions, please ask. 
Identifiers will be removed from your samples and from any private information that 
has been collected about you. This means that no one looking at the labels or at other 
information will know that the samples or information came from you.  
Extra samples are stored in a secure central place called a repository. Your samples 
will be stored in the ACTG repository located in the United States. 
There is no limit on how long your extra samples will be stored. [Site: Revise the 
previous sentence to insert limits if your regulatory authority imposes them.] 
When a researcher wants to use your samples and information, their research plan 
must be approved by the ACTG. Also, the researcher’s institutional review board 
(IRB) or ethics committee (EC) will review their plan. [Site: If review by your 
institution’s IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs 
protect the rights and well-being of people in research. If the research plan is 
approved, the ACTG will send your samples to the researcher’s location. This means 
that researchers who are not part of the protocol team may use your samples without 
asking you again for your consent.  
You will not be paid for your samples. Also, a researcher may make a new scientific 
discovery or product based on the use of your samples. If this happens, there is no 
plan to share any money with you.  
You may withdraw your consent for research on your extra samples at any time, and 
the specimens will be discarded. 
Please choose the response that matches what you want by putting your initials in 
the space provided. Please ask the staff any questions that you have before you 
indicate your selection. 
Research without Human Genetic Testing  
If you agree, your extra samples may be stored (with usual protection of your identity) 
and used for ACTG-approved HIV-related research that does not include human 
genetic testing. 
Step 1: 
____ (initials) I understand and I agree to this storage and possible use of my 
samples  
OR 


Letter of Amendment #3 
          Page 21 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
____ (initials) I understand but I do not agree to this storage and possible use of my 
samples 
Step 2, if applicable: 
____ (initials) I understand and I agree to this storage and possible use of my 
samples  
OR 
____ (initials) I understand but I do not agree to this storage and possible use of my 
samples 
Research with Human Genetic Testing  
Your extra samples will not be used for human genetic testing unless you sign a 
consent form for A5128 or A5243.  
The ACTG has two different studies that collect samples for genetic testing. 
If you live in the US, this study is called ACTG A5128, Plan for Obtaining Informed 
Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified 
Analyses. 
If you live outside of the US, this study is called ACTG A5243, Plan for Obtaining 
Human Biological Samples at Non-US Clinical Research Sites for Currently 
Unspecified Genetic Analyses. 
Your site might ask you if you would like to participate in one of these studies if it is 
being done where you live. If you would like to participate, you will sign a separate 
consent form. 


Letter of Amendment #3 
          Page 22 of 22 
09 Sep 2020 
ACTG A5380 Protocol Version 1.0 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute 
Hepatitis C Virus Infection (PURGE-C) 
SIGNATURE PAGE 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
Principal Investigator: _____________________________________________________ 
Print/Type 
Signed: _______________________________________________Date: _____________ 
Name/Title 


Letter of Amendment #2 
          Page 1 of 3 
14 Aug 2020 
ACTG A5380 Protocol Version 1.0 
Letter of Amendment #2 for: 
A5380 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for 
Acute Hepatitis C Virus Infection (PURGE-C) 
A Multicenter Trial of Advancing Clinical Therapeutics Globally (ACTG) 
NIAID CRMS # 38553 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems , a DLH Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3000 
Fax: 301-628-3302 
LETTER OF AMENDMENT 
DATE: 
August 14, 2020 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5380 Protocol Team  
SUBJECT: 
Letter of Amendment #2 for Protocol A5380 
The following information affects the A5380 study and must be forwarded to each site’s 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) must be approved by the 
IRB/EC before implementation.  
The following information may also affect the Sample Informed Consent. The site IRB/EC 
is responsible for determining the process of informing participants of the contents of 
this LOA. 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit an 
LOA registration packet to the DAIDS Protocol Registration Office (PRO) at the 
Regulatory Support Center. Sites will receive a registration notification for the LOA once 
the DAIDS PRO verifies that all required LOA registration documents have been received 
and are complete. An LOA registration notification from the DAIDS PRO is not required 
prior to implementing the LOA. A copy of the LOA registration notification, along with 
this letter and any IRB/EC correspondence, should be retained in the site’s regulatory 


Letter of Amendment #2 
          Page 2 of 3 
14 Aug 2020 
ACTG A5380 Protocol Version 1.0 
file. 
The main reason for this LOA is to provide guidance on Step 2 registration, in follow-up to the 
COVID-19-related Clarification Memo #2 (CM #2), dated 04/20/20, as US and non-US sites 
begin to open to research visits in the presence of the ongoing COVID-19 pandemic. However, 
enrollment into the study (i.e., Step 1 entry) will remain paused until a Study Monitoring Review 
occurs on 08/17/20, per the protocol, for the first 10 participants who were enrolled prior to the 
temporary closure in March 2020 due to the COVID-19 pandemic. Follow-up for these 10 
enrolled participants remains ongoing with modifications to allow for a mix of virtual and in-
person visits.  
At this time, any of the 10 participants who are currently in Step 1 of the study, and who qualify 
for Step 2, may now register to Step 2. The Data Management Center will open the Step 2 
registration screens upon release of this LOA. Sites should follow Final Protocol Version 1.0, 
and subsequent CMs #1 and #2, and LOA #1 for the Step 2 registration procedures.   
For sites who have any of the 10 participants on Step 1, in-person visits are permitted at this 
time for these participants if the site is able to conduct in-person visits. The COVID-related CM 
#2, dated 04/20/20, was written in a way to allow flexibility for remote visits with the only 
stipulation being that the week 16/SVR12 visit occur in person.  
Additional guidance is forthcoming from the team to allow for further flexibility in light of 
uncertainties in regards to the COVID-19 pandemic.  
The following is a change to A5380, Version 1.0, 06/07/19, titled "A Phase II Trial of 
Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute Hepatitis C Virus 
Infection (PURGE-C).” This change will be included in the next version of the A5380 protocol if it 
is amended at a future date.  
1.
Step 2 registration may proceed.
2.
A Protocol Signature Page (PSP) is appended for submission to DAIDS Protocol
Registration System (DPRS) as part of the LOA registration packet.


Letter of Amendment #2 
          Page 3 of 3 
14 Aug 2020 
ACTG A5380 Protocol Version 1.0 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute 
Hepatitis C Virus Infection (PURGE-C) 
SIGNATURE PAGE 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
Principal Investigator: _____________________________________________________ 
Print/Type 
Signed: _______________________________________________Date: _____________ 
Name/Title 


Clarification Memo #2 
          Page 1 of 3 
20 Apr 2020 
ACTG A5380 Protocol Version 1.0 
Clarification Memo #2 for: 
A5380 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for 
Acute Hepatitis C Virus Infection (PURGE-C) 
A Multicenter Trial of Advancing Clinical Therapeutics Globally (ACTG) 
NIAID CRMS # 38553 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3000 
Fax: 301-628-3302 
CLARIFICATION MEMO 
DATE: 
April 20, 2020 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5380 Protocol Team  
SUBJECT: 
Clarification Memo #2 for Protocol A5380- Impact of COVID-19 
This clarification memo (CM) does not result in a change in the protocol informed 
consent document. The Division of AIDS (DAIDS) has determined that these protocol 
changes and clarifications should be implemented immediately in response to the 
COVID-19 pandemic, which poses a safety risk to participants and site staff. Sites do not 
need local institutional review board (IRB) approval prior to implementing this CM. 
DAIDS does not require you to forward this CM to your IRB; however, you must follow 
your IRB's policies and procedures. If IRB review of CMs is required at your site, please 
submit this document for review. 
Each site should file a copy of this CM with the protocol for reference. 
The following are clarifications (noted in bold or strikethrough) to Protocol A5380, Version 1.0, 
06/07/19, titled "A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment 
for Acute Hepatitis C Virus Infection (PURGE-C),” in response to the COVID-19 pandemic.  
As of March 18, 2020, 10 participants have enrolled into the study and all subsequent 


Clarification Memo #2 
          Page 2 of 3 
20 Apr 2020 
ACTG A5380 Protocol Version 1.0 
enrollment has been put on hold during the ongoing COVID-19 pandemic. Therefore, this CM is 
only pertinent for these 10 participants, and is follow up to the memo sent to sites on March 18, 
2020.  
1.
Section 6.2.3 (Post-Entry Evaluations): This section has been revised to read:
All post-entry evaluations occur in reference to the start of study therapy.
All Step 1 study visits for the 10 participants enrolled on or before March 18, 2020 can
occur remotely (via telephone), except for the Step 1 week 16/SVR12 visit, which must
remain an in-person visit, if this visit can be conducted safely.
The safety of participants and study staff must be taken into account when
scheduling this visit and any remote contact prior to this visit, with the consideration
of delaying visits if needed. If there is a need to limit in-person interactions at the site,
the in-person component can be restricted to the blood draw, and the remaining visit
evaluations can be completed via telephone.
If the blood draw at this visit is limited, then prioritize sample use as follows:
•
local testing for safety
•
HCV RNA
•
HIV-1 RNA
•
CD4+ (for participants living with HIV-1 infection)
•
storage
Until further notice, store samples for central testing (e.g., HCV RNA and HIV-1 RNA) 
in accordance with the guidance distributed by the ACTG Lab Center on 3/17/2020.  
On-Treatment Evaluations  
Study visits must be scheduled on the weeks indicated in Tables 6.1-1 and 6.1-2, within the 
visit windows described below, as appropriate for the visit.  
NOTE: Step 2 entry may be deferred until further notice. 
Step 1 (remote, via telephone):  
•
Weeks 1 and 2 have a window of ±3 days.
•
Week 4 has a window of -7 days and +14 days.
Step 2 (deferred until further notice): 
•
Week R+2 has a window of ±3 days.
•
Weeks R+4, R+8, R+12, and R+16 have a window of -7 days and +14 days.
Treatment Completion Evaluations  
Clinical assessment and laboratory evaluation, as outlined in section 6.1, will be performed 
at treatment completion (Step 1: week 4, Step 2: week R+8, R+12, or R+16).  
NOTE: Step 2 entry may be deferred until further notice. 
Post-Treatment Evaluations  


Clarification Memo #2 
          Page 3 of 3 
20 Apr 2020 
ACTG A5380 Protocol Version 1.0 
Following treatment completion, participants will undergo evaluations as outlined in Tables 
6.1-1 and 6.1-2, within the study windows, as indicated below.  
NOTE: Step 2 entry may be deferred until further notice. 
After the last dose of study drugs, the post-treatment study visits have the following 
windows:  
Step 1 (remote, via telephone, EXCEPT week 16): 
•
Study weeks 8 and 12, and 16: -5 days and +21 days
•
Study week 16: -14 days and +42 days
•
Study week 28: -7 days and +28 days
NOTE: In the midst of the COVID-19 pandemic, for study week 28, all evaluations 
should be conducted remotely, and the week 28 specimen can be collected at a future 
date, prior to study closure, up until 36 weeks post treatment completion, as long as 
the week 16/SVR12 visit was conducted in-person. Participants should only have the 
week 28 visit in person if the week 16/SVR12 visit and sample were missed.  
If a participant has successfully attended the week 16/SVR12 visit and the blood 
sample has been collected, then that participant does not need to have an in-person 
visit at week 28. 
Step 2 (deferred until further notice): 
•
Study week R+20, R+24, or R+28 (12 weeks after re-treatment completion for those not
receiving RBV depends on Step 2 treatment duration): -5 days and +28 days
•
Study week R+32, R+36, or R+40 completion (for those receiving RBV): -14 days and +
28 days
2.
Section 6.3.10 (Virologic Studies): The second subsection has been revised to read:
Plasma HCV RNA (real-time, on-study evaluations)
At the entry and post-entry visits, HCV RNA quantification will be performed as follows:
Plasma HCV RNA real-time testing will be collected, processed, and shipped to the
designated testing laboratory (see A5380 LPC for directions). These results will be reported
within 2 weeks after specimen receipt for both Steps 1 and 2.
NOTE A: For Step 1, HCV RNA should only be done at the week 16/SVR12 visit for the
10 participants enrolled on or before March 18, 2020.
NOTE B: For Step 2, an increase in plasma HCV RNA at any time point meeting HCV
virologic response-based treatment stopping criteria must be confirmed with repeat testing
within 2 weeks of receipt of results. For more information please see section 6.2.4.


Letter of Amendment #1 
          Page 1 of 5 
18 Dec 2019 
ACTG A5380 Protocol Version 1.0 
Letter of Amendment #1 for: 
A5380 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute 
Hepatitis C Virus Infection (PURGE-C) 
A Multicenter Trial of Advancing Clinical Therapeutics Globally (ACTG) 
NIAID CRMS # 38553 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems  
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3000 
Fax: 301-628-3302 
LETTER OF AMENDMENT 
DATE: 
December 18, 2019 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5380 Protocol Team 
SUBJECT: 
Letter of Amendment #1 for Protocol A5380 (Glecaprevir/Pibrentasvir Fixed-dose 
Combination Treatment for Acute Hepatitis C Virus Infection [PURGE-C]) 
The following information affects the A5380 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) must be approved by your 
IRB/EC before implementation. 
The following information may also affect the Sample Informed Consent. Your IRB/EC is 
responsible for determining the process of informing participants of the contents of this 
LOA. 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit an 
LOA registration packet to the DAIDS Protocol Registration Office (PRO) at the 
Regulatory Support Center. Sites will receive a registration notification for the LOA once 
the DAIDS PRO verifies that all required LOA registration documents have been received 
and are complete. An LOA registration notification from the DAIDS PRO is not required 
prior to implementing the LOA. A copy of the LOA registration notification, along with 
this letter and any IRB/EC correspondence, should be retained in the site’s regulatory 


Letter of Amendment #1 
          Page 2 of 5 
18 Dec 2019 
ACTG A5380 Protocol Version 1.0 
file. 
This LOA is being implemented for the following reasons: 
•
A team decision has been made to clarify the meaning of active, serious infection prior to
study entry. In response, the following sections have been updated: 4.2.7 and 4.4.5.
•
A team decision has been made to create separate rows for “Less than 30 mL/min” and
“Hemodialysis” creatinine clearance categories for RBV dose. In response, the following
table has been updated: 5.1.1-2.
•
A team decision has been made to clarify the requirements for fentanyl testing. In response,
the following section has been updated: 6.3.8.


Letter of Amendment #1 
          Page 3 of 5 
18 Dec 2019 
ACTG A5380 Protocol Version 1.0 
The following are changes (noted in bold or strikethrough) to A5380, Version 1.0, 06/07/19,  
titled "Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute Hepatitis C Virus 
Infection (PURGE-C).” These changes will be included in the next version of the A5380 protocol 
if it is amended at a future date. Changes that have already been made (either by Letter of 
Amendment or by Clarification Memo) have been incorporated in the excerpted text shown 
below (and are no longer presented in bold or strikethrough). 
1.
A Protocol Signature Page (PSP) is appended for submission to DAIDS Protocol
Registration System (DPRS) as part of the LOA registration packet.
2.
Section 4.2 (Step 1 Exclusion Criteria), exclusion criterion 4.2.7: This exclusion criterion has
been revised to read:
Active, serious infection (other than HIV-1 or HCV) requiring parenteral antibiotics, antivirals,
or antifungals) within 30 days prior to at the time of study entry.
NOTE: Entry may occur when the infection is considered inactive, defined by:
•
Minimum duration of antibiotic, antiviral, or antifungal treatment of 72 hours, AND
•
Improved and stable clinical status as determined by a site investigator.
3.
Section 4.4 (Step 2 Exclusion Criteria), exclusion criterion 4.4.5: This exclusion criterion has
been revised to read:
Active, serious infection (other than HIV-1 or HCV) requiring parenteral antibiotics, antivirals,
or antifungals) within 28 days prior to study at the time of Step 2 entry.
NOTE: Entry may occur when the infection is considered inactive, defined by:
•
Minimum duration of antibiotic, antiviral, or antifungal treatment of 72 hours, AND
•
Improved and stable clinical status as determined by a site investigator.
4.
Table 5.1.1-2 (Renal Dosing for RBV): The “less than 30 mL/min” and “hemodialysis”
creatinine clearance categories have been separated for clarity as shown below:
Table 5.1.1-2: Renal Dosing for RBV 
Creatinine Clearance 
RBV Dose 
30-50 mL/min
Alternating doses, 200 mg (1 tablet) daily 
alternating with and 400 mg (2 tablets) 
every other day daily 
Less than 30 mL/min 
and Hemodialysis 
200 mg (1 tablet) daily 
Hemodialysis 
200 mg (1 tablet) daily 


Letter of Amendment #1 
          Page 4 of 5 
18 Dec 2019 
ACTG A5380 Protocol Version 1.0 
5.
Section 6.3.8 (Laboratory Evaluations): The first paragraph within the Urine Sample for
Substance Use Screen subsection has been revised to read:
Urine Sample for Substance Use Screen
Urine substance use screening must be done using a CLIA-waived urine drug use screening
tool with these common drugs of abuse: amphetamines, buprenorphine, benzodiazepines,
cocaine, ecstasy, methadone, methamphetamine, barbiturates, marijuana, opiates,
oxycodone, fentanyl, and phencyclidine. The screening will be assessed by urine test and
must include the following ancillary testing, pH and creatinine to help in confirmation of
sample against adulterants. The following results would be used as confirmation of an
unadulterated human urine sample; pH of 4.5 – 8.0 and urine creatinine ≥20 mg/dL. Urine
fentanyl testing will be done using a test which is not currently FDA approved or
CLIA-waived.


Letter of Amendment #1 
          Page 5 of 5 
18 Dec 2019 
ACTG A5380 Protocol Version 1.0 
Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute Hepatitis C Virus 
Infection (PURGE-C) 
SIGNATURE PAGE 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
Principal Investigator: 
Print/Type 
Signed: Date: 
 Name/Title 


Clarification Memo #1 
          Page 1 of 3 
15 Oct 2019 
ACTG A5380 Protocol Version 1.0 
Clarification Memo #1 for: 
A5380 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for 
Acute Hepatitis C Virus Infection (PURGE-C) 
A Multicenter Trial of Advancing Clinical Therapeutics Globally (ACTG) 
NIAID CRMS # 38553 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3000 
Fax: 301-628-3302 
CLARIFICATION MEMO 
DATE: 
October 15, 2019 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5380 Protocol Team  
SUBJECT: 
Clarification Memo #1 for Protocol A5380 
This clarification memo (CM) does not result in a change in the protocol informed 
consent document. The Division of AIDS does not require you to forward it to your 
institutional review board (IRB); however, you must follow your IRB's policies and 
procedures. If IRB review of clarification memos is required at your site, please submit 
this document for review. 
Each site should file a copy of this CM with the protocol for reference. 
The protocol clarifications contained in this memo should be implemented immediately. 
The following are clarifications (noted in bold or strikethrough) to Protocol A5380, Version 1.0, 
06/07/19, titled "A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment 
for Acute Hepatitis C Virus Infection (PURGE-C).” These clarifications will be included in the 
next version of the A5380 protocol if it is amended at a future date. 


Clarification Memo #1 
          Page 2 of 3 
15 Oct 2019 
ACTG A5380 Protocol Version 1.0 
1.
Section 4.1.5 (Inclusion Criteria [Step 1]): The laboratory requirements have been revised to
read:
HCV genotype obtained within 24 weeks prior to entry by any US laboratory that has a
Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or at any
network-approved non-US laboratory that is Virology Quality Assurance (VQA) certified.
operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in
appropriate external quality assurance programs.
2.
Section 4.1.7 (Inclusion Criteria [Step 1]): The laboratory requirements have been revised to
read:
For HIV-1 co-infected participants on ART, screening HIV-1 RNA must be <50 copies/mL or
<LLOQ of local assay if LLOQ is >50 copies/mL obtained within 28 days prior to study
entry as measured by any US laboratory that has a CLIA certification or its equivalent, or at
any network-approved non-US laboratory that is VQA certified. operates in accordance
with GCLP and participates in appropriate external quality assurance programs.
3.
Section 4.1.8b (Inclusion Criteria [Step 1]): The laboratory requirements have been revised
to read:
For HIV-1 co-infected participants, HIV-1 ART should meet one of the following criteria:
a) ART untreated due to (1) lack of indication per provider (CD4+ T-cell count ≥500
cells/mm3) or (2) decision by provider and participant to defer ART during the G/P dosing
period (4 weeks).
OR 
b) On a stable, protocol-defined compatible ART regimen (per sections 2.2 [Rationale for
Inclusion of Concomitant ART Regimens] and 5.4.1) for >2 weeks prior to starting G/P with a
CD4+ T-cell count >100 cells/mm3 obtained within 180 days prior to the screening visit.
Laboratory testing can be done by at any US laboratory that has a CLIA certification or its
equivalent, or at any network-approved non-US laboratory that is Immunology Quality
Assessment (IQA) certified. operates in accordance with GCLP and participates in
appropriate external quality assurance programs.
4.
Section 6.2.4 (Event-Driven Evaluations- HIV-1 Virologic Breakthrough): The third
paragraph in the HIV-1 Virologic Breakthrough subsection has been revised to read:
The increase in plasma HIV-1 RNA should be confirmed with repeat central or local testing
as soon as possible (not to exceed 4 weeks); see HIV-1 Virologic Breakthrough
Confirmation in Tables 6.1-1 and 6.1-2. For participants with confirmed HIV-1 viral
breakthrough (≥200 copies/mL), a plasma specimen should be sent for HIV genotyping and
sent to the designated A5380 VSL for evidence of HIV-1 drug resistance. Results will be
reported back to sites in real-time from the designated A5380 VSL. See section 6.3.10,
Stored Serum and Plasma for HIV-1/HCV Studies.


Clarification Memo #1 
          Page 3 of 3 
15 Oct 2019 
ACTG A5380 Protocol Version 1.0 
5.
Section 6.3 (Instructions for Evaluations): The following paragraph has been added as the
first paragraph of this section.
Each study site and laboratory involved in this study will comply with the DAIDS
policy on Requirements for Laboratories Performing Testing for DAIDS-Supported
and/or Sponsored Clinical Trials, which is available at:
https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf.
6.
Section 6.3.8 (Laboratory Evaluations): The last paragraph has been revised to read:
HCV Ab HCV Ab must be obtained by any FDA-approved test at any local laboratory that
has a CLIA certification or its equivalent (US sites) or VQA certification (non-US sites).
HCV Ab is only to be sent at screening and at a subsequent visit if the result is negative on
the preceding visit. Once a single positive Ab is recorded, no further HCV antibody testing is
required.
7.
Section 6.3.9 (Immunologic Studies): The CD4+/CD8+ requirement at screening have been
revised to read:
CD4+/CD8+ (For participants with HIV-1 infection only)
Screening Obtain absolute CD4+/CD8+ count and percentages must be performed within
28 days prior to study entry from at a laboratory that possesses a CLIA certification or
equivalent (US sites) or IQA certification (non-US sites).
8.
Section 6.3.10 (Virologic Studies): The laboratory requirements in the first paragraphs of the
Plasma HCV RNA (screening), Plasma HCV Genotype, and Plasma HIV-1 RNA subsections
have been revised to read: 
Plasma HCV RNA (screening)  
The screening HCV RNA result must be obtained by any FDA-approved test for quantifying 
HCV RNA at any local laboratory that has a CLIA certification or its equivalent (US sites) or 
VQA certification (non-US sites). Screening HCV RNA must be obtained within 28 days 
prior to study entry. 
Plasma HCV Genotype 
At Step 1 screening, the HCV genotype result will be obtained locally (real-time) from any 
laboratory that has a CLIA certification or its equivalent (US sites) or VQA certification 
(non-US sites). ONLY IF IT IS NOT AVAILABLE LOCALLY should it be done (real-time) at 
the designated testing laboratory (see A5380 LPC). 
Plasma HIV-1 RNA 
For participants with documented HIV-1 infection, a documented plasma HIV-1 RNA level 
must be noted within 28 days prior to Step 1 study entry from any laboratory that has a CLIA 
certification or its equivalent (US sites) or VQA certification (non-US sites). On-study HIV-
1 RNA is only required for HIV-1-infected participants and should be performed at the ACTG 
central laboratory. See the A5380 LPC for processing, shipping, and storage information. 


A5380 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for 
Acute Hepatitis C Virus Infection (PURGE-C) 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
Sponsored by: 
National Institute of Allergy 
and Infectious Diseases 
Industry Support Provided by: 
AbbVie 
IND # 
The ACTG Hepatitis  
Transformative Science Group: 
Susanna Naggie, MD, MHS, Chair 
Protocol Chair: 
Arthur Y. Kim, MD 
Protocol Vice Chairs: 
Susanna Naggie, MD, MHS 
David Wyles, MD 
DAIDS Clinical Representative: 
Leonard Sowah, MBChB, MPH, FACP 
Clinical Trials Specialist: 
Chanelle Houston, BS 
FINAL Version 1.0 
June 07, 2019 


A5380 
 
 
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A5380 
 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute 
Hepatitis C Virus Infection (PURGE-C) 
 
SIGNATURE PAGE 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
Name/Title 
 
 
 


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TABLE OF CONTENTS 
Page 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ............................................................................................................. 9 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 11 
SCHEMA .................................................................................................................................. 13 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 15 
1.1 
Hypothesis ......................................................................................................... 15 
1.2 
Primary Objectives ............................................................................................. 15 
1.3 
Secondary Objectives ........................................................................................ 15 
1.4 
Exploratory Objectives ....................................................................................... 15 
2.0 
INTRODUCTION ........................................................................................................... 16 
2.1 
Background ........................................................................................................ 16 
2.2 
Rationale ........................................................................................................... 20 
2.3 
Overall Risk/Benefit Assessment ....................................................................... 24 
2.4 
Adherence Measures ......................................................................................... 26 
2.5 
Cost-effectiveness Analysis ............................................................................... 26 
3.0 
STUDY DESIGN ........................................................................................................... 26 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 27 
4.1 
Step 1 Inclusion Criteria ..................................................................................... 27 
4.2 
Step 1 Exclusion Criteria .................................................................................... 31 
4.3 
Step 2 Inclusion Criteria ..................................................................................... 32 
4.4 
Step 2 Exclusion Criteria .................................................................................... 35 
4.5 
Study Enrollment Procedures............................................................................. 37 
4.6 
Co-enrollment Guidelines ................................................................................... 38 
5.0 
STUDY TREATMENT ................................................................................................... 38 
5.1 
Regimens, Administration, and Duration ............................................................ 39 
5.2 
Study Product Formulation and Preparation ....................................................... 41 
5.3 
Pharmacy: Study Product Supply, Distribution, and Accountability .................... 42 
5.4 
Concomitant Medications ................................................................................... 42 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 48 
6.1 
Schedule of Evaluations (SOE) .......................................................................... 48 
6.2 
Timing of Evaluations ......................................................................................... 55 
6.3 
Instructions for Evaluations ................................................................................ 59 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 70 
7.1 
Definition of AEs ................................................................................................ 70 
7.2 
AE Collection Requirements for This Protocol .................................................... 71 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 71 
7.4 
Study Monitoring ................................................................................................ 73 


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CONTENTS (Cont’d) 
Page 
 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 73 
8.1 
Toxicity .............................................................................................................. 73 
8.2 
Pregnancy.......................................................................................................... 75 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 76 
9.1 
Premature Treatment Discontinuation ................................................................ 76 
9.2 
Premature Study Discontinuation ....................................................................... 77 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 77 
10.1 
General Design Issues ....................................................................................... 77 
10.2 
Outcome Measures ............................................................................................ 78 
10.3 
Randomization ................................................................................................... 80 
10.4 
Sample Size and Accrual ................................................................................... 80 
10.5 
Data and Safety Monitoring ................................................................................ 81 
10.6 
Analyses ............................................................................................................ 82 
11.0 
PHARMACOLOGY PLAN .............................................................................................. 83 
11.1 
Pharmacology Objectives .................................................................................. 83 
11.2 
Pharmacology Study Design .............................................................................. 84 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis .............................. 84 
11.4 
Anticipated Outcomes ........................................................................................ 84 
12.0 
DATA COLLECTION AND MONITORING ..................................................................... 85 
12.1 
Records to Be Kept ............................................................................................ 85 
12.2 
Role of Data Management ................................................................................. 85 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 85 
13.0 
PARTICIPANTS ............................................................................................................ 85 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 85 
13.2 
Participant Confidentiality ................................................................................... 86 
13.3 
Study Discontinuation ........................................................................................ 86 
14.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 86 
15.0 
BIOHAZARD CONTAINMENT ...................................................................................... 86 
16.0 
REFERENCES .............................................................................................................. 87 
APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT .......................................................... 92 
APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT ....................................................... 113 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
A5380 is a multicenter study open to all US clinical research sites (CRSs) and limited to select 
non-US CRSs. The non-US sites that are eligible for participation in the study can be found on 
the A5380 protocol-specific web page (PSWP). 
 


 
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PROTOCOL TEAM ROSTER 
 
Chair 
Arthur Y. Kim, MD 
Massachusetts General Hospital (MGH) 
CRS 
Cox 6, 55 Fruit Street 
Boston, MA 02114 
Phone: 617-724-3230 
Email: akim1@mgh.harvard.edu 
 
Vice Chairs 
Susanna Naggie, MD, MHS 
Duke University Medical Center CRS 
2400 Pratt St 
Room 0311 Terrace Level 
Durham, NC 27705 
Phone: 919-684-2584 
Email: susanna.naggie@duke.edu 
 
David Wyles, MD 
University of Colorado Hospital CRS 
P.O. Box 6511 
Aurora, CO 80045 
Phone: 303-602-5148 
Email: david.wyles@dhha.org 
 
DAIDS Clinical Representative  
Leonard Sowah, MBChB, MPH, FACP  
CCRB/TRP/DAIDS/NIAID/NIH/DHHS 
Therapeutics Research Program 
5601 Fishers Lane, Room 9F52 
Rockville, MD 20852 
Phone: 301-761-7231 
Fax: 240-627-3107 
Email: leonard.sowah@nih.gov 
 
Clinical Trials Specialist 
Chanelle Houston, BS 
ACTG Network Coordinating Center 
Social & Scientific Systems 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3367 
Fax: 301-628-3302 
Email: chouston@s-3.com 
 
Statisticians 
Minhee Kang, PhD 
Statistical and Data Analysis Center 
Harvard School of Public Health 
651 Huntington Avenue 
FXB Building, Room 503 
Boston, MA 02115-6017 
Phone: 617-432-2819 
Fax: 617-432-3163 
Email: mkang@sdac.harvard.edu 
 
Vincent Vu, MPH 
ACTG Statistical & Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 608 
Boston, MA 02115 
Phone: 617-432-1352 
Email: vvu@sdac.harvard.edu 
 
Data Manager 
Apsara Nair, MSc 
Frontier Science & Technology Research 
Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7293 
Email: nair@fstrf.org 
 
DAIDS Pharmacists 
Cynthia Parker, PharmD 
OSCO, DAIDS, NIAID, NIH, PAB 
Pharmaceutical Affairs Branch 
5601 Fishers Lane 
Room 9D37 
Rockville, MD 20852 
Phone: 301-761-7199 
Email: cindy.parker@nih.gov


 
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TEAM ROSTER (Cont’d) 
06/07/19 
 
DAIDS Pharmacists (Cont'd) 
Katherine Shin, PharmD 
Division of AIDS 
Pharmaceutical Affairs Branch 
5601 Fishers Lane 
Room 9D30 
Rockville, MD 20852 
Phone: 240-627-3047 
Email: kashin@niaid.nih.gov 
 
Immunologist 
Georg Lauer, MD, PhD 
Massachusetts General Hospital and 
Harvard Medical School 
Liver Center 
Warren 10, 55 Fruit Street, 
Boston, MA 02114 
Phone: 617-724-7515 
Email: glauer@mgh.harvard.edu 
 
Virologist 
Raymond Chung, MD 
Massachusetts General Hospital (MGH) 
CRS 
Gastroenterology Unit 
GRJ 724 
Boston, MA 02114 
Phone: 617-724-7562 
Email: rtchung@partners.org 
 
Pharmacologist 
Jennifer Kiser, PharmD 
University of Colorado Hospital CRS 
Pharmaceutical Sciences 
12850 E Montview Boulevard, C238 
Aurora, CO 80045 
Phone: 303-724-6131 
Email: jennifer.kiser@ucdenver.edu 
 
Investigators 
Jagpreet Chhatwal, PhD 
Harvard Medical School 
Institute for Technology Assessment, 
Massachusetts General Hospital 
101 Merrimac Street, Suite #1010 
Boston, MA 02114 
Phone: 617-724-4487 
Fax: 617-726-9414 
Email: JagChhatwal@mgh.harvard.edu 
 
Daniel Fierer, MD 
Weill Cornell Chelsea CRS 
5 East 98th Street, 11th Floor 
New York, NY 10029 
Phone: 212-241-3150 
Email: daniel.fierer@mssm.edu 
 
Dimas Kliemann, MD 
Hospital Nossa Senhora da Conceicao CRS  
Servico de Infectologia 
Av. Francisco Trein, 596 
Cristo Redentor 
Porto Alegre 91350-200 
Rio Grande do Sul, Brazil 
Phone: +55-51-33572126 
Email: dimaskliemann@gmail.com 
 
Annie Luetkemeyer, MD 
University of California, San Francisco 
HIV/AIDS CRS 
P.O. Box 0874 
995 Potrero Avenue 
San Francisco, CA 94110-2897 
Phone: 415-476-4082 Ext. 130 
Email: aluetkemeyer@php.ucsf.edu 
 
Sunil Solomon, MBBS, PhD, MPH 
The Johns Hopkins University CRS 
1830 E Monument Street, Room 444 
Baltimore, MD 21205 
Phone: 410-614-1356  
Email: sss@jhmi.edu 
 


 
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TEAM ROSTER (Cont’d) 
06/07/19 
 
Field Representative 
Michelle Saemann, RN 
University of Cincinnati CRS 
Eden Avenue and Albert Sabin Way 
Cincinnati, OH 45267-0405 
Phone: 513-584-2245 
Fax: 513-584-8454 
Email: saemanmd@uc.edu 
 
Laboratory Technologist 
Dean Soko, MSc 
Blantyre CRS 
Queen Elizabeth Central Hospital 
Johns Hopkins Project, Chipatala Avenue 
Box 1131 
Blantyre 265 
Malawi 
Phone: 265-1-874872 
Email: dsoko@jhu.medcol.mw 
 
Community Scientific Subcommittee (CSS) 
Representative  
Dichaba B. Siane  
Gaborone CRS 
Northring Road 
Plot 1836  
P.O. Box Private Bag BO 320 
Gaborone 9999 
Botswana 
Phone (Primary): 267-73870951 
Phone (Secondary): 267-73903540 
Email:  dichabasiane@gmail.com   
 
ACTG International Site Specialist 
Allegra Cermak, MFA 
ACTG Network Coordinating Center 
Social & Scientific Systems 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3312 
Fax: 301-628-3302 
Email: acermak@s-3.com 
 
Industry Representative  
Jens J. Kort, MD, PhD 
Senior Medical Director 
US Medical Affairs, Abbvie 
Department R4N8, Building ABV1-2SE 
26525 North Riverwoods Boulevard 
Mettawa, IL 60045 
Phone: 847-935-9198 
Email: jens.kort@abbvie.com 
 
Laboratory Data Manager 
Kacey Matecki, BS 
Frontier Science & Technology Research 
Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14266 
Phone: 716-834-0900 Ext. 7272 
Email: matecki@fstrf.org 
 
Laboratory Specialist 
Frances Whalen, MPH 
IMPAACT Network Laboratory Center 
University of California Los Angeles 
11075 Santa Monica Blvd. Suite #200 
Los Angeles, CA 90025 
Phone: 704-422-4055 
Email: fwhalen@milabcentral.org 
 


 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5380@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5380@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5380 e-mail group. 
Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org.  
 
