Clinical trial NCT01718301
Conditions: Hepatitis C HIV Infections COINFECTION
Keywords: HCV HIV Coinfection
Sponsor: Anna Cruceta
Start date: 2013-03-10; Completion date: 2015-06-30
Enrollment: 108 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the safety and efficacy of a Response Guided Therapy of boceprevir 800 mg dosed three times a day (TID) orally (PO) in combination with Peginterferon (either alpha 2b or alpha 2a) and Ribavirin in HIV/HCV genotype 1 infected patients that failed to previous HCV therapy.

Detailed description:
In a total number of 108 patients the protocol was evaluated but only in 102 the protocol efectively was presented. In the remaining 6 patients we don't believe the trial could be performed.

Arms: arm 1: boceprevir 800 mg three times a day (v.o.) in combination with peginterferon (alfa-2b or alfa-2a) and ribavirin
Interventions: intervention 1: boceprevir intervention 2: Ribavirin intervention 3: Peginterferon alfa-2a intervention 4: Peginterferon alfa-2b
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
1 
  
CLINICAL TRIAL PROTOCOL WITH DRUGS  
  
  
  
  
  
Open-label Phase III Study to Evaluate the Efficacy and Safety of 
Boceprevir Treatment in Patients  
co-infected with HIV and HCV (genotype 1), who have failed 
previous treatment with peginterferon and ribavirin  
  
  
  
Protocol Code: BOC-HIV  
  
  
  
  
  
  
  
  
Version / Date: 1.0, dated 18 September 2012.  
EudraCT number: 2012-003984-23  
ClinicalTrials.gov ID: NCT01718301 
  
 
 
SPONSOR: Fundació Clínic per a la Recerca Biomèdica Principal 
Investigator and coordinator of the study:  
Dr. Josep Mallolas Masferrer.  
Head of HIV Day Hospital.  
Infectious Diseases Service.  
Hospital Clínic de Barcelona.  
Spain.  
  
Phone: +34 932274747 / +34-649914304.  
Email: mallolas@clinic.ub.es  
  
  
  
  
  
  
 CONFIDENTIAL  
  
  
  
  
  
 


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
2 
1. SUMMARY  
  
  
1.0. Type of application:   
  
Open-label, phase III, prospective, multicenter study.  
  
1.1. Identification of the developer:   
  
  
Fundació Clínic per a la Recerca Biomèdica  
  
Manager: Ms. Pastora Martínez Samper  
  
C. Roselló, 143  
  
08036 Barcelona  
  
1.2. Title of the clinical trial:   
  
Phase III open-label study to evaluate the efficacy and safety of boceprevir treatment in patients co-
infected with HIV and HCV (genotype 1), who have failed prior treatment with peginterferon and 
ribavirin.  
  
Version / Date: 1.0, dated 18 September 2012.  
  
  
1.3. Protocol code: BOC-HIV  
  
EudraCT number: 2012-003984-23  
  
1.4. Principal Investigator and Study Coordinator: Dr. Josep Mallolas Masferrer  
  
Collaborating researchers: Dr. Montserrat Laguno Centeno.  
  
  
1.5. Centres in which the trial is planned to be carried out:   
  
The centres where the trial is planned to be carried out are detailed in the document "List of 
participating centres and researchers".  
  
  
1.6. Clinical Research Ethics Committees that have approved the trial:  
  
The trial has been presented to all the CEICs corresponding to the participating centers, and the CEIC 
of the Hospital Clínic de Barcelona has also been assigned as a reference CEIC.    
  
  
1.7. Name and qualification of the person responsible for monitoring:   
  
Dr. Anna Cruceta.   
Clinical Trials Unit.  
CTU Clinic. Clinical Pharmacology Service.  
(Hospital Clínic de Barcelona).  
Head of the CTU: Dr Joan Albert Arnaiz  
  
 
 
  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
3 
1.8. Study drug information:  
  
Boceprevir: The drug has final approval by the Ministry of Health. As stated in its technical sheet (see 
annexes).  
  
1.9. Phase of the clinical trial: Phase III.  
  
1.10. Objectives:  
  
1.10.1. Main objective:   
  
The primary objective of this study is to evaluate the safety and efficacy of response-guided therapy 
with boceprevir 800 mg three times daily orally (o.v.) in combination with peginterferon (alpha-2b or 
alpha-2a) and ribavirin in genotype 1 HIV- and HCV-infected patients in whom prior HCV treatment 
with ribavirin-associated pegylated interferon had failed.  
  
1.10.2. Secondary objectives:  
  
● 
To define predictors of sustained virologic response (SVR), such as epidemiological factors, 
disease characteristics, clinical status of HIV infection, and response during treatment, especially 
at weeks 4, 8, 12, and at the end of treatment.  
● 
To determine the percentage of patients with undetectable HCV RNA at treatment weeks (ST) 4, 
8, and 12 and at the end of treatment.  
● 
Evaluate virologic response based on baseline characteristics   
● 
To investigate HCV resistance following virological failure with a regimen containing boceprevir 
(BOC). Blood samples should be obtained at baseline, at the time of virological failure (VF) (VF: 
two consecutive samples with signs of HCV replication after HCV was undetectable – below the 
lower limit of detection – or HCV RNA rebound equal to or greater than one logarithmic unit with 
respect to the RNA nadir) and six months after virological failure. The evaluation of resistance will 
be carried out in a single center (coordinating center: Hospital Clínic, Barcelona) by means of 
population sequencing of the genome that encodes the HCV protease.  
1.11. Design:   
  
Open-label, Phase III, prospective, multicenter study.  
  