Clinical Management:  
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the Clinical Management committee (CMC).  
• 
Send an e-mail message to actg.cmcA5380@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to immunologic, virologic, or pharmacologic laboratory tests, 
contact the Protocol Immunologist, Virologist, or Pharmacologist.  
• 
Send an e-mail message to actg.teamA5380@fstrf.org (ATTENTION: Georg Lauer – 
immunologist; Raymond Chung - virologist; Jennifer Kiser - pharmacologist). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), registration, and other data management issues, contact the data manager. 
Completion guidelines for eCRFs and participant-completed CRFs can be downloaded from 
the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Apsara Nair 
(nair@fstrf.org) directly.  
• 
For other questions, send an e-mail message to actg.teamA5380@fstrf.org (ATTENTION: 
Apsara Nair).  
• 
Include the protocol number, PID, and a detailed question. 
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. 
• 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist.  
• 
Send an e-mail message to actg.teamA5380@fstrf.org (ATTENTION: Chanelle Houston). 
 


 
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Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@s-3.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation at US sites, contact the clinical trials specialist.  
• 
Send an e-mail message to actg.teamA5380@fstrf.org (ATTENTION: Chanelle Houston, 
CHouston@s-3.com) 
 
For questions related to protocol activation at non-US sites contact the ACTG Site Coordination 
Group.  
• 
Send an email message to actgsitecoordination@s-3.com 
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Cynthia Parker and Katherine Shin, Protocol Pharmacists, at 301-496-8213.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
The IND number will be available on the protocol-specific web page (PSWP) within 30 days of 
the submission to the Food and Drug Administration (FDA). For any questions related to the 
IND submission, contact the DAIDS RSC at Regulatory@tech-res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Telephone Calls 
Sites are responsible for documenting telephone calls made to A5380 team members.  
• 
Send an e-mail message to actg.teamA5380@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
ALT 
alanine aminotransferase 
APTT 
activated partial thromboplastin time 
ARV(s) 
antiretroviral(s) 
ART 
antiretroviral therapy 
CLIA 
Clinical Laboratory Improvement Amendments 
CMC 
Clinical Management Committee 
CSA 
colony stimulating agents 
DAA 
direct-acting antiviral 
DBS 
dried blood spot 
DOT 
directly observed therapy 
E/CIA 
enzyme or chemiluminescence immunoassay  
FACS 
fluorescence-activated cell sorting 
FDC 
fixed dose combination 
FSH 
follicle stimulating hormone-release factor 
GCLP 
Good Clinical Laboratory Practices  
G/P 
glecaprevir/pibrentasvir 
HAV 
hepatitis A virus 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HLA 
human leukocyte antigen 
HVR1 
hypervariable region 1 
IFN 
interferon 
IEG 
interferon effector gene 
ISG 
interferon-stimulated gene 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
LDV/SOF 
ledipasvir/sofosbuvir 
LFT 
liver function test 
LLOQ 
lower limit of quantification 
mITT 
modified intention to treat 
MOPS 
Manual of Procedures 


 
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MSM 
men who have sex with men 
pegIFN 
pegylated interferon  
PTT 
partial thromboplastin time 
PI 
Principal Investigator  
PPI 
proton-pump inhibitor 
PSWP 
protocol specific web page 
PT 
prothrombin time 
PWID 
people who inject drugs 
PYFU 
person-years of follow-up  
QOL 
quality of life 
RASs 
resistance-associated substitutions 
RBV 
ribavirin 
RTV 
ritonavir 
SNP 
single nucleotide polymorphism 
SOF 
sofosbuvir 
SVR 
sustained virologic response 
TD 
target detected  
TND 
target not detected  
ULN 
upper limit of the normal range 
WB 
weight-based 
 


 
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SCHEMA 
 
A5380 
 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute 
Hepatitis C Virus Infection (PURGE-C) 
 
DESIGN 
This is a phase II single-arm, open-label study to assess the efficacy of a 
fixed dose combination (FDC) of glecaprevir/pibrentasvir (G/P) given for 4 
weeks in acute hepatitis C (HCV)-infected participants, with and without 
HIV-1 coinfection. 
 
 
The study has two steps:  
 
Step 1: Four weeks of treatment for acute HCV infection and up to 24 
weeks of follow-up. Post-treatment follow-up visits in Step 1 will occur at 
4, 8, 12, and 24 weeks after the end of study treatment (G/P). Participants 
with HCV recurrence (reinfection, suspected relapse or undefined post-
treatment viremia) or HCV virologic failure before or at the week 
16/SVR12 (sustained virologic response 12 weeks post-treatment) visit 
during Step 1 will be eligible for re-treatment (Step 2). 
 
Step 2: Re-treatment will be with G/P with or without ribavirin (RBV) for up 
to 16 weeks. Post-treatment follow-up for Step 2 will include visits for 
SVR12 determination. 
 
DURATION 
Up to 28 weeks in Step 1: 4 weeks on treatment and 24 weeks of post-
treatment follow-up. 
 
 
Up to 40 weeks in Step 2: up to 16 weeks of re-treatment and up to 24 
weeks of post-treatment follow-up. 
 
SAMPLE SIZE 
Minimum of 44 participants, including at least 10 participants living with 
HIV-1 co-infection. If a participant discontinues early for reasons 
unrelated to study treatment and is not evaluable for SVR12 while 
registration is ongoing, then an additional participant may be enrolled as 
determined by the study team to attain an adequate number for key 
supporting analysis on SVR12. Additional enrollment may occur more 
than once, up to maximum enrollment of 50 participants. 
 
POPULATION 
Men and women age ≥18 years with acute HCV-infection (may be first 
HCV infection or re-infection) of any genotype, living with or without HIV-1 
co-infection.  


 
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SCHEMA (Cont'd) 
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REGIMEN 
Participants will receive a FDC of G/P administered orally once daily for 4 
weeks. A subset of participants who have HCV recurrence (reinfection, 
suspected relapse, or undefined post-treatment viremia) or HCV virologic 
failure after receipt of G/P for 4 weeks will receive re-treatment with FDC 
of G/P administered orally once daily with or without weight-based RBV 
for up to 16 weeks. 
 
NOTE: Alterations in the re-treatment regimen for suspected relapses and 
virologic failures are permitted based on local standard of care at the 
discretion of the site Principal Investigator (PI) upon discussion with 
A5380 Clinical Management Committee (CMC; 
actg.cmcA5380@fstrf.org). Acceptable alternate regimens are found in 
section 5.1.1 and in the A5380 Manual of Procedures (MOPS). 
 
 


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
The fixed dose combination (FDC) of glecaprevir/pibrentasvir (G/P) given for 4 weeks 
will achieve sustained virologic response 12 weeks post-treatment (SVR12) greater than 
80% for the treatment of acute hepatitis C virus (HCV) infection, with an acceptable 
safety profile and shorter length of therapy than is currently recommended for chronic 
HCV infection. 
 
1.2 
Primary Objectives 
 
1.2.1 To evaluate acute HCV treatment response to G/P given for 4 weeks as 
assessed by sustained virologic response 12 weeks post-treatment (SVR12, 
defined as HCV RNA <lower limit of quantification [LLOQ], either target detected 
[TD] or target not detected [TND]). 
 
1.2.2 To evaluate the safety and tolerability of combination oral antiviral therapy with 
G/P given for 4 weeks in persons with acute HCV-infection, regardless of 
genotype and HIV status. 
 
1.3 
Secondary Objectives 
 
1.3.1 To evaluate the antiviral efficacy of G/P given for 4 weeks for the treatment of 
acute HCV infection, as measured by the proportion of participants with HCV 
RNA <LLOQ (TD or TND) at study weeks 1, 2, 4, 8 (SVR4), 12 (SVR8), and 28 
(SVR24). 
 
1.3.2 To evaluate evidence of virologic failure, defined as failure to achieve HCV RNA 
<LLOQ (TD or TND at end of treatment) and confirmed increase in HCV RNA >1 
log10 from on-treatment nadir. 
 
1.3.3  To evaluate the antiviral efficacy of G/P given for 4 weeks by HIV status. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To estimate incidence of relapse, defined as HCV RNA <LLOQ (TD or TND) at 
end of treatment or during follow-up and confirmed HCV RNA >LLOQ during 
follow-up with phylogenetics excluding a new HCV viral infection. 
 
1.4.2 To estimate incidence of re-infection, defined as HCV RNA <LLOQ (TD or TND) 
at end of treatment or during follow-up and confirmed HCV RNA >LLOQ during 
follow-up with phylogenetics consistent with a new HCV viral infection. 
 
1.4.3 To assess the emergence of viral resistance to glecaprevir and/or pibrentasvir in 
participants with relapse or virologic failure, when 4 weeks of G/P is administered 
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1.4.4 To evaluate re-treatment strategies for study participants with post-treatment 
viremia. 
 
1.4.5 To characterize active substance use in the study population. 
 
1.4.6 To assess the pharmacokinetic-dynamic associations for G/P. 
 
1.4.7    To evaluate potential drug interactions between common drugs of abuse, 
antiretrovirals (ARVs), and G/P. 
 
1.4.8 To evaluate participants’ adherence by using several tools, including self-report, 
pill count, and drug concentrations. 
 
1.4.9 To evaluate novel serologic and virologic biomarkers of acute immunologic host 
response in early HCV infection. 
 
1.4.10 To evaluate whether successful direct-acting antiviral (DAA)-based therapy 
during acute HCV infection induces more profound T-cell recovery than treatment 
during chronic infection and alleviates type I interferon (IFN)-induced immune 
dysfunction during acute HCV infection. 
 
1.4.11 To evaluate the long-term clinical impact and cost-effectiveness of 4 weeks of 
G/P treatment for acute HCV infection compared with the standard of care, that 
is, wait for 6 months and treat only those who develop chronic HCV infection 
(referred to as “treat chronic HCV” strategy). 
 
2.0 
INTRODUCTION 
 
2.1 
Background  
 
Rationale for identifying and treating of acute HCV 
Hepatitis C virus infection affects more than 4 million persons and causes at least 
20,000 deaths annually in the United States, exceeding the mortality burden due to HIV 
[1, 2]. Recently, incidence of acute HCV has been rising [3], with the Centers for Disease 
Control and Prevention (CDC) estimating that there are about 30,000 new cases of 
acute HCV per year, with a range of 24,200-104,200 cases [4]. The two groups at 
highest risk for acute HCV infection are people who inject drugs (PWID) and HIV positive 
men who have sex with men (MSM). For a variety of reasons, only a fraction of persons 
with acute HCV are reported to public health authorities [5]. Those with recent infection, 
if unaware of their status, are at high-risk for transmission to others. Early identification 
of acute HCV infection is essential to provide preventive counseling and, if necessary, 
curative treatment to clear virus and prevent onward transmission. Models suggest that 
clearance of HCV among high-risk individuals may reduce overall prevalence and 
incidence, despite risks for re-infection [6]. 
 


 
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During the era of IFN-based treatments, early identification and treatment of HCV during 
the acute phase has resulted in significantly higher response rates with less intensive 
and shorter durations of therapy, in both HCV mono-infected and HIV/HCV co-infected 
individuals [7-10]. A meta-analysis of IFN-treated HCV mono-infected individuals with 
acute HCV infection (N=602) reported an overall sustained virologic response rate (SVR) 
of 78%, significantly higher than those individuals not receiving any therapy (55%, 
OR=3.08; 95% CI 1.8-4.8) [9]. A majority of individuals were treated with pegylated 
interferon (pegIFN) mono-therapy with an average duration of therapy of 19.7 weeks. 
The above meta-analysis also reported that those individuals initiated on treatment 
within the first 12 weeks of diagnosis had the highest SVR rates [9]. The first approved 
protease inhibitors, boceprevir and telaprevir, were also used for the treatment of acute 
HCV in combination with pegIFN and ribavirin (RBV); these also suggested that the 
duration of overall therapy could be shortened to as low as 12 weeks with enhanced 
efficacy compared to those receiving treatment in the chronic phase [11,12]. Moreover, a 
randomized controlled trial of immediate versus delayed treatment found improved SVR 
rates in the immediate treatment group, in part due to lack of follow-up for those 
assigned to the delayed arm [13]. In sum, these studies suggested that the timing of IFN-
based therapy matters in determining efficacy and improving follow-up when utilizing 
shortened IFN-based treatment courses.  
 
For the DAA era, current guidance provided at http://hcvguidelines.org recommends that 
treatment for acute HCV in many cases can be delayed for at least 12 weeks [12]. This 
recommendation is based on (1) the extraordinarily low frequency of fulmination during 
acute HCV infection; (2) the possibility of spontaneous clearance which is maximal in 
that timeframe, especially if female or jaundiced [14, 15]; and (3) the availability of safe 
and effective antiviral treatments in the chronic phase of infection. This strategy avoids 
overtreatment, especially for those who would have spontaneously cleared. However, 
the guidance also states that benefits of early treatment may outweigh the cost-savings 
of waiting for HCV clearance, especially for those at highest risk for onwards 
transmission. As HCV is increasing in incidence in the United States, a “test and treat” 
approach similar to many communicable diseases may be appropriate to combat this 
epidemic. Recent data from the Netherlands, where large scale roll out of DAA therapy 
has been achieved, have shown a dramatic decrease in incident HCV infections among 
HIV positive MSM [16, 17].  
 
However, it is equally important to note the high incidence of re-infection of HCV among 
individuals with elevated risk for acquisition. A meta-analysis showed that for HCV 
monoinfected "high-risk" participants (n = 771), the pooled recurrence rate was 
22.32/1000 person-years of follow-up (PYFU), leading to a summary 5-year risk of 
10.67%. For the 4 studies of HIV/HCV coinfected participants, the pooled recurrence 
rate was 32.02/1000 PYFU leading to a summary 5-year risk of 15.02% [18]. These 
individuals are monitored routinely for re-infection and will be an optimal population 
where shorter duration of treatment could play a key role in reducing costs. Additionally, 
curing these infections earlier (as these individuals are more likely to engage in high-risk 
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As chronic HCV infection is associated with dysregulation of innate and adaptive 
immune responses, earlier treatment may also prevent dysregulation that may interfere 
with protective immunity for future infections [19-22]. 
 
Antiviral treatment in the acute phase with regimens of shorter duration than those used 
in the chronic phase with similar SVR rates may mitigate concerns regarding costs 
associated with overtreatment, with potential societal cost saving due to both shorter 
duration of treatment and reduced risk of transmission [23]. As in the IFN-era, shorter 
duration regimens are also compelling for patient acceptability and adherence. 
 
Thus far, clinical trials using novel DAAs to cure acute HCV have produced mixed 
results. Initial attempts at using sofosbuvir (SOF) plus RBV for genotype 1 infection with 
much abbreviated duration compared to courses used in the chronic phase have 
resulted in suboptimal SVR rates. The DARE-C II trial treated 19 participants with 6 
weeks of SOF plus RBV and only achieved 32% SVR [24]. ACTG A5327 titled, 
“Sofosbuvir-Containing Regimens without Interferon for Treatment of Acute HCV in HIV-
1 Infected Individuals (SWIFT-C),” Cohort 1 included 17 participants treated with 12 
weeks of SOF plus RBV and only achieved 59% SVR [25]. A smaller study suggested a 
higher SVR rate with this regimen [26]. The more potent regimen of ledipasvir/sofosbuvir 
(LDV/SOF) has been applied for 6-8 weeks for acute HCV with genotypes 1 or 4. For 
HIV positive MSM, 6 weeks of LDV/SOF achieved more robust cure rates for 22 out of 
26 individuals (85% SVR); of note, the four relapses all had high HCV RNA levels 
>9,000,000 IU/mL at the time of treatment initiation [27]. More encouragingly, a recent 
trial in 20 HIV negative individuals with symptomatic acute HCV showed a 100% SVR 
rate with 6 weeks of LDV/SOF; HCV RNA at time of initiation was lower than the above 
trials [28]. The ACTG A5327 SWIFT-C Cohort 2 achieved SVR in all 27 participants with 
8 weeks of LDV/SOF [26]. Other DAA regimens are also currently being studied 
including 8 weeks of elbasvir/grazoprevir (EBR/GZR), although like LDV/SOF, will be 
limited to genotypes 1 and 4. In sum, these data suggest that more potent regimens may 
achieve acceptable cure rates, with shorter durations compared to the 8-12 weeks 
necessary to cure chronic infection. As shown in Table 2.1-1, studies of DAAs during 
acute HCV have tended to focus on persons with HIV and those infected with either 
genotypes 1 or 4 infection. 
 
Table 2.1-1: Clinical Trials of Acute HCV with DAAs, IFN-sparing [24-29] 
Study 
Location/N 
HIV 
included? 
GT Design/ 
Regimen 
Status 
SVR 
DARE-C II 
Australia 
N=19 
Both 
mono and 
co 
All 
SOF/RBV 
x 6 weeks 
Completed 
32% 
(6/19) 
NYAHCSN-
1 
NYC 
N=12 
All HIV 
1 
SOF/RBV 
x 12 weeks 
Completed 
92% 
(11/12) 
SWIFT-C 
Group 1 
US (ACTG) 
N-17 
All HIV 
All 
SOF/RBV 
x 12 weeks 
Completed 
59% 
(10/17) 
SOL 
Europe, multi-
center 
All HIV 
1,4 LDV/SOF x 
6 weeks 
Completed 
85% 
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Study 
Location/N 
HIV 
included? 
GT Design/ 
Regimen 
Status 
SVR 
N=26 
HepNet 
Acute HCV 
IV 
Europe, multi-
center 
N=20 
No 
1 
LDV/SOF x 
6 weeks 
Completed 
100% 
(20/20) 
SWIFT-C 
Group 2 [29] 
US (ACTG) 
N=27 
All HIV 
1,4 LDV/SOF x 
8 weeks 
Completed 
100% 
(27/27) 
NYAHCSN-
2 [30] 
US (NYC) 
N=25 
All HIV 
1,4 LDV/SOF x 
8 weeks 
Completed 
100% 
(25/25) 
Target 3D 
[31] 
Europe, 
Australia N=30 
Both 
mono and 
co 
1 
PrOD + 
RBV x 8 
weeks 
Completed 
96% 
(29/30) 
DAHHS-2 
[32] 
Netherlands 
Belgium N=80 
All HIV 
1,4 EBR/GZR 
x 8 weeks 
Active, not 
recruiting 
98% 
(62/63)* 
SAHIV 
France N=50 
All HIV 
1,4 EBV/GZR 
x 8 weeks 
Recruiting 
 
REACT 
Europe, North 
America, 
Australia 
N=250 
Both 
mono and 
co 
All 
RCT 
SOF/VEL 6 
vs 12 
weeks 
Recruiting 
 
*Boerekamps et al. [32] presented interim results from 63 of 80 enrolled participants. 
LDV/SOF = ledipasvir/sofosbuvir, PrOD = paritaprevir/ritonavir/ombitasvir + dasabuvir, 
EBR/GZR = elbasvir/grazoprevir, SOF/VEL = sofosbuvir/velpatasvir 
 
Efficacy and safety of glecaprevir/pibrentasvir 
Glecaprevir (GLE), an NS3/4A protease inhibitor, and pibrentasvir (PIB), an NS5A 
inhibitor were approved together as a pangenotypic FDC for the treatment of chronic 
HCV infection in August 2017. Administered as three 100 mg/40 mg FDC pills, clinical 
trials have shown proven efficacy and is recommended for all major 6 genotypes. Eight 
weeks is recommended for most individuals without cirrhosis, whereas a longer course 
of 12 weeks is recommended for those with cirrhosis. Treatment extension to 12-16 
weeks is also recommended for those with previous exposure to either HCV protease or 
NS5A inhibitors (but not recommended for dual class failures). Neither GLE nor PIB are 
significantly metabolized nor eliminated by the kidneys, allowing use in chronic kidney 
disease, including patients on dialysis. The safety profile of G/P is favorable, with an 
overall proportion of participants receiving 8-16 weeks in clinical trials permanently 
discontinuing treatment due to adverse reactions of 0.1%. The most common adverse 
reactions including all grades in greater or equal to 5% of participants were headache 
(13%), fatigue (11%), and nausea (8%), with 80% of all adverse reactions classified as 
mild in severity. [Mavyret USPI; AbbVie Inc., North Chicago, IL; August 2018]    
 
For HIV-1/HCV co-infected individuals, the safety and efficacy of glecaprevir and 
pibrentasvir were evaluated in the phase III, multicenter EXPEDITION-2 study [33]. This 
study evaluated 8 weeks of the daily FDC of glecaprevir (G) 300 mg/pibrentasvir (P) 120 
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participants without cirrhosis and 12 weeks of G/P in 16 HIV/HCV-co-infected 
participants with compensated cirrhosis. Treatment-naïve and treatment-experienced 
participants with genotype 1, 2, 3, 4, or 6 infection were enrolled. Participants were 
either antiretroviral (ARV)-naïve with a CD4 cell count ≥500/mm3, or on a stable 
antiretroviral therapy (ART) regimen for at least 8 weeks with a CD4 cell count 
≥200/mm3. Overall SVR12 was 100% (136/136) among those without cirrhosis on the 8-
week regimen, and 93% (14/15) in those with compensated cirrhosis on the 12-week 
regimen. Four serious adverse events (AEs) were reported, none of which were DAA-
related. One of these led to treatment discontinuation (cerebral hemorrhage) [31]. 
 
2.2 
Rationale 
 
The combination regimen of G/P is an ideal candidate for the treatment of acute 
infection. This regimen has broad efficacy across HCV genotypes, is dosed once daily, 
avoids RBV, and is associated with minimal side effects. Together, these medications 
have an extremely high barrier to development of resistance and are potent against NS3 
and NS5 resistance-associated substitutions (RASs). In contrast to other DAA regimens 
studied in acute HCV infection, 8 weeks of therapy with G/P is highly effective across a 
wide variety of populations with chronic HCV infection and specifically addresses 
genotype 3, which represents a significant proportion of new cases in the U.S. In phase 
III trials of participants without cirrhosis, the 8-week regimen had high SVR rates, ~95-
100%, for all genotypes and regardless of baseline HCV RNA level [34, 35]. In addition, 
the pharmacokinetics (PK) of this nucleotide-sparing regimen result in rapid steady state 
exposure in the liver tissue, providing biologic plausibility for the potential to shorten 
length of therapy in acute HCV. The efficacy and appropriate duration of G/P in the 
acute phase is unknown but we hypothesize that SVR rates with a shorter duration of 
the highly potent G/P regimen for 4 weeks may supersede 90% based on the above 
reported studies. 
 
The study is designed to conclude with reasonable evidence that the true SVR12 
proportion is greater than 80% in the study population. The 80% SVR threshold was 
chosen as an adjusted average rate from three studies that similarly used half of the 
treatment regimen recommended at that time for chronic HCV: LDV/SOF x 6 weeks [25] 
and two studies examining SOF/RBV x 12 weeks [25, 26]. 
 
Based on the success of the LDV/SOF arm of the two-arm study A5327, which 
examined shortened courses of SOF-based regimens, we propose a phase II trial of G/P 
FDC treatment for acute HCV infection (PURGE-C), an open-label study in which 
participants receive 4 weeks of G/P FDC. 
 
Rationale for Inclusion of HIV Negative Participants and Minimum Number of HIV-1 
Positive Participants 
Unlike A5327, those uninfected with HIV-1 will be included in this trial. As the majority of 
those with HIV and acute HCV are men, this broader inclusion criteria would be 
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primary risk factor. However, given the mission and emphasis of the ACTG, a minimum 
of 10 participants with HIV-1 will be enrolled. There is no maximum limit to the 
enrollment of HIV-1-infected participants. 
 
Rationale for Inclusion of Concomitant ART Regimens 
Formal drug-drug interaction studies in HIV/HCV seronegative individuals have been 
performed with G/P and the following antiretroviral agents:  
• 
abacavir/lamivudine/dolutegravir 
• 
atazanavir/ritonavir 
• 
darunavir/ritonavir 
• 
lopinavir/ritonavir 
• 
raltegravir 
• 
rilpivirine 
• 
tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat 
• 
tenofovir disoproxil fumarate/emtricitabine/efavirenz 
 
No clinically significant interactions were observed with abacavir, lamivudine, 
dolutegravir, raltegravir, rilpivirine, tenofovir alafenamide, tenofovir disoproxil fumarate or 
emtricitabine. Interactions were observed and/or are expected with atazanavir, efavirenz, 
and etravirine and ritonavir and cobicistat-based regimens [Mavyret USPI]. A description 
of the potential for clinically significant interactions follows. 
 
Co-administration of efavirenz with G/P did not affect efavirenz levels but glecaprevir 
and pibrentasvir exposures were significantly lower compared to historical data. 
Etravirine has similar potential for drug interactions and while not formally studied to 
date, is not recommended for coadministration with G/P. In contrast, coadministration 
with rilpivirine resulted in similar glecaprevir and pibrentasvir levels to controls and while 
rilpivirine levels were increased (Cmax by 105%, AUC by 84%), no safety issues were 
identified [36, 37].  
 
Ritonavir-boosted protease inhibitors increase glecaprevir exposures. When G/P was 
co-administered with atazanavir and ritonavir, glecaprevir Cmax and AUC were 
increased 4-fold and 6.5-fold, respectively and asymptomatic (Grades 1 and 2) ALT 
elevations were observed. When G/P was co-administered with darunavir and ritonavir, 
glecaprevir Cmax and AUC were increased to 3.1 and 5.0-fold, respectively compared to 
controls, but no ALT elevations were observed [Mavyret USPI]. Given this study will 
enroll non-cirrhotic individuals and the duration of co-administration is limited to 4 weeks, 
we will allow participants on ritonavir-boosted darunavir. LFTs will be monitored at 
Weeks 1 and 2 of G/P therapy. Ritonavir-boosted atazanavir will not be allowed.   
 
The pharmacologic booster cobicistat when administered as part of a combination 
(tenofovir alafenamide, emtricitabine, cobicistat, elvitegravir) resulted in increases of 
Cmax and AUC for both glecaprevir (150 to 205%) and pibrentasvir (24-57%), while 
elvitegravir and cobicistat levels were increased by 29-47%. No attributable AEs were 
reported [38]. Cobicistat-boosted darunavir will be allowed.  
 


 
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The EXPEDITION-2 trial included HIV/HCV co-infected participants on abacavir, 
dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, tenofovir alafenamide, and 
tenofovir disoproxil fumarate. One patient received elvitegravir/cobicistat [33]. 
 
To summarize, drug-drug interaction studies and trial data support the concomitant use 
of raltegravir, dolutegravir, rilpivirine, tenofovir disoproxil fumarate, tenofovir 
alafenamide, abacavir, emtricitabine, and lamivudine. Bictegravir is expected to have 
similar properties as dolutegravir and will be allowed. Cobicistat with elvitegravir, 
cobicistat with darunavir and ritonavir-boosted darunavir will be allowed as the exposure 
of G/P is only 4 weeks and participants are non-cirrhotic.  
 
Neither glecaprevir nor pibrentasvir have any activity against HIV-1 in vitro; their use in 
participants infected with HIV-1 who meet criteria for being off therapy is therefore 
considered safe from a virologic standpoint. 
 
Rationale for Retreatment Approaches 
This study will re-treat participants with viral recurrence or virologic failure.  
 
Viral relapse rates are very low after 8-16 weeks of G/P treatment in NS5A-inhibitor 
naïve populations with chronic infection (0-1%). However, for the small percentage of 
individuals that do experience viral relapse, RASs in NS3 and/or NS5A are present in 
the majority (89%) [39]. Given that the use of ultra-short duration of treatment for acute 
HCV infection could be associated with increased viral relapse rates and there are no 
data to inform the risk of RAS selection with 4 weeks of G/P treatment, a retreatment 
strategy within the study is desirable. When G/P alone was assessed as a retreatment 
strategy for individuals who had failed prior DAA-containing therapy with multiple drug 
class exposure, the presence of concurrent NS3 and NS5A RASs adversely impacted 
outcomes. In part 1 of the MAGELLAN-1 study, a small number of participants with prior 
DAA treatment were retreated with G/P plus RBV (n=22) or G/P alone (n=22) for 12 
weeks [40]. The modified intention to treat (mITT) SVR12 was the same in both groups, 
95%. In the subset with prior exposure to both NS3 and NS5A inhibitors, 5/6 (83%) and 
8/9 (89%) treated with 12 weeks plus RBV and 12 weeks without RBV, respectively 
achieved SVR12. In part 2 of the MAGELLAN-1 study, SVR12 was 100% for those 
without RASs or only NS3 RASs, 89% NS5A RASs and 56% for those with both NS3 
and NS5A RASs [39]. The duration of G/P retreatment (12 vs 16 weeks) had no clear 
impact on responses in those with dual class (NS3 and NS5A) exposure with 79% (CI: 
52-92%) treated for 12 weeks (n=14) achieving SVR and 81% (CI: 57-93%) in those 
treated for 16 weeks. While supporting the potential impact of RASs on retreatment with 
G/P after DAA failure, none of the participants in this study had prior exposure to G/P 
limiting the applicability to the current study and retreatment approaches. However, in 
the Magellan 3 study retreatment of 23 prior GT1, 2, and 3 G/P treatment failures with 16 
weeks of G/P plus SOF plus RBV was highly efficacious with an SVR rate of 96% 
(22/23) [41]. 
 
In the DAA era, re-treatment with longer durations using the same agent(s) has been 
attempted with success. For instance, 9 HIV-1/HCV co-infected individuals experienced 
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with 24 weeks of LDV/SOF plus RBV [42]. In an HCV-mono-infected cohort, participants 
failing 8 weeks of sofosbuvir/velpatasvir/voxilaprevir were retreated with 12 weeks of the 
same regimen with 100% (17/17) SVR12 [43]. In addition preliminary data suggest that 
Sof/Vel/Vox may be also be a suitable retreatment regimen for G/P treatment failures 
with 13/14 G/P treatment failures achieving SVR12 following 12 weeks of Sof/Vel/Vox 
retreatment [44].  
 
In sum, the limited data remain inconclusive on the benefits of adding RBV or extending 
duration when using G/P to retreat individuals previously exposed to both NS3 and 
NS5A DAAs. Extrapolation of data from other re-treatment studies does suggest some 
benefit of treatment extension and/or the addition of RBV. Given the ultra-short duration 
of treatment in the current study and that participants are not yet in the chronic phase 
and will not have cirrhosis, 16 weeks of G/P plus RBV could be an effective treatment 
strategy for recurrence and virologic failures. However, acknowledging the more robust 
data on the use of SOF-based triple DAA regimens for re-treatment of DAA failures, site 
investigators will have discretion to use a SOF-based triple DAA treatment regimen for 
re-treatment of participants. SOF-based treatments will not be provided by this study and 
may require insurance approval. 
 
For viral recurrence that is clearly re-infection (defined by new genotype/subtype), the 
participant will receive the standard regimen used for chronic HCV (8 weeks of G/P) 
during Step 2. In such circumstances, despite diagnosis of a new acute re-infection, the 
participant may not be “re-enrolled” into Step 1. 
 
Rationale for IL28-B and Human Leukocyte Antigen (HLA) Testing 
IL28-B is a gene polymorphism associated with natural clearance of HCV infection and 
of innate IFN stimulation. IL28-B polymorphism and HLA typing determination will be 
important for interpretation of immunologic studies. IL28-B genotyping is also important 
in acute HCV infection studies to characterize the study population’s innate potential for 
natural clearance. 
 
 
Rationale for Rapid Treatment of Acute HCV  
Guidelines have suggested a waiting period to assess for spontaneous clearance before 
treatment of acute HCV. Reported rates of spontaneous clearance of HCV among HIV-
1-infected individuals are highly variable due to small sample sizes and significant 
variance across study populations. On average it is reported that 5-15% of HIV-1 
infected individuals acutely infected with HCV will spontaneously clear the infection [38, 
45-49]. Multiple baseline factors have been reported as predictive of clearance including 
female sex, host genetic factors including the IL28-B favorable genotype, and early 
favorable HCV-RNA kinetics [14, 50, 51]. There are studies assessing viral kinetics in 
the early infection period and report ranges from 6%-48% of participants having 
detectable HCV RNA 12 weeks after first clinical evidence of infection and go on to 
spontaneously clear the infection [52-54]. Indeed on rare occasions participants have 
been reported to spontaneously clear the infection after 12-13 months or even longer 
[41, 55]. Many of these are very small, single center studies; however, the bulk of 
studies suggest that the majority of participants with acute HCV infection will develop 
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clearance among HIV positive MSM was only 11.9%; as the majority of the remainder 
received relatively early antiviral treatment, the true rate of clearance may be somewhat 
higher [55, 56]. Ultimately, if antivirals are offered for acute HCV it is a minority (6-10%) 
of participants who may receive treatment unnecessarily. Moreover, these data must be 
balanced with the evidence that suggests a delay in initiation of therapy for acute HCV 
decreases the chance of achieving a SVR. A meta-analysis of early treatment in 417 
HCV mono-infected participants reported that those participants who delayed therapy 
>12 weeks) from diagnosis had lower SVR (67%) than those treated at or within 12 
weeks of diagnosis (83%) [9]. Delayed therapy was also associated with decreased SVR 
in a large pooled cohort of injection drug users [57]. In ACTG A5327 Cohort 1, those with 
a “less active” immunologic profile had a lower rate of SVR. Preliminary data also 
indicate that earlier treatment may preserve multi-specific HCV-specific T-cell 
responses, which are thought to be critical to the ability to prevent HCV viral persistence 
[Lauer et al., unpublished data]. Especially for those with HIV, where spontaneous 
clearance rates are as low as 11.9%, a “test and treat” strategy similar to other infectious 
diseases is justified, especially if the cost-saving strategy of shortened DAA courses is 
validated [23]. 
 