  
1.12. Disease under study:   
  
HCV (hepatitis C virus) co-infection (genotype 1 (subtype a or b)) + HIV (acquired immunodeficiency 
virus)  
  
  
1.13. Assessment variables:   
  
  
1.13.1. Main  
  
- Primary efficacy endpoint: achievement of SVR (sustained virologic response, defined as 
an undetectable plasma HCV RNA at follow-up week (SS) 24. If SS24 data are not 
available in a patient and the HCV RNA in SS12 is undetectable, SVR will be considered 
to be present.  
 
  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
4 
1.13.2. Secondary  
  
- 
Percentage of patients with virologic response (HCV RNA undetectable at weeks 4, 8, or 12) 
in those who achieve SVR.  
- 
Percentage of patients with HCV RNA undetectable in SS12.  
- 
Percentage of patients with undetectable HCV RNA 72 weeks after randomization.  
- 
To investigate the resistances that appear after virological failure. Blood samples will be 
obtained at baseline, at the time of virological failure (VF) (VF defined as two consecutive 
samples with detectable HCV-RNA after the HCV-RNA is undetectable – below the lower limit 
of detection – or HCV-RNA rebound equal to or greater than one logarithmic unit with respect 
to the RNA nadir) and six months after virological failure. The evaluation of resistance will be 
carried out in a single center (coordinating center: Hospital Clínic, Barcelona) by means of 
population sequencing of the genome encoding the HCV protease  
- 
Safety  
  
  
1.14. Study population and total number of patients:   
  
Adult patients with well-controlled chronic HIV infection and chronic hepatitis with genotype 1 C virus 
(subtype a or b), who have failed previous treatment with pegylated interferon associated with ribavirin.  
  
A total of 128 patients will be included.   
  
  
1.15. Duration of treatment:    
  
The approximate expected duration for the inclusion of patients is 12 months, and the duration of 
treatment and follow-up of the included patients will be extended by a maximum of 72 weeks.  
  
  
1.16. Schedule and expected completion date:   
  
The study is expected to begin, once the permits have been obtained, in March 2013. The recruitment 
period will be 12 months. Patients will be followed for 6 months after the end of treatment. The study 
is expected to be completed in November 2015.  
 
 


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
5 
2. INDEX  
  
  
1. SUMMARY  
  
2. INDEX  
  
3. OVERVIEW  
  
4. JUSTIFICATION  
  
5. OBJECTIVE AND PURPOSE OF THE TRIAL  
  
6. ESSAY DESIGN  
  
7. SUBJECT SELECTION AND WITHDRAWAL  
  
8. TREATMENT OF SUBJECTS  
  
9. ASSESSMENT OF EFFECTIVENESS  
  
10. SAFETY RATING  
  
11. STATISTICS  
  
12. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS  
  
13. ETHICS  
  
14. DATA MANAGEMENT AND ARCHIVING OF RECORDS  
  
15. FINANCING AND INSURANCE  
  
16. PRIVACY POLICY  
  
  
  
Annexes and documents:  
  
List of participating centres and researchers, version 1.0 dated 18 September 2012.  
  
Annex I   
Technical data sheets  
Annex II  
Protocol Acceptance IP Document  
Annex III  
Patient Information Sheet and Study Informed Consent  
Annex IV  
Toxicity grading table (WHO)  
Annex V  
Serious Adverse Event Reporting Form.  
Annex VI  
Data collection notebook. List of CRD variables  
Annex VII  
Economic Report  
Annex VIII  
Declaration of Helsinki.   
Annex IX  
Liability Insurance  
 
 
 


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
6 
3. General Information  
  
3.1 Identification of the test  
  
Title:   
Phase III open-label study to evaluate the efficacy and safety of boceprevir treatment in patients co-
infected with HIV and HCV (genotype 1) who have failed prior treatment with peginterferon and 
ribavirin.  
Open-label, Phase III, prospective, multicenter study.  
  
Version / Date: 1.0 (18-09-2012)  
EudraCT number: 2012-003984-23  
  
  
3.2 Identification of the promoter   
  
Fundació Clinic per a la Recerca Biomèdica.  
C/ Rossello 143  
08036 Barcelona  
  
  
3.3 Identification of the promoter's representative  
  
Manager: Dr. Pastora Martínez Samper Fundació 
Clinic per a la Recerca biomedica.  
C/ Rossello 143 08036 
Barcelona  
e-mail: PMARTIN2@clinic.ub.es  
  
  
3.4 Identification of researchers of the promoting entity  
  
Hospital Clínic  
Principal Investigator and Study Coordinator:  
Dr. Josep Mallolas Masferrer   
Infectious Diseases Service. mallolas@clinic.ub.es  
  
Collaborating researchers:   
Dr. Montserrat Laguno Centeno, Infectious Diseases Service mlaguno@clinic.ub.es  
  
  
  
3.5 Identification of principal investigators from participating centres  
  
The identification of the principal investigators as well as the centers participating in the trial are 
detailed in the document "List of centers and principal investigators".  
  
  
3.6 Identification of researchers from other services involved  
  
Microbiology: Dr. Josep Costa   
Pharmacy: Anna Estafell and Begoña Gómez  
Biostatistician: Iñaki Pérez  
Nurse: Amparo Tricas  
Laboratory Technician: Pilar Callau  
  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
7 
  
3.7 Information on the laboratories or technical departments involved  
  
Daily clinical evaluation of patients enrolled in the study, routine blood/urine laboratory determinations, 
and viral determinations (HCV and HIV), will be performed in the corresponding services at each center 
participating in the study.   
  