2.3 
Overall Risk/Benefit Assessment 
 
No clinical safety issues specifically related to G/P have been identified to date in HCV 
mono-infected or HIV-1/HCV co-infected participants without cirrhosis or with 
compensated cirrhosis.  
 
The expected benefits to participants being treated with G/P is a rapid and durable 
eradication of HCV virus and a shortened treatment period. Potential risks include 
unforeseen safety issues and unknown implications of virologic failure due to the 
emergence of resistant virus. 
 
For the population of HIV-1/HCV co-infected participants, the potential benefit of 
achieving SVR with 4 weeks of an IFN-free regimen outweighs the risks associated with 
the possible development of previously unidentified safety issues or the emergence of 
quasi-species resistant to glecaprevir or pibrentasvir [58]. Furthermore, the benefits of 
limiting the potential for onward transmission carries significant societal benefit and cost 
savings. For participants who experience recurrence or virologic failure after 4 weeks of 
treatment, a re-treatment regimen will be offered, minimizing risk of participating in this 
study. 
 
If high rates of SVR can be obtained with a shortened, IFN-free regimen, without 
frequent emergence of resistant HCV, the anticipated improvements in safety and 
tolerability would offer a favorable risk-benefit determination for individuals with acute 
HCV infection. 
 
Other risks of the study are outlined below including risks associated with blood draws, 
risks of study drugs, risks of changing ART or other medications in order to qualify for 
the study, and the small risk of HBV reactivation.  
 


 
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Risks of Drawing Blood 
Drawing blood could result in some discomfort, lightheadedness, bleeding, swelling, or 
bruising where the needle enters the body, and in rare cases, fainting, or infection for the 
participant. 
 
Risks of Study Drugs 
The drugs used in this study may have side effects, such as headaches, fatigue, 
diarrhea, nausea, asthenia, pruritic skin, and abnormal liver function tests. There is a risk 
of serious and/or life-threatening side effects when certain non-study medications are 
taken with the study drugs.  
 
Drug interactions may increase the chances of side effects, may affect the levels of 
ARVs or other medications and/or cause changes in liver enzymes and other abnormal 
blood tests. Certain HIV medications may be changed to reduce this risk. For certain 
HMG-CoA reductase inhibitors (statins), others may require dose adjustment or careful 
monitoring. For digoxin, the dose should be reduced and closely monitored while on 
G/P. Drug interactions that lower the levels of glecaprevir or pibrentasvir may decrease 
the participant’s chances for a cure of hepatitis C and/or select for drug resistance. 
Certain drugs known to cause lower levels of glecaprevir or pibrentasvir will be avoided.  
 
 
Some people with HCV and HBV coinfection receiving DAA therapy for HCV, have 
experienced reactivation of HBV. Some of these cases have led to severe hepatitis, liver 
failure and death. This has been reported mostly in individuals who are positive for 
HBsAg and extremely rarely in those who appear to have resolved HBV infection by lab 
tests. Those with HBsAg will be excluded, while those with resolved HBV infection will 
be monitored.  
 
Ribavirin may be used in Step 2 for those with detection of viremia after 4 weeks of 
glecaprevir/pibrentasvir in Step 1. The most common AE of RBV therapy is anemia due 
to hemolysis. Anemia typically occurs within 1 to 2 weeks of initiating RBV therapy and 
usually resolves within 4 to 8 weeks of drug discontinuation or dose reduction. Indirect 
bilirubin elevation is commonly seen in those participants with anemia secondary to 
RBV-induced hemolysis.  
 
Another major side effect of RBV is its teratogenicity. It is therefore strongly 
recommended that pregnant women or breastfeeding women and men with pregnant 
sexual partners not receive RBV. Women who become pregnant on study and men on 
study whose partners become pregnant must discontinue study treatment and complete 
the discontinuation evaluations as indicated in section 8.2. 
 
Risks of Delaying HIV Therapy 
While participants with HIV are not required to be on ARVs to enter the study and, 
although the HCV treatment period is 4 weeks for Step 1, a delay in necessary HIV 
medications could allow for progression of HIV disease, which can increase the risk of 
opportunistic infections and long-term after effects for participants living with HIV.  
 


 
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2.4 
Adherence Measures 
 
The efficacy of G/P for the treatment of acute HCV may be influenced by participants’ 
adherence to the study medications. There is no perfect measure of adherence, but 
tools include pill counts, pharmacy refill records, self-report, directly observed therapy 
(DOT), measurement of drug concentrations, and electronic monitoring (video DOT). 
This study will use some of these measures (see section 6.3.14).  
 
2.5 
Cost-effectiveness Analysis 
 
The cost of treating chronic HCV infection has been a major concern since the beginning 
of the DAA era. While treatments have been extremely successful, this has come at 
major cost to the health care system [23]. The potential for treating acute infection with a 
4-week course has the potential to not only improve outcomes, but also to provide cost 
savings or extremely good value for the resources spent. A questionnaire on self-report 
resource use and quality of life (QOL) will be used to assess the number of outpatient 
visits, hospital days (if any), and quality of life associated with G/P treatment, and a 
microsimulation model [23] for assessment of the cost-effectiveness of the strategy (see 
section 6.3.16).  
 
Using the microsimulation model, the life expectancy, quality-adjusted life years, total 
costs, and reduction in HCV transmission for the following two strategies: (1) 4-week 
G/P treatment of acute HCV; and (2) wait for 6 months and treat only those who develop 
chronic HCV infection (referred to as “treat chronic HCV” strategy) will be estimated. In 
both strategies, simulated patients that get re-infected may get re-treatment. The 
incremental cost-effectiveness ratio of “treat acute HCV” compared to “treat chronic 
HCV” strategy will be estimated. The above outcomes separate for HCV/HIV co-infected 
patients and HCV mono-infected patients will be presented. A one-way and probabilistic 
sensitivity analysis to assess the robustness of cost-effectiveness results will also be 
conducted. 
 
3.0 
STUDY DESIGN 
 
A5380 is a phase II single-arm, open-label study to assess the efficacy of FDC G/P in 
acute HCV-infected participants, with and without HIV-1 coinfection, given for 4 weeks. 
This study will assess whether G/P confers successful treatment, superior to a cure rate 
of 80%. The study will entail 2 steps: Step 1—treatment of acute infection with 4 weeks 
of G/P, and Step 2—re-treatment of participants experiencing post-treatment viremia in 
Step 1 with 8-16 weeks of G/P with or without RBV with modifications to the retreatment 
regimen allowed at the discretion of the site PI after discussion with the A5380 CMC.  
 
Prospective participants will be enrolled in Step 1 if diagnosed with acute infection, 
defined below in section 4.1.3. Both HIV infected and HIV uninfected participants will be 
included, and participants with HIV who are taking protocol-defined compatible ARVs, as 
per discretion of the local provider. A minimum of 10 participants with HIV will be 
enrolled. 
 


 
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Step 1 post-treatment follow-up visits for all participants will occur at 4, 8, 12, and 24 
weeks after the last dose of study drug (FDC G/P). 
 
The primary outcome will be SVR12 (i.e., HCV RNA <LLOQ, either TD or TND, at 12 
weeks after end of treatment).  
 
Participants experiencing documented viral recurrence before or at the week 16 or 
SVR12 visit will proceed to Step 2 and be classified as either re-infection or suspected 
relapse, prior to re-treatment. The type of viral recurrence (suspected relapse versus re-
infection) will be determined by the A5380 team chair, co-chairs, and virologist 
(actg.cmcA5380@fstrf.org) based initially on genotype/subtype information and 
resistance testing and then reported to the sites by email to inform them of the 
recommended re-treatment regimen for Step 2. If a re-infection, they will be re-treated 
with 8 weeks of FDC G/P. If a suspected relapse, they will be re-treated with a treatment 
regimen of 16 weeks of FDC G/P with or without weight-based RBV, irrespective of 
genotype. Participants experiencing virologic failure (failure to achieve HCV RNA <LLOQ 
and confirmed increase in HCV RNA >1 log10 from nadir) will also proceed to Step 2 and 
will be re-treated with 16 weeks of FDC G/P with or without weight-based RBV. 
Participants experiencing post-treatment HCV viremia not otherwise defined as re-
infection, suspected relapse or virologic failure will also proceed to Step 2 and will be re-
treated with 16 weeks of FDC G/P with or without weight-based RBV. At the discretion of 
the site PI and upon discussion with the A5380 CMC (actg.cmcA5380@fstrf.org), 
participants experiencing suspected relapse, virologic failure, or undefined post-
treatment HCV viremia may be re-treated with an alternative, non-study provided 
regimen. Retreatment options are outlined in the Manual of Procedures (MOPS).   
 
Participants who meet criteria for Step 2, but opt out of therapy will continue study visits 
on the Step 1 schedule. 
  
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Step 1 Inclusion Criteria 
 
4.1.1 Ability and willingness of participant to provide written informed consent for Step 
1. 
 
4.1.2 Men and women age ≥18 years 
 
4.1.3 A documented confirmation of acute HCV infection within 24 weeks prior to entry 
or HCV reinfection as described below:  
 
Acute HCV infection will be defined as meeting one of the following criteria, 
depending on whether the participant was never previously infected or previously 
infected with clearance (treatment induced or natural) and after exclusion of other 
causes of acute hepatitis:  
 


 
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Never Previously Infected:  
New (<24 weeks prior to Step 1 entry) ALT elevation to ≥5X upper limit of normal 
(ULN) OR >250 U/L in participants with documented normal ALT in the preceding 
52 weeks or ≥10 x ULN OR >500 U/L in participants with abnormal or no 
measured ALT baseline in the 52 weeks prior to study entry with detectable HCV 
RNA.  
 
OR  
 
Detectable HCV RNA with prior negative anti-HCV antibody (Ab) within 24 weeks 
prior to study entry or prior undetectable HCV RNA within 24 weeks prior to study 
entry.  
 
Previously Infected: 
For those with evidence of previous infection (as evidenced by positive anti-HCV 
Ab), documentation of clearance of prior infection either spontaneously with two 
negative HCV RNA a minimum of 12 weeks apart or after treatment with negative 
HCV RNA a minimum of 12 weeks after last dose of anti-HCV treatment AND 
meeting one of the following criteria in addition to exclusion of other causes of 
acute HCV:  
 
New (<24 weeks prior to Step 1 entry) ALT elevation to ≥5 x ULN OR >250 U/L in 
participants with documented normal ALT in the preceding 52 weeks or ≥10 x 
ULN OR >500 U/L in participants with abnormal or no measured ALT baseline in 
the preceding 52 weeks with detectable HCV RNA.  
 
OR  
 
Detectable HCV RNA with prior undetectable HCV RNA within 24 weeks prior to 
study entry.  
 
4.1.4 Detectable HCV RNA at the screening visit. 
 
4.1.5 HCV genotype obtained within 24 weeks prior to entry by any US laboratory that 
has a Clinical Laboratory Improvement Amendments (CLIA) certification or its 
equivalent, or at any network-approved non-US laboratory that operates in 
accordance with Good Clinical Laboratory Practices (GCLP) and participates in 
appropriate external quality assurance programs. 
 
4.1.6 HIV-1 infection status documented as either absent or present, as defined below: 
 
For participants self-reporting as HIV-1 negative, HIV-1 infection testing should 
be performed at screening via rapid HIV-1 and/or enzyme or chemiluminescence 
immunoassay (E/CIA) test kit. 
 
OR 
 


 
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HIV-1 infection, documented by any licensed rapid HIV-1 test or HIV-1 E/CIA test 
kit at any time prior to study entry and confirmed by a licensed Western blot or a 
second antibody test by a method other than the initial rapid HIV-1 and/or E/CIA, 
OR by HIV-1 p24 antigen, OR documented plasma HIV-1 RNA viral load >LLOQ 
at any time prior to study entry. 
 
NOTE: The term “licensed” refers to a FDA-approved kit, which is required for all 
IND studies. For sites that are unable to obtain an FDA-approved kit, a kit that 
has been certified or licensed by an oversight body within the country and 
validated internally is acceptable.  
 
WHO (World Health Organization) and CDC (Centers for Disease Control and 
Prevention) guidelines mandate that confirmation of the initial test result must 
use a test that is different from the one used for the initial assessment. A reactive 
initial rapid test should be confirmed by either another type of rapid assay or an 
E/CIA that is based on a different antigen preparation and/or different test 
principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 
RNA viral load.  
 
4.1.7 For HIV-1 co-infected participants on ART, screening HIV-1 RNA must be <50 
copies/mL or <LLOQ of local assay if LLOQ is >50 copies/mL within 28 days 
prior to entry, as measured by any laboratory that has a CLIA certification or its 
equivalent or at any network-approved non-US laboratory that operates in 
accordance with GCLP and participates in appropriate external quality assurance 
programs.  
 
NOTE: A single value ≥50 copies/mL but below 200 copies/mL at screening 
should be repeated within the screening window before screen-fail determination 
can be made; if repeat values are <50 copies/mL then the participant remains 
eligible. 
 
4.1.8 For HIV-1 co-infected participants, HIV-1 ART should meet one of the following 
criteria: 
 
a) ART untreated due to (1) lack of indication per provider (CD4+ T-cell count 
≥500 cells/mm3) or (2) decision by provider and participant to defer ART 
during the G/P dosing period (4 weeks). 
 
OR 
 
b) On a stable, protocol-defined compatible ART regimen (per sections 2.2 
[Rationale for Inclusion of Concomitant ART Regimens] and 5.4.1) for >2 
weeks prior to starting G/P with a CD4+ T-cell count >100 cells/mm3 within 
180 days prior to the screening visit. Laboratory testing can be done by any 
laboratory that has a CLIA certification or its equivalent or at any network-
approved non-US laboratory that operates in accordance with GCLP and 
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4.1.9 The following laboratory values obtained within 28 days prior to study entry by 
any US laboratory that has a CLIA certification or its equivalent, or at any 
network-approved non-US laboratory that operates in accordance with GCLP 
and participates in appropriate external quality assurance programs. 
• 
International normalized ratio (INR) <1.5  
NOTE: INR ≥1.5 x ULN is acceptable in participants with known hemophilia 
or stable on an anticoagulant regimen affecting INR, at the discretion of the 
site PI. 
• 
Albumin ≥3.0 g/dL 
 
4.1.10 Female participants of reproductive potential (defined as a person who has not 
been post-menopausal for at least 24 consecutive months, i.e., who has had 
menses within the preceding 24 months, or women who have not undergone 
surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or 
bilateral salpingectomy), must have a negative serum or urine pregnancy test 
within 48 hours prior to study entry by any US clinic or laboratory that has a CLIA 
certification or its equivalent, or is using a point-of-care (POC)/CLIA-waived test 
or at any network-approved non-US laboratory or clinic that operates in 
accordance with GCLP and participates in appropriate external quality assurance 
programs. The serum, urine, or POC pregnancy test must have a sensitivity of at 
least 25 mIU/mL. 
 
4.1.11 All participants of reproductive potential must agree not to participate in a 
conception process (e.g., active attempt to become pregnant, in vitro fertilization) 
while on study treatment and for 6 weeks after stopping protocol-specified 
medication. 
 
4.1.12 When participating in sexual activity that could lead to pregnancy, all participants 
of reproductive potential must agree to use at least one reliable form of 
contraception while receiving protocol-specified medication, and for 6 weeks after 
stopping the medication. Such methods include: 
• 
Condoms (either self or require their partner to use one) with spermicide  
• 
Diaphragm or cervical cap with spermicide  
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive (not ethinyl-estradiol containing) 
• 
Tubal ligation 
 
NOTE: Providers and participants should be advised that not all contraceptive 
choices listed above can prevent HIV transmission and that some may actually 
increase the risk of HIV acquisition. Study participants who are sexually active 
should be advised that they need to consider effective strategies for reducing the 
risk of HIV transmission, as well as meeting the requirement for effective 
contraception during their participation in the study. Study participants should 
discuss contraceptive choices and HIV risk reduction methods with their health 
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4.1.13  Participants who are not of reproductive potential (participants who have been 
post-menopausal for at least 24 consecutive months or have undergone 
hysterectomy and/or bilateral oophorectomy or salpingectomy or who have 
documented azoospermia or undergone vasectomy) are eligible without requiring 
the use of contraceptives. Acceptable documentation of sterilization and 
menopause is specified below.  
 
Written or oral communication by clinician or clinician’s staff of one of the 
following: 
• 
Physician report/letter/operative report or other source documentation in the 
medical record (a laboratory report of azoospermia is required to document 
successful vasectomy)  
• 
Discharge summary 
• 
Follicle stimulating hormone-release factor (FSH) measurement elevated into 
the menopausal range as established by the reporting laboratory 
 
4.2 
Step 1 Exclusion Criteria 
 
4.2.1 Received investigational drug or device within 60 days prior to study entry.  
 
4.2.2 Any preceding administration of HCV treatment during the current acute HCV 
infection episode. 
 
4.2.3 Known preexisting cirrhosis, whether compensated or decompensated. 
 
4.2.4 Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s 
disease, α1 antitrypsin deficiency, primary sclerosing cholangitis). 
 
4.2.5 Acute HIV-1 infection defined as the phase immediately following infection during 
which anti-HIV-1 antibodies are not detected and with detectable HIV-1 RNA. 
 
NOTE: Participants with early HIV-1 infection, defined as within the first 6 months 
of infection and with a positive HIV-1 antibody, should be discussed with the 
A5380 CMC. These participants may be considered for inclusion in the study on 
a case-by-case basis with the specific documented approval of the protocol 
chairs. 
 
4.2.6 Presence of active or acute AIDS-defining opportunistic infections within 30 days 
prior to study entry.  
 
NOTE: A list of AIDS-defining opportunistic infections as defined by the CDC, 
can be found in Appendix B of the following document: 
http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm 
 
4.2.7 Active, serious infection (other than HIV-1 or HCV) requiring parenteral 
antibiotics, antivirals, or antifungals within 30 days prior to study entry.  


 
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4.2.8 Infection with hepatitis B virus (HBV) defined as HBsAg or HBc IgM positive.  
 
4.2.9 Evidence of current acute hepatitis A infection defined as hepatitis A virus (HAV) 
IgM positive. 
 
4.2.10 Chronic use of systemically administered immunosuppressive agents (e.g., 
prednisone equivalent to >10 mg/day). 
 
4.2.11 History of solid organ transplantation. 
 
4.2.12 History of a gastrointestinal disorder (or post-operative condition) that could 
interfere with the absorption of the study drug as determined by the site PI. 
 
4.2.13 History of significant or symptomatic pulmonary disease, cardiac disease, or 
porphyria as determined by the site PI. 
 
4.2.14 History of clinically significant illness or any other major medical disorder that 
may interfere with participant treatment, assessment, or compliance with study 
requirements as determined by the site PI. 
 
4.2.15 For non-antiretroviral medications, use of any prohibited concomitant 
medications within 28 days prior to study entry.  
 
NOTE: Use of prohibited ARVs within 14 days prior to study entry is not allowed. 
See section 5.4.1. 
 
4.2.16 Use of daily proton pump inhibitor (PPI) at doses ≥40 mg of omeprazole (or 
equivalent) within 5 days prior to study entry. See the A5380 protocol specific 
web page (PSWP) for information on equivalents to omeprazole.  
 
NOTE: PPI can be discontinued or dose reduced to 20 mg/day of omeprazole (or 
equivalent) at least 5 days prior to study entry. 
 
4.2.17 Known hypersensitivity to glecaprevir or pibrentasvir, the metabolites, or 
formulation excipients or any other contraindication to the use of G/P. 
 
4.2.18 Pregnant or breastfeeding, including males with pregnant female partner. 
 
4.3 
Step 2 Inclusion Criteria 
 
4.3.1 Ability and willingness of participant to provide written informed consent for Step 
2. 
 
4.3.2 Completion of Step 1 treatment regimen and meeting any of the below criteria, 
before or at the week 16 (SVR12) Step 1 visit: 
 


 
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Suspected relapse, defined as HCV RNA <LLOQ (TD or TND) at end of 
treatment (week 4) or during follow-up, and including confirmation of HCV RNA 
>LLOQ with the same genotype. 
 
NOTE: Suspected relapse is documented by the email receipt of relapse 
determination by the designated A5380 team member. 
 
OR 
 
Re-infection, defined as HCV RNA <LLOQ (TD or TND) at end of treatment 
(week 4) or during follow-up, and including confirmation of HCV RNA >LLOQ with 
new genotype consistent with a new HCV viral infection.  
 
NOTE: Re-infection is documented by the email receipt of re-infection 
determination by the designated A5380 team member. 
 
OR 
 
Virologic failure, defined as failure to achieve HCV RNA <LLOQ (TD or TND) and 
confirmed increase in HCV RNA >1 log10 from nadir. 
 
OR 
 
Post-treatment HCV viremia, defined as HCV RNA >LLOQ at any point after end 
of treatment (week 4) or during follow-up, not otherwise meeting definition of 
suspected relapse, re-infection, or virologic failure. 
 
4.3.3 Detectable HCV RNA from the confirmatory sample (see section 6.2.4) collected 
within 56 days of Step 2 entry. 
 
4.3.4 HIV-1 infection status documented as absent or present, as defined below: 
 
For participants self-reporting as HIV-1 negative, HIV-1 infection testing should 
be performed prior to Step 2 entry via rapid HIV-1 and/or E/CIA test kit. 
 
OR 
 
HIV-1 infection, documented by any licensed rapid HIV-1 test or HIV-1 E/CIA test 
kit at any time prior to study entry and confirmed by a licensed Western blot or a 
second antibody test by a method other than the initial rapid HIV-1 and/or E/CIA, 
OR by HIV-1 p24 antigen, OR documented plasma HIV-1 RNA viral load >LLOQ 
at any time prior to study entry. 
 
NOTE: The term “licensed” refers to a FDA-approved kit, which is required for all 
IND studies. For sites that are unable to obtain an FDA-approved kit, a kit that 
has been certified or licensed by an oversight body within the country and 
validated internally is acceptable.  


 
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WHO (World Health Organization) and CDC (Centers for Disease Control and 
Prevention) guidelines mandate that confirmation of the initial test result must 
use a test that is different from the one used for the initial assessment. A reactive 
initial rapid test should be confirmed by either another type of rapid assay or an 
E/CIA that is based on a different antigen preparation and/or different test 
principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 
RNA viral load.  
 
4.3.5 The following laboratory values obtained within 56 days prior to Step 2 entry by 
any US laboratory that has a CLIA certification or its equivalent, or at any 
network-approved non-US laboratory that operates in accordance with GCLP 
and participates in appropriate external quality assurance programs. 
• 
INR <1.5  
NOTE: INR ≥1.5 is acceptable in participants with known hemophilia or stable 
on an anticoagulant regimen affecting INR at the discretion of the site PI. 
• 
Albumin ≥3.0 g/dL 
NOTE: For INR and albumin values, values from the virologic 
failure/recurrence results in Step 1 can be used and there is no need to draw 
additional samples. 
• 
For participants receiving RBV, hemoglobin ≥12 g/dL for male, ≥11 g/dL for 
female.  
 
4.3.6 Female participants of reproductive potential (defined as women who have not 
been post-menopausal for at least 24 consecutive months, i.e., who have had 
menses within the preceding 24 months, or women who have not undergone 
surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or 
bilateral salpingectomy) must have a negative serum or urine pregnancy test 
within 48 hours prior to Step 2 entry by any laboratory or clinic that has a CLIA 
certificate or its equivalent, or is using a POC/CLIA-waived test or at any 
network-approved non-US laboratory or clinic that operates in accordance with 
GCLP and participates in appropriate external quality assurance programs. The 
serum, urine or POC pregnancy test must have a sensitivity of at least 25 
mIU/mL.  
 
4.3.7  All participants must agree not to participate in a conception process (e.g., active 
attempt to become pregnant or to impregnate, sperm donation, in vitro 
fertilization).  
 
NOTE: Female candidates who are pregnant or breastfeeding are not eligible for 
Step 2 of the study. A male candidate who has a pregnant female partner is also 
not eligible for Step 2. 
 


 
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4.3.8  When participating in sexual activity that could lead to pregnancy, all participants 
of reproductive potential must agree to use at least one reliable form of 
contraception simultaneously while receiving protocol-specified medications, and 
for 6 weeks after stopping the medication. For participants on RBV two forms of 
birth control, for 6 months after stopping the medications. Such methods include:  
• 
Condoms (either self or require their partner to use one) with spermicide  
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Tubal ligation 
• 
Hormone-based contraceptive (not ethinyl-estradiol containing) 
 
NOTE: Providers and participants should be advised that not all contraceptive 
choices listed above can prevent HIV transmission and that some may actually 
increase the risk of HIV-1 acquisition. Study participants who are sexually active 
should be advised that they need to consider effective strategies for reducing the 
risk of HIV-1 transmission, as well as meeting the requirement for effective 
contraception during their participation in the study. Study participants should 
discuss contraceptive choices and HIV risk reduction methods with their health 
care provider.  
 
4.3.9 Participants who are not of reproductive potential (participants who have been 
post-menopausal for at least 24 consecutive months or have undergone 
hysterectomy and/or bilateral oophorectomy or salpingectomy or have 
documented azoospermia or undergone vasectomy) are eligible without requiring 
the use of contraceptives. Acceptable documentation of sterilization and 
menopause is specified below.  
 
Written or oral communication by clinician or clinician’s staff of one of the 
following:  
• 
Physician report/letter/operative report or other source documentation in the 
medical record (a laboratory report of azoospermia is required to document 
successful vasectomy)  
• 
Discharge summary 
• 
FSH measurement elevated into the menopausal range as established by 
the reporting laboratory.  
 
4.4 
Step 2 Exclusion Criteria  
 
4.4.1 Known preexisting cirrhosis, whether compensated or decompensated 
discovered since Step 1 entry. 
 
4.4.2 Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s 
disease, α1 antitrypsin deficiency, primary sclerosing cholangitis). 
 


 
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4.4.3 Acute HIV-1 infection defined as the phase immediately following infection during 
which anti-HIV-1 antibodies are not detected, and with detectable HIV-1 RNA 
after enrollment to Step 1.  
 
NOTE: Participants with early HIV-1 infection, defined as within the first 6 months 
of infection and with a positive HIV-1 antibody, should be discussed with the 
A5380 CMC. These participants may be considered for participation in Step 2 on 
a case-by-case basis with the specific documented approval of the protocol 
chairs. 
 
4.4.4 Presence of active or acute AIDS-defining opportunistic infections within 28 days 
prior to Step 2 entry.  
 
NOTE: A list of AIDS-defining opportunistic infections as defined by the CDC, can 
be found in Appendix B of the following document: 
http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm 
 
4.4.5 Active, serious infection (other than HIV-1 or HCV) requiring parenteral 
antibiotics, antivirals, or antifungals within 28 days prior to Step 2 entry.  
 
4.4.6 Infection with HBV defined as HBsAg or HBc IgM positive discovered after 
enrollment to Step 1.  
 
4.4.7 Evidence of acute hepatitis A infection defined as HAV IgM positive discovered 
after enrollment to Step 1. 
 
4.4.8 Current use of systemically administered immunosuppressive agents (e.g., 
prednisone equivalent to >10 mg/day). 
 
4.4.9 Diagnosis of a gastrointestinal disorder (or post-operative condition) that could 
interfere with the absorption of the study drug discovered after enrollment to Step 
1, as determined by the site PI. 
 
4.4.10  Significant or symptomatic pulmonary disease, cardiac disease, or porphyria 
after enrollment to Step 1, as determined by the site PI. 
 
4.4.11 Identification of clinically significant illness or any other major medical disorder 
after enrollment to Step 1 that may interfere with participant treatment, 
assessment, or compliance with study requirements. 
 
4.4.12 For non-antiretroviral medications, use of any prohibited concomitant 
medications within 28 days prior to Step 2 entry.  
 
NOTE: Use of prohibited antiretrovirals within 14 days prior to Step 2 entry is not 
allowed. See section 5.4.1. 


 
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4.4.13 Use of daily PPI doses ≥40 mg of omeprazole (or equivalent) within 5 days prior 
to Step 2 entry. See the A5380 PSWP for information on equivalents to 
omeprazole.  
 
NOTE: PPI can be discontinued or dose reduced to 20 mg/day of omeprazole (or 
equivalent) at least 5 days prior to Step 2 entry. 
 
4.4.14 Discovery of hypersensitivity to glecaprevir or pibrentasvir, the metabolites, or 
formulation excipients, or any other contraindication to the use of G/P and 
alternative regimens after enrollment to Step 1. 
 
4.4.15 Pregnant or breastfeeding, including males with pregnant female partner. 
   
4.5 
Study Enrollment Procedures 
 
4.5.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 
Center (RSC). The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received.  
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all required documents have been received. Site-specific ICF(s) 
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant will be asked to read and sign the 
approved protocol consent form.  


 
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For Step 1 and Step 2, participants from whom a signed informed consent has 
been obtained may be screened and enrolled, if they otherwise qualify. An ACTG 
Screening Checklist must be entered through the DMC Participant Enrollment 
System.  
 
4.5.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment.  
 
4.5.3 Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database.  
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures.  
 
4.6 
Co-enrollment Guidelines  
 
• 
US sites are encouraged to co-enroll participants in A5128, “Plan for Obtaining 
Informed Consent to Use Stored Human Biological Materials (HBM) for Currently 
Unspecified Analyses.” Co-enrollment in A5128 does not require permission from the 
A5380 protocol chairs.  
• 
Non-US sites are encouraged to co-enroll participants in A5243, “Plan for Obtaining 
Human Biological Samples at Non-U.S. Clinical Research Sites for Currently 
Unspecified Genetic Analyses.” Co-enrollment in A5243 does not require permission 
from the A5380 protocol chairs.  
• 
For specific questions and approval for co-enrollment in other studies, sites should 
first check the PSWP or contact the A5380 CMC via e-mail as described in the Study 
Management section. 
 
5.0 
STUDY TREATMENT 
 
Study treatment for all participants in Step 1 of the study is glecaprevir/pibrentasvir.  
 
For participants proceeding to Step 2, study-provided treatment refers to 
glecaprevir/pibrentasvir with or without RBV only. 
 
NOTE: Participants experiencing HCV suspected relapse, virologic failure, or undefined 
post-treatment viremia may, at the discretion of the site PI and with approval of the 
A5380 CMC, be re-treated in Step 2 with a sofosbuvir (SOF)-based triple DAA regimen 
depending on local standard of care (see A5380 MOPS for additional options). These 
participants would continue follow-up per protocol based on the duration of their Step 2 
treatment regimen. 
 


 
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Only glecaprevir/pibrentasvir and RBV (when administered with glecaprevir/pibrentasvir) 
will be provided by the study. All other required DAA drugs, chosen by the site PI based 
on local standards of care for Step 2, will not be provided by the study.  
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimens 
 
Step 1 (4-week duration) 
Upon entry, all eligible participants will receive glecaprevir 100 mg/pibrentasvir 
40 mg FDC tablets to be taken as 3 tablets orally once daily with food for 4 
weeks. The total daily dose administered is glecaprevir 300 mg/pibrentasvir 120 
mg. 
 
A prescription must be provided to the site pharmacist at participant entry that 
includes the Step number, PID, and study identification (SID). 
 
Step 2 (8-16-week duration) 
Any participant who experiences viral re-infection, suspected relapse, virologic 
failure, or undefined post-treatment HCV viremia will proceed to Step 2 for re-
treatment. Based on both the classification of recurrence and the site PI 
preference, participants proceeding to Step 2 will be placed on one of the 
following re-treatment regimens: 
 
Participants with viral re-infection will be re-treated with regimen 2A. 
• 
Regimen 2A:  
Glecaprevir 100 mg/pibrentasvir 40 mg FDC tablet to be taken as 3 tablets 
orally once daily with food for 8 weeks. 
 
For participants experiencing virologic relapse, virologic failure, or undefined 
post-treatment HCV viremia (not otherwise defined as re-infection, relapse, or 
virologic failure), re-treatment options are either regimen 2B or 2C.  
• 
Regimen 2B: 
Glecaprevir 100 mg/pibrentasvir 40 mg FDC tablet to be taken as 3 tablets 
orally once daily with food, plus RBV 200 mg tablets taken orally twice daily 
with food. RBV is to be dosed per Table 5.1.1-1 (Weight-based RBV Dose) 
and Table 5.1.1-2 (Renal Dosing for RBV) with renal dosing superseding 
weight-based dosing as applicable. Treatment duration is 16 weeks. 
• 
Regimen 2C: 
Glecaprevir 100 mg/pibrentasvir 40 mg FDC tablet to be taken as 3 tablets 
orally once daily with food for 16 weeks. 
 
The site PI may choose to re-treat these participants with an alternative SOF-
based triple DAA regimen in accordance with the local standard of care. The re-
treatment regimen choice will be made by the site PI upon discussion with the 
A5380 CMC. All products for alternative regimens, except for 
glecaprevir/pibrentasvir, will need to be obtained locally by the site outside of the 


 
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study. An example that may use both study product and non-study product is 
defined in Regimen 2D. Additional possible DAA regimens to be considered for 
Step 2 can be found in the A5380 MOPS. 
• 
Regimen 2D: 
Glecaprevir/pibrentasvir plus an appropriate third locally-sourced HCV DAA 
product for a minimum of 12 weeks, administered in accordance with 
manufacturer’s package insert and per site clinician’s discretion. The HCV 
DAA product selected by the site PI must be discussed with A5380 CMC prior 
to therapy initiation. 
 
For study products provided through the study in regimens 2A-2D, a new 
prescription must be provided to the site pharmacist at Step 2 initiation that 
includes the Step number, PID, and SID. If participant is being prescribed RBV, 
the prescription must also include weight (kg) and CrCl.  
 