Determinations of HCV mutations that confer resistance to boceprevir in patients with virological failure 
will be carried out centrally in the Microbiology Laboratory of the Hospital Clínic de Barcelona.   
  
  
3.8 Monitoring  
  
CTU (clinical Trial Unit).  
Responsible for monitoring:  
Dr. Anna Cruceta. acruceta@clinic.ub.es  
Tel 932275400 ext 4380 fax 932279877   
  
Head of the CTU:  
Dr. Joan Albert Arnaiz.  
Clinical Pharmacology Service.  
Hospital Clínic de Barcelona  
  
4. Justification  
  
Currently, the standard of care for chronic hepatitis C virus (HCV) in patients with concurrent HIV and 
HCV infection is peginterferon plus ribavirin for 48 weeks. Although the sustained virologic response 
rate (SVR) has improved markedly in recent years, in most studies it remains below 50%-55%.  
  
As a result, more than 50% of patients who fail treatment have no treatment options and will develop 
progressive liver fibrosis. In fact, end-stage liver disease is the main cause of morbidity and mortality 
in patients co-infected with HIV and HCV, and its incidence is higher in patients without SVR to 
treatment with peginterferon plus ribavirin.  
  
New approaches are needed to try to improve response in these patients. Recently, excellent results 
have been presented with a triple therapy based on peginterferon, ribavirin and the new HCV protease 
inhibitors telaprevir and boceprevir in patients with HCV monoinfection.  
  
Although triple therapy achieves a higher rate of SVR, it is also true that the use of three drugs can be 
more toxic and will be more expensive. Preliminary data suggest that response-guided therapy (TGR) 
(32 weeks of triple therapy) in patients with HCV monoinfection can achieve the same virological 
outcomes as standard triple therapy (44 weeks) but with lower toxicity and lower cost. This point will 
be investigated in the present study.  
 
Of the patients in whom previous treatment with peginterferon plus ribavirin has failed, the most difficult 
subgroup to rescue is those with no viral response. There are currently doubts about what the response 
to triple therapy will be in patients with a zero viral response to dual therapy and whether 44 weeks of 
treatment will be necessary in this subgroup of patients or whether the TGR approach can be applied. 
Information on this field is not available in patients with co-infection with HCV and HIV, and we believe 
that our study can provide valuable information on this important topic.  
Results from a phase II, double-blind, comparative study of boceprevir and placebo in patients with 
controlled HIV co-infection who had not received HCV treatment have recently been published. 
Efficacy and safety results were similar to those previously described in patients with HCV 
monoinfection. The overall sustained viral response was 61% in patients treated with boceprevir, 
compared with no more than 39% in those treated with peginterferon/ribavirin. Although the efficacy 
data are encouraging, response-guided therapy has not been formally investigated.  
  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
8 
Several studies are underway to evaluate the efficacy and safety of HCV protease inhibitor triple 
therapy in HIV-HCV co-infected patients previously treated with peginterferon and ribavirin, but 
response-guided therapy has not been evaluated so far. The main hypothesis of this proposal is that 
response-guided triple therapy with boceprevir could obtain better SVR than classic treatment with 
peginterferon plus ribavirin.  
 
 
4.1 Identification of the investigational medicinal product  
  
Generic name: Boceprevir  
  
Trade name: Victrelis®   
Composition: boceprevir 200 mg.   
  
Pharmaceutical form: hard gelatin capsules.  
  
Generic name: Peginterferon (alpha-2b or alpha-2a)  
Trade name: Pegintron®  or Pegasys®   
Composition: peginterferon alfa-2b 80-150mcg or peginterferon alfa-2a: 180 micrograms 
Pharmaceutical form: solution for injection  
  
Generic name: Ribavirin Trade name: 
Ribavirin Teva®.  
Composition: ribavirin: 200 mg  
Dosage form: hard capsule  
 
  
4.2 Investigational Drug Information  
  
Boceprevir: The drug has final approval by the Ministry of Health. Date of first authorisation 18/07/2011.  
  
4.3 Treatment Regimen  
  
PEG-IFN alfa-2a or 2b and ribavirin will be provided by each hospital and will be administered 
in accordance with the approved technical data sheets.  
  
BOC (Boceprevir). Provided by the study sponsor.  
  
Description:   
 
BOC is supplied in 200 mg capsules. Each capsule contains 200 mg of BOC, sodium lauryl sulfate, 
microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, pregelatinized starch, and 
magnesium stearate packaged in number 0 hard gelatin capsules. Each capsule contains 
approximately 56 mg of lactose monohydrate. In people with lactase deficiency, the clinical 
manifestations of lactose intolerance require 3 to 5 g of lactose (4 to 7 times the total amount of BOC 
capsules) to appear.  
  
Route of administration: oral   
Dosage: total daily 2400 mg, (12 capsules).   
  
Storage: keep in the fridge at a temperature between 2ºC and 8ºC. The products of the study must 
be stored in a safe place with limited access and in the storage conditions specified on the supply 
label.  
  
Dosage Schedule:  
  
Boceprevir is administered three times a day using a dosing schedule of 4 capsules every 8 hours. 
Actual times of dose administration may be modified to fit the patient's schedule, although 7- to 9-hour 


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
9 
intervals between administrations should be maintained. All doses of boceprevir will be given with food 
(a small snack is sufficient).   
  