Table 5.1.1-1: Weight-based RBV Dose 
Weight (kg) 
Morning Dose 
Evening Dose 
<75 kg 
600 mg (3 tablets) 
400 mg (2 tablets) 
≥75 kg 
600 mg (3 tablets) 
600 mg (3 tablets) 
The total RBV daily dose has been divided into two doses. The dose of RBV will 
be based on participant’s weight at Step 2 entry or at confirmation visit. Changes 
in weight after Step 2 entry do not require a change in dose. Doses will only be 
changed for toxicity management. 
 
For Step 2 participants with reduced CrCl, RBV can be dosed based on Table 
5.1.1-2 below. 
 
Table 5.1.1-2: Renal Dosing for RBV 
Creatinine Clearance 
RBV Dose 
30-50 mL/min 
Alternating doses, 200 mg (1 tablet) daily 
alternating with 400 mg (2 tablets) daily 
Less than 30mL/min 
and Hemodialysis 
200 mg (1 tablet) daily 
 
5.1.2 Administration 
 
Glecaprevir/pibrentasvir is to be administered as three (3) tablets taken orally 
once daily with food.   
 
Glecaprevir/pibrentasvir should be taken on a regular dosing schedule. If a 
participant does not take a dose at the regular time, and it is less than 18 hours 
from the usual time the participant administers the dose, it should be taken as 
soon as they remember on the same day. Participant should then resume their 


 
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usual dosing schedule the next day. If it has been longer than 18 hours from the 
usual time the participant administers the dose, the missed dose should not be 
taken, and dosing should resume with the next scheduled dose taken at the 
participant’s usual time. 
 
Participants should not take more than 3 tablets of glecaprevir/pibrentasvir in a 
day. 
 
RBV is to be taken orally as prescribed twice a day, approximately 12 hours 
apart, with food. If participants miss a dose of RBV, the missed dose should be 
taken as soon as possible with food during the same day. If an entire day has 
gone by, then the missed dose should be skipped, and the normal dosing 
schedule should be resumed.  
 
Both glecaprevir/pibrentasvir and RBV tablets should not be cut, split, or, 
crushed. 
 
Participants should not double the next dose of either study product to "make up" 
the missed dose. 
 
NOTE: All study-required products obtained locally by the site will be 
administered in accordance with the manufacturer’s package insert, per site 
clinician’s discretion. 
 
5.1.3 Duration 
 
For Step 1, participants will take study treatment for a total of 4 weeks.  
 
For participants proceeding to Step 2, treatment will be taken for 8 to 16 weeks 
based on the indication and the regimen for re-treatment.  
 
5.2 
Study Product Formulation and Preparation 
 
5.2.1 Formulation 
 
Glecaprevir 100 mg/pibrentasvir 40 mg (glecaprevir/pibrentasvir) is a film-coated, 
FDC tablet.  
 
Ribavirin (RBV) 200 mg tablets are light pink to pink, capsule-shaped, film-coated 
tablets.  
 
5.2.2 Storage  
 
Glecaprevir 100 mg/pibrentasvir 40 mg tablets are to be stored at 15° to 25°C 
(59° to 77°F).  
 


 
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RBV tablets are to be stored at 20° to 25°C (68° to 77°F); excursions permitted to 
15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep the 
bottle tightly closed. 
 
5.3 
Pharmacy: Study Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
Glecaprevir/pibrentasvir is manufactured and supplied by AbbVie. 
 
Ribavirin (RBV) for the study is manufactured by Aurobindo and purchased with 
funding support from the ACTG Leadership and Operations Center (LOC).  
 
Glecaprevir/pibrentasvir and RBV will be available through the NIAID Clinical 
Research Products Management Center (CRPMC). The site pharmacist should 
obtain the study drug(s) for this protocol by following the instructions in the 
manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks.  
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. At US CRSs, all 
unused study products must be returned to the NIAID CRPMC (or as otherwise 
directed by the sponsor) after the study is completed or terminated. The 
procedures to be followed are provided in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks. At non-US CRSs, the site 
pharmacist must follow the instructions in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks for the destruction of unused 
study products. 
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at http://tprc.pharm.buffalo.edu/home/di_search/. 
 
5.4.1 Prohibited Medications 
 
The following medications are considered exclusionary if used within 28 days 
prior to entry into either Step 1 or Step 2:  
• 
Aliskiren 
• 
Allylisopropylacetylurea 


 
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• 
Amobarbital 
• 
Atorvastatin 
• 
Bosentan 
• 
Carbamazepine 
• 
Comfrey (herbal) 
• 
Dabigatran 
• 
Eltrombopag 
• 
Eslicarbazepine 
• 
Ethinyl estradiol 
• 
Hyoscyamine 
• 
Hyperforin 
• 
Lovastatin 
• 
Lumacaftor/Ivacaftor 
• 
Monacolin K 
• 
Oxcarbazepine 
• 
Pentobarbital 
• 
Phenobarbital 
• 
Phenytoin 
• 
Pimozide 
• 
Primidone 
• 
Rifabutin 
• 
Rifampin 
• 
Rifapentine 
• 
Stress Granule Combination granules (acetaminophen, isopropylantipyrine, 
allylisopropylacetylurea, caffeine) 
• 
Silodosin 
• 
Simvastatin 
• 
Spasfon (phloroglucinol) 
• 
St John’s wort 
• 
Terfenadine 
• 
Troleandomycin  
• 
Vinblastine 
• 
Vincristine 
 
The following medications are considered exclusionary if used within 14 days 
prior to entry into either Step 1 or Step 2:  
• 
Atazanavir, atazanavir/cobicistat, and atazanavir/ritonavir 
• 
Efavirenz 
• 
Etravirine 
• 
Fosamprenavir/ritonavir 
• 
Indinavir/ritonavir 
• 
Lopinavir/ritonavir 
• 
Nelfinavir 
• 
Nevirapine 


 
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• 
Saquinavir/ritonavir 
• 
Tipranavir/ritonavir 
 
The following medications are considered exclusionary if used within 28 days 
prior to entry into Step 2 AND RBV is being used in the Step 2 regimen:  
• 
Didanosine 
• 
Stavudine 
• 
Zidovudine 
 
5.4.2 Precautionary Medications 
 
Table 5.4.2-1 Precautionary Medications and Instructions Regarding Use during Study 
Participation 
Medication Category 
Precautionary 
Concomitant Agents 
Instructions Regarding Use During 
Study Participation 
Antiarrhythmics 
Amiodarone, digoxin, 
dronedarone 
Amiodarone/Dronedarone: monitor 
for toxicity, ECG monitoring 
Digoxin: measure digoxin level at 
baseline, decrease digoxin dose by 
50% and continue to monitor digoxin 
levels 
 
Antibiotics 
Erythromycin, 
Rifaximin 
Erythromycin: Consider ECG 
monitoring if at risk for QTc 
prolongation 
Rifaximin: Monitor closely for 
efficacy of both rifaximin and 
glecaprevir/pibrentasvir; avoid if 
possible 
Antidiabetic 
Glyburide, 
repaglinide  
Monitor blood glucose and for 
signs/symptoms of hypoglycemia 
Antifungals 
Ketoconazole, 
posaconazole  
Consider additional LFT monitoring 
Anti-gout agents 
Colchicine 
Consider decreasing colchicine dose 
Antihypertensives 
Carvedilol, diltiazem, 
enalapril, 
eplerenone, 
irbesartan, 
olmesartan, 
telmisartan, 
verapamil 
Monitor heart rate and blood 
pressure 
Enalapril: use at lowest dose 
Eplerenone: start at low dose 
Antimalarial 
Mefloquine, 
quinidine, quinine 
Monitor for cardiotoxicity 
(bradycardia, arrest/asystole, PR, 
QRS, or QT prolongation, depressed 
contractility), neuropsychiatric 
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Medication Category 
Precautionary 
Concomitant Agents 
Instructions Regarding Use During 
Study Participation 
panic attacks, insomnia), 
anticholinergic effects (dry mouth, 
mydriasis, delirium, rigors, fever), 
nausea/vomiting/diarrhea, and 
hypotension/pulmonary edema 
Antiplatelet  
Ticagrelor 
Monitor for signs/symptoms of 
bleeding 
Antipsychotics  
Aripiprazole, 
quetiapine   
Monitor for toxicities, including CNS 
sedation, tachycardia, tremors, 
irritability 
Quetiapine: ECG monitoring for QTc 
prolongation if at increased risk 
Asthma 
Theophylline 
Monitor theophylline concentrations 
and for signs/symptoms of toxicity 
Cholesterol-lowering 
(non-statin) 
Ezetimibe, 
gemfibrozil 
Ezetimibe: Consider use of lowest 
possible ezetimibe dose. Monitor for 
adverse effects (diarrhea, abdominal 
pain, arthralgia, fatigue) 
Gemfibrozil: Consider using lowest 
possible gemfibrozil dose or holding 
for duration of treatment if possible. 
Monitor for adverse effects (GI 
disturbance, muscle pain) 
Corticosteroids 
Dexamethasone 
Monitor for increased toxicity (blood 
pressure, blood glucose, mood, 
weight) 
Direct Oral 
Anticoagulants  
Betrixaban, 
apixaban, edoxaban, 
rivaroxaban 
Consider use of low molecular 
weight heparins instead of direct oral 
anticoagulants 
Ergot derivatives 
Dihydroergotamine, 
ergonovine, 
ergotamine, 
methylergonovine 
Monitor for ergot toxicity 
(nausea/vomiting, vasospasms, 
cardiac toxicity, neurological deficits) 
Female hormones 
17-beta estradiol, 
conjugated 
estrogens, estradiol 
hemihydrate, 
estradiol valerate, 
estriol, estrone 
Consider additional liver function test 
monitoring 
HMG CoA reductase 
inhibitors 
Fluvastatin, 
pitavastatin, 
pravastatin, 
rosuvastatin 
Patients with high ASCVD risk, 
consider dose reduction (not to 
exceed 10mg daily for rosuvastatin) 
and monitor liver function tests 
 


 
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Medication Category 
Precautionary 
Concomitant Agents 
Instructions Regarding Use During 
Study Participation 
Patients with low ASCVD risk, 
reduce dose or consider holding 
HMG CoA reductase inhibitor during 
GP therapy  
Hyperkalemia 
Polystyrene 
sulfonate 
Separate administration by at least 3 
hours 
Immunosuppressants 
Cyclosporine, 
Everolimus, 
Tacrolimus, 
Sirolimus  
Chronic use of systemically 
administered immunosuppressive 
agents is an exclusion criterion for 
study participation. 
Cyclosporine: 
glecaprevir/pibrentasvir not 
recommended if require 
cyclosporine doses >100 mg/day 
Everolimus/sirolimus/tacrolimus: 
monitor concentrations and adjust 
doses accordingly 
Other cardiac 
medications 
Ranolazine 
Consider decreasing ranolazine 
dose 
Pain 
Fentanyl, 
hydrocodone, 
oxycodone 
Consider dosage reduction and 
closely monitor for respiratory 
depression 
Rheumatoid Arthritis, 
Ulcerative Colitis, and 
Crohn’s 
Methotrexate, 
sulfasalazine 
Methotrexate: Monitor renal function, 
hepatic function, CBC, respiratory 
function, and signs/symptoms of 
adverse effects (nausea, vomiting, 
diarrhea) 
Sulfasalazine: Monitor for 
signs/symptoms of toxicity (tinnitus, 
vertigo, headache, confusion, 
drowsiness, sweating, seizures, 
hyperventilation, dyspnea, vomiting, 
diarrhea) 
Stimulant 
Modafinil 
May decrease 
glecaprevir/pibrentasvir 
concentrations; avoid if possible 
 


 
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Table 5.4.2-2 Precautionary Medications and Instructions Regarding Use during Study 
Participation (this list only applies to participants on Ribavirin in Step 2) 
Medication Category 
Precautionary 
Concomitant Agents 
Instructions Regarding Use During 
Study Participation 
Immunosuppressants 
Azathioprine 
Concomitant use may induce severe 
pancytopenia and increase risk of 
Azathioprine induced myelotoxicity. 
Monitor CBC and platelets weekly 
for the first month and then twice a 
month for the 3rd and 4th month and 
then monthly after that. Both drugs 
should be discontinued if participant 
develops pancytopenia. 
Antiretrovirals 
Abacavir, Tenofovir, 
lamivudine, 
emtricitabine 
Hepatic decompensation has been 
reported in cirrhotic HIV/HCV 
coinfected patients on NRTIs and 
RBV. Monitor for liver toxicity and 
anemia. Reduce dose or discontinue 
Ribavirin if toxicity is suspected. 
 
5.4.3  Colony Stimulating Agents 
 
Under no circumstances are potential participants to be treated with colony 
stimulating agents (CSA) during Step 1 to elevate hematology laboratory 
parameters to facilitate entry into Step 2 of the study. CSAs, such as 
erythropoiesis-stimulating agents or granulocyte colony-stimulating factor, will not 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
6.1 
Schedule of Evaluations (SOE) 
 
Table 6.1-1: SOE: Step 1 - Study Visits for 4-week Treatment and Post-Treatment Follow-up 
 
Evaluation 
Screening 
Entry (Day 0)  
On 
Treatment 
Treatment 
Completion 
Post-treatment 
HCV 
Recurrence/
Virologic 
Failure 
Confirmation 
(see Event-
Driven 
Evaluations  
in section 
6.2.4)  
HIV-1 
Virologic 
Breakthrough 
Confirmation(
see Event-
Driven 
Evaluations in 
section 6.2.4) 
Premature 
Study and /or 
Treatment 
Discontinuation 
Evaluations 
Weeks; See section 6.2.3 for study windows 
1 
2 
4 
8 
12  
14 
16/SVR12  
28 
Documentation of HIV-1 (if 
applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of Acute  
HCV Infection  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of Cirrhosis 
Status  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of Historical 
Labs (see section 6.3.4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments (see 
section 6.3.7) 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Chemistries 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 


 
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Evaluation 
Screening 
Entry (Day 0)  
On 
Treatment 
Treatment 
Completion 
Post-treatment 
HCV 
Recurrence/
Virologic 
Failure 
Confirmation 
(see Event-
Driven 
Evaluations  
in section 
6.2.4)  
HIV-1 
Virologic 
Breakthrough 
Confirmation(
see Event-
Driven 
Evaluations in 
section 6.2.4) 
Premature 
Study and /or 
Treatment 
Discontinuation 
Evaluations 
Weeks; See section 6.2.3 for study windows 
1 
2 
4 
8 
12  
14 
16/SVR12  
28 
Liver Function Tests (LFTs) 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Calculated CrCl 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
 
X 
Coagulation Markers 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
Urine Sample for Substance 
Use Screen 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
FSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Serologies  
X 
X  
(see section 6.3.8) 
X 
 
 
HCV Antibody  
X 
X 
 (see section 6.3.8) 
 
 
 
CD4+/CD8+ (for participants 
with HIV-1 infection) 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Stored Plasma and PBMC 
for Immunologic Studies 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
Plasma HCV RNA 
(screening performed at 
local lab, see section 6.3.10) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma HCV RNA (real-
time, see section 6.3.10) 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X  
 
X 


 
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Evaluation 
Screening 
Entry (Day 0)  
On 
Treatment 
Treatment 
Completion 
Post-treatment 
HCV 
Recurrence/
Virologic 
Failure 
Confirmation 
(see Event-
Driven 
Evaluations  
in section 
6.2.4)  
HIV-1 
Virologic 
Breakthrough 
Confirmation(
see Event-
Driven 
Evaluations in 
section 6.2.4) 
Premature 
Study and /or 
Treatment 
Discontinuation 
Evaluations 
Weeks; See section 6.2.3 for study windows 
1 
2 
4 
8 
12  
14 
16/SVR12  
28 
Plasma HCV Genotype 
(screening performed at 
local lab unless unavailable, 
see section 6.3.10) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Plasma HIV-1 RNA (for 
participants with HIV-1 
infection) 
(real-time, see section 
6.3.10) 
X 
X 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Stored Serum for HIV-
1/HCV Studies (see section 
6.3.10) 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Stored Plasma for HIV-
1/HCV Studies (see section 
6.3.10 
 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Plasma for PK Testing (see 
section 11.2) 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Dried Blood Spots (DBS) for 
PK (see section 11.2) 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
Optional Hair Sampling for 
PK (see section 11.2) 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 


 
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Evaluation 
Screening 
Entry (Day 0)  
On 
Treatment 
Treatment 
Completion 
Post-treatment 
HCV 
Recurrence/
Virologic 
Failure 
Confirmation 
(see Event-
Driven 
Evaluations  
in section 
6.2.4)  
HIV-1 
Virologic 
Breakthrough 
Confirmation(
see Event-
Driven 
Evaluations in 
section 6.2.4) 
Premature 
Study and /or 
Treatment 
Discontinuation 
Evaluations 
Weeks; See section 6.2.3 for study windows 
1 
2 
4 
8 
12  
14 
16/SVR12  
28 
IL-28B Genotype and HLA 
Typing  
 
X 
 
X  
(See section 6.3.12; IL-28B genotype/HLA typing may be 
performed on any PBMC sample collected at any time 
during the study.) 
 
 
 
Pregnancy Prevention 
Counseling 
X 
X 
 
 
X 
X 
 
 
 
 
X 
 
X 
Adherence Assessments  
(see section 6.3.14) 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
Study Drug Dispensing/First 
Dose Observed  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Risk Factor Assessment 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
Health Outcomes 
Questionnaire (EQ-5D) 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
Health Care Utilization 
Questionnaire 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
Reinfection Prevention 
Counseling 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
Collection and Updating of 
Locator Information  
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
Remote Contact Reminder 
for Week 16 Visit  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 


 
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Table 6.1-2: SOE: Step 2- Repeat Treatment for Suspected Relapse/Virologic Failure/Post-treatment Viremia or Re-infection 
Evaluation 
Re-Treatment Entry/ Initiation 
On-Retreatment 
(Weeks) 
R = Step 2 Entry  
 
ReTx=Retreatment 
 
Post-Retreatment 
HCV Recurrence/Virologic Failure (see 
Event Driven Evaluations in section 6.2.4) 
Confirmation  
HIV-1 Virologic Breakthrough 
Confirmation (see Event-Driven 
Evaluations  in section 6.2.4)  
Premature Study and /or Treatment  
Discontinuation Evaluations 
R+2 
(RBV 
regime
ns 
only) 
R+4 
R+8 
R+12 
(12 & 
16 
weeks 
ReTx 
only) 
R+16 
(16 
weeks 
ReTx 
only) 
SVR12 visit 
(R+20, R+24 
or R+28, 
depending 
on re-
treatment 
duration) 
Only for 
RBV 
exposed 
(R+32, 
R+36 or 
R+40, 
depending 
on re-
treatment 
duration) 
See section 6.2.3 for study windows 
Evaluation of Step 2 Entry 
Requirements (see 
section 6.3.20) 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments (see 
section 6.3.7) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology, Chemistries 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
LFTs (see section 6.3.8) 
 
 
 
 
 
 
 
 
X 
 
 
Serologies (see section 
6.3.8) 
X 
 
 
 
 
 
 
 
X 
 
 
Calculated CrCl (if on 
RBV) 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Pregnancy Testing (see 
section 6.3.8) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 


 
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Evaluation 
Re-Treatment Entry/ Initiation 
On-Retreatment 
(Weeks) 
R = Step 2 Entry  
 
ReTx=Retreatment 
 
Post-Retreatment 
HCV Recurrence/Virologic Failure (see 
Event Driven Evaluations in section 6.2.4) 
Confirmation  
HIV-1 Virologic Breakthrough 
Confirmation (see Event-Driven 
Evaluations  in section 6.2.4)  
Premature Study and /or Treatment  
Discontinuation Evaluations 
R+2 
(RBV 
regime
ns 
only) 
R+4 
R+8 
R+12 
(12 & 
16 
weeks 
ReTx 
only) 
R+16 
(16 
weeks 
ReTx 
only) 
SVR12 visit 
(R+20, R+24 
or R+28, 
depending 
on re-
treatment 
duration) 
Only for 
RBV 
exposed 
(R+32, 
R+36 or 
R+40, 
depending 
on re-
treatment 
duration) 
See section 6.2.3 for study windows 
CD4+/CD8+ (for 
participants with HIV-1 
infection) 
X 
 
 
X 
 
X 
X 
 
 
 
X 
Stored Plasma and PBMC 
(see section 6.3.9) 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
Plasma HCV RNA (real-
time, see section 6.3.10) 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Plasma HCV Genotype 
(see section 6.3.10) 
 
 
 
 
 
 
 
 
X 
 
 
Plasma HIV-1 RNA (for 
participants with HIV-1 
infection, real-time, see 
section 6.3.10) 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Stored Serum for HIV-
1/HCV Studies (see 
section 6.3.10) 
 
X 
X 
   
X 
X 
 
X 
 
X 
X 
X 


 
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Evaluation 
Re-Treatment Entry/ Initiation 
On-Retreatment 
(Weeks) 
R = Step 2 Entry  
 
ReTx=Retreatment 
 
Post-Retreatment 
HCV Recurrence/Virologic Failure (see 
Event Driven Evaluations in section 6.2.4) 
Confirmation  
HIV-1 Virologic Breakthrough 
Confirmation (see Event-Driven 
Evaluations  in section 6.2.4)  
Premature Study and /or Treatment  
Discontinuation Evaluations 
R+2 
(RBV 
regime
ns 
only) 
R+4 
R+8 
R+12 
(12 & 
16 
weeks 
ReTx 
only) 
R+16 
(16 
weeks 
ReTx 
only) 
SVR12 visit 
(R+20, R+24 
or R+28, 
depending 
on re-
treatment 
duration) 
Only for 
RBV 
exposed 
(R+32, 
R+36 or 
R+40, 
depending 
on re-
treatment 
duration) 
See section 6.2.3 for study windows 
Stored Plasma for HIV-
1/HCV Studies (see 
section 6.3.10) 
 
X 
X 
   
X 
X 
 
X 
 
X 
X 
X 
Plasma for PK Testing 
(see section 11.2) 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
Pregnancy Prevention 
Counseling 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Study Drug Dispensing  
X 
 
X 
X 
X 
 
 
 
 
 
 
Risk Factor Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Reinfection Prevention 
Counseling 
X 
 
 
 
 
X 
X 
 
 
 
X 


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur prior to the participant starting any study 
medications, treatments, or interventions. 
 
For Step 1, screening evaluations to determine eligibility must be completed 
within 28 days prior to entry unless otherwise specified. For Step 2, participants 
can enter Step 2 up to 56 days after the confirmatory HCV RNA sample date 
completed as part of Step 1.  
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a Screening Failure Results form and entered into the ACTG database. 
 
6.2.2 Entry Evaluations 
 
Entry evaluations must occur at least 24 hours after screening evaluations unless 
otherwise specified. For Step 1, participants must begin treatment within 24 
hours after registration and upon completion of entry evaluations. The first dose 
of G/P will be provided to the participant and taking the first dose will be 
observed by study staff. 
 
For participants entering Step 2, treatment must be started within 72 hours of 
Step 2 entry. 
 
6.2.3 Post-Entry Evaluations 
 
All post-entry evaluations occur in reference to the start of study therapy.  
 
On-Treatment Evaluations  
Study visits must be scheduled on the weeks indicated in Tables 6.1-1 and 6.1-2, 
within the visit windows described below, as appropriate for the visit. 
 
Step 1:  
• 
Weeks 1 and 2 have a window of ±3 days.  
• 
Week 4 has a window of -7 days and +14 days. 
 
Step 2:  
• 
Week R+2 has a window of ±3 days.  
• 
Weeks R+4, R+8, R+12, and R+16 have a window of -7 days and +14 days. 
 


 
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Treatment Completion Evaluations  
Clinical assessment and laboratory evaluation, as outlined in section 6.1, will be 
performed at treatment completion (Step 1: week 4, Step 2: week R+8, R+12, or 
R+16). 
 
Post-Treatment Evaluations  
Following treatment completion, participants will undergo evaluations as outlined 
in Tables 6.1-1 and 6.1-2, within the study windows, as indicated below. 
 
After the last dose of study drugs, the post-treatment study visits have the 
following windows:  
 
Step 1: 
• 
Study weeks 8, 12, and 16: -5 days and +21 days 
• 
Study week 28: -7 days and +28 days 
 
Step 2: 
• 
Study week R+20, R+24, or R+28 (12 weeks after re-treatment completion 
for those not receiving RBV depends on Step 2 treatment duration): -5 days 
and +28 days 
• 
Study week R+32, R+36, or R+40 completion (for those receiving RBV): -14 
days and + 28 days 
 
6.2.4 Event-Driven Evaluations  
 
HCV Viral Recurrence/Virologic Failure  
In Step 1, all cases of confirmed HCV recurrence/virologic failure occurring 
before or at the week 16/SVR12 visit will undergo evaluation for preliminary 
determination of suspected relapse versus re-infection (see Table 6.1-1, A5380 
MOPS, and A5380 Laboratory Processing Chart [LPC]). Viral recurrence is 
defined as confirmed HCV RNA value >LLOQ after achieving HCV RNA <LLOQ 
(TD or TND). Virologic failure is defined as failure to achieve HCV RNA <LLOQ 
(TD or TND) and confirmed increase in HCV RNA >1 log10 from nadir. These 
participants will enter Step 2. This confirmatory sample should be collected within 
56 days of Step 2 entry. 
 
Participants should have this confirmatory evaluation done, per Table 6.1-1, 
before initiation of Step 2 therapy. Participants should be re-tested with HCV 
RNA and hepatic panel (LFTs) as soon as possible after viral recurrence or 
virologic failure to confirm the HCV RNA >LLOQ or >1 log10 from nadir, 
respectively.  
 
If HCV RNA is >1000 IU/mL, as part of Step 2 entry, each available post-
treatment viremic sample will be sent for HCV genotyping and RAS analysis. A 
stored baseline sample will also be sent for RAS analysis. Results from these 
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(actg.cmcA5380@fstrf.org) by the designated Virology Specialty Laboratory 
(VSL) and initial determination of suspected relapse versus re-infection will be 
made. If HCV RNA is persistently less than or equal to 1000 IU/mL, the 
participant may still meet the criteria of virologic failure and/or post-treatment 
HCV viremia described in section 4.3.1. 
 
Results of repeat HCV genotype and RAS analysis will be delivered to the A5380 
CMC (actg.cmcA5380@fstrf.org). If the genotype/subtype has switched, this will 
be classified as a re-infection. If the same genotype/subtype and there are 
emergent RASs, this will be initially classified as a suspected relapse. For other 
situations (e.g., same genotype/subtype without emergent RASs), the 
classification will be determined later by phylogenetic analysis (with samples sent 
from the repository, see virologic studies in section 6.3.10), but for Step 2 these 
will be classified as “undefined post-treatment viremia” but treated as a 
suspected relapse. Per section 6.3.8, HAV IgM, HBc IgM Ab, total HBcAb, and 
HBsAg will be done during the Event-driven Evaluations outlined in the SOE with 
results available prior to Step 2 entry. 
 
Following determination of suspected relapse versus re-infection versus 
undefined post-treatment viremia, a member of the A5380 CMC will contact the 
site coordinator and site PI to discuss the re-treatment approach for the 
participant.  
 
For all participants with recurrence of the same genotype/subtype, stored 
samples from the repository will be batched and sent for sequencing, 
phylogenetic analysis, and definitive determination of relapse versus re-infection 
(see virologic studies in section 6.3.10). Suspected relapse or undefined post-
treatment viremia may then be reclassified as confirmed relapse or re-infection 
for the purposes of exploratory objective 1.4.1. 
 
HIV-1 Virologic Breakthrough 
In this study, HIV-1 viral breakthrough is defined as follows (this only applies for 
participants on ART): 
 
Among participants with HIV-1 RNA <50 copies/mL at study entry, a confirmed 
increase to ≥200 copies/mL at any time after entry into Step 1 and Step 2. 
 
The increase in plasma HIV-1 RNA should be confirmed with repeat central or 
local testing as soon as possible (not to exceed 4 weeks); see HIV-1 Virologic 
Breakthrough Confirmation in Tables 6.1-1 and 6.1-2. For participants with 
confirmed HIV-1 viral breakthrough (≥200 copies/mL), a plasma specimen should 
be sent for HIV genotyping and sent to the designated A5380 VSL for evidence 
of HIV-1 drug resistance. Results will be reported back to sites in real-time from 
the designated A5380 VSL. See section 6.3.10, Stored Serum and Plasma for 
HIV-1/HCV Studies. 
 
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handled by local site PI according to current HIV treatment guidelines and local 
standard of care. The A5380 CMC should be contacted before switching ART. 
 
HCV medications should be continued unless safety events warrant the 
discontinuation of these medications, as outlined in section 8.1 of the protocol. 
 
These criteria only apply to participants currently on ART treatment. They do not 
apply to participants meeting the ART untreated parameters outlined in section 
4.1. 
 
6.2.5 Study Completion Evaluations 
 
For those not proceeding to Step 2, the final study visit occurs at study week 28.  
 
For those proceeding to Step 2, the final study visit occurs 12 weeks after re-
treatment completion, with extension to 24 weeks after re-treatment completion if 
the participant receives RBV.  
  
6.2.6 Discontinuation Evaluations 
 
Evaluations for Registered Participants Who Do Not Start Study Treatment 
All eCRFs must be keyed for the period up to and including the entry visit. 
 
Premature Treatment Discontinuation Evaluations  
The A5380 CMC must be informed, as soon as possible, when a participant 
comes off study treatment due to an AE. Participants who permanently 
discontinue study treatment for toxicity or any other reason, and who have not 
met the HCV virologic failure criteria below, will also follow the schedule in Table 
6.1-2. If applicable, additional or more frequent post-treatment toxicity follow-up 
may be determined by the site PI. 
 
Participants who prematurely discontinue study treatment (i.e., prior to 
completion of the last dose of G/P per the assigned dosing period) will complete 
the premature treatment discontinuation evaluations. Participants will then follow 
the post-treatment schedule in Table 6.1-2. 
 
NOTE: In Step 2 where applicable: If G/P is discontinued, participants 
should discontinue RBV. Under no condition should the participant remain 
on RBV monotherapy. In contrast, participants who discontinue RBV in 
Step 2 can continue G/P to complete their planned G/P regimen.  
 
HCV Virologic Failure  
Participants who experience for HCV virologic failure (see details in section 
6.2.4) in Step 1 will have the option to enter Step 2 for re-treatment, otherwise 
the participants will be followed on study/off treatment through week 28. 
 


 
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Participants who permanently discontinue study treatment for HCV virologic 
failure (see details in section 6.2.4) in Step 2 will be followed through 12 weeks 
(or 24 weeks, if RBV given) after the treatment completion. No further treatment 
will be provided by the study. 
 
Virologic evidence of recurrence, defined as HCV RNA ≤LLOQ at end of 
treatment but HCV RNA quantifiable (>LLOQ) during follow-up, will require 
confirmation and should be performed in real time at the designated VSL as soon 
as possible but within 2 weeks after determination of initial observation. The 
results will be provided to the co-chairs and site investigators within 2 weeks of 
specimen receipt.  
 
HCV Virologic Response-Based Treatment Stopping Criteria in Step 2 
The following on-treatment HCV virologic response-based treatment stopping 
criteria will be utilized for all participants in Step 2: 
• 
Confirmed increase in HCV RNA >LLOQ if HCV RNA previously declined to 
≤LLOQ (detected or not detected) AND 
• 
Confirmed ≥1 log10 IU/mL HCV RNA on-treatment increase from nadir 
• 
Confirmation will be required for all stopping criteria and should be performed 
as soon as possible but within 2 weeks after determination of initial 
observation (see HCV Recurrence/VF Confirmation in Table 6.1-2). 
 
HCV RNA measurement to confirm treatment failure will be performed in real-
time at the designated VSL and the results will be provided to the site PI within 2 
weeks of specimen receipt. If treatment failure is confirmed, then all study 
treatment should be stopped. However, participants should be followed as per 
section 6.2.6. 
 
Pregnancy 
Pregnancy will result in immediate and permanent discontinuation of the study 
medications. Please see section 8.2 for detailed information regarding participant 
management. 
 
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue from the study will have the study 
discontinuation evaluations performed prior to being taken off the study. 
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the DAIDS AE Grading Table and AE reporting of 
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6.3.1 Documentation of HIV-1 
 
Section 4.1.6 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is recorded on the eCRF. 
 
6.3.2 Documentation of Acute HCV Infection 
 
Section 4.1.3 specifies assay requirements for HCV documentation. HCV 
documentation is not recorded on the eCRF. 
 
6.3.3 Documentation of Cirrhosis Status 
 
Sections 4.2.3 and 4.4.1 specify requirements for known cirrhosis status 
documentation. Cirrhosis status documentation is not recorded on the eCRF. 
 
6.3.4 Documentation of Historical Labs 
 
For all participants in Step 1, record on eCRFs all available lab values (including 
specimen dates) for LFTs (AST, ALT, and total bilirubin), HCV RNA, and HCV 
antibody (Ab) (positive/negative) tests performed within the last 12 months prior 
to study entry. 
 
6.3.5 Medical History 
 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days. In addition, the following 
diagnoses should be recorded regardless of when the diagnosis was made: 
• 
AIDS-defining conditions 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.3.6 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history and recorded on 
the eCRF.  


 
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Table 6.3.6-1: Medication History  
Medication Category 
Complete History or 
Timeframe 
Antiretroviral therapy for HIV 
treatment 
Within 42 days prior to 
entry 
HCV treatment 
Complete history 
Prescription drugs for treatment 
of opportunistic infections 
Within 42 days prior to 
entry 
Prescription drugs for 
prophylaxis of opportunistic 
infections 
Within 42 days prior to 
entry 
Other prescription drugs  
Within 42 days prior to 
entry 
Non-prescription drugs 
Within 42 days prior to 
entry 
Complementary and alternative 
therapies 
Within 42 days prior to 
entry 
Illicit Drug Use 
Within 42 days prior to 
entry 
Sex-hormone medications or 
sex-hormone analogues or 
antagonists* 
Last 12 months except as 
noted below 
*Includes: hormone-releasing IUDs (e.g., Mirena inserted in the last 5 years); 
oral, injectable, implanted, or patch contraceptives; vaginal ring, creams, or 
inserts; estrogen, progesterone, or testosterone therapy; leuprolide or other 
synthetic gonadotropin-releasing hormone; tamoxifen, raloxifene, aromatase 
inhibitors or any other androgen, estrogen, or progesterone analogue or 
antagonist therapy. 
 