  
Study period and treatment:   
  
All patients will receive an initial 4 weeks of bitherapy with Peg-Interferon and ribavirin (PR).  
-If there is a decrease in HCV RNA greater than 1 logarithm with respect to baseline HCV-RNA, the patient will 
be included in the treatment scheme detailed below.   
  
  
  
 
  
  
  
-If the RNA drop is ≤ 1 log at week 4, PR/boceprevir will be administered for an additional 44 weeks.  All cirrhotic 
patients will receive PR for 4 weeks, followed by RP/boceprevir for another 44 weeks   
  
4.4 Compliance Statement  
  
The study will be carried out in accordance with the principles emanating from the Declaration of 
Helsinki, and according to the legal regulations in force (Royal Decree 223/2004), and will not begin 
until the approval of the reference CEIC and the approval of the AEMPS have been obtained.  
  
Patients will be informed orally and in writing and all relevant information tailored to their level of 
understanding will be communicated to participants.   
  
(See Attachment III: Patient Information Sheet and Attachment III: Written Consent Sheet.)  
The patient will be informed that their participation in the study will be treated with the same 
confidentiality as their clinical documentation and that only the people involved in the study will have 
access to their data. The patient's name will not appear in any publication or communication of the 
results of the study.  
  
  
4.5 Study population  
  
Adults with controlled HIV-1 infection and chronic HCV hepatitis genotype 1 (subtype a or b) who did 
not achieve SVR with prior treatment with any peginterferon alfa plus ribavirin.  
  
  
  
  
Weeks  
Response-guided treatment 
Boceprevir + PEG + RBV 32 weeks  
 if HCV RNA undetectable in ST8 and ST12   
PEG +  
RBV  
4   
  
if HCV RNA detectable in ST8 and undetectable   
enST12 
Follow-up24 weeks   
Follow-up 24 weeks 
  
PEG +  
RBV 4  
Sem  
PEG + RBV 


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
10 
4.6 Relevant bibliography  
  
- 
Laguno M, Murillas J, Blanco JL, Martínez E, Miquel R, Sánchez-Tapias JM, Bargallo X, 
GarcíaCriado A, de Lazzari E, Larrousse M, León A, Loncá M, Milinkovic A, Gatell JM, Mallolas J. 
Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of 
HIV/HCV co-infected patients. AIDS. 2004 Sep 3; 18(13):27-36.  
- 
Laguno M, Mallolas J. Treatment of chronic hepatitis C in patients with HIV coinfection. 
Gastroenterol Hepatol. 2006 Oct; 29 Suppl 2:154-7.   
-Laguno M, Cifuentes C, Murillas J, Veloso S, Larrousse M, Payeras et al. Randomized trial comparing 
pegylated interferon alpha-2b versus pegylated interferon alpha-2a, both plus ribavirin, to treat chronic 
hepatitis C in human immunodeficiency virus patients. Hepatology. 2009 Jan; 49(1):2231.   
-Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, 
Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-
2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011 Mar 
31; 364(13):1195-206.  
  
-Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, 
Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 
Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011 
Mar 31; 364(13):1207-17.  
  
-Sulkowski M, Pol S, Cooper C, Fainboim H, Slim J, Rivero A, Laguno M, Thompson S, Wahl J, and 
Greaves W. Boceprevir + Pegylated Interferon + Ribavirin for the Treatment of HCV/HIV-co-infected 
Patients: End of Treatment (Week-48) Interim Results. 19th Conference on Retroviruses and 
Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 47.  
  
-Naggie S, Sulkowski MS. Management of patients coinfected with HCV and HIV: a close look at the 
role for direct-acting antivirals. Gastroenterology. 2012 May; 142(6):1324-1334.  
-Thomas DL, Bartlett JG, Peters MG, Sherman KE, Sulkowski MS, Pham PA. Provisional guidance on 
the use of hepatitis C virus protease inhibitors for treatment of hepatitis C in HIV-infected persons. Clin 
Infect Dis. 2012 Apr; 54(7):979-83. Epub 2012 Feb 4.  
  
-Wilby KJ, Greanya ED, Ford JA, Yoshida EM, Partovi N. A review of drug interactions with boceprevir 
and telaprevir: implications for HIV and transplant patients. Ann Hepatol. 2012 MarApr; 11(2):179-85.  
  
-Seden K, Back D. Directly acting antivirals for hepatitis C and antiretrovirals: potential for drug-drug 
interactions. Curr Opin HIV AIDS. 2011 Nov; 6(6):514-26.  
  
-Susser S, Welsch C, Wang Y, Zettler M, Domingues FS, Karey U, Hughes E, Ralston R, Tong X, 
Herrmann E, Zeuzem S, Sarrazin C. Characterization of resistance to the protease inhibitor boceprevir 
in hepatitis C virus-infected patients. Hepatology. 2009 Dec; 50(6):1709-18.  
  
-Susser S, Vermehren J, Forestier N, Welker MW, Grigorian N, Füller C, Perner D, Zeuzem S, Sarrazin 
C. Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease 
after treatment with telaprevir or boceprevir. J Clin Virol. 2011 Dec; 52(4):321-7. Epub 2011 Sep 15.  
   