6.3.7 Clinical Assessments 
 
Complete Physical Examination 
A complete physical examination must be performed at screening and is to 
include at a minimum an examination of the head, neck and thyroid; eyes, ears, 
nose, throat, mouth and tongue; chest (excluding breasts); respiratory; 
cardiovascular; lymph nodes, abdomen; skin, hair, nails; musculoskeletal; 
neurological. The complete physical examination will also include signs and 
symptoms, diagnoses, and vital signs (height, weight, temperature, pulse, 
respiration rate, and blood pressure).  
 
Targeted Physical Examination 
A targeted physical examination must be performed at entry and all subsequent 
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resting blood pressure) and is to be driven by any previously identified or new 
signs or symptoms including diagnoses that the participant has experienced 
since the last visit. 
 
Height 
Height (in cm) will be collected at entry. 
 
Weight 
Weight (in kg) will be collected at Step 1 screening, entry, week 4 (treatment 
completion), weeks 16 and 28, and in cases of HCV virologic failure or premature 
study and/or treatment discontinuation evaluations.  
 
Weight (in kg) will be collected at Step 2 entry, weeks R+2, R+4, R+8, R+12 (if 
on study treatment), R+16 (if on study treatment), and in premature study and/or 
treatment discontinuation evaluations. 
 
NOTE A: Weight should be done with inner clothing and without shoes. 
 
NOTE B: The weight recorded at entry to each Step will be used as the weight 
for PK analysis. 
 
Post entry, see section 8.2 for collection requirements for pregnancy. 
 
Diagnoses 
Post-entry, record all targeted diagnoses per the A5380 diagnoses list (located 
on the A5380 PSWP) regardless of grade. 
 
Refer to section 7.2 for AE collection requirements.   
 
Concomitant Medications 
Post-entry, the following new and discontinued concomitant medications must be 
recorded on the eCRFs: 
• 
Sex-hormone medications or sex-hormone analogues or antagonists (see 
Table 6.3.6-1 for examples). 
• 
Prescription and nonprescription medications taken since the last on-
treatment study visit. 
 
Start and stop dates of all prescription and nonprescription medications will be 
recorded on the eCRF. 
 
Study Treatment and ART Modifications 
Record all study drug and ART (for HIV-positive participants) modifications, 
including initial doses, participant-initiated and/or protocol-mandated 
modifications, inadvertent and deliberate interruptions of >1 day at each visit. 
Record any permanent discontinuation of treatment. 
 


 
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6.3.8 Laboratory Evaluations 
 
At Step 1 and Step 2 screening and entry, all laboratory values must be recorded 
on the eCRF, including repeat testing. For post-entry assessments, record on the 
eCRF all Grade ≥2 laboratory values; record abnormal laboratory findings as per 
section 7.2.  
 
Hematology 
Hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC), white 
blood cell count (WBC) with differential (absolute and percentage) including 
lymphocytes, monocytes, neutrophils, eosinophils, basophils, reticulocyte count, 
and MCV. 
 
Chemistries 
Creatinine, glucose, lipase, potassium, and sodium.  
 
Liver Function Tests (LFTs) 
Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT), albumin, alkaline phosphatase, total bilirubin, direct bilirubin. 
 
Calculated CrCl 
Estimated each time that a creatinine level is determined during the study period 
per Tables 6.1-1 and 6.1-2.  
 
NOTE: Please refer to the A5380 PSWP for the website link to calculate CrCl 
using the Cockcroft-Gault calculator. 
 
Coagulation Markers 
INR, prothrombin time (PT), activated partial thromboplastin time (APTT). 
 
Urine Sample for Substance Use Screen 
Urine substance use screening must be done using a CLIA-waived urine drug 
use screening tool with these common drugs of abuse: amphetamines, 
buprenorphine, benzodiazepines, cocaine, ecstasy, methadone, 
methamphetamine, barbiturates, marijuana, opiates, oxycodone, fentanyl, and 
phencyclidine. The screening will be assessed by urine test and must include the 
following ancillary testing, pH and creatinine to help in confirmation of sample 
against adulterants. The following results would be used as confirmation of an 
unadulterated human urine sample; pH of 4.5 – 8.0 and urine creatinine ≥20 
mg/dL. 
 
Testing will be done per Table 6.1-1 on each scheduled study visit and 
participants with positive screens will be counseled before and/or at the next 
scheduled visit with regard to potential impact on medication adherence, health-
related risks, as well as in accordance with prevailing local laws. 
 


 
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FSH 
For female participants, FSH should be measured at screening if they are 
believed to not be of reproductive potential but lack medical record.  
 
NOTE: Female participants who have not had menses for at least 24 consecutive 
months and have an FSH >40 international units (IU) documented by medical 
record or have documentation of a hysterectomy, bilateral oophorectomy and/or 
bilateral salpingectomy, do not require an FSH at screening. 
 
Pregnancy Testing 
For women with reproductive potential: a serum β-HCG, urine or POC/CLIA-
waived test documenting a negative result will be required within 48 hours prior 
to Step 1 or Step 2 entry. The test should have a sensitivity of at least 25 
mIU/mL. 
 
Once a participant has enrolled with a negative documented serum or urine 
pregnancy test and begins using contraceptives (per sections 4.1.12 and 4.3.8, 
depending on current step) to prevent pregnancy, further testing per section 6.1 
(during study drug dosing and in post treatment follow-up) can be urine testing. 
Urine test must have a sensitivity of at least 50 mIU/mL. 
  
In the event of a positive urine pregnancy result, participants will be instructed to 
stop study drugs immediately and return to the clinic as soon as possible for a 
serum pregnancy test with β-HCG. See section 8.2 for detailed information 
regarding study management.  
 
For participants taking RBV on Step 2, pregnancy testing will be done per Table 
6.1-2, and at the last study visit.  
 
Serologies 
HCV Ab, HAV IgM, HBc IgM Ab, total HBcAb, and HBsAg will be done during 
screening with results available prior to Step 1 entry. 
 
HAV IgM, HBc IgM Ab, total HBcAb, and HBsAg will be done during the Event-
driven Evaluations (section 6.2.4) with results available prior to Step 2 entry. 
 
If HCV Ab is negative at Step 1 entry, HCV Ab will be repeated at each 
subsequent study visit until positive. Once positive, no further HCV Ab testing is 
required. 
 
If a historical positive HIV Ab or detectable HIV RNA result test result (i.e., used 
for HIV-1 infection documentation to meet inclusion criterion 4.1.6) is not 
available, an HIV Ab test will also be done at Step 1 screening with the result 
available prior to study entry. For those reporting HIV-1 negative status, testing 
should be sent to confirm (see section 4.1.6). 
 


 
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HCV Ab 
HCV Ab must be obtained by any FDA-approved test at any local laboratory that 
has a CLIA certification or its equivalent. HCV Ab is only to be sent at screening 
and at a subsequent visit if the result is negative on the preceding visit. Once a 
single positive Ab is recorded, no further HCV antibody testing is required. 
 
6.3.9 Immunologic Studies 
 
CD4+/CD8+ (For participants with HIV-1 infection only) 
Obtain absolute CD4+/CD8+ count and percentages within 28 days prior to entry 
from a laboratory that possesses a CLIA certification or equivalent (US sites) or 
IQA certification (non-US sites). 
 
For entry and post-entry evaluations, all laboratories must possess a CLIA 
certification or equivalent (US sites) or IQA certification (non-US sites). 
 
Stored Plasma and PBMC 
PBMC will be collected, processed, and shipped to the designated immunology 
laboratory for analysis of HCV-specific T-cell responses (see A5380 LPC) and for 
IFN-stimulated gene (ISG)/IFN effector gene (IEG) responses. Based on human 
leukocyte antigen (HLA) typing results, participants will be screened for the 
presence of HCV-specific CD4+ and CD8+ T-cell responses using class I and 
class II HLA multimers. Based on the results HCV-specific T-cell populations will 
then be analyzed longitudinally using flow cytometry and/or fluorescence-
activated cell sorting (FACS) followed by population or single cell RNA 
sequencing. Additional immune cell populations might be studied if warranted by 
data emerging during the trial. Findings will be compared to samples from 
chronic HCV already collected by the protocol immunologist. 
 
Plasma will be analyzed for selected cytokines and chemokines and correlated 
with ISG/IEG and T-cell responses.  
 
DNA for HLA typing and host polymorphisms: DNA will be extracted from the cell 
fraction of a PBMC tube and stored for HLA typing (class I and class II) and 
single nucleotide polymorphism (SNP) testing for key loci.  
 
6.3.10 Virologic Studies 
 
Plasma HCV RNA (screening) 
The screening HCV RNA result must be obtained by any FDA-approved test for 
quantifying HCV RNA at any local laboratory that has a CLIA certification or its 
equivalent. Screening HCV RNA must be obtained within 28 days prior to study 
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Plasma HCV RNA (real-time, on-study evaluations) 
At the entry and post-entry visits, HCV RNA quantification will be performed as 
follows: 
 
Plasma HCV RNA real-time testing will be collected, processed, and shipped to 
the designated testing laboratory (see A5380 LPC for directions). These results 
will be reported within 2 weeks after specimen receipt for both Steps 1 and 2. 
 
NOTE: For Step 2, an increase in plasma HCV RNA at any time point meeting 
HCV virologic response-based treatment stopping criteria must be confirmed with 
repeat testing within 2 weeks of receipt of results. For more information please 
see section 6.2.4. 
 
Plasma HCV RNA (real-time) 
After the treatment is completed in Step 1, for participants entering Step 2 (Viral 
Recurrence [Reinfection/Suspected Relapse/Undefined Post-Treatment Viremia] 
or virologic failure): a detectable HCV RNA after the end of treatment after 
achieving HCV RNA <LLOQ is virologic evidence of recurrence which will require 
confirmation and should be performed in real-time at the designated testing lab 
as soon as possible but no later than 2 weeks. 
 
Plasma HCV Genotype 
At Step 1 screening, the HCV genotype result will be obtained locally (real-time) 
from any laboratory that has a CLIA certification or its equivalent. ONLY IF IT IS 
NOT AVAILABLE LOCALLY should it be done (real-time) at the designated 
testing laboratory (see A5380 LPC).  
 
At viral recurrence or virologic failure (prior to Step 2 entry), HCV genotype will 
be performed on stored samples (near-time) at the designated testing lab (see 
A5380 LPC). 
 
Plasma HIV-1 RNA  
For participants with documented HIV-1 infection, a documented plasma HIV-1 
RNA level must be noted within 28 days prior to Step 1 study entry from any 
laboratory that has a CLIA certification or its equivalent. On-study HIV-1 RNA is 
only required for HIV-1-infected participants and should be performed at the 
ACTG central laboratory. See the A5380 LPC for processing, shipping, and 
storage information.  
 
Participants on ART who later experience HIV-1 viral breakthrough while on HIV 
therapy should be managed as per section 6.2.4. 
 
Stored Serum and Plasma for HIV-1/HCV Studies 
Serum and plasma samples will be collected and stored for HCV and potential 
HIV sequencing and other virology studies. For processing and shipping 
instructions, refer to the A5380 LPC. 
 


 
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• 
HIV Genotyping 
Using stored samples for HIV-1/HCV studies above, for participants with 
confirmed HIV-1 viral breakthrough (≥200 copies/mL), a plasma specimen will 
be sent to the designated A5380 VSL for evidence of HIV-1 drug resistance. 
Results will be reported back to sites in real-time from the designated A5380 
VSL. 
 
• 
HCV RAS testing 
Using stored samples for HIV-1/HCV studies above, resistance genotype 
near-time sequencing will be carried out for NS3 and NS5A genes on 
participants experiencing confirmed virologic failure or recurrence. 
Sequencing will be performed on baseline and post-treatment recurrence 
samples with HCV RNA >1,000 IU/mL. 
 
• 
Phylogenetic Assessment of Relapse versus Re-infection 
Using stored samples for HIV-1/HCV studies above, viral phylogenies utilizing 
envelope hypervariable region 1 (HVR1) sequences compared between 
baseline and viral recurrence time points will be used to confirm 
determinations of re-infection versus suspected relapse made based on 
genotype and RAS assessments. This assessment will not be used for 
determination of eligibility for Step 2. Ultra-deep sequencing will be performed 
on baseline and post-treatment recurrence samples with HCV RNA >1,000 
IU/mL. The genetic diversity threshold for re-infection will be set at nucleotide 
substitutions per site greater than 3% [43, 59] and verified by cluster analysis. 
These assessments will be performed by the chairs, co-chairs, and virologist. 
 
6.3.11 PK Sampling 
 
For DBS, hair (optional), and plasma for PK, please refer to the Pharmacology 
Plan in section 11.0. 
 
6.3.12 IL-28B Genotype and HLA Typing 
 
DNA will be isolated from PBMCs collected during the study; these DNA samples 
will be analyzed for IL-28B genotype and HLA typing to inform immunologic 
studies. IL-28B genotype and HLA will be determined by polymerase chain 
reaction (PCR) amplification by the designated immunology laboratory (see 
A5380 LPC). For processing and shipping instructions, refer to the A5380 LPC. 
 
The IL-28B genotype and HLA typing will be performed only on participants who 
consent to this genetic test collection and are subsequently enrolled into the 
study. 
 
IL-28B genotype/HLA typing only needs to be performed once and may be 
performed on any PBMC sample collected at any time during the study. At Step 1 
entry, samples for IL-28B genotype/HLA typing will be collected. 
 


 
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6.3.13 Pregnancy Prevention Counseling 
 
Counseling on pregnancy prevention will be conducted as per site’s standard of 
care. This information is not recorded on the eCRF. 
 
6.3.14 Adherence Assessments  
 
This study will use a combination of measures of adherence for Step 1 study 
medication (G/P) and ARVs (if applicable) via the self-reported 4-day recall 
questionnaire at weeks 1, 2 and 4 for G/P and at entry, and weeks 1, 2 and 4 for 
ARVs. 
 
Pill counts for G/P should be collected at weeks 1, 2 and 4 and should only cover 
study medication since the participant’s last visit.  
 
Both the 4-day recall and pill counts will only be done as a part of Step 1.   
 
No adherence assessments will be done for Step 2.  
 
The adherence questionnaire is posted on the DMC Portal in the Forms 
Management Utility. 
 
6.3.15  Study Drug Dispensing/First Dose Observed 
 
For Step 1, study drug will be dispensed at study entry. Study staff will observe 
the first dose taken by the participant before he/she leaves the site and record 
this observation on an eCRF. 
 
For Step 2, study drug will be dispensed at Step 2 entry and every 4 weeks as 
indicated in Table 6.1-2 based on the length of therapy. Due to the different 
potential lengths of therapy for Step 2, in addition to entry, drug will be dispensed 
at R+4 for participants receiving 8 weeks of therapy, at R+4 and R+8 for 
participants receiving 12 weeks of therapy, and at R+4, R+8, and R+12 for 
participants receiving 16 weeks of therapy. 
 
Participants must be instructed to bring back all packages of study drugs in the 
original container at the post-entry study visits. 
 
6.3.16 Questionnaires 
 
Questionnaires are posted on the DMC Portal in the Forms Management Utility. 
 
Risk Factor Assessment 
As indicated in Tables 6.1-1 and 6.1-2, survey will be administered that will query 
participants on risk behaviors. The survey may be self-administered, interviewer-
administered or a combination of both. At baseline, the survey will ask about risk 
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about risk behaviors since the prior visit. The questionnaire will capture 
information related to sexual (e.g., history of unprotected receptive anal 
intercourse) and injection drug use practices (e.g., history of sharing of injection 
paraphernalia) as well as other practices that place individuals at a high-risk for 
HCV acquisition. Participants will be made aware they have the option to decline 
to answer any of the questions in the survey but still be included in the study.  All 
information from the risk assessment questionnaire will be recorded on the 
eCRF. 
Health Outcomes Questionnaire (EQ-5D) 
The EQ-5D is a validated instrument used to collect data about quality of life 
(http://www.euroqol.org). The instrument asks questions and each has three 
possible responses (EQ5D-3L version). The instrument asks respondents to 
comment on their degree of mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression, and then ask participants to record their current health-
related quality of life state using a vertical visual analogue scale (0-100 range). 
The instrument has been translated into a variety of languages and is available 
as a paper form, a computer-based form, a tablet/cell phone form, or as an 
interview. 
Responses must be recorded on an eCRF. Questionnaires will be administered 
per Table 6.1-1. 
Health Care Utilization Questionnaire 
The health care utilization questionnaire solicits participant-reported health care 
utilization in the past 4 weeks including: 1) nights spent in a hospital bed, 2) visits 
to an emergency department, and 3) visits to a doctor’s office. Responses must 
be recorded on an eCRF. This questionnaire will be administered per Table 6.1-
1.   
 
6.3.17 Reinfection Prevention Counseling 
 
HCV reinfection prevention counseling will be administered to all participants per 
Tables 6.1-1 and 6.1-2. This information is not recorded on the eCRF. See the 
A5380 MOPS for further details.    
 
6.3.18 Collection and Updating of Locator Information 
 
Given the limited sample size, it is imperative that additional measures are taken 
to ensure that retention at SVR12 is as close to 100% as possible. Consequently, 
locator information will be captured and updated periodically until the SVR 
assessment for Step 1. At Step 1 entry (day 0), detailed information on the 
primary mode of contact (e.g., mobile phone, email, social media messaging 
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mobile phone, email, social media messaging services, etc.). Additionally, 
information on a second person who may be contacted if the participant cannot 
be contacted will also be captured. This person could be a spouse, sibling, family 
member, sexual/injection partner, or a friend. 
 
At Step 1 week 4 (treatment completion) and post-treatment Step 1 weeks 8 and 
12, locator information will be confirmed with the participant to ensure that the 
information provided is up-to-date. If there are any changes in the information, 
the locator form will be updated accordingly to reflect the changes.     
 
A locator form has been included as part of the study documents available on the 
A5380 PSWP. It is not mandatory that sites use this form but it is strongly 
RECOMMENDED that sites use this form to capture and update locator 
information. It is recognized that some sites may already have site-specific 
locator forms to track study participants. Sites can opt to use these forms as 
opposed to the form provided with this protocol if they are more comfortable with 
the existing form. However, it is REQUIRED that sites capture and update locator 
information as per Table 6.1-1 by using either the study-specific locator 
information form or an alternate site-specific locator information form. Locator 
information is not recorded on the eCRF.   
 
6.3.19 Remote Contact Reminder for Week 16 Visit 
 
Participants will be contacted 2 weeks prior to the week 16 visit via the locator 
information provided and reminded that they are due for their SVR assessment. If 
the participant cannot be reached after 3 attempts, the secondary contact will be 
contacted. This information is not recorded on the eCRF. 
 
6.3.20 Evaluation of Step 2 Entry Requirements  
 
Sections 4.3 and 4.4 specify requirements for Step 2 entry. Recurrence and 
virologic failure should be documented. Determination of suspected relapse 
versus reinfection versus undefined post-treatment viremia by communication 
with the designated team member should be documented. These should be 
recorded on the eCRF. 
 
The informed consent form for Step 2 must be reviewed and signed by the 
participant prior to Step 2 entry.  
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
7.1 
Definition of AEs 
 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or diagnosis that occurs in a study participant during the conduct of 
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treatment/study product/device or procedure/intervention). This includes any occurrence 
that is new in onset or aggravated in severity or frequency from the baseline condition.   
 
7.2 
AE Collection Requirements for This Protocol 
 
From study enrollment, all AEs must be recorded on the eCRFs if any of the following 
criteria have been met: 
• 
All Grade ≥2 AEs 
• 
All AEs that led to a change in study treatment/intervention regardless of grade or 
attribution. 
• 
All AEs meeting SAE definition or EAE reporting requirement 
 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an Internet-based reporting 
system. 
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, which can be 
found on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above). 
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
7.3.1 Expedited Reporting of Adverse Events to DAIDS 
Requirements, definitions and methods for expedited reporting of AEs are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC 
website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for EAE reporting to DAIDS. In the event of 
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EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety 
Office at (DAIDSRSCSafetyOffice@tech-res.com). 
 
7.3.2 Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
• 
The study agents for which expedited reporting are required are: 
glecaprevir/pibrentasvir (G/P) FDC and ribavirin (RBV) 
• 
Though not an AE, the study investigator must report to the sponsor or 
designee, within 3 business days of identification, any pregnancy occurring in 
a female participant or a female partner of a male participant, during the 
study or within 24 weeks of the last dose of RBV. Any complication of 
pregnancy affecting a female participant or female partner of a male 
participant, and/or fetus, and/or newborn that meets SAE criteria must be 
reported as an SAE. See section 8.2 for pregnancy reporting requirements.  
 
7.3.3 Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, 
must be used and is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-
tables. 
 
 
7.3.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is week 0 to week 28 for all 
participants except those who proceed to Step 2. For individuals who proceed 
to Step 2, the reporting period would be dependent on the length of their Step 
2 regimen. Each Step 2 participant will have expedited AE reporting up to 12 
weeks after their last dose of study drug except for RBV for which expedited 
AE reporting would continue till week 24 after last medication dose. For Step 
2 of this study expedited AEs would only be collected on Step 2 participants 
who are on study drugs (G/P) or G/P and RBV.    


 
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• 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the EAE Manual, will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
 
7.4 
Study Monitoring 
 
A5380 core team members (including study chairs, medical officer, and statisticians) will 
monitor the conduct and safety of the study via regular summaries of accrual, AEs, study 
conduct (including premature study discontinuations and premature study treatment 
discontinuations), data completeness, and specimen collection, as appropriate. The core 
team will review the individual participant-level HCV virology data as outlined in section 
10.5. 
 
The DAIDS clinical representative will review and assess select EAE reports for potential 
impact on the study participant safety and protocol conduct as per DAIDS policies, 
guidance documents, and standard operating procedures (SOPs), as applicable. 
Additionally, the DAIDS clinical representative will review aggregated AE summaries 
prepared every 3 months by the Statistical and Data Analysis Center (SDAC). 
 
The study will undergo interim review at least annually by an ACTG-appointed Study 
Monitoring Committee (SMC). The first planned interim review will occur when the study 
week 8 data are available from the first 10 participants or one year after the enrollment 
of the first study participant, whichever occurs first. An interim review may also be 
convened if a concern is identified by the DAIDS clinical representative, the study chairs, 
or study statistician in consultation with the team. See section 10.5 for statistical and 
other considerations related to interim monitoring. 
 
Detailed plans for study monitoring will be outlined in a Study Progress, Data, and Safety 
Monitoring Plan (SPDSMP) developed by the Statistical and Data Management Center 
(SDMC) prior to enrollment of the first participant.  
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity  
 
It is possible that some participants will experience transient or prolonged AEs during the 
trial. To minimize the effects of these dosing modifications on the eventual evaluation of 
the safety, tolerability, and activity of study treatment, the principles in the following 
sections will be used to determine the appropriate dose adjustment. 
 
Grades 1 and 2 AEs associated with G/P or RBV require no change in study treatment 
but close follow-up; with the exception that modifications of RBV dosing for Grades 1 
and 2 anemia are provided in section 8.1.2. 
 


 
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8.1.1 Management of Side Effects of G/P 
 
Most AEs are expected to be mild in severity. However, if a SAE occurs, 
administration of G/P may be discontinued due to clinical or laboratory events. 
For participants also on a ritonavir (RTV)-boosted HIV PI or a cobicistat-
containing regimen there is potential for higher exposures.  
  
Dose reduction of G/P will not be allowed in the study. If G/P is stopped for 
toxicity, it will not be restarted.  
 
All participants must complete weeks 8, 12, 16, and 28 visits (Step 1) or one of 
the following visits in Step 2 depending on re-treatment duration: week R+20, 
R+24, or R+28, R+32, R+36, and R+40 visits.  
 
Participants who meet any of the following laboratory criteria should stop 
treatment with G/P: 
• 
Confirmed elevation of ALT and/or AST >3 x values measured upon study 
entry  
• 
Confirmed direct bilirubin >2x values measured upon study entry  
• 
Any  ≥Grade 3 rash associated with constitutional symptoms 
• 
Any Grade 4 event assessed as related to treatment with G/P 
 
8.1.2 Management of Side Effects of RBV (Step 2 participants with suspected relapse, 
virologic failure, or undefined post-treatment viremia) 
 
The most common AE of RBV therapy is anemia due to hemolysis. Anemia 
typically occurs within 1 to 2 weeks of initiating RBV therapy and usually resolves 
within 4 to 8 weeks of drug discontinuation or dose reduction. Indirect bilirubin 
elevation is commonly seen in those participants with anemia secondary to RBV-
induced hemolysis.  
 
Another major side effect of RBV is its teratogenicity. It is therefore strongly 
recommended that pregnant women or breastfeeding women and men with 
pregnant sexual partners not receive RBV. Women who become pregnant on 
study and men on study whose partners become pregnant must discontinue 
study treatment and complete the discontinuation evaluations as indicated in 
section 8.2. 
 
RBV dosing in this study will be based on weight at Step 2 entry (see section 
5.0). Dose reduction of RBV is the recommended management for RBV-
associated anemia and should be performed according to the product label. 
Information is summarized in Table 8.1.2-1. It is recommended that sites contact 
the A5380 CMC with questions regarding difficult anemia management and/or if it 
is felt RBV discontinuation is required. Participants will continue to take G/P if 
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Table 8.1.2-1: Suggested RBV Dose Reduction in the Event of Anemia 
Laboratory Values 
Reduce RBV Dose to 600 
mg/day if: 
Hold RBV if: 
Hemoglobin in participants 
with no cardiac disease 
<10 g/dL 
<8.0 g/dL 
Hemoglobin in participants 
with history of stable cardiac 
disease 
≥2 g/dL decrease in 
hemoglobin during any 4-
week treatment period  
<10 g/dL despite 4 weeks at 
reduced dose 
Symptomatic drop in hemoglobin to be managed at the discretion of the site investigator and 
can be discussed with the protocol chairs.  
 
Reintroduction of RBV 
If RBV is temporarily stopped due to anemia, the hemoglobin must be rechecked 
within 2 weeks and at 2-week intervals until stable. Once RBV has been withheld 
due to either a laboratory abnormality or clinical manifestation, an attempt may 
be made to restart RBV at 600 mg daily in two divided doses and further increase 
the dose to 800 mg daily in two divided doses. However, it is not recommended 
that RBV be increased to the original assigned dose. Please refer to the table 
below for dosing intervals.  
 
Table 8.1.2-2: Dosing Intervals to Restart RBV 
Daily Dose 
Morning Dose 
Evening Dose 
600 mg 
400 mg (2 tablets) 
200 mg (1 tablet) 
800 mg 
400 mg (2 tablets) 
400 mg (2 tablets) 
 
NOTE A: The half-life of RBV in participants with normal renal function is 290 
hours. 
 
NOTE B: The ranges of hemoglobin values used as criteria for triggering dose 
reduction of RBV do not correspond to those used to grade toxicities in 
the DAIDS AE Grading Table, corrected Version 2.1, July 2017. 
Therefore, sites are expected to use specific criteria shown in Table 
8.1.2-1 above. 
 
8.2 
Pregnancy  
 
Pregnancy and pregnancy outcome will be recorded on the eCRFs. For co-infected 
participants, pregnancies that occur on study should be reported prospectively to The 
Antiretroviral Pregnancy Registry. More information is available at www.apregistry.com. 
Telephone: 800-258-4263; Fax: 800-800-1052. (For studies conducted at sites outside 
the United States, report to The Antiretroviral Pregnancy Registry—Telephone: 910-679-
1598; Fax: 44-1628-789-666 or 910-256-0637.) 
 


 
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Pregnancy Outcomes and Reporting 
If a woman has completed the study or chooses to discontinue from the study before the 
end of the pregnancy, then site staff should request permission to contact her regarding 
pregnancy outcomes at the end of pregnancy. If the information is obtained, pregnancy 
outcomes will be submitted on an eCRF at the end of the pregnancy.  
 
Pregnancy will result in immediate discontinuation of the study drugs and initiation of 
counseling regarding the lack of information of safety in pregnancy with G/P and for 
those in Step 2 receiving RBV, regarding the teratogenicity of RBV. Participants who 
become pregnant while on study will be followed on study/off treatment until study 
completion. A visit 6 months following the end of pregnancy will be conducted for 
evidence of AEs in the participant and infant, and an outcome eCRF will be completed.  
 
In Step 2, male participants taking RBV whose partners become pregnant will undergo 
treatment discontinuation and remain on study for continued follow-up until the end of 
the study. They will receive counseling on RBV teratogenicity and the same follow-up 
visit at 6 months after their partners’ delivery as outlined for pregnant women. This same 
risk of teratogenicity is not seen with G/P, thus pregnancy of female partner in Step 1 is 
not an indication for treatment discontinuation. 
 
All participants including female partners of male participants who become pregnant 
while taking the study treatment will have their pregnancy reported to AbbVie via the 
sponsor.  
 
If a female participant or male participant with a pregnant female partner has completed 
the study or chooses to discontinue from the study before the end of the pregnancy, site 
staff should request permission to contact the female participant or male participant with 
a pregnant female partner regarding pregnancy outcomes at the end of pregnancy. If the 
information is obtained, pregnancy outcomes will be submitted on an eCRF at the end of 
the pregnancy.  
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Premature Treatment Discontinuation 
 
• 
Drug-related toxicity (see section 8.1). 
• 
Pregnancy in a female participant. 
• 
Participant request to discontinue for any reason. 
• 
Requirement for prohibited concomitant medications (see section 5.4). 
• 
Breastfeeding. 
• 
Clinical reasons believed life threatening by the physician, even if not 
addressed in the toxicity section of the protocol. 
• 
For Step 2 only: Pregnancy in female partner of a male participant taking 
RBV. 
• 
HCV virologic failure during Step 2 (see section 6.2.6).  
 


 
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NOTE: It is important to determine whether the treatment discontinuation is 
primarily due to an AE, lack of efficacy, or other reason. 
 
9.2 
Premature Study Discontinuation 
 
• 
Request by the participant to withdraw. 
• 
At the discretion of the ACTG, IRB/EC, FDA, NIAID, Office for Human Research 
Protections (OHRP), any other government agency as part of their duties, 
investigator, or industry supporter. 
• 
The Study Monitoring Committee (SMC) recommends that the study be stopped 
early.  
 
10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
A5380 is a prospective, phase II, single-arm study in treatment of acute HCV infection in 
participants with and without HIV-1 coinfection. The study will enroll participants at US 
and non-US sites. The key study objective is to evaluate the efficacy of a 4-week 
treatment of a FDC of glecaprevir/pibrentasvir (G/P), using SVR12 as the primary 
outcome measure. SVR12 is defined as unquantifiable HCV RNA at 12 weeks after 
treatment discontinuation (week 16 visit). 
 
The study is designed to conclude with reasonable evidence that the true SVR12 
proportion is greater than 80% in the study population. This will be assessed by 
examining if a two-sided 90% confidence interval (CI) for the sample proportion is 
entirely above 80%. This is equivalent to showing that the SVR12 proportion is higher 
than 80% in a one-sided test with a type I error of 5%, where the aim is to rule out 
SVR12 proportions below or equal to 80%. The threshold of 80% was chosen based on 
past studies (see section 2.2). 
 
The sample size of 44 participants for the evaluation was chosen to provide good power 
(90%) to show that the SVR12 proportion is not worse than or equal to 80%, assuming 
that the underlying SVR12 proportion is 95% with the 4-week treatment. The team 
considers SVR12 proportion of 95% to be plausible based on the results of studies in 
chronically HCV infected persons using 8 weeks of treatment and considering higher 
success with acute HCV infection (see section 2.2). This sample size is deemed to 
provide reasonable precision around the estimated SVR12 proportion to provide useful 
information in the treatment of acute HCV. 
 
The primary analysis on SVR12 will include all participants who initiate the treatment. As 
such, participants who discontinue the treatment early for whatever reason will be 
included in the primary analysis. Similar to the recently completed acute HCV study 
conducted in the ACTG (A5327), not achieving unquantifiable HCV RNA at the study 
visit corresponding to the SVR12 evaluation will be considered failure for SVR12 
determination in the primary analysis, regardless of the reason. By this definition, early 
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regardless of the reason, and re-infection prior to the SVR12 visit will also be considered 
a failure. Understanding reasons for SVR failure is important, and reasons for SVR 
failure will be described for the anticipated small number of non-SVRs. In addition, an 
important secondary analysis will be an SVR12 analysis that excludes participants who 
discontinue the study prior to the SVR12 evaluation for reasons clearly not related to 
study treatment and participants who become re-infected prior to when SVR12 can be 
assessed. Reasons for discontinuation unrelated to study treatment may include: 
participant moved away, participant cannot get to the clinic, participant cannot be 
located. To ensure that the study is well-powered for this important secondary analysis, 
additional participants may be enrolled if the study is still enrolling participants when the 
team becomes aware of such early study discontinuations. The maximum replacement 
number will be 6 for the study, so that study enrollment will not be greater than 50. 
 
The primary outcome at 12 weeks after treatment discontinuation (week 16) may be 
evaluated for each participant prior to the completion of study. The primary analysis 
timeline will be driven by the last participant’s completion of the primary outcome visit, 
rather than the study completion date. Results from the primary analysis on SVR12 may 
be presented publicly, for example at a conference, when the data related to such 
analysis are complete, prior to study database finalization. 
 
10.2 
Outcome Measures  
 
Primary and secondary outcome measures listed below will be addressed in the study’s 
primary Statistical Analysis Plan, which will define the content of the Primary Analysis 
Report. This report will form the basis for the primary study manuscript and results 
reporting to ClinicalTrials.gov. Outcomes of interest for secondary and exploratory 
objectives intended for subsequent publications are to be listed under “Other Outcome 
Measures”. 
 
10.2.1 Primary Outcome Measures  
 
10.2.1.1 
SVR12 defined as achieving unquantifiable HCV RNA (<LLOQ TD or 
TND) at the study visit occurring at 12 weeks after treatment 
discontinuation (week 16). The sample within the visit window for 
week 12, as defined in section 6.0, will be used. If a participant does 
not have any HCV RNA measurements in this time period then the 
participant will be considered as SVR12 failure, unless there are 
preceding and subsequent HCV RNA measurements that are both 
LLOQ (either TD or TND). 
 
10.2.1.2 
Any reported AE occurring after initiation of study treatment through 
the study visit occurring 4 weeks after the treatment completion. 
 
10.2.1.3 
Tolerability, defined as completion of 4 weeks of treatment without 
discontinuation due to AEs. 
 


 
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10.2.2 Secondary Outcome Measures  
 
10.2.2.1 
HCV RNA <LLOQ (TD or TND) at study visits, using the visit windows 
as defined in section 6.0. 
 
10.2.2.2 
Virologic failure, defined as failure to achieve unquantifiable HCV 
RNA and confirmed increase in HCV RNA >1 log10 from on-treatment 
nadir. 
 
10.2.3 Other Outcome Measures  
 
10.2.3.1 
Re-infection, defined as confirmed quantifiable HCV RNA during 
follow-up after achieving unquantifiable HCV RNA at the end of 
treatment or during follow-up, with phylogenetic results supporting 
new infection. 
 
10.2.3.2 
Relapse, defined as confirmed quantifiable HCV RNA during follow-up 
after achieving unquantifiable HCV RNA at the end of treatment or 
during follow-up, with phylogenetic results excluding new infection. 
 
10.2.3.3 
HCV resistance profile at study entry. The set of mutations to be 
considered will be defined prior to analysis based on the latest 
information. 
 
10.2.3.4 
Development of HCV resistance mutation(s) in SVR12 failures. 
 
10.2.3.5 
SVR12 for re-treatment, defined as achieving unquantifiable HCV 
RNA (<LLOQ TD or TND) at the study visit occurring at 12 weeks 
after treatment discontinuation For the participants receiving 8 weeks 
of re-treatment, study visit at Step 2 week R+20 will be used for 
SVR12 evaluation. For the participants receiving 12 weeks of re-
treatment, study visit at Step 2 week R+24 will be used for SVR12 
evaluation. For the participants receiving 16 weeks of re-treatment, 
Step 2 week R+28 will be used for the SVR12 evaluation. 
 
10.2.2.6 
Substance use. 
 
10.2.2.7 
Self-reported adherence measured by the number of missed doses.   
 
10.2.2.8 
Adherence measured by the pill count. 
 
10.2.3.9 
Serologic and virologic markers of acute immunologic host response 
(to be defined at the time of assay determination).  
 
10.2.3.10 CD4+ T-cell recovery (to be defined at the time of assay 
determination). 
 


 
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10.2.3.11 Type I IFN-induced immune dysfunction (to be defined at the time of 
assay determination). 
 
10.2.3.12 Cost-effectiveness measure (to be determined by assessing the 
resource use and cost of care). 
 
10.3 
Randomization  
 
There is no randomization in this study. All enrolled participants will receive the study 
treatment. The minimum number of HIV-1-infected participants is 10, and there is no 
maximum. 
 
10.4 
Sample Size and Accrual  
 
The sample size was determined to provide good power to show that SVR12 proportion 
is greater than 80%. The true SVR12 proportion is assumed to be 95% when treated 
with 4 weeks of the G/P regimen. With 44 participants, there is at least 90% power to 
show that proportion achieving SVR12 is greater than 80% in a one-sided exact binomial 
test with a targeted significance level of 5%. Table 10.4-1 below shows the study power 
for a range of values for the underlying SVR12 proportion. 
 
Table 10.4-1: Study Power for the Underlying SVR12 Proportion 
True SVR12 
Proportion 
Power 
90%  
54% 
92% 
72% 
95%  
93% 
97%  
99% 
 
With a sample size of 44 participants, the Wilson confidence interval for the true SVR12 
proportion will be entirely above 80% if 40 or more participants achieve SVR12 out of 44 
participants. The table 10.4-2 below shows two-sided 90% CIs for various potential 
observed SVR12 proportions in a sample of 44 participants. The width of the CI 
indicates precision around the SVR12 estimate. 
 
Table 10.4-2: CIs for Various Potential Observed SVR12 Proportions 
Observed  
SVR12 Proportion 
90% CI for the True 
SVR12 Proportion 
86.4% (38/44)  
(75.7%, 92.8%) 
88.6% (39/44) 
(78.4%, 94.4%) 
90.9% (40/44) 
(81.2%, 95.9%) 
93.2% (41/44) 
(84.1%, 97.2%) 
95.5% (42/44) 
(87.2%, 98.5%) 
97.7% (43/44) 
(90.4%, 99.5%) 
 


 
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Accrual of about three participants per month is expected, to complete enrollment in 15 
months. Should accrual of additional participants be needed for a key secondary 
analysis on SVR12, which excludes participants who are re-infected with HCV or 
discontinue early for reasons not related to study treatment (see section 10.1), the 
enrollment period may be extended. 
 
10.5 
Data and Safety Monitoring  
 
The study will be monitored by an ACTG SMC, which will review the study at least 
annually after the first participant is enrolled. The reviews will include information about 
accrual, baseline characteristics, retention, completeness of key laboratory 
measurements (HCV RNA), AEs, and available HCV RNA results at study visits. See 
section 7.4 for an overview of study monitoring. In addition, the following interim 
monitoring is planned for A5380.  
 
10.5.1 Interim Monitoring Guidelines 
 
HCV RNA results will be closely monitored in the first 10 participants by the 
A5380 core team (including study chairs, medical officer and statisticians) for 
consideration of study modification, in case there is evidence of an unacceptable 
number of participants not achieving unquantifiable HCV RNA, excluding 
reinfection (referred to as simply “failures” in this interim monitoring section) with 
the proposed 4 weeks of treatment.   
 
HCV RNA results will be reviewed as the data become available for the first 10 
participants. The following guideline will be used to assess failures based on 
early interim data on 10 participants that may trigger an SMC review:   
 
If 3 or more of the first 10 participants experience failures by the visit occurring 4 
weeks after the end of treatment (week 8), further enrollment will be suspended 
while the core team and the SMC review the data closely and determination is 
made on the future conduct of the study. 
 
The table below shows the probabilities of meeting the above criteria under 
various assumed probabilities for failures shown by the visit occurring 4 weeks 
after the end of treatment, using binomial distributions. We want a high 
probability of meeting the guideline when the probability of failure is unacceptably 
high, so that the study can be modified. For example, when the true probability of 
failure is as high as 50%, then there is 95% probability of meeting the guideline 
to modify the study. On the other hand, we want a low probability of meeting the 
guideline when the true probability of failure is low. For example, when the true 
probability of failure is as low as 5%, then there is only 1% probability of meeting 
the guideline. When the true probability of failure is 30%, the probability of 
meeting the guideline to consider modifying the trial is 62%. 
 


 
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Table 10.5.1-1: Probability of Meeting the Guideline 
True Probability of Failure  
Probability of Meeting the Guideline 
0.05 
0.012 
0.10 
0.070 
0.15 
0.180 
0.20 
0.322 
0.25 
0.474 
0.30 
0.617 
0.35 
0.738 
0.40 
0.833 
0.45 
0.900 
0.50 
0.945 
 
The criteria described here are meant to serve as a guideline, and the team may 
request an SMC review at any time for other reasons. 
 
10.5.2 Analysis Plan 
 
For the purpose of the early interim looks, the report will consist of listing of all 
available HCV RNA results, genotype results, baseline demographics and key 
clinical characteristics (including HIV status, ALT), study treatment duration, 
treatment status, and other data that may be related to re-infection. The report 
will be sent to the A5380 core team (mentioned in sections 7.4 and 10.5.1) 
frequently for review until the 10th participant has week 8 HCV RNA data 
available.  
 
10.6 
Analyses  
 
The primary efficacy objective will be addressed by estimating the proportion of 
participants who achieve SVR12 (section 10.2.1.1 describes this primary endpoint). All 
enrolled participants who receive any study treatment will be included in the primary 
analysis. A two-sided 90% CI will be calculated around the estimated SVR12 proportion 
using the Wilson method for binomial data. If this CI is entirely above 80%, then it will be 
concluded that there is evidence that the underlying SVR12 proportion is greater than 
80%.   
 
For the primary safety analysis, the AEs occurring after initiation of study treatment 
through the study visit occurring 4 weeks after the treatment completion will be 
summarized. The proportion of study participants with AEs will be estimated with a two-
sided 95% CI around the estimate. As a secondary analysis, all reported AEs (which 
include events that occur after the time frame defined for the primary safety analysis) will 
be summarized. A two-sided 95% CI will also be provided for the proportion of study 
participants with AEs. The Wilson method will be used. 
 
As a secondary analysis, SVR12 will be assessed in the analysis set that excludes 
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treatment and participants who became re-infected with HCV prior to SVR12 visit.  
Reasons not related to study treatment include: participant moved away, participant 
cannot get to the clinic, participant cannot be located. The analysis will use methods 
similar to the primary analysis. SVR12 results will also be described separately by HIV-1 
infection status. 
 
The secondary HCV RNA endpoints (HCV RNA <LLOQ at study visits) will also be 
assessed with proportion estimates with two-sided 90% CI using the Wilson method, 
similar to the primary efficacy analysis on SVR12. 
 
Tolerability failures and virologic failures, as defined in section 10.2.2, will be listed and 
described. A tolerability failure listing will be accompanied by treatment duration and the 
associated AE(s). Listings on virologic failure will be accompanied by HCV RNA results 
and any available information on HCV genotype/subtype, RAS and phylogenetic results. 
 
11.0 
PHARMACOLOGY PLAN 
 
Within the context of this trial, adherence to G/P and potentially ARVs using a variety of 
assessments including self-report, pill count, and drug concentrations in plasma, cells, 
and/or hair will be assessed. Concentration-effect associations (e.g., glecaprevir 
exposures and acute LFT elevations or the relationship between G/P exposures and 
likelihood of achieving SVR) may also be investigated. The former is relevant for this 
study since participants on ritonavir-boosted darunavir and elvitegravir/cobicistat will be 
included. Exposures of glecaprevir are higher with these ART agents which may 
theoretically increase the risk for hepatotoxicity. There are limited PK and safety data 
with G/P and ritonavir-boosted darunavir and elvitegravir/cobicistat in individuals with 
HIV/HCV coinfection, so this study may provide a unique opportunity to examine any 
associations between exposures and LFT elevations. Also, though there is not a plan to 
investigate this prior to limit costs and because what type of ART and substances study 
participants may use will not be known, samples and data will also be collected that 
allow the assessment of potential drug interactions with drugs and ART agents with G/P. 
There is not a pharmacologic basis to expect a significant drug interaction between G/P 
and drugs, but formal drug interaction studies with substances are lacking. 
 
11.1 
Pharmacology Objectives 
 
11.1.1 To evaluate participants’ adherence by using several tools, including self-report, 
pill count and drug concentrations 
 
11.1.2 To assess the pharmacokinetic-dynamic associations for G/P  
 
11.1.3 To evaluate potential drug interactions between common drugs of abuse, ARVs, 
and G/P. 
 


 
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11.2 
Pharmacology Study Design 
 
For Step 1, plasma for PK, DBS samples, and hair samples (optional) will be obtained 
per Table 6.1-1. Please see A5380 MOPS for details regarding optional hair sample 
collection. Samples are collected prior to treatment initiation and after discontinuing G/P 
treatment in the event there is a need to retrospectively evaluate the potential for ART or 
drug interactions or adherence, but these samples will not be analyzed prior to limit 
costs and because it is not known what ART or drugs study participants will be taking. 
Record dose information (date/time) of last three doses of study drug and ARVs on 
eCRF. 
 
For Step 2, plasma will be obtained per Table 6.1-2. DBS and hair samples will not be 
collected during Step 2. Record dose information (date/time) of last three doses of study 
drug and ARVs on eCRF. 
 
Substance use will be assessed using urine screens and participant self-report and 
potential drug concentrations.   
 
NOTE: The weight recorded at entry to each step will be used as the weight for the 
corresponding PK analysis. 
 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
To address pharmacology objective 11.1.1, adherence (measured by pill count, self-
report, and/or drug concentrations) may be used as a predictor variable in evaluations of 
associations with viral response, summarized using descriptive statistics, or for ARV, 
compared before, during, and after G/P treatment.  
 
To address pharmacology objective 11.1.2, we will investigate glecaprevir exposures 
and LFT elevations or the relationship between G/P exposures and likelihood of 
achieving SVR.  
 
To address pharmacology objective 11.1.3, if we have a sufficient number of 
participants on a particular ART or drug, we may explore the potential for drug 
interactions between G/P and these agents.  
 
11.4 
Anticipated Outcomes 
 
Pharmacology-related objectives for this study may provide clinical context to study 
findings (e.g., if adherence contributed to observed SVR rates, or if LFT elevations were 
associated with glecaprevir exposures) or potentially identify unexpected drug 
interactions between G/P, ARV, and/or drugs.   
 


 
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12.0 
DATA COLLECTION AND MONITORING  
 
 
12.1 
Records to Be Kept 
 
Electronic case report form (eCRF) screens will be made available to sites for data entry. 
Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon registration. 
 
12.2 
Role of Data Management 
 
12.2.1 Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
12.3.1 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, eCRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 
12.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the ACTG, IRB/EC, 
FDA, the NIAID, the OHRP, the industry supporters or designee, other local, US, 
and international regulatory entities for confirmation of the study data.  
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I and II) and any 
subsequent modifications will be reviewed and approved by the IRB or EC responsible 
for oversight of the study. A signed consent form will be obtained from the participant (or 
legal guardian, or person with power of attorney for participants who cannot consent for 
themselves). The consent form will describe the purpose of the study, the procedures to 
be followed, and the risks and benefits of participation. A copy of the consent form will 
be given to the participant, or legal guardian, and this fact will be documented in the 
participant’s record. 


 
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13.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other local, US, and international regulatory entities as part of their duties, or the 
industry supporters or designee.  
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
other “country-specific” government agencies as part of their duties to ensure that 
research participants are protected, or the industry supporters. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporters prior to submission.  
 
15.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  


 
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16.0 
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APPENDIX I: STEP 1 SAMPLE INFORMED CONSENT 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
For protocol: A5380 
 
FINAL VERSON 1.0, 06/07/19: A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose 
Combination Treatment for Acute Hepatitis C Virus Infection (PURGE-C) 
 
SHORT TITLE: Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute Hepatitis 
C Virus Infection Including Persons with HIV 
 
PART 1 SUMMARY 
 
PURPOSE 
The purpose of Part 1 of this study is to see if 4 weeks of the hepatitis C 
(HCV) drug, glecaprevir/pibrentasvir (G/P), cures your acute HCV. People 
with acute HCV have a good chance of being cured of the infection when 
they are treated with a combination of two drugs within the first 6 months 
of getting HCV. 
 
The study will also look at the safety of 4 weeks of G/P and if it is 
tolerated by your body. 
 
NUMBER OF  
PARTICIPANTS 
There will be 2 parts of the study for a total of up to 50 participants. 
 
LENGTH OF  
STUDY 
Part 1 of the study will last about 28 weeks for most people. Part 2 of  
the study will last about 20-40 weeks because additional treatment is 
required.  
 
For Part 1, you will need to come back to the clinic 9 more times in the 
first 28 weeks. 
 
REQUIRED 
ACTIVITIES 
Blood and urine collections 
• 
At most visits, some blood will be collected from a vein in your arm. At 
a few visits, you will be asked to provide a urine sample.  
  
Special procedures  
• 
You will be asked about the best way to reach you by telephone, 
email, etc., between visits.  
• 
You will be asked questions about potential risks of becoming infected 
with HCV, and your quality of life.  
• 
Some of your hair will be collected, if you choose. 
 


 
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RISKS 
The following are possible: 
• 
People outside of the study may find out that you are participating in 
this study and treat you unfairly. 
• 
Discomfort, lightheadedness, bleeding, swelling, or bruising from 
drawing blood 
• 
Side effects from the study medication 
• 
Drug resistance, making your HCV more difficult to treat 
• 
If you are living with HIV, drug interactions with your HIV drugs while 
taking the study medication. 
• 
If you have hepatitis B (HBV) and HCV, reactivation of HBV. 
 
BENEFITS 
You may be cured of your HCV but no guarantee can be made. 
 
OTHER CHOICES 
Instead of being in this study, you have the option of continuing with your 
current treatment, starting a new treatment under the care of your regular 
doctor or other health care provider, or no treatment at all. Your 
participation in this study is completely voluntary.  
 
INTRODUCTION 
 
You are being asked to take part in this research study because you have a recent infection with 
the hepatitis C virus (HCV, a virus that affects the liver). You may also be living with human 
immunodeficiency virus (HIV, the virus that causes AIDS). This study is sponsored by the 
National Institutes of Health. The doctor in charge of this study at this site is: (insert name of 
Principal Investigator). Before you decide if you want to be a part of Part 1 of this study, we want 
you to know about Part 1 of the study. 
 
This is a consent form. It gives you information about Part 1 of this study. The study staff will 
talk with you about this information. You are free to ask questions about this study at any time. If 
you agree to take part in Part 1 of this study, you will be asked to sign this consent form. You 
will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
People who are recently infected with a new case of HCV are often considered to have acute 
HCV. People with acute HCV have a good chance of being cured of the infection when they are 
treated with a combination of two drugs within the first 6 months of being diagnosed. This study 
is being done to see if 4 weeks of the HCV drug, glecaprevir/pibrentasvir (G/P), cures your 
HCV, and if 4 weeks of G/P is safe for you and can be tolerated by your body. This study will 
include up to two parts: 
 
Part 1 (shorter course of treatment- 4 weeks) - You will take 3 tablets of G/P by mouth daily for 
4 weeks. If you are not cured of HCV from this 4-week treatment, or you are infected again, you 
will have the option to enroll into Part 2. 


 
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Part 2 (longer course of treatment- more than 4 weeks, and the treatment may differ from Part 
1) - If you require retreatment approximately 12 weeks after completing the treatment in Part 1, 
you will take 3 tablets of G/P by mouth daily for either 8, 12, or 16 weeks. It is possible another 
drug named ribavirin (RBV) will be added to G/P. The length of treatment will be decided from 
various lab tests. It is possible that the study doctor will suggest a different  
HCV drug based on your local standard of care. You are not signing up for Part 2 at this time. A 
separate consent form will be obtained in the event you become eligible for Part 2. 
 
The medications that is provided in this study is approved by the Food and Drug Administration 
(FDA) for use in persons who have been diagnosed with HCV. 
 
You will be monitored for safety and viral response (how your body is responding to treatment 
and whether the amount of HCV in your body is decreasing) while on treatment. After 
completing treatment, you will be evaluated to see how your body responded to treatment at 
various time points up to 24 weeks in each part of the study.   
 
This is a consent form for Part 1 of the study. You may be asked to join Part 2 of the study if, 
after treatment in Part 1, you still have HCV. Details on Part 2 of the study will be reviewed with 
you should that occur, and you will be asked to sign another consent form. Right now, you are 
not signing up for Part 2 of the study. 
 
 
WHAT DO I HAVE TO DO IF I AM IN STEP 1 OF THIS STUDY? 
 
If you would like to be in this study, after you have read and signed this informed consent form, 
you will come to the clinic for a screening visit to make sure you meet the requirements for 
joining the study. You may have as little as 2.5 tablespoons to as much as 11 tablespoons of 
blood collected at any one visit. Over the course of the study, the amount of blood collected 
from you will be within approved limits. 
 
If you are also living with HIV, you will continue taking your current anti-HIV drugs 
(antiretrovirals [ARVs]- medications to control HIV) if you are receiving them. If you are not 
currently on ARVs and your provider does not think you will need ARVs for the next 4 weeks, 
this is also acceptable. If your HIV regimen includes atazanavir, efavirenz, etravirine, 
fosamprenavir/ritonavir, indinavir/ritonavir, lopinavir/ritonavir, nelfinavir, nevirapine, 
saquinavir/ritonavir, or tipranavir/ritonavir, you will need to be switched to another HIV regimen. 
You will need to be sure that your HIV provider discusses all changes to your HIV regimen with 
the study doctor. See section I for a description of the study visits. 
 
After the entry visit, you will be given your study medication (G/P) for all 4 weeks of treatment to 
take home. You will need to store the medications in a safe place at room temperature (between 
15º to 25ºC [59º to 77ºF]). You will take three pills every day for 4 weeks. After you have 
completed 4 weeks of treatment with G/P, you will continue to have follow-up visits for 24 
weeks. 
 


 
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Everyone who enters this study will take a fixed-dose combination (FDC) of G/P, which will be 
given for free by the study. If you have HIV, your ARVs will not be provided by the study. These 
will be provided by your regular non-study HIV provider. 
 
While you are in Part 1 of this study, you will need to be seen in the clinic about 9 times during 
the study. The study staff will tell you about how long each visit could be. You will have blood 
drawn for study related tests during each visit both to monitor your response to the study 
medication and to look for any side effects that may be caused by the medication.  
For both parts of the study, you may need to make extra visits to the clinic if you have side 
effects or if you switch or take new ARVs. More information about the study tests is given below. 
During the study, you will get the results from any routine tests that are done during the study 
when they are available.  
 
A5380 Part 1 Study Visits 
The study staff can answer any questions you have about individual study visits, the evaluations 
that will occur, or how long each visit will be. The table below can be used as a quick reference 
for you, along with the explanations that follow. 
 
Appendix I Table 1: Part 1 Study Schedule 
Evaluation or 
Test 
Screening Entry 
Post-Entry Visits 
Unplanned 
Visits 
HCV Virologic 
Failure 
Confirmation  
HIV Virologic 
Failure 
(Breakthrough) 
Confirmation  
Early 
Discontinuation 
Weeks 
1 and 
2 
Week 
4 
Weeks 
8, 12, 
14, 16, 
28 
Consent 
 
 
 
 
 
 
 
 
 
Documentation 
of HIV, HCV, 
and Cirrhosis 
Status, and Past 
Labs 
 
 
 
 
 
 
 
 
 
Medical & 
Medication 
History 
 
 
 
 
 
 
 
 
 
Clinical 
Assessments 
 
 
 
 
 
 
 
 
 
Blood Collection 
& Laboratory 
Testing 
 
 
 
 
 
 
 
 
 
Urine Sample 
for 
Substance/Drug 
Use Test 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
 
 
 
 
 
 
 
 
 


 
9 6  
A 5 3 8 0  
FI N A L V er si o n 1. 0  
 
 
0 6 /0 7/ 1 9  
 
E v al u ati o n or 
T e st  
S cr e e ni n g  E ntr y  
P o st -E ntr y Vi sit s  
U n pl a n n e d 
Vi sit s  
H C V Vir ol o gi c 
F ail ur e 
C o nfir m ati o n  
HI V Vir ol o gi c 
F ail ur e 
( Br e a kt hr o u g h) 
C o nfir m ati o n  
E arl y 
Di s c o nti n u ati o n  
W e e k s 
1 a n d 
2 
W e e k 
4 
W e e k s 
8, 1 2, 
1 4, 1 6, 
2 8  
Bl o o d C oll e cti o n 
f or 
P h ar m a c o ki n eti c 
( P K) St u di e s 
 
 
 
 
 
( w k s 8, 
1 2, 1 6)  
 
 
 
 
O pti o n al H air 
C oll e cti o n f or P K 
St u di e s  
 
 
 
 
 
( w k 
1 6)  
 
 
 
 
Pr e g n a n c y 
Pr e v e nti o n 
C o u n s eli n g  
 
 
 
 
 
( w k 8) 
 
 
 
 
A d h er e n c e 
A s s e s s m e nt s  
 
 
 
 
 
 
 
 
 
H C V Ri s k 
F a ct or s 
A s s e s s m e nt 
 
  
 
 
  
( w k s 8, 
1 6, 2 8)  
 
 
 
 
H e alt h 
O ut c o m e s 
Q u e sti o n n air e  
 
 
 
 
   
( w k s 
1 6, 2 8)  
 
 
 
 
 H e alt h C ar e 
Utili z ati o n 
Q u e sti o n n air e  
 
 
 
 
   
( w k s 
1 6, 2 8)  
 
 
 
 
St u d y 
M e di c ati o n  
Di stri b uti o n  
 
 
 
 
 
 
 
 
 
H C V R ei nf e cti o n 
Pr e v e nti o n 
C o u n s eli n g  
 
  
 
  
  
( w k s 8, 
1 6,  2 8)  
 
 
 
 
C o nt a ct 
I nf or m ati o n 
 
   
  
  
( w k s, 
8, 1 2)  
 
 
 
 
R e mi n d er 
f or W e e k 1 6 
Vi sit  
 
 
 
 
 
  
( w k 
1 4)  
 
 
 
 
 
 
 


 
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I. Description of Part 1 Study Visits 
 
Part 1 Screening 
After you have read and signed the consent form, you will be asked questions about your 
health, medical history, and medication history. You will have several tests, including blood 
tests, to make sure that you qualify to join this study. Some of the blood taken will be shipped to 
a testing lab. Your new HCV diagnosis and approximately how long you’ve been diagnosed with 
HCV will be confirmed. This visit will take about 1-2 hours. At this visit: 
• 
Your HIV status will be confirmed. If there is no record available, another HIV test will be 
done. You may have to sign a separate consent form before this is done. 
• 
Your HCV diagnosis status will be confirmed. HCV RNA (to measure the level of the HCV in 
the blood) and genotype (to determine the genetic makeup of your HCV) will also be done. If 
available, information about cirrhosis (liver damage) status will be collected. 
• 
Your lab results from the past 12 months (if available) will be documented for liver function 
and HCV tests. 
• 
You will be asked questions about your medical history and any medications you are taking 
or have taken in the past. 
• 
You will have a complete physical exam, including vital signs (temperature, pulse, 
respiration rate [the number of breaths you take in a minute], and blood pressure), and 
weight.  
• 
You will have blood drawn to see if you are diagnosed with the hepatitis A or B virus (an 
infection of the liver); for routine lab tests for safety; for virologic studies (to help study the 
virus); for serologic studies (to study how your immune system responds HCV); if you are 
living with HIV, to measure the amount of HIV in your blood, and to measure your CD4+ and 
CD8+ cell counts (cells that help fight infection). Some of the blood you provide will be 
stored for future protocol-required testing. 
• 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy. You will also receive counseling on pregnancy prevention. Men will also be 
counseled on ways to not impregnate a woman while taking study medication. 
• 
For female participants, who report not being able to get pregnant, and have no medical 
record to confirm, follicle stimulating hormone-release factor (FSH) will be measured.  
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not qualify to take part in this study, we 
will still use some of your information. As part of the screening visit, some demographic (for 
example, age, sex at birth, race), clinical (for example, disease condition, diagnosis), and 
laboratory (for example, CD4+ T-cell count, viral load) information is being collected from you so 
that ACTG researchers may see if there are patterns or common reasons why people do not 
join a study. 
 
Part 1 Entry 
If all of the results from your screening tests show that you are eligible and you decide to take 
part, you will be enrolled in this study.  
• 
You will be asked about your health and any changes in your medicines since your last visit. 
You will have a brief physical exam including vital signs, height, and weight.  


 
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• 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy. 
• 
You will provide a urine sample to look for the use of drugs.  
• 
You will have blood drawn for routine lab tests for safety, virologic, immunologic (to test how 
your body fights infection), and pharmacokinetic studies (to look at your body’s response to 
the study medication). If you are living with HIV, blood will be drawn to measure the amount 
of HIV in your blood, and to measure your CD4+ and CD8+ cell counts. Some of the blood 
you provide will be stored for future protocol-required testing. 
• 
You will provide a hair sample for PK studies (this helps us learn more about how your body 
handles the study medication). This is optional. 
• 
You will receive 4 weeks of study medication (G/P) to take home with you. 
• 
You will receive adherence counseling as described below. 
• 
You will be asked questions about how well you take your ARVs (if applicable). 
• 
If you are a woman and able to get pregnant, you will be counseled on ways to not become 
pregnant while taking study medication. Men will also be counseled on ways to not 
impregnate a woman while taking study medication. 
• 
You will be asked questions about the use of drugs. 
• 
You will be asked questions about risk factors for HCV. 
• 
You will receive counseling on how not to become re-infected with HCV. 
• 
You will be asked for your primary preferred contact information as well as a second contact 
(spouse, friend, neighbor, etc.) in order for the study staff to reach you throughout the study. 
If you are not able to be reached through the primary contact information, then the study 
staff will try to reach you through the second contact you provide. 
 
Study Medication 
At your entry visit (for Part 1), the study staff will give you your study medication for the whole 4-
weeks of treatment to take home. You will need to store the medications in a safe place at room 
temperature (between 15º to 25 ºC [59º to 77ºF]).You need to take the study medication G/P for 
Part 1 with food. You will take three pills every day for 4 weeks. If you forget to take the study 
medication at the correct time, you may take it later in the day as soon as you remember. Then 
the next day you should continue with the usual schedule that you take the study medication. 
You should always take all 3 pills together. If you miss doses entirely, simply resume 3 pills the 
next day and do not ever double the dose (do NOT take 6 pills). Do not split or crush the pills or 
the split the medication doses. After you have completed 4 weeks of treatment with G/P, you will 
continue to have follow-up visits for 24 weeks. 
 
Everyone who enters this study will take a FDC of G/P, which will be given for free by the study. 
For those who are living with HIV, your ARVs will not be provided by the study. These will be 
provided by your regular non-study HIV provider. 
 
Part 1 Post-entry Visits 
After your entry visit, you will come to the clinic at weeks 1, 2, 4 (end of treatment), 8, 12, 16, 
and 28. These visits will last about 1-1½ hours each. 
 
Reminder for Week 16 Visit 
Study staff will contact you at week 14 in Part 1, to schedule your week 16 visit.  


 
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During Most Study Visits for Part 1 
• 
You will be asked about your health and any changes in your medicines since your last visit. 
• 
You will have a brief physical exam including vital signs and weight (weight only done 
Weeks 4, 16, and 28).   
• 
You will have blood drawn for routine lab tests for safety, virologic, immunologic, 
pharmacokinetic, and serologic studies (if needed); to measure the amount of HCV in your 
blood. If you are living with HIV, the amount of HIV in your blood and your CD4+ and CD8+ 
counts will be measured. Some of the blood you provide will be stored for future protocol-
required testing. 
• 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy at all on-treatment and post-treatment visits and study discontinuation. 
• 
You will provide a urine sample to look for the use of drugs. 
• 
You will provide a hair sample for PK studies at weeks 4 and 16. This is optional. 
• 
You will be asked questions about how well you take your ARVs (if applicable) at weeks 1, 
2, and 4. 
• 
All participants, male and female, will be counseled on the risk of the study medication in 
pregnancy and on how to prevent pregnancy while taking study medication at weeks 4, and 
8. 
• 
You will be asked questions about the use of drugs at weeks 1, 2, 4, 8, 16, and 28. 
• 
You will be asked questions about risk factors for HCV at weeks 1, 2, 4, 8, 16, and 28. 
• 
You will receive counseling on how not to become re-infected with HCV at weeks 4, 8, 16, 
and 28.  
• 
Study staff will update your contact information at weeks 4, 8, and 12. This contact 
information will be used to remind you about upcoming study visits. If study staff are unable 
to reach you after two tries, they will try to reach you via your second contact. 
 
Unplanned visits 
During the study, you may have to come back to the clinic for extra visits for testing of any lab 
results that are not normal, or to follow up on a specific side effect or symptom. 
 
HCV Virologic Failure Confirmation  
If laboratory tests show there is evidence of virologic failure (the amount of HCV in your blood is 
still detectable when tested), you will be asked to return to the clinic to confirm your lab results. 
At this visit:  
• 
You will have a brief physical exam including vital signs and weight.  
• 
You will have blood drawn for routine lab tests for safety, serologic, virologic, immunologic, 
and pharmacokinetic studies, and to measure the amount of HCV in your blood, for an HCV 
resistance test (resistance means that the drugs are not likely to fight the HCV in your body). 
If you are living with HIV, the amount of HIV in your blood will be measured. Some of the 
blood you provide will be stored for future protocol-required testing. 
• 
A urine sample will be taken for the substance use screen.  
• 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy. You will also receive counseling on pregnancy prevention. Men will also be 
counseled on ways to not impregnate a woman while taking study medication. 
• 
You will be asked to stay on the study and complete all of the study visits. 


 
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• 
If you choose, you will provide a hair sample for PK studies. 
 
HIV Virologic Failure (Breakthrough) Confirmation  
If laboratory tests show there is evidence of HIV virologic failure (the amount of HIV in your 
blood is still detectable when tested) you will be asked to return to the clinic to confirm your lab 
results. At this visit: 
• 
You will have a brief physical exam including vital signs.  
• 
You will have blood drawn for routine lab tests for safety and pharmacokinetic studies and to 
measure the amount of HIV in your blood, for an HIV resistance test (resistance means that 
the drugs are not likely to fight the HIV in your body).  
• 
If you choose, you will provide a hair sample for PK studies. 
• 
You will be asked to stay on the study and complete all of the study visits. 
 
Early discontinuation 
If HCV virologic failure is confirmed, you will then complete an early discontinuation visit. You 
will have the option to enroll in Part 2 of the same study after your discontinuation evaluations 
have been completed in Part 1. There are three types of discontinuation (early discontinuation 
of Part 1, stopping study treatment early, or leaving the study early) in which you will be asked 
to come to the clinic for an extra visit.  
 
1. Early discontinuation of Part 1 
You stop taking medications or stop follow up in Part 1 for HCV virologic failure and have 
the option to transition to Part 2. 
 
2. Stop study treatment early 
You or your doctor may decide to stop the study medication that you began at entry. If you 
must stop taking the study medication early, the study doctor may ask you to stay in the 
study and come in for some tests. You would not have the option to enter Part 2. 
 
3. Leave study early 
You or your doctor decides that you will no longer stay in the study or you are notified that 
the study is stopped early. You will be asked to complete some evaluations before being 
taken off the study. You would not have the option to enter Part 2. 
 
II. Description of Part 1 Study Evaluations 
 
Consent 
After you read this consent form and have had a chance to ask questions about the study, you 
will sign this consent form if you want to continue to be tested to see if you qualify for the study. 
 
Documentation of HCV, HIV, cirrhosis status, and previous labs 
Study staff will check your medical records for the availability of test results for HCV, HIV, and 
cirrhosis. Study staff will also check your medical records for the availability of liver function 
tests from the previous 12 months. 
 


 
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Clinical Assessments 
You will have the following clinical evaluations in this study: 
 
Physical examination 
You will have a physical exam. The study staff will check the different systems in your body 
such as head, neck, eyes, ears, nose, throat, mouth and tongue, chest (excluding breasts) for 
respiratory, heart for cardiovascular, abdomen, skin, hair, nails, and muscles and joints. The 
study staff will also check your vital signs such as temperature, pulse, blood pressure, and 
respiratory rate. Your height and weight will not be recorded at every visit.  
 
Medical and medication history 
You will be asked questions about your health and any medicines you have taken or are taking 
now. Once you are on treatment, you will be asked about any signs or symptoms that you are 
experiencing and any changes in other medications that you have had since your last visit.  
 