  
 
 
 


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
11 
5. Objective and Purpose of the Trial  
  
Main:  
  
The primary objective of this study is to evaluate the safety and efficacy of response-guided therapy 
with boceprevir 800 mg three times daily orally (o.v.) in combination with peginterferon (alpha-2b or 
alpha-2a) and ribavirin in genotype 1 HIV- and HCV-infected patients in whom prior HCV treatment 
with ribavirin-associated pegylated interferon had failed.  
  
  
Side:  
  
● 
To define predictors of sustained virologic response (SVR), such as epidemiological factors, 
disease characteristics, clinical status of HIV infection, and response during treatment, especially 
at weeks 4, 8, 12, and at the end of treatment.  
● 
To determine the percentage of patients with undetectable HCV RNA at treatment weeks (ST) 4, 
8, and 12 and at the end of treatment.  
● 
To evaluate the virological response according to baseline characteristics.  
● 
To investigate HCV resistance after virological failure with a boceprevir-containing regimen (BOC). 
Blood samples should be obtained at baseline, at the time of virological failure (VF) (VF: two 
consecutive samples with signs of HCV replication after HCV was undetectable – below the lower 
limit of detection – or HCV RNA rebound equal to or greater than one logarithmic unit with respect 
to the RNA nadir) and six months after virological failure. The evaluation of resistance will be 
carried out in a single center (coordinating center: Hospital Clínic, Barcelona) by means of 
population sequencing of the genome that encodes the HCV protease.  
  
6. Trial Design  
  
Open-label, Phase III, prospective, multicenter study.  
  
6.1 Main and secondary variables:  
  
Primary endpoint:   
  
The primary efficacy endpoint is the achievement of SVR, defined as an undetectable plasma 
HCV RNA at follow-up week (SS) 24.   
  
If SS24 data are not available in a patient and the HCV RNA in SS12 is undetectable, SVR 
will be considered to be present.  
 
 
Rules of futility:  
HCV treatment failure is defined as follows:  
  
● 
HCV RNA in serum >100 IU/mL at week 12  
Or  
● 
Confirmed increase in serum HCV RNA to >1,000 IU/mL at any time after week 12  
Or  
● 
detectable HCV RNA (above the lower limit of detection of HCV assay  
COBAS® Taqman® v2.0. de Roche ) in week 24  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
12 
Secondary endpoints:  
  
● 
Percentage of patients with virologic response (HCV RNA undetectable at weeks 4, 8, or 12) in 
those who achieve SVR.  
● 
Percentage of patients with HCV RNA undetectable in SS12.  
● 
Percentage of patients with undetectable HCV RNA 72 weeks after randomization.  
● 
HCV resistance after treatment with BOC-containing therapy. Blood samples will be obtained at 
baseline and after HCV virological failure, and at the end of the study a resistance analysis will be 
performed in a single center (Hospital Clínic, Barcelona).  
● 
Safety.  
6.2 Design  
  
Phase III studies are usually randomized, often with one group receiving the current standard 
treatment. These studies may or may not be placebo-controlled. However, the population with co-
infection with HCV and HIV is difficult to treat and has very few treatment options. In this population, 
the use of a standard care group is difficult to justify ethically because response rates with such a 
regimen are low and because the toxicity of the current standard of care (i.e., PEGIFN + RBV) is 
considerable.  
  
In this regard, we could establish that SVR in the historical control group is between the  
10% (95% confidence interval [CI]: 5%-18%) in previously treated patients and 26% described in the 
placebo control group in the phase II study of HCV-infected patients not previously treated with 
boceprevir  
  
 
 


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
13 
STUDY PROCEDURES   
Selection Evaluations  
 
Clinical Evaluations  
Selection  
Informed consent  
X  
Inclusion and exclusion criteria  
X  
Assignment of the selection number  
X  
Vital signs  
X  
Weight Determination  
X  
Height determination  
X  
Demographics  
X  
Medical history  
X  
Physical examination  
X  
Adverse events  
X  
Concomitant medications  
X  
Liver biopsy or Fibroscan (not necessary if performed prior to 18 months)  
X  
Ultrasound (in patients with bridge fibrosis or cirrhosis) (6 months prior)  
X  
Confirmation of the use of contraceptive methods by the patient and his or her partner  
X  
  
Treatment Visit Schedule  
 
 
Clinical 
Evaluations  
Day 
1  
ST 
2  
ST 
4  
ST 
6  
ST 
8  
ST 
10  
ST 
12  
ST 
16  
ST 
20  
ST 
24  
ST 
30  
ST 
36  
ST 42  
ST 
48/ 
dF 
T  
Inclusion and 
exclusion criteria  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital signs  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Weight  
X  
  
  
  
  
  
  
  
  
X  
  
  
  
X  
Physical 
examination  
X  
  
X  
  
  
  
X  
  
  
X  
  
X  
  
X  
Adverse events  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Concomitant 
medications  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Confirmation of 
the use of 
contraceptive 
methods by the 
patient and his or 
her partner  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Simplified 
Compliance 
Questionnaire  
X  
X  
X  
  
X  
  
X  
  
X  
X  
  
X  
X  
X  
Haematology  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
14 
TP/TTP  
X  
  
  
  
  
  
X  
  
  
X  
  
  
  
X  
Blood 
biochemistry  
(simplified, fasting)  
  
X  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
Blood 
biochemistry  
X  
  
  
X  
  
  
  
X  
  
X  
  
X  
  
X  
(complete, without 
fasting)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyrotropin (TSH)  
X  
  
  
  
  
  
X  
  
  
X  
  
X  
  
X  
Serum pregnancy 
test (women only)  
X  
  
  
  
  
  
  
  
  
  
  
  
  
X  
Test of  
pregnancy in  
urine (in women 
only)  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Samples for 
pharmacogenetics  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
HCV RNA CPR*  
X  
  
X  
  
X  
  
X  
  
  
X  
  
  
  
X  
  
All laboratory specimens should be obtained prior to administration of the first dose of study 
medication.  
* Samples will be obtained for genotypic resistance testing if the patient has >100 IU/mL at week 12 
or later.  
  