Sample collections and laboratory testing 
You will have the following samples collected and tested in this study: 
 
Blood collected 
Blood will be taken from a vein in your arm for various tests during the study. These may 
include: routine safety lab tests such as hematology (the study of blood), coagulation markers 
(how your blood clots), kidney and liver function, and HCV viral load (a test that shows how 
much HCV is in your blood). For those who are living with HIV, HIV viral load (a test that shows 
how much HIV is in your blood), and CD4+/CD8+ counts (a test that shows how many infection-
fighting cells you have in your blood) will be done. 
 
Resistance testing 
Blood will be drawn and stored for future HCV/HIV resistance testing that is required for this 
study. A resistance test is used to determine if the HCV/HIV viruses still respond to your 
medications.  
 
Genetic testing  
Some of your blood cells will be tested to see if your responsiveness to the therapy is 
associated with different genes related to the immune system that fights viruses. You will not 
receive the results of these studies because they will be done in the future. 
 
Your initials below confirm your voluntary decision to give permission for the collection, storage, 
and use of your blood for this genetic testing. 
 
You do not have to give permission for storage of these samples. This will not affect your 
participation in the study, and you may withdraw your permission for genetic testing sample 
storage at any time.   
 
________ YES                     ________ NO 
 


 
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PK Studies 
Blood will be drawn and hair samples taken to measure the levels of the drugs in your blood and 
to understand how the drugs interact with your body and how your body responds to the drugs. 
Hair sampling is optional.  
 
Your initials below confirm your voluntary decision to give permission for the collection, storage, 
and use of your hair samples. 
 
You do not have to give permission for storage of these samples. This will not affect your 
participation in the study, and you may withdraw your permission for hair sample storage at any 
time. 
 
________ YES                     ________ NO 
 
 
Pregnancy test 
If you are a woman who is able to become pregnant, you will have blood or urine taken for 
pregnancy testing, or have a Point of Care (POC) (a test with results available the same day) 
test done, prior to study entry. After you enter the study, you will be asked to provide blood or 
urine samples for pregnancy testing. 
 
Urine Sample for Substance/Drug Use  
Urine sample for substance use screening will be done at study entry, and at every Part 1 study 
visit, HCV virologic failure confirmation, and early discontinuation visits. 
   
Pregnancy prevention counseling 
All participants, male and female, will be counseled on the risk of the study medication in 
pregnancy and how to prevent pregnancy.  
 
Adherence counseling and assessment 
You will be asked about how well you take your medications. The study staff will give you 
information and encouragement to help you take your medications as prescribed. 
 
Study medication distribution 
You will be given a 4-week supply of study medication at entry. You will be asked to store the 
study medication as instructed on the medicine bottle label and to bring any leftover study 
medication back to the clinic at week 4.  
 
Questionnaires 
You will be asked to fill out the following questionnaires:  
 
Risk Factor Assessment 
You will be asked questions about drug use, sexual habits, and other risk factors for getting 
HCV. 
 


 
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Health Outcomes Questionnaire  
You will be asked questions about how you are feeling and how you are doing with your daily 
activities. 
 
Health Care Utilization Questionnaire 
You will also be asked questions if you have stayed at a hospital or been to an emergency 
room. 
 
HCV Reinfection Counseling 
You will be counseled by study staff on how HCV can be passed onto others and how to reduce 
your risk for HCV reinfection. Study staff will talk with you about how you could become re-
infected with HCV after being cured and ways to decrease risk of reinfection. 
 
Contact Information 
Study staff will ask you about the best way to reach you when they need to contact you 
remotely. They will also ask you for a second way to contact you (for example, through a 
spouse or friend) if they are unable to reach you.  
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
Some of your blood will be stored and used for study-required pharmacologic, immunologic, and 
virologic testing. For non-US locations, biological specimens will be shipped and/or stored 
outside of the country from which they are collected. 
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you.  
 
The tests described above are required by this study. If you do not agree to the storage or 
testing that has been described above, you should not join this study.  
  
Some blood that is collected from you during the study may be left over after all required study 
testing is done. This blood will be stored and, if you give your consent below, may be used for 
ACTG-approved research. This means that researchers who are not part of the protocol team 
may use your samples without asking you again for your consent. As noted above, none of your 
samples will have any private information about you on their labels.  
 
You may decide whether this “extra” blood may be stored and, if so, whether additional testing 
may be performed on it. None of this testing will be used for commercial profit.  
 
At this time, we do not know whether any of the research will include testing of your genes or 
your DNA (your own genetic information). We do not know whether a type of testing called 
whole genome sequencing, or WGS, might be done. In WGS, researchers look at all of your 
genes and at almost all of your DNA. In “standard” genetic testing, researchers look at specific 


 
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genes or subsets of genes, but not at all genes. Some possible genetic testing is described 
below. 
  
For each of the questions below, choose the response that matches what you want by putting 
your initials in the space provided. Please ask the staff any questions that you have before you 
indicate your selections. 
  
Research Without Human Genetic Testing – OPTIONAL (Research on leftover blood; no human 
genetic testing) 
If you agree, some of your blood that is left over after all required study testing is done may be 
stored (with usual protection of your identity) and used for ACTG-approved HIV-related research 
that does not include human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my blood.  
 
OR 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 
 
Research With Human Genetic Testing – OPTIONAL (Human genetic research on leftover 
blood) 
If you agree, some of your blood that is left over after all required study testing is done may be 
stored (with usual protection of your identity) and used for ACTG-approved HIV-related research 
that includes human genetic testing, and may include whole genome sequencing (WGS).  
 
____ (initials) I understand and I agree to this storage and possible use of my blood.  
 
OR 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 
 
Sharing Genetic Data - OPTIONAL  
Genetic Research Databases: If you agreed to possible genetic testing of your blood above, 
researchers may want to share genetic information (with protection of your identity) with other 
researchers around the world, so that they can learn more about the causes and treatment of 
diseases. They may store this information in dbGaP, a genetic database maintained by the 
National Institutes of Health, as well as in other protected databases. 
____ (initials) I understand and I agree to this possible sharing of my genetic data.  
 
OR 
____ (initials) I understand but I do not agree to this possible sharing of my genetic data. 
 
 


 
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HOW MANY PEOPLE WILL TAKE PART IN PART 1 OF THIS STUDY? 
 
Up to 50 people (men and women age 18 years and older) will take part in Part 1 of this study. 
  
 
HOW LONG WILL I BE IN PART 1 OF THIS STUDY? 
 
You will be in Part 1 of this study for approximately 28 weeks. If you are not cured of HCV or are 
infected again with HCV in Part 1, and you agree, you will enter Part 2 of the study, and you will 
be in Part 2 for 20-40 weeks. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF PART 1 OF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
the study is cancelled. 
• 
a Study Monitoring Committee (SMC) recommends that the study be stopped early (An 
SMC is an outside group of experts who monitor the study for safety). 
• 
your doctor thinks the study is no longer in your best interest. 
• 
the site investigator thinks that you are at significant risk of failing to comply with the 
requirements of the protocol.  
 
The study doctor may also need to take you off the study medication without your permission if: 
• 
you become pregnant. 
• 
you are breastfeeding. 
• 
continuing the study medication may be harmful to you. 
• 
you need a treatment that you may not take while on the study. 
• 
you are not able to take the study medication as required by the study. 
• 
you have not had, or are not able to have the required study visits and evaluations. 
 
If you must stop taking the study medication earlier than indicated by the study, the study doctor 
will ask you to remain on the study and complete post-discontinuation visits from the date that 
you took the last dose of study medication. 
 
If I have to permanently stop taking study medication during Part 1 of the study, or once I leave 
the study, how can I get study medication? 
If you must permanently stop taking study medication before the study is over, the study staff 
will talk with you about other options. 
 
After you have finished the study, you will not be able to get G/P through the study. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
No clinical safety issues specifically related to G/P have been identified to date in HCV mono-
infected or HIV-1/HCV co-infected participants without cirrhosis or with compensated cirrhosis 
(the liver is heavily scarred but can still perform many important bodily functions). 


 
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Risks of Social Harm 
Although the study site will make every effort to protect your privacy and confidentiality, it is 
possible that others could find out that you are participating in this study and that social harm 
may result (because you could become labeled as being diagnosed with HCV and/or living with 
HIV). For example, you could be treated unfairly or discriminated against by family members, 
friends, and/or the community. 
 
Risks of Drawing Blood 
Drawing blood may cause some discomfort, lightheadedness, bleeding, swelling, or bruising 
where the needle enters the body, and in rare cases, fainting, or infection. 
 
Risks of Study Medication 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that this list does not include all the side effects seen with this medication. These lists include 
the more serious or common side effects with a known or possible relationship. If you have 
questions concerning study medication side-effects, please ask the medical staff at your site. To 
assist you in understanding your risk of side effects we have included reported percentages of 
these events in clinical studies of the medications concerned. 
 
Glecaprevir/pibrentasvir (G/P) 
• 
Headaches- 9-16% 
• 
Fatigue- 11-14% 
• 
Diarrhea- 3-7% 
• 
Nausea- 6-12% 
• 
Asthenia (abnormal physical weakness or lack of energy) – 7% 
• 
Pruritic skin (itchy skin) – 17% 
• 
Abnormal liver function tests- 3.5% 
 
There is a risk of serious and/or life-threatening side effects when some non-study medications 
are taken with the study medication. For your safety, you must tell the study doctor or nurse 
about all medications you are taking before you start the study and before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. If you believe you are having side effects from any of 
the study medications make sure to immediately inform your study team.  
 
Bradycardia, or slow heart rate, may happen in persons who are taking digoxin (a medicine that 
is used to treat heart failure and heart rhythm problems) particularly for those with a heart 
disorder and/or advanced kidney disease. Because of this risk the dose of digoxin must be 
reduced by about half in persons taking G/P and be closely monitored. It is also not 
recommended to take G/P with cholesterol lowering medications such as simvastatin, lovastatin, 
or atorvastatin. Other cholesterol lowering medications such as fluvastatin, pravastatin, 
pitavastatin, and rosuvastatin can be used but either at lower doses or at the same dose with 
careful monitoring; you will need to check with your doctor.  
 


 
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Drug interactions that increase the levels of medicine in your blood may increase the chances of 
side effects. Drug interactions that could affect the levels of G/P or HIV medicines in your blood 
could cause changes in liver enzymes and other abnormal blood tests. For certain ARVs, we  
may ask you to change them to another medication to reduce this risk. Drug interactions that 
lower the levels of glecaprevir or pibrentasvir in your blood may decrease your chances for a 
cure of hepatitis C and/or cause drug resistance (the virus changes form and drugs that used to 
work, no longer work). 
 
For those persons taking HIV medicines, efavirenz can lower the levels glecaprevir or 
pibrentasvir in your blood and affect the potency of this drug in the fighting hepatitis C virus. The 
HIV medication atazanavir when it is taken together with G/P can cause increases in liver 
enzymes and the combination should be avoided. Study staff will review the list of all 
medications that should not be taken while in this study. Examples of other medications that 
should not be taken with G/P include: 
• 
St. John’s wort 
• 
Carbamazepine 
• 
Rifampin 
• 
Ethinyl estradiol containing birth control pills 
 
Drug resistance may prevent other medicines from working in the future. HCV viral load will be 
monitored regularly to ensure that evidence of early failure of the HCV regimen is identified 
quickly. Development of resistance after failing G/P has not been studied that well. However, 
studies so far suggest that use of G/P could select for mutations (permanent changes in genetic 
material) in the NS3 and NS5A gene which could cause varying levels of resistance to 
glecaprevir and pibrentasvir. The impact of these resistance associated mutations is still not 
known. 
 
Some people with HCV and HBV coinfection receiving therapy for HCV with direct-acting 
antivirals (DAA) like G/P have experienced reactivation of the HBV. Some of these cases have 
led to severe hepatitis, liver failure and death. This has been reported in people who are positive 
for HBsAg (HBV surface antigen [a foreign substance in your body that cause antibodies {cells 
that fight infection} to develop]) and those who appear to have resolved HBV infection by lab 
tests. If you have ever been diagnosed with HBV let your study doctor/nurse know. 
 
 
ARE THERE RISKS RELATED TO DELAYING HIV THERAPY? 
 
You are not required to be on ARVs to enter this study. If you are not on ARVs at the time you 
are diagnosed with HCV and you and your doctor do not think you need to start ARVs, you will 
not be excluded from the study. Also, it is not recommended that the start of HIV therapy be 
delayed for entry into the study if your doctor feels they are medically necessary. Although the 
dosing period of the study HCV medication is short, a delay in necessary HIV therapy could 
allow for progression of HIV disease, which can increase your risk of opportunistic infections 
and long-term effects of living with HIV. If you have any concerns about these risks, you should 
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WHAT IF I AM DIAGNOSED WITH HIV DURING THIS STUDY?  
 
If you are diagnosed with HIV during this study, study staff will tell you about any available care. 
Study staff will counsel you about HIV. They will also tell you how to lower the risks of giving 
HIV to others. Researchers may ask you to continue with this study. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
The drugs or drug combinations in this study may be unsafe for unborn babies. Therefore, 
becoming pregnant is not allowed. If you are having sex that could lead to pregnancy, you must 
agree not to become pregnant. If you become pregnant, you will be followed after delivery.  
 
Because of the potential risk involved and due to the uncertainty of risk to the fetus, you and 
your partner must use birth control. In Part 1, you must use one of the birth control methods, 
listed below, while receiving study medication, and for 6 weeks after stopping the medication. 
• 
Condoms (either self or require their partner to use one) with spermicide  
• 
Diaphragm or cervical cap with spermicide  
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive (not ethinyl-estradiol containing) 
• 
Tubal ligation 
 
If you can become pregnant, you must have a pregnancy test within 48 hours before starting the 
study medication. The test must show that you are not pregnant. Pregnancy tests will also be 
performed at most study visits. 
 
If you are man who gets a woman pregnant, then you will be asked to report this event to study 
staff. You may also be asked to report on your partner’s pregnancy outcomes. 
 
Some of the methods listed above may not prevent the spread of HIV to other people. If you are 
living with HIV, you should discuss your contraceptive choices with your health care provider to 
choose the best way for you to both prevent pregnancy as required by this study and to prevent 
the spread of HIV to your partner.  
 
If you think you may be pregnant or are a male who impregnates a female at any time during 
the study, tell your study staff right away. Pregnancy will result in immediate discontinuation of 
the study medications. You will be followed on study until study completion. You will be asked to 
return to the clinic 6 months after the end of your pregnancy to follow up on any side effects. 
Pregnancy complications and/or pregnancy outcomes will be reported to the company that 
makes G/P, AbbVie, by way of the sponsor (NIAID). If you are also living with HIV and become 
pregnant while on study, pregnancy complications and/or pregnancy outcomes will be reported 
to the Antiretroviral Pregnancy Registry. 
 
It is not known if G/P is present in breast milk in women who are breastfeeding. Studies done in 
animals however show that there are low concentrations of the drug in breast milk in laboratory 


 
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rats. This did not appear to affect these animals. Breastfeeding is not allowed while on G/P.  
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you (your HCV may be cured), but 
no guarantee can be made. Your health may be watched more closely than usual while you are 
in this study, which may help you to feel better. It is also possible that you may receive no 
benefit from being in this study. Information learned from this study may help others who have 
HCV and/or living with HIV. Also, the benefits of limiting the potential transmission of HCV to 
others, benefits others in society and saves in cost of treatment for others. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study, you have the choice of: 
• 
treatment with other prescription drugs currently available to you 
• 
treatment with other experimental regimens, if you qualify  
• 
no treatment; some people may clear HCV on their own over the first year of infection 
 
Please talk to your doctor about these and other treatment choices available to you and the 
risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For Sites in the US 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the US Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally.  
  
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site) institutional review board (IRB) (a 
committee that protects the rights and safety of participants in research), National Institutes of 
Health (NIH), study staff, study monitors, drug companies supporting this study, and their 
designees. Having a Certificate of Confidentiality does not prevent you from releasing 
information about yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. law. 
This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 


 
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For Sites outside the US 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the US FDA, the ACTG, the US Office for Human Research 
Protections (OHRP), or other local, US, and international regulatory entities as part of their 
duties, (insert name of site) institutional review board (IRB) or Ethics Committee (a committee 
that protects the rights and safety of participants in research), National Institutes of Health 
(NIH), study staff, study monitors, drug companies supporting this study, and their designees.  
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by US law. 
This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study medications, the study visits, physical examinations, 
laboratory tests or other tests required by the study. You or your insurance company, or your 
health care system will be responsible for the costs of your regular medical care as well as for 
the costs of drugs not given by the study. In some cases, it is possible that your insurance 
company will not pay for these costs because you are taking part in a research study.   
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[Sites: Please indicate whether you will provide payment to participants. If so, please describe 
the amount to be paid or reimbursed, the payment schedule, and any prorated schedule should 
the participant decide to withdraw or is withdrawn early by the investigator. Please also include 
that an incentive of USD XX will be provided to participants in addition to routine compensation 
if they complete the post-treatment week 12 visit within the visit window.]  
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of taking part in this study, you will be given treatment right away 
for your injuries and be referred for further treatment, if necessary. However, you or your 
insurance company may have to pay for this care. There is no program for compensation either 
through this institution or the NIH. You will not be giving up any of your legal rights by signing 
this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. The care that you would normally receive will not be affected if 


 
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you decide not to take part. Your decision will not affect other studies done by NIH in which you 
may be taking part, and will not lead to any penalty or loss of benefits that you have the right to 
expect. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or decision to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
Name of the investigator or other study staff 
• 
Telephone number of above  
 
For questions about your rights as a research participant, contact: 
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
Telephone number of above 


 
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SIGNATURE PAGE ACTG Study A5380 Part 1 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 


 
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APPENDIX II: STEP 2 SAMPLE INFORMED CONSENT 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
For protocol: A5380 
 
FINAL Version 1.0, 06/07/19: A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-dose 
Combination Treatment for Acute Hepatitis C Virus Infection (PURGE-C) 
 
SHORT TITLE: Glecaprevir/Pibrentasvir Fixed-dose Combination Treatment for Acute Hepatitis 
C Virus Infection Including Persons with HIV 
 
PART 2 SUMMARY 
 
PURPOSE 
The purpose of Part 2 of this study is to see if longer treatment cures your 
hepatitis C (HCV). People with acute HCV have a good chance of being 
cured of the infection when they are treated with a combination of two 
drugs within the first 6 months of getting HCV. 
 
NUMBER OF  
PARTICIPANTS 
There will be 2 parts of the study for a total of up to 50 participants. 
 
LENGTH OF  
STUDY 
 
Part 2 of the study will last about 20-40 weeks.  
 
You will need to come back to the clinic up to 8 more times in the next 20-
40 weeks. 
 
REQUIRED  
ACTIVITIES 
 
Blood and urine collections 
At most visits, some blood will be collected from a vein in your arm. At a 
few visits, you will be asked to provide a urine sample.  
  
Special procedures  
You will be asked questions about potential risks of becoming infected 
with HCV. 
 
RISKS 
The following are possible: 
• 
People outside of the study may find out that you are participating in 
this study and treat you unfairly. 
• 
Discomfort, lightheadedness, bleeding, swelling, or bruising from 
drawing blood 
• 
Side effects from the study medications 
• 
Drug resistance, making your HCV more difficult to treat 


 
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• 
If you are living with HIV, drug interactions with your HIV drugs while 
taking the study medications. 
• 
If you have hepatitis B (HBV) and HCV, reactivation of HBV. 
 
BENEFITS 
You may be cured of your HCV but no guarantee can be made. 
 
OTHER CHOICES 
Instead of being in this study, you have the option of continuing with your 
current treatment, starting a new treatment under the care of your regular 
doctor or other health care provider, or no treatment at all. Your 
participation in this study is completely voluntary.  
 
INTRODUCTION 
 
You are being asked to continue to take part in Part 2 of this research study because your HCV 
was not cured in Part 1 of the study or you may have been infected again after getting cured. 
This study is sponsored by the National Institutes of Health. The doctor in charge of this study at 
this site is: (insert name of Principal Investigator). Before you decide if you want to be a part of 
Part 2 of this study, we want you to know about Part 2 of the study.   
 
This is a consent form. It gives you information about Part 2 of this study. The study staff will 
talk with you about this information. You are free to ask questions about this study at any time. If 
you agree to take part in Part 2 of this study, you will be asked to sign this consent form. You 
will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
As mentioned in Part 1 of this study, people who are recently infected with a new case of HCV 
are often considered to have acute HCV. People with acute HCV have a good chance of being 
cured of the infection when they are treated with a combination of two drugs within the first 6 
months of being diagnosed. However, after 4 weeks of the HCV drug, glecaprevir/pibrentasvir 
(G/P), in Part 1 of this study, the HCV is present again in your blood. It is also possible that you 
may have been infected again with hepatitis C after you were cured in Part 1. Therefore, this 
Part 2 of the study is being done to see if a longer course of treatment will cure your HCV. In 
Part 2 of this study, you will take 3 tablets of G/P by mouth daily for either 8, 12, or 16 weeks. It 
is possible another drug named ribavirin (RBV) will be added. The length of treatment will be 
decided from various lab tests. It is also possible that the study doctor will suggest a different 
HCV drug. 
 
The medication that is provided in this study is approved by the Food and Drug Administration 
(FDA) for use in persons who have been diagnosed with HCV. 
 
You will be monitored for safety and viral response (how your body is responding to treatment 
and whether the amount of HCV in your body is decreasing) while on treatment. After 
completing treatment, you will be evaluated to see how your body responded to treatment at 
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WHAT DO I HAVE TO DO IF I AM IN PART 2 OF THIS STUDY? 
 
If you decide to be in Part 2 of this study, after you have read and signed this informed consent 
form, you will come to the clinic for an entry visit to make sure you meet the requirements to 
continue treatment for your HCV in this part of the study.  
 
You may have as little as 2.5 tablespoons to as much as 11 tablespoons of blood collected at 
any one visit. Over the course of the study, the amount of blood collected from you will be within 
approved limits. 
 
If you are also living with HIV, you will continue taking your current anti-HIV drugs 
(antiretrovirals [ARVs]- medications to control HIV) if you are receiving them. If you are not 
currently on ARVs and your provider does not think you will need ARVs for the next 8, 12, or 16 
weeks, this is also acceptable. If your HIV regimen includes atazanavir, atazanavir/cobicistat, 
and atazanavir/ritonavir, efavirenz, etravirine, fosamprenavir/ritonavir, indinavir/ritonavir, 
lopinavir/ritonavir, nelfinavir, nevirapine, saquinavir/ritonavir, or tipranavir/ritonavir, you will need 
to be switched to another HIV regimen. You will need to be sure that your HIV provider 
discusses all changes to your HIV regimen with the study doctor. See section I for a description 
of the study visits. 
 
After the entry visit, you will be given your study medication for the first 4 weeks of treatment to 
take home. Study medication (G/P and possibly RBV) will be given to you for free by the study. 
If you have HIV, your ARVs will not be provided by the study. These will be provided by your 
regular non-study HIV provider. Your study physician may also decide to treat your HCV based 
on local standard of care, and these medications would not be provided by the study. Details on 
study medication for Part 2 of this study can be found below under Description of Part 2 Study 
Visits. After you have completed 8, 12, or 16 weeks treatment with G/P, you will continue to 
have follow-up visits for 24 weeks (depending in whether you also take RBV). Alternatively, your 
study doctor may choose a sofosbuvir-containing regimen for you. If so, you may continue to 
have follow-up visits in the study. 
 
While you are in Part 2 of the study, you will need to be seen in the clinic about 5-8 times. The 
number of required clinic visits will depend on which HCV medications you are taking and the 
length of treatment. The study staff will tell you about how long each visit could be. You will 
have blood drawn for study-related tests at each visit to monitor your response to the study 
medications and to look for any side effects that may be caused by the medications. 
 
You may need to make extra visits to the clinic if you have side effects or if you switch or take 
new ARVs. More information about the study tests is given below. During the study, you will get 
the results from any routine tests that are done during the study when they are available.  
 
A5380 Part 2 Study Visits 
The study staff can answer any questions you have about individual study visits, the evaluations 
that will occur, or how long each visit will be. The table below can be used as a quick reference 
for you, along with the explanations that follow. 
 


 
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Appendix II, Table 1: Part 2 Study Schedule 
Evaluation or Test 
Entry 
Post-Entry Visits 
Unplann
ed Visits 
HCV 
Virologic 
Failure 
Confirmatio
n 
HIV 
Virologic 
Failure 
(Breakthr
ough) 
Confirmat
ion 
Early 
Discontinuatio
n 
On-
treatment 
Visits 
Off-
treatment 
Visits 
Clinical assessments 
 
 
 
 
 
 
 
Blood collection & 
laboratory testing 
 
 
 
 
 
 
 
Blood Collection for PK 
Studies 
 
 
 
 
 
 
 
Pregnancy test 
 
 
 
 
 
 
 
Pregnancy prevention 
counseling 
 
 
 
 
 
 
 
Re-infection Prevention 
Counseling 
 
 
 
 
 
 
 
Questionnaire 
 
 
 
 
 
 
 
Distribution of Study 
Medication 
 
 
 
 
 
 
 
 
I. Description of Part 2 Study Visits 
 
Part 2 Entry 
Once HCV confirmation results are available for the study doctor to review and it is confirmed 
that you meet all the other eligibility criteria, you will be enrolled into Part 2 of the study. This 
visit will take about 1-2 hours. At this visit: 
• 
Documentation of Step 2 eligibility will be confirmed.  
• 
Your HIV status will be confirmed.  
• 
You will be asked about your health and any changes in your medicines since your last visit. 
You will have a brief physical exam including vital signs and weight.  
• 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy. Such women will also be counseled on ways to not become pregnant while 
taking study medications. Men will also be counseled on ways to not impregnate a woman 
while taking study medications. 


 
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• 
You will have blood drawn to see if you are diagnosed with the HAV or HBV (an infection of 
the liver), for routine lab tests for safety, for virologic studies (to help study the virus), and 
immunologic studies (to test how your body fights infection). If you are living with HIV, you 
will have your blood drawn to measure the amount of HIV in your blood, and to measure 
your CD4+ and CD8+ cell counts (a test that shows how many infection-fighting cells you 
have in your blood). Some of the blood you provide will be stored for future protocol-required 
testing. 
• 
You will receive study medications to take home with you. 
• 
You will be asked questions about risk factors for HCV. 
• 
You will receive counseling on how not to become re-infected with HCV. 
• 
You will agree to continue taking combination ARVs as prescribed throughout the entire 
study. 
 
Study Medication 
At your Part 2 entry visit, study staff will give you your study medications for the first 4 weeks of 
treatment to take home. You will need to store the medications in a safe place at room 
temperature (between 15º to 25ºC [59º to 77ºF]). You would need to take the study medication, 
G/P, with food. You will take three pills every day for 8, 12, or 16 weeks, as instructed by the 
study doctor/nurse. If you forget to take the study medication at the correct time, it may be taken 
later in the day as soon as you remember. Then the next day you should continue with the usual 
schedule that you take the study medications. You should always take all 3 pills together. If you 
miss doses entirely, simply resume 3 pills the next day and do not ever double the dose (do 
NOT take 6 pills). Do not split the pills or the medication doses. After you have completed 8, 12, 
or 16 weeks of treatment with G/P as may be determined by your study investigator, you will 
continue to have follow-up visits for 24 weeks (depending in whether you also take RBV). 
 
Some participants who enroll in Part 2 will also take RBV, which will be provided by the study. If 
you need to take RBV, it must be taken with food for it to work well. RBV should be taken twice 
a day. All other HCV medications other than these will be used at the discretion of your study 
provider based on local standard of care in discussion with the study team. These other 
medications will not be provided by the study and as such any risks related to other alternate 
regimens will not be covered under this consent. If you and your study doctor choose that option 
in Part 2 you could still remain on the study on that regimen and continue all required study 
visits up to 12 weeks after completing your given regimen.  
 
Part 2 Post-entry Visits 
After your entry visit for Part 2, you will come to the clinic at weeks 2, 4, 8, 12, and 16, and 
weeks 20, 24, or 28 (depending on study regimen chosen by your doctor), and weeks 32, 36, or 
40 (if necessary). These visits will last about 1-1½ hours each. 
• 
For this part of the study, there will be about 4 study medication regimens with varying visit 
schedules. Study staff will talk to you about this visit schedule according to the drug regimen 
chosen for you. 
During Most Study Visits for Part 2 
• 
You will be asked about your health and any changes in your medicines since your last visit. 
• 
You will have a brief physical exam including vital signs and weight.   


 
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• 
You will have blood drawn for routine lab tests for safety, virologic, immunologic, and 
pharmacokinetic (to look at your body’s response to the study medication) studies; and to 
measure the amount of HCV in your blood. If you are living with HIV, the amount of HIV in 
your blood and your CD4+ and CD8+ counts will be measured. Some of the blood you 
provide will be stored for future protocol-required testing. 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy at all on-treatment and post-treatment visits and study discontinuation.  
• 
All participants, male and female, will be counseled on the risk of the study medications in 
pregnancy and on how to prevent pregnancy while taking study medications.  
• 
You will be asked questions about drug use, sexual habits, and other risk factors for getting 
HCV. 
• 
You must return any remaining study medication before your last study visit. 
 
Unplanned visits 
During the study, you may have to come back to the clinic for extra visits for testing of any lab 
results that are not normal, or to follow up on a specific side effect or symptom. During any 
unplanned visits, you may have the following tests done: clinical assessments, blood collection 
(including for PK studies) and laboratory testing, and complete a questionnaire.  
 
HCV Virologic Failure Confirmation  
If laboratory tests show there is evidence of virologic failure (the amount of HCV in your blood is 
still detectable when tested), you will be asked to return to the clinic to confirm your lab results. 
At this visit:  
• 
You will have a brief physical exam including vital signs and weight done.  
• 
You will have blood drawn for routine lab tests for safety, virologic, immunologic, and 
pharmacokinetic studies, to measure the amount of HCV in your blood, and for an HCV 
resistance test (resistance means that the drugs are not likely to fight the HCV in your body). 
If you are living with HIV, to measure the amount of HIV in your blood.  Some of the blood 
you provide will be stored for future protocol-required testing. 
• 
You will be asked to stay on the study and complete all of the study visits. 
 
HIV Virologic Failure (Breakthrough) Confirmation  
If laboratory tests show there is evidence of HIV virologic failure (the amount of HIV in your 
blood is still detectable when tested), you will be asked to return to the clinic to confirm your lab 
results. At this visit: 
• 
You will have blood drawn for pharmacokinetic studies, HIV RNA (to measure the level of 
the HIV in the blood) and for an HIV resistance test (resistance means that the drugs are not 
likely to fight the HIV in your body; also known as genotyping) will also be done.  
• 
You will be asked to stay on the study and complete all of the study visits. 
 
Early discontinuation 
If HCV virologic failure is confirmed, you will then complete an early discontinuation visit. There 
are two types of discontinuation (stopping study treatment early or leaving the study early) in 
which you will be asked to come to the clinic for an extra visit. Participants in Step 2 who have  


 
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HCV virologic failure confirmed will be followed through 12 weeks (or 24 weeks, if RBV is given) 
after treatment completion or is discontinued, and no further treatment will be provided by the 
study. 
 
1. Stop study treatment early 
You or your doctor may decide to stop the study medication that you began at entry. If you 
must stop taking the study medication early, the study doctor may ask you to stay in the 
study and come in for some tests.  
 
2. Leave study early 
You or your doctor may decide that you will no longer stay in the study or you are notified 
the study is stopped early. You will be asked to complete some evaluations before being 
taken off the study.  
 
II. Description of Part 2 Study Evaluations 
 
Clinical Assessments 
You will have a brief physical exam. The study staff will check your vital signs such as 
temperature, pulse, blood pressure, respiratory rate, and weight. You will be asked about any 
signs or symptoms that you are experiencing and any changes in other medications that you 
have had since your last visit.  
 
Sample collections and laboratory testing 
You will have the following samples collected and tested in this study: 
 
Blood collected 
Blood will be taken from a vein in your arm for various tests during the study. These may 
include: routine safety lab tests such as hematology (the study of blood), kidney and liver 
function; and HCV viral load (a test that shows how much HCV is in your blood). For those who 
are living with HIV, HIV viral load and CD4+/CD8+ counts. 
 
Resistance testing 
Blood will be drawn and stored for future HCV/HIV resistance testing that is required for this 
study. A resistance test is used to determine if the HCV/HIV viruses still respond to your 
medications.  
 
PK Studies 
Blood will be drawn to measure the levels of the drugs in your blood and to understand how the 
drugs interact with your body and how your body responds to the drugs.  
 
Pregnancy test 
If you are a woman who is able to become pregnant, you will have blood or urine taken for 
pregnancy testing, or have a Point of Care (POC) test (a test with results available the same 
day) test done prior to study entry. After you enter the study, you will be asked to provide blood 
or urine samples for pregnancy testing. 
 


 
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Pregnancy prevention counseling 
All participants, male and female, will be counseled on the risk of the study medications in 
pregnancy and how to prevent pregnancy.  
 
Study medication distribution  
Due to the longer treatment course (compared to Part 1 of the study), you will be given a 4-
week supply of study medication at your return study visits as indicated based on the length of 
therapy. You will be asked to bring any leftover study medication back to the clinic up to week 
16 (depending on your drug regimen in Part 2). 
 
Questionnaire 
You will be asked to fill out the following questionnaire:  
 
Risk Factor Assessment 
You will be asked questions about drug use, sexual habits, and other risk factors for getting 
HCV. 
 
HCV Reinfection Counseling 
You will be counseled by study staff on how HCV can be passed onto others and how to reduce 
your risk for HCV reinfection. Study staff will talk with you about how you could become re-
infected with HCV after being cured and ways to decrease risk of reinfection. 
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
Some of your blood will be stored and used for study-required pharmacologic, immunologic, and 
virologic testing. For non-US locations, biological specimens will be shipped and/or stored 
outside of the country from which they are collected. 
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you.  
 
The tests described above are required by this study. If you do not agree to the storage or 
testing that has been described above, you should not join this study.  
  
Some blood that is collected from you during the study may be left over after all required study 
testing is done. This blood will be stored and, if you give your consent below, may be used for 
ACTG-approved research. This means that researchers who are not part of the protocol team 
may use your samples without asking you again for your consent. As noted above, none of your 
samples will have any private information about you on their labels.  
 
You may decide whether this “extra” blood may be stored and, if so, whether additional testing 
may be performed on it. None of this testing will be used for commercial profit.  
 


 
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At this time, we do not know whether any of the research will include testing of your genes or 
your DNA (your own genetic information). We do not know whether a type of testing called 
whole genome sequencing, or WGS, might be done. In WGS, researchers look at all of your 
genes and at almost all of your DNA. In “standard” genetic testing, researchers look at specific 
genes or subsets of genes, but not at all genes. Some possible genetic testing is described 
below. 
 
For each of the questions below, choose the response that matches what you want by putting 
your initials in the space provided. Please ask the staff any questions that you have before you 
indicate your selections. 
  
Research Without Human Genetic Testing – OPTIONAL (Research on leftover blood; no human 
genetic testing) 
If you agree, some of your blood that is left over after all required study testing is done may be 
stored (with usual protection of your identity) and used for ACTG-approved HIV-related research 
that does not include human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my blood.  
 
OR 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 
 
Research With Human Genetic Testing – OPTIONAL (Human genetic research on leftover 
blood) 
If you agree, some of your blood that is left over after all required study testing is done may be 
stored (with usual protection of your identity) and used for ACTG-approved HIV-related research 
that includes human genetic testing, and may include whole genome sequencing (WGS).  
 
____ (initials) I understand and I agree to this storage and possible use of my blood.  
 
OR 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 
 
Sharing Genetic Data - OPTIONAL  
Genetic Research Databases: If you agreed to possible genetic testing of your blood above, 
researchers may want to share genetic information (with protection of your identity) with other 
researchers around the world, so that they can learn more about the causes and treatment of 
diseases. They may store this information in dbGaP, a genetic database maintained by the 
National Institutes of Health, as well as in other protected databases. 
 
____ (initials) I understand and I agree to this possible sharing of my genetic data.  
 
OR 


 
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____ (initials) I understand but I do not agree to this possible sharing of my genetic data. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
The number of people who enroll in Part 2 will depend upon participants’ responses to the study 
medication in Part 1.  
 
 
HOW LONG WILL I BE IN PART 2 OF THIS STUDY? 
 
You will be in Part 2 of this study for approximately 20-40 weeks. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF PART 2 OF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
the study is cancelled. 
• 
a Study Monitoring Committee (SMC) recommends that the study be stopped early (An 
SMC is an outside group of experts who monitor the study for safety). 
• 
your doctor thinks the study is no longer in your best interest. 
• 
the site investigator thinks that you are at significant risk of failing to comply with the 
requirements of the protocol.  
 
The study doctor may also need to take you off the study medications without your permission 
if: 
• 
you experience HCV treatment failure. 
• 
you become pregnant. 
• 
if you are a male whose female partner becomes pregnant (only if you are taking RBV). 
• 
you are breastfeeding. 
• 
continuing the study medications may be harmful to you. 
• 
you need a treatment that you may not take while on the study. 
• 
you are not able to take the study medications as required by the study. 
• 
you have not had, or are not able to have, the required study visits and evaluations 
 
If you must stop taking the study medication earlier than indicated by the study, the study doctor 
will ask you to remain on the study and complete the post discontinuation visits from the date 
that you took the last dose of study medication.  
 
If I have to permanently stop taking study medications during Part 2 of the study, or once I leave 
the study, how can I get study medications? 
If you must permanently stop taking study medications before the study is over, the study staff 
will talk with you about other options. 
 
After you have finished the study, you will not be able to get G/P through the study. 
 


 
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WHAT ARE THE RISKS OF THE STUDY? 
 
No clinical safety issues specifically related to G/P have been identified to date in HCV mono-
infected or HIV-1/HCV co-infected participants, without cirrhosis or with compensated cirrhosis 
(the liver is heavily scarred but can still perform many important bodily functions). 
 
Risks of Social Harm 
Although the study site will make every effort to protect your privacy and confidentiality, it is 
possible that others could find out that you are participating in this study and that social harm 
may result (because you could become labeled as being diagnosed with HCV and/or living with 
HIV). For example, you could be treated unfairly or discriminated against by family members, 
friends, and/or the community. 
 
Risks of Drawing Blood 
Drawing blood may cause some discomfort, lightheadedness, bleeding, swelling, or bruising 
where the needle enters the body, and in rare cases, fainting, or infection. 
 
Risks of Study Medications 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning study medication side-effects, please ask the medical staff at your site. To 
assist you in understanding your risk of side effects we have included reported percentages of 
these events in clinical studies of the medications concerned. 
 
Glecaprevir/pibrentasvir (G/P) 
• 
Headaches- 9-16% 
• 
Fatigue- 11-14% 
• 
Diarrhea- 3-7% 
• 
Nausea- 6-12% 
• 
Asthenia (abnormal physical weakness or lack of energy) – 7% 
• 
Pruritic skin (itchy skin) – 17% 
• 
Abnormal liver function tests- 3.5% 
 
Ribavirin (RBV) 
Since RBV was given with IFN in most previous studies the risk of side-effects described here 
may be much lower than what could happen to you.  
• 
Anemia (low iron in your blood) - 12% 
• 
Severe hypersensitivity (your body’s inability to tolerate RBV) - up to 1% 
• 
Severe skin reactions (Stevens Johnson Syndrome)- up to 1% 
• 
Liver Failure – up to 1% 
• 
Bone marrow suppression (decrease in production of cells responsible for providing 
immunity, carrying oxygen, and/or those responsible for normal blood clotting) – up to 10% 


 
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• 
Pancreatitis (inflammation of the pancreas [the organ responsible for releases digestive 
enzymes into the small intestine to aid the digestion of food, and releases the hormones 
insulin and glucagon into the bloodstream, which help the body control how it uses food for 
energy.]) – up to 1% 
• 
Pulmonary pneumonitis (infection of the lungs that causes inflammation of the lung tissue) – 
up to 1% 
 
RBV must always be taken along with another hepatitis C medication; RBV alone is not effective 
for treatment of hepatitis C. RBV has been shown to cause birth defects in all animals that are 
exposed to this drug. Participants who are put on this medication in this study must agree to be 
on/use two different forms of birth control. Both men and women taking this drug must take 
extra care to avoid pregnancy while they are taking this drug and for 6 months after the last 
dose of RBV. Additional pregnancy testing will be done if you are a woman of child bearing 
potential taking this drug. RBV can also cause severe anemia which could cause life threatening 
heart attacks in people with underlying heart disease.  
 
Interactions between RBV and the HIV drugs didanosine (DDI), stavudine (D4T) or zidovudine 
(AZT) can cause increased risk of side effects of these drugs and as such if you are on any of 
these medications, your HIV provider would need to change your regimen if you need to take 
RBV in Part 2.   
 
There is a risk of serious and/or life-threatening side effects when some non-study medications 
are taken with the study medication. For your safety, you must tell the study doctor or nurse 
about all medications you are taking before you start the study and before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. If you believe you are having side effects from any of 
the study medications make sure to immediately inform your study team.  
 
Bradycardia, or slow heart rate, may happen in persons who are taking digoxin (a medicine that 
is used to treat heart failure and heart rhythm problems) particularly for those with a heart 
disorder and/or advanced kidney disease. Because of this risk the dose of digoxin must be 
reduced by about half in persons taking G/P and be closely monitored. It is also not 
recommended to take G/P with cholesterol lowering medications such as simvastatin, lovastatin, 
atorvastatin. Other forms of cholesterol lowering medications such as fluvastatin, pravastatin, 
pitavastatin, and rosuvastatin can be used either at lower doses or at the same dose with 
careful monitoring; you will need to check with your doctor.  
 
Drug interactions that increase the levels of medicine in your blood may increase the chances of 
side effects. Drug interactions that could affect the levels of G/P or HIV medicines in your blood 
could cause changes in liver enzymes and other abnormal blood tests. For certain HIV 
medications, we may ask you to change them to another medication to reduce this risk. Drug 
interactions that lower the levels of glecaprevir or pibrentasvir in your blood may decrease your 
chances for a cure of hepatitis C and/or cause drug resistance (the virus changes form and 
drugs that used to work, no longer work). 
 


 
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For those persons taking HIV medicines, efavirenz can lower the levels of glecaprevir or 
pibrentasvir in your blood and affect the potency of this drug in fighting hepatitis C virus. The 
HIV medication atazanavir when it is taken together with G/P can cause increases in liver 
enzymes and the combination should be avoided. Examples of other medications that should 
not be taken with G/P include: 
• 
St. John’s wort 
• 
Carbamazepine 
• 
Rifampin 
• 
Ethinyl estradiol containing birth control pills 
 
Drug resistance may prevent other medicines from working in the future. HCV viral load will be 
monitored regularly to ensure that evidence of early failure of the HCV regimen is identified 
quickly. Development of resistance after failing G/P has not been studied that well. However, 
studies so far suggest that use of G/P could select for mutations (permanent changes in genetic 
material) in the NS3 and NS5A gene which could cause varying levels of resistance to 
glecaprevir and pibrentasvir. The impact of these resistance associated mutations is still not 
known.   
 
Some people with HCV and HBV coinfection receiving therapy for HCV with direct-acting 
antivirals (DAA) like glecaprevir/pibrentasvir have experienced reactivation of HBV. Some of 
these cases have led to severe hepatitis, liver failure and death. This has been reported in 
people who are HBsAg (HBV surface antigen [a foreign substance in your body that cause 
antibodies {cells that fight infection} to develop]) and those who appear to have resolved HBV 
infection by lab tests. If you have ever been diagnosed with HBV let your study doctor/nurse 
know. 
 
 
ARE THERE RISKS RELATED TO DELAYING HIV THERAPY? 
 
You are not required to be on ARVs to enter Part 2 of this study. If you are not on ARVs at the 
time of your HCV diagnosis and you and your doctor do not think you need to start ARVs, you 
will not be excluded from the study. Also it is not recommend that that of ARVs is delayed for 
entry into the study if your doctor feels they are medically necessary. Although the dosing period 
of the study HCV medications is limited, a delay in necessary HIV medications could allow for 
progression of HIV disease, which can increase your risk of opportunistic infections and long-
term effects of living with HIV. If you have any concerns about these risks, you should discuss 
them with your medical provider. 
 
 
WHAT IF I AM DIAGNOSED WITH HIV DURING THIS STUDY?  
 
If you are diagnosed with HIV during this study, study staff will tell you about any available care. 
Study staff will counsel you about HIV. They will also tell you how to lower the risks of giving 
HIV to others. Researchers may ask you to continue with this study. 
 
 


 
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ARE THERE RISKS RELATED TO PREGNANCY? 
 
The drugs or drug combinations in this study may be unsafe for unborn babies. There is also 
evidence that the use of RBV can result in birth defects. Therefore, becoming pregnant is not 
allowed. If you are having sex that could lead to pregnancy, you must agree not to become 
pregnant. Note that if you become pregnant or if you are a man whose female partner becomes 
pregnant, the study medications will be stopped, and you will be followed after delivery. 
 
Because of the potential risk involved and due to the uncertainty of risk to the fetus, you and 
your partner must use birth control. You must use one form of the birth control methods listed 
below, while receiving study medication and for 6 weeks after stopping the medication. If you 
are taking RBV in Part 2, you must use two forms of birth control up to 6 months after your last 
RBV dose: 
• 
A condom (male or female) with spermicide 
• 
Diaphragm or cervical cap with spermicide 
• 
An intrauterine device (IUD) 
• 
Tubal ligation 
• 
Hormone-based contraceptives  
 
If you can become pregnant, you must have a pregnancy test within 48 hours before starting the 
study medications. The test must show that you are not pregnant. Pregnancy tests will also be 
performed at most study visits. 
 
Some of the methods listed above may not prevent the spread of HIV to other people. You 
should discuss your contraceptive choices with your health care provider to choose the best 
way for you to both prevent pregnancy as required by this study and to prevent the spread of 
HIV to your partner.  
 
If you think you may be pregnant at any time during the study or if you are a man whose female 
partner becomes pregnant, tell your study staff right away. Pregnancy will result in immediate 
discontinuation of the study medications. You will be followed on study until study completion. 
You will be asked to return to the clinic 6 months after the end of your pregnancy to follow up on 
any side effects. In addition, pregnancy complications and/or pregnancy outcomes will be 
reported to the company that makes G/P, AbbVie, by way of the sponsor (NIAID). If you are also 
living with HIV and become pregnant while on study, pregnancy complications and/or pregnancy 
outcomes will be reported to the Antiretroviral Pregnancy Registry. 
 
It is not known if G/P is present in breast milk in women who are breastfeeding. Studies done in 
animals however show that there are low concentrations of the drug in breast milk in laboratory 
rats. This did not appear to affect these animals. Breastfeeding is not allowed while on G/P.  It is 
not known if RBV is present in breast milk, however because of possible side effects to breast 
fed babies, breastfeeding is not recommended in women taking RBV. 
 
If you are a man whose female partner becomes pregnant, then you will be asked to report this 
event to study staff and discontinue therapy. You may also be asked to report on your partner’s 
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ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you (your hepatitis C may be 
cured), but no guarantee can be made. Your health may be watched more closely than usual 
while you are on the study, which may help you to feel better. It is also possible that you may 
receive no benefit from being in this study. Information learned from this study may help others 
who have HCV and/or living with HIV. Also, the benefits of limiting the potential transmission of 
HCV to others, benefits others in society and saves in cost of treatment for others. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES PART 2 OF THIS STUDY? 
 
Instead of being in this study, you have the choice of: 
• 
treatment with other prescription drugs currently available to you 
• 
treatment with other experimental regimens, if you qualify  
• 
no treatment; some people may clear HCV on their own over the first year of infection 
 
Please talk to your doctor about these and other treatment choices available to you and the 
risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For Sites in the US 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the US Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally.  
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site) institutional review board (IRB) (a 
committee that protects the rights and safety of participants in research), National Institutes of 
Health (NIH), study staff, study monitors, drug companies supporting this study, and their 
designees. Having a Certificate of Confidentiality does not prevent you from releasing 
information about yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. law. 
This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 


 
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For Sites outside the US 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the US FDA, the ACTG, the US Office for Human Research 
Protections (OHRP), or other local, US, and international regulatory entities as part of their 
duties, (insert name of site) institutional review board (IRB) or Ethics Committee (a committee 
that protects the rights and safety of participants in research), National Institutes of Health 
(NIH), study staff, study monitors, drug companies supporting this study, and their designees.  
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by US law. 
This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study medication, the study visits, physical examinations, 
laboratory tests or other tests required by the study. You or your insurance company, or your 
health care system will be responsible for the costs of your regular medical care as well as for 
the costs of drugs not given by the study. In some cases, it is possible that your insurance 
company will not pay for these costs because you are taking part in a research study.   
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[Sites: Please indicate whether you will provide payment to participants. If so, please describe 
the amount to be paid or reimbursed, the payment schedule, and any prorated schedule should 
the participant decide to withdraw or is withdrawn early by the investigator. Please also include 
that an incentive of USD XX will be provided to participants in addition to routine compensation 
if they complete the post-treatment week 12 visit within the visit window.]  
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of taking part in this study, you will be given treatment right away 
for your injuries and be referred for further treatment, if necessary. However, you or your 
insurance company may have to pay for this care. There is no program for compensation either 
through this institution or the NIH. You will not be giving up any of your legal rights by signing 
this consent form. 
 
 


 
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WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. The care that you would normally receive will not be affected if 
you decide not to take part. Your decision will not affect other studies done by NIH in which you 
may be taking part, and will not lead to any penalty or loss of benefits that you have the right to 
expect.   
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or decision to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
Name of the investigator or other study staff 
• 
Telephone number of above  
 
For questions about your rights as a research participant, contact: 
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
Telephone number of above 


 
130 
A5380 
FINAL Version 1.0 
 
 
06/07/19 
 
SIGNATURE PAGE ACTG Study A5380 Part 2 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 

SAP_001.pdf: 
This is ACTG A5380 Primary SAP Version 1.5 with names of authors, names of 
publication writing team members and analysis timeline redacted. 
 
 
A5380 
A Phase II Trial of Glecaprevir/Pibrentasvir Fixed-Dose 
Combination Treatment for Acute Hepatitis C Virus Infection 
(PURGE-C) 
Protocol Version 1.0 
ClinicalTrials.gov Identifier: NCT04042740 
 
 
Primary Statistical Analysis Plan 
Version 1.5 
October 20, 2020 
 
 
Created by: A5380 Study Statisticians 
 
ACTG Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 


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Page 1 of 9 
Table of Contents 
 
VERSION HISTORY ...................................................................................................................... 2 
1 
INTRODUCTION ...................................................................................................................... 3 
1.1 
Purpose .......................................................................................................................... 3 
1.2 
Version History.............................................................................................................. 3 
2 
STUDY OVERVIEW ................................................................................................................. 4 
2.1 
Study Design ................................................................................................................. 4 
2.2 
Hypotheses .................................................................................................................... 4 
2.3 
Study Objectives ........................................................................................................... 4 
2.3.1 
Primary Objectives .............................................................................................. 5 
2.3.2 
Secondary Objectives .......................................................................................... 5 
2.4 
Overview of Sample Size Considerations ................................................................... 5 
2.5 
Overview of Formal Interim Monitoring ...................................................................... 5 
3 
OUTCOME MEASURES ......................................................................................................... 6 
3.1 
Primary Outcome Measures ......................................................................................... 6 
3.2 
Secondary Outcome Measures .................................................................................... 6 
4 
STATISTICAL PRINCIPLES ................................................................................................... 7 
4.1 
General Considerations ................................................................................................ 7 
4.2 
Analysis Approaches .................................................................................................... 7 
5 
REPORT CONTENTS ............................................................................................................. 8 
 
 
 


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Version History 
 
Version 
Changes Made 
Date Finalized 
1.0 
Original Version per Protocol Version 1.0 
July 11, 2019 
1.1 
Protocol amendment review (V1.0, LOA #1) 
January 2, 2020 
1.2 
Changes due to the study visits affected by COVID-19 outlined 
in CM #2. Correction of typos. 
April 24, 2020 
1.3 
Protocol amendment review (V1.0, LOA #2) 
August 19, 2020 
1.4 
Protocol amendment review (V1.0, LOA #3) 
September 21, 2020 
1.5 
Protocol amendment review (V1.0, LOA #4) 
October 20, 2020 
 
 
 
 
 
 


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1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcome 
measures and additional outcome measures of the A5380 study that will be included in the 
primary manuscript.  They address the major primary and secondary objectives of the study. The 
Primary SAP outlines the general statistical approaches that will be used in the analysis of the 
study. It has been developed to facilitate discussion of the statistical analysis components and to 
provide agreement among the study team members regarding the statistical analyses to be 
performed and presented in the primary analysis report. It also describes the results for the 
primary and secondary outcome measures that will be posted on ClinicalTrials.gov.  
Detailed outlines of tables, figures, and coding descriptions that will be included in the Primary 
Analysis Report are included in the Analysis Implementation Plan (AIP).  
Analyses for the Primary Analysis Report will be finalized once the last participant has completed 
the Week 28 study visit (primary completion date, PCD), all queries have been resolved, and the 
study database closure/data lock has been completed.   
Outlines of analyses for other objectives and outcome measures not included in the Primary SAP, 
including outcome measures after the Week 28 study visit, will be provided in a separate SAP for 
Other Objectives. 
1.2 
Version History 
• 
Version 1.0 was developed based on Protocol Version 1.0, dated June 07, 2019. 
• 
No changes after review of Protocol Version 1.0, Letter of Amendment #1, dated December 
18, 2019. 
• 
Changes due to the study visits affected by COVID-19 outlined in CM #2, dated April 20, 
2020. Changes were made in Section 2.5 (HCV interim monitoring), Section 3.1.1 (about 
primary outcome on SVR12 HCV RNA), Section 3.1.2 (clarification of timeframe) and Section 
4.2 first bullet (about HCV RNA data for SVR12 analysis).  Typos in 3.1 after asterisk were 
also corrected. Changes from Version 1.0 are in bold text.  
• 
No changes after review of Protocol Version 1.0, Letter of Amendment #2, dated August 14, 
2020. 
• 
No changes after review of Protocol Version 1.0, Letter of Amendment #3, dated September 
9, 2020. 
• 
No changes after review of Protocol Version 1.0, Letter of Amendment #4, dated October 13, 
2020. 


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2 
Study Overview 
2.1 
Study Design 
A5380 is a prospective, phase II, single-arm study in treatment of acute HCV infection in 
participants with and without HIV-1 coinfection.  The minimum number of HIV-1 infected 
participants for the study is 10, and there is no maximum set for the study.  The key study 
objective is to evaluate the efficacy of a 4-week treatment of a fixed-dose combination of 
glecaprevir/pibrentasvir (G/P), using SVR12 as the primary outcome measure.  SVR12 (sustained 
virologic response 12 weeks post-treatment) is defined as unquantifiable HCV RNA at 12 weeks 
after treatment discontinuation (Week 16 visit).   
The study is designed to conclude with reasonable evidence that the true SVR12 proportion is 
greater than 80% in the study population.  This will be assessed by examining if a two-sided 90% 
confidence interval for the sample proportion is entirely above 80%.  The study sample size of 44 
is deemed to provide reasonable precision around the estimated SVR12 proportion to provide 
useful information in the treatment of acute HCV. 
The primary analysis will occur when all the study participants can be evaluated for SVR12. 
Accounting for the possible imputation for the outcome measure (described in Section 3.1 below), 
the primary analysis is expected to be finalized upon completion of Week 28 study visits.  The 
finalization of primary analysis may occur while the study follow-up is ongoing. 
The study is monitored by an independent Study Monitoring Committee (SMC) appointed by the 
AIDS Clinical Trials Group (ACTG).  In addition, HCV RNA results will be closely monitored by the 
protocol core team (including study chairs, medical officer and statisticians) in the first 10 
participants who have such data for evaluability by the visit occurring 4 weeks after the end of 
treatment (Week 8).  Interim HCV RNA monitoring for this purpose is described further in Section 
2.5 below.  If the guidelines described in Section 2.5 are met, then the SMC will review the study 
results to make recommendation on the future conduct of the study.  The first planned SMC 
review will be held when the interim HCV RNA monitoring review can occur or one year after the 
enrollment of the first study participant, whichever occurs first.  The study will undergo interim 
data review at least annually by the appointed SMC. 
2.2 
Hypotheses 
The fixed dose combination (FDC) of glecaprevir/pibrentasvir (G/P) given for 4 weeks will achieve 
sustained virologic response 12 weeks post-treatment (SVR12) greater than 80% for the 
treatment of acute hepatitis C virus (HCV) infection, with an acceptable safety profile and shorter 
length of therapy than is currently recommended for chronic HCV infection.    
2.3 
Study Objectives 
This Primary SAP addresses the following primary and secondary objectives listed in the study 
protocol. Other study objectives in the protocol will be addressed in subsequent analysis plans.  


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2.3.1 
Primary Objectives 
1. To evaluate acute HCV treatment response to G/P given for 4 weeks, as assessed by 
sustained virologic response 12 weeks post-treatment (SVR12, defined as HCV RNA 
<lower limit of quantification [LLOQ], either target detected [TD] or target not detected 
[TND]). 
2. To evaluate the safety and tolerability of G/P given for 4 weeks in persons with acute 
HCV infection, regardless of genotype and HIV status. 
2.3.2 
Secondary Objectives 
1. To evaluate the antiviral efficacy of G/P given for 4 weeks for the treatment of acute HCV 
infection, as measured by the proportion of participants with HCV RNA <LLOQ (TD or 
TND) at study weeks 1, 2, 4, 8 (SVR4), 12 (SVR8), and 28 (SVR24). 
2. To evaluate evidence of virologic failure, defined as failure to achieve HCV RNA <LLOQ 
(TD or TND at the end of treatment) and confirmed increase in HCV RNA >1 log10 from 
on-treatment nadir. 
3. To evaluate the antiviral efficacy of G/P given for 4 weeks by HIV status. 
 
This SAP addresses the outcome measures obtained out to study week 28.  For the outcome 
measures obtained after Week 28, a separate SAP will be drafted.  
2.4 
Overview of Sample Size Considerations 
The study is designed to conclude with reasonable evidence that the true SVR12 proportion is 
greater than 80% in the study population. This will be assessed by examining if a two-sided 90% 
confidence interval (CI) for the sample proportion is entirely above 80%. This is equivalent to 
showing that the SVR12 proportion is higher than 80% in a one-sided test with a type I error of 
5%. With 44 participants, there is at least 90% power to show that proportion achieving SVR12 is 
greater than 80% in a one-sided exact binomial test with a targeted significance level of 5%. The 
true SVR12 proportion is assumed to be 95%, when treated with 4 weeks of the G/P regimen.  
With a sample size of 44 participants, the Wilson confidence interval for the true SVR12 
proportion will be entirely above 80% if 40 or more participants achieve SVR12 out of 44 
participants. 
2.5 
Overview of Formal Interim Monitoring 
The study will undergo interim review at least annually by an ACTG-appointed Study Monitoring 
Committee (SMC). The first interim review was initially planned to occur when the study week 8 
data are available from the first 10 participants, or one year after the enrollment of the first study 
participant, whichever occurs first. Due to the study visits affected by COVID-19 outlined in 
CM #2, the first SMC interim review will occur when SVR12 results are available from the 
first 10 participants. 
In this study, HCV RNA results will be closely monitored by the protocol core team in the first 10 
participants with HCV RNA data available to assess early evidence of potential harm in the short 
treatment duration of 4 weeks. The following guideline will be used to assess evidence of an 


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unacceptable number of participants not achieving unquantifiable HCV RNA excluding 
reinfections (failures), based on early interim data on 10 participants that may trigger an SMC 
review.  Failures include HCV RNA relapse and virologic failure, defined in protocol section 
10.2.3.2 and 10.2.2.2, respectively.  
If 3 or more of the first 10 participants experience failures, further enrollment will be 
suspended while the Core Team and the SMC review the data closely and determination is 
made on the future conduct of the study. 
The HCV RNA outcome for interim monitoring was initially planned to use data out to 4 weeks 
after the end of treatment.  Due to the study visits affected by COVID-19, HCV RNA results 
may not be available until Week 16 (SVR12 visit) for some participants. If Week 8 results 
are not available, Week 16 results will be used for the purpose of assessing potential harm 
with the abbreviated treatment duration of 4 weeks.  Formal interim analysis on the primary 
outcome measure SVR12 is not planned for this study. 
3 
Outcome Measures 
3.1 
Primary Outcome Measures 
1. [For Primary Objective 1]  SVR12 defined as achieving unquantifiable HCV RNA (<LLOQ 
TD or TND) at the study visit occurring at 12 weeks after treatment discontinuation (week 
16). The sample within the visit window for week 12, as defined in Protocol V1.0 Section 
6.0, will be used. If a participant does not have any HCV RNA measurements in this time 
period, then the participant will be considered as SVR12 failure, unless there are 
preceding and subsequent HCV RNA measurements* that are both LLOQ (either TD or 
TND), or the participants’ visit schedule was affected by COVID-19 as outlined in 
CM #2. 
2. [For Safety in Primary Objective 2]  Any reported AE occurring after initiation of study 
treatment through 4 weeks after the treatment discontinuation. 
3. [For Tolerability in Primary Objective 2]  Tolerability, defined as completion of 4 weeks of 
treatment without discontinuation due to AEs. 
 
* The scheduled HCV RNA visits that may be used for the SVR12 determination in case 
of the missed measurement in the Week 16 visit window are weeks 8, 12 and 28. 
Unscheduled HCV RNA visits may also be used, if applicable.  See Section 4.2 below on 
the analysis approach to SVR12. 
3.2 
Secondary Outcome Measures 
1. [For Secondary Objectives 1 and 3]  HCV RNA <LLOQ (TD or TND) at study visits, using 
the visit windows as defined in Protocol Section 6.0. 
2. [For Secondary Objective 2]  Virologic failure, defined as failure to achieve unquantifiable 
HCV RNA and confirmed increase in HCV RNA >1 log10 from on-treatment nadir. 


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Outcomes at study visits after Week 28 will be obtained after the primary completion date (PCD) 
and will be addressed in a separate analysis plan.  For the outcome measures obtained after 
PCD, the results will be posted to ClinicalTrials.gov after the initial results submission and no later 
than one year after the last participant’s study completion. 
4 
Statistical Principles 
4.1 
General Considerations 
• 
The analysis will include all participants who initiate the study treatment. 
• 
Baseline refers to study evaluation closest to Week 0 prior to initiation of study treatment. 
• 
For summaries of outcomes at specified study visits (e.g. HCV RNA at study visits for 
Secondary Outcome Measure 1), study visit windows as specified in Protocol Section 6.0 will 
be used, unless specified otherwise. In the event of multiple results within a study window, 
the result closest to the scheduled evaluation week based on the time since study entry 
randomization date will be used. 
• 
Continuous variables will be summarized with min, Q1, median, Q3, and max, unless 
specified otherwise. Mean and standard deviation may also be reported, if there are sufficient 
numbers to make these statistics meaningful. 
4.2 
Analysis Approaches 
• 
For the primary analysis:  
o 
As described in Section 3.1 above on Primary Outcome Measures, if a participant does 
not have any HCV RNA measurements in the SVR12 visit window, then the participant 
will be considered SVR12 failure, unless there are preceding and subsequent HCV RNA 
measurements that are both LLOQ (either TD or TND).  The latest available preceding 
and the earliest available subsequent HCV RNA measurements around the targeted 
SVR12 visit window will be used.  If the participant’s visit schedule was affected by 
COVID-19 as outlined in CM #2 and (1) only one HCV RNA sample is available after 
the study treatment, and (2) the sample is collected after the SVR12 visit window, 
then this result will be used as the primary outcome. 
o 
Otherwise, not achieving unquantifiable HCV RNA at the study visit corresponding to the 
SVR12 evaluation will be considered failure for SVR12 determination in the primary 
analysis regardless of the reason.  As such, early discontinuation of the study prior to the 
SVR12 visit and reinfection prior to the SVR12 visit will be considered a failure. 
o 
For the SVR12 analysis, a supplementary analysis will be conducted in the analysis set 
that excludes (1) participants who discontinued the study for reasons not related to the 
study treatment, and (2) participants who became re-infected with HCV prior to SVR12 
visit.  Reasons not related to study treatment may include, but are not limited to: 
participant moved away, participant cannot get to the clinic, participant cannot be located.   
• 
All available data for the indicated study visits from the participants who initiate the study 
treatment will be used in the analysis, and the number of participants with available data will 
be specified for each analysis. 
• 
Confidence intervals around proportions will be provided using the Wilson method for 
binomial data.  


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• 
Subgroup analyses based on the screening HIV infection status will be conducted for the 
HCV RNA analyses to address Secondary Objective 3. 
5 
Report Contents 
Additional details will be provided in an Analysis Implementation Plan (AIP). In addition to results 
for primary and secondary outcome measures, key baseline characteristics and study status are 
reported in ClinicalTrials.gov. 
1. CONSORT Diagram 
2. Study history 
a. A summary of changes to and clarifications of the protocol. 
b. A brief summary of the SMC reviews. 
3. Study entry  
a. Screening: Number of participants screened for the study 
b. Accrual: Tables of accrual by month and by site 
4. Baseline characteristics 
a. Demographics: age, sex, IV drug use and race/ethnicity 
b. Weight and BMI  
c. HCV genotype 
d. HCV RNA viral load 
e. HIV status and for those HIV-infected: HIV-1 RNA level, ARV regimen, CD4+ and 
CD8+ T-cell count 
f. 
Liver function tests: total and direct bilirubin, INR, ALT/SGPT, AST/SGOT, albumin, 
alkaline phosphatase 
5. Study status  
a. Listing of premature study discontinuations with reasons. For premature 
discontinuations, the number of weeks on study will be provided. 
b. Number of participants who did not start study treatment. 
6. Study treatment status  
a. Listing of premature study treatment discontinuations with reasons.  For premature 
discontinuations, the number of weeks on study treatment will be provided. 
7. Adverse events and deaths 
a. Summary of all adverse events defined in Section 7.2 of the protocol by MedDRA  
system organ class (SOC) and preferred term (PT) and by grade. 
b. Summary of the participants who died, including primary cause of death with weeks 
from study entry. 
c. Listing and narratives of deaths. 
8. Pregnancies  
a. Listing and description of all available information related to pregnancy and outcome 
9. Analysis of Primary Outcome Measure 1 described in Section 3.1 
a. Primary Objective 1 described in Section 2.3.1 will be addressed by estimating the 
proportion of participants who achieve SVR12, using the approach described in 
Section 4.2.  A two-sided 90% CI will be calculated around the estimated SVR12 
proportion. If this CI is entirely above 80%, then it will be concluded that there is 
evidence that the underlying SVR12 proportion is greater than 80%.   


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b. As a supplementary analysis, SVR12 will be assessed in the analysis set that 
excludes participants who discontinued the study early for reasons clearly not related 
to the study treatment and participants who became re-infected with HCV prior to 
SVR12 visit, as described in Section 4.2.   
10. Analysis of Primary Outcome Measure 2 described in Section 3.1 
a. To address safety in Primary Objective 2 described in Section 2.3.1, the AEs 
occurring after initiation of study treatment through the study visit occurring 4 weeks 
after the treatment completion will be summarized. The proportion of study 
participants with AEs will be estimated with a two-sided 95% CI around the estimate.  
b. As a supplementary safety analysis, all reported AEs (which include events that 
occur after the time frame defined above for Primary) will be summarized. A two-
sided 95% CI will also be provided for the proportion of study participants with AEs. 
11. Analysis of Primary Outcome Measure 3 described in Section 3.1 
a. To address tolerability in Primary Objective 2 described in Section 2.3.1, tolerability 
failures will be listed and described.  
b. The tolerability failure listing will be accompanied by treatment duration and the 
associated AEs. 
12. Analysis of secondary outcome measures 
a. To address Secondary Objective 1, HCV RNA measurements at study visits will be 
assessed with proportion estimates with two-sided 90% CI.   
b. To address Secondary Objective 2, virologic failures will be listed and described. 
Listings on virologic failure will be accompanied by HCV RNA results and any 
available information on HCV genotype/subtype, RAS and phylogenetic results. 
c. To address Secondary Objective 3, SVR12 analysis described above in 9.a will be 
presented separately by HIV-1 infection status. In addition, HCV RNA measurements 
at study visits described above will be assessed with proportion estimates with two-
sided 90% CI for the subgroup consisting of HIV-1 infected participants.