Complete blood biochemistry: ALT, AST, creatinine, alkaline phosphatase, gammaglutamyltransferase 
(GGT), total bilirubin (direct and indirect), total proteins, albumin, uric acid, urea nitrogen, glucose, 
HbA1C (in patients diagnosed with diabetes, whether they are receiving pharmacological treatment or 
controlled with diet), amylase, lipase, sodium, potassium, chloride, phosphorus, calcium, triglycerides, 
and cholesterol.  
  
Simplified blood biochemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
creatinine, alkaline phosphatase, total bilirubin (direct and indirect), urea nitrogen, total proteins, 
albumin, uric acid and glucose.  
  
Fibrosis evaluation: This will be done by liver biopsy or Fibroscan. In patients without cirrhosis on 
histology or Fibroscan, evaluation must have been performed no more than 18 months prior. A result 
of 12 kilopascals or more on the Fibroscan test would allow the patient to be considered cirrhotic.  
  
Ultrasound: Patients with bridge fibrosis or cirrhosis must have an ultrasound performed within 6 
months prior to inclusion in the study.  
  
            6.3 Guidelines for BOC Dose Modification  
  
The dose of BOC cannot be reduced in the study.   
Grade 1 and 2 AEs require close follow-up but no change in treatment.  
  
All grade 3 toxicities will be treated by the facility investigator as appropriate. Any grade 4 toxicity 
that, in the opinion of the centre's investigator, is directly related to BOC, will be treated with the 
permanent suspension of the latter.  
  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
15 
In case of intolerance to the BOC, its administration will be suspended; The dose cannot be reduced. 
If BOC is temporarily or permanently stopped, patients may continue to receive PEG-IFN and RVB.  
  
6.4 Trial treatments  
  
DRUG SUPPLY AND LABELLING  
  
In this study, 2 drugs already on the market and authorized for use in HIV-HCV co-infected patients 
will be used; peginterferon and ribavirin; The study drug, boceprevir, will be provided by MSD 
throughout the study and distributed by the Coordinating Center. For clinical trials carried out in Spain, 
relabelling in Spanish is mandatory.   
  
See section 4.3  
  
  
6.5 Duration of the trial  
  
 The approximate expected duration for the inclusion of patients is 2 months, and the duration of 
treatment and follow-up of the included patients will be extended by a maximum of 72 weeks  
  
6.6 Termination and/or Discontinuation Criteria  
  
The treatment will be compulsorily terminated during the study for any of the following reasons:  
  
● 
Patient with HCV RNA >100 IU/mL in ST12 or detectable HCV RNA in ST24.  
● 
Suicide or homicide thoughts or attempts.  
● 
Severe depression or major depressive episode.  
● 
Positive test result for non-prescription opioids, methamphetamines, or cocaine.  
● 
Pregnancy during the study.  
● 
Virological rebound, defined as:  
Any patient who obtains an undetectable HCV RNA and subsequently presents an HCV 
RNA > 1,000 IU/ml.  
Once virologic rebound has been identified, genotypic resistance will be characterized by HCV RNA 
sequencing in suitable samples, such as those collected at the time of rebound and during the follow-
up period.  
  
Treatment may be terminated during the study for any of the following reasons:  
  
● 
The medical investigator determines that a SAE is possibly or likely related to the study drug.  
● 
Failure to administer, evaluate, or other study requirements.  
  
6.7 End of test  
  
The end of the trial will be considered the time of the last visit of the last subject recruited.  
  
 
 
 
  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
16 
7. Subject Selection  
  
7.1 Criteria for inclusion of subjects  
A patient must meet ALL of the criteria listed below in order to participate:  
  
1. To participate in the study, patients must have been treated with peginterferon alfa-2a plus ribavirin 
or peginterferon alfa-2b plus ribavirin for a minimum of 12 weeks. If a patient has received more 
than one of these guidelines, the most recent one will be considered.  
2. The patient must have a previously documented HCC caused by genotype 1 virus (subtype a or 
b). Patients with other genotypes or with mixed genotypes will not be able to participate. The HCV 
RNA result at the screening visit should confirm genotype 1 virus infection and be >10,000 IU/mL.  
3. The patient must have a liver biopsy with HCC-compatible histology and no other etiology or 
evaluation with Fibroscan. In the event of:  
a. Absence of cirrhosis. Biopsies or Fibroscan must have been done within 18 months 
prior to the screening visit.  
b. Cirrhosis No specific time frame is required.  
4. All patients with cirrhosis should have an ultrasound scan performed within 6 months prior to the 
screening visit.  
5. Patients must be receiving stable antiretroviral therapy with a CD4 lymphocyte count greater than 
100/mm3 and an undetectable HIV plasma viral load (< 50 copies/mL) for more than 6 months. 
Antiretroviral therapy should contain raltegravir (at least for the past 6 weeks).  
6. The patient must be 18 years of age or older.  
7. HIV treatment should not contain EFV, NVP, ddI, d4T, AZT, or HIV protease inhibitors.   
8. The patient should weigh between 40 and 125 kg.  
9. The patient and partner must commit to acceptable contraception from at least 2 weeks prior to 
Day 1 and until at least 6 months after the last dose of study drug. (negative pregnancy test in 
women of childbearing potential) (Postmenopause is defined as the absence of menstruation 
during the year prior to study entry.)  
  
10. Patients must be willing to give written informed consent and, in the opinion of the investigator, be 
able to follow the protocol visit design.  
  
  
7.2 Criteria for exclusion of subjects  
  
Patients who meet ANY of the following criteria will be excluded from the study:  
  
1. Patients with confirmed hepatitis B virus co-infection (HBsAg positivity).   
2. Patients with chronic HCV infection of genotypes other than 1  
3. CD4 lymphocyte count <100 cells/mm3.  
4. HIV RNA in plasma greater than 50 copies/mL  
5. Platelet count less than 80,000/mm3  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
17 
6. Patients who had to discontinue prior interferon or ribavirin therapy due to a serious adverse event 
that the investigator considered possible or probably related to ribavirin or interferon.  
7. Treatment with ribavirin in the previous 90 days and with any interferon alfa in the month prior to 
the screening visit.  
8. Hepatitis C treatment with any investigational product. Previous treatments with phytotherapy 
products with known hepatotoxicity are grounds for exclusion.  
9. Participation in another clinical trial within 30 days prior to randomization or intention to participate 
in another clinical trial during participation in the present study.  
10. History of hemoglobinopathy (e.g., thalassemia) or other cause of hemolysis, or hemolytic 
tendency.  
11. Signs of decompensated liver disease, such as a history or presence of clinical ascites, 
hemorrhagic varicose veins, or hepatic encephalopathy.  
12. Diabetic or hypertensive patients with signs of clinical importance on ophthalmological 
examination.  
13. Pre-existing, unstable, or untreated psychiatric illness.  
14. Any known pre-existing medical conditions that could interfere with the patient's participation in 
the trial and its completion.  
15. Any current signs of alcoholism or other drug use.  
16. Patients receiving opioid agonist substitution therapy but not participating in any opioid substitution 
maintenance program. 
  
7.3 Withdrawal criteria  
  
Treatment with the study drug will be terminated  immediately during the study for any of the following 
reasons:  
  
● 
Patient with HCV RNA >100 IU/mL in ST12 or detectable HCV RNA in ST24.  
● 
Suicide or homicide thoughts or attempts.  
● 
Major depression, major depressive episode.  
● 
Positive test result for non-prescription opioids, methamphetamines, or cocaine.  
● 
Pregnancy during the study.  
● 
Express wish of the patient  
● 
Virological rebound, defined as:  
Any patient who obtains an undetectable HCV RNA and subsequently presents an HCV RNA > 
1,000 IU/ml.  
Once virologic failure has been identified, genotypic resistance will be characterized by HCV RNA 
sequencing in suitable samples, such as those collected at the time of failure and during the follow-
up period.  
  
Treatment with the study drug may be terminated during the study for any of the following reasons:  
  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
18 
● 
The medical investigator determines that a SAE is possibly or likely related to the study drug.  
● 
Failure to administer, evaluate, or other study requirements.  
  
8. Treatment of Subjects  
  
8.1 Treatment branches  
  
An open-label, single-arm, multicenter study to evaluate the safety and efficacy of a regimen with 
boceprevir in polytherapy with peginterferon alfa-2b 1.5 μg/kg or peginterferon alfa-2a 180 μg/kg once 
weekly subcutaneously (s.c.) and oral ribavirin in adult patients with controlled HIV coinfection in whom 
prior treatment of chronic hepatitis C with peginterferon and ribavirin has failed.  
  
Since early response to peginterferon (PEG-IFN) and ribavirin (RVB) at week 4 is predictive of 
response to treatment, either SVR or null response (high negative predictive value: 96%), the duration 
of response-guided treatment with BOC will depend on the response in ST4, ST8, and ST12.  
  
Patients who achieve a reduction in HCV RNA viral load greater than or equal to one logarithmic unit 
at week 4 (after the bitherapy phase) will then undergo triple therapy for 32 weeks. If HCV RNA is 
undetectable at week 8, they will end the tto after 32 weeks of triple therapy and will be followed for 
another 24 weeks. If HCV RNA is detectable at week 8, at the end of the 32 weeks of triple therapy, 
patients will receive dual therapy with pegylated interferon and ribavirin for an additional 12 weeks and 
then follow up for 24 weeks.  
  
Patients who do not achieve a decrease in HCV RNA viral load greater than one logarithmic unit at 
week 4 after the initial phase of bitherapy (or those who have grade 4 fibrosis - cirrhosis) will receive 
triple therapy for 44 weeks and will be followed for an additional 24 weeks.  
  
  
8.2 Concomitant and rescue medication  
  
Any concomitant medication must be reflected in the CRF in an appropriate way (detailing the product, 
dosage, route, days of administration, reason for treatment, etc.).  
  
Treatments not allowed:   
The administration of treatments that are contraindicated with the study drugs will not be allowed. (see 
annex technical sheets) and section 10 of the protocol  
 
8.3 Compliance Monitoring  
  
Adherence: to ensure the control and registration of medication, an adherence questionnaire will be 
added to the data collection notebook. At each visit, the investigator will ask the patient about treatment 
adherence.  
  
Tablet count: The patient will be asked to bring any leftover medication or empty bottles with them to 
check whether or not they have taken all the capsules or tablets of the medication since the previous 
visit.  
  
9. Effectiveness Assessment  
  
9.1 Efficiency parameters  
 
Virological tests to. 
 
Viral RNA  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
19 
Plasma will be obtained for viral RNA analysis prior to the start of the study and according to 
the study schedule.   
Virological failure shall be defined as described in paragraph 6.1  
  
b.  
Methods of Analysis and Sensitivity  
A routine analysis of HIV RNA approved for clinical use will be performed with a lower limit of 
quantification of 50 copies/mL. The test used on each patient should be the same throughout 
the trial.  
A routine analysis of HCV RNA approved for clinical use will be performed with a lower limit 
of quantification of 15IU/mL.  
  
10. Safety Rating  
  
10.1 Detection and Recording of Adverse Events  
  
It is the investigator's responsibility to detect and document any event that meets the criteria and 
definitions of adverse event (AE) or serious adverse event (SAE) as set forth in this protocol. During 
the study, the existence of adverse events, whether serious or not, will be checked in accordance with 
the definition given in this section of the protocol.   
  
a) Minimum information to be specified:  
  
Description/definition:  
  
Adverse event (AE) is any adverse health event in a patient or clinical trial subject treated 
with a medicine, even if it is not necessarily causally related to that treatment. Therefore, it can be any 
unfavorable and unintended signs (including an abnormal laboratory finding), symptom, or illness 
temporarily associated with the use of an investigational drug, whether or not related to the 
investigational drug.  
  
Laboratory abnormalities of clinical importance that meet one or more of the following criteria are also 
considered AEs:  
  
● 
It requires additional intervention or treatment.  
● 
Requires a modification of the dose.  
● 
It is accompanied by a clinical manifestation.  
Any analytical anomaly that the investigating physician considers to be of clinical importance must be 
recorded as such in the printed copy of the laboratory report, indicating the physician's initials and the 
date of revision. An AA is also considered to be any event associated or observed in conjunction with 
an accidental or intentional overdose of the product, or with abuse or withdrawal of the product.  
All AEs will be recorded in the subject's medical record and in the eCRDe. The start and end dates of 
each AA, the intensity and the relationship with the study drug will be recorded.  
  
The criteria for subject treatment, dose discontinuation, dosage adjustment, withdrawal, or treatment 
changes will only apply to toxicities attributable to the study drugs (i.e., BOC, PEG-IFN, and RBV).  
  
The classification system for drug toxicity is set out in the DAIDS Table for Grading the Intensity of 
Adverse Events in Adults and Children, which can be found on the DAIDS RSC website: http://rsc.tech-
res.com/safetyandpharmacovigilance/.  
  
In addition, for each AA, the measures taken or the outcome (e.g. hospitalization, discontinuation of 
treatment) will be recorded.  
   


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
20 
Adverse reaction (AR) is any harmful, unintended reaction to an investigational drug, 
regardless of the dose administered. In this case, there is a suspicion of a causal relationship between 
the investigational drug and the adverse event.  
  
Serious adverse event (SAE) is any adverse event that, at any dose, results in death, 
threatens the life of the subject, makes hospitalization necessary or prolonged hospitalization, results 
in permanent or significant disability or disability, or results in a congenital anomaly or malformation. 
For the purposes of notification, suspected adverse events that are considered medically significant, 
even if they do not meet the above criteria, will also be treated as serious, including major medical 
events that require intervention to prevent one of the consequences described above from occurring. 
Likewise, all suspected transmission of an infectious agent through a drug will be reported as serious. 
Examples of these events include allergic bronchospasm requiring intensive treatment in an 
emergency department or at the individual's home, blood dyscrasia or seizures that do not require 
hospitalization, or the development of drug dependence or abuse.  
  
Medical and scientific judgement should be used to decide whether other situations that have not 
resulted in the outcomes listed in the above definitions should be reported as SAGs.  
  
A life-threatening term is defined as a situation where, in the opinion of the physician, the patient at 
the time of the adverse event or adverse reaction is at real risk of death.  
  
Hospitalization or prolongation of a hospitalization is a criterion for considering an AA to be serious. 
Only admission in which the patient spends the night in the hospital should be considered as 
hospitalization. The following situations will not meet the AAG criteria:  
  
- 
if hospitalization or prolongation of hospitalization is necessary to perform a procedure 
required by the protocol (for example, if day or night visits will be made for biopsies or surgeries 
required by the protocol).  
  
- 
if hospitalization or prolongation of hospitalization is part of the facility's routine procedure 
(e.g., removal of a stent after surgery)  
  
- 
in case of scheduled hospitalization for a pre-existing process that has not worsened (e.g. 
scheduled hospitalization for the implantation of a knee prosthesis for a previous osteoarthritis 
process)  
  
  
Grade IV laboratory alterations will be considered AAG. 
DO NOT confuse the concept of "serious" with "severe" which refers to the intensity of the adverse 
event or adverse reaction.  
  
Unexpected serious adverse reaction (RAGI) is a serious adverse reaction whose nature 
or severity does not correspond to the information regarding the product (for example, the investigator's 
manual in the case of an investigational medicinal product not authorised for marketing or the product 
label in the case of an authorised medicinal product).  
  
b) Imputability criteria.  
  
The causal relationship between the investigational product and the occurrence of AA/AAG shall be 
established on the basis of clinical judgment. To this end, other causes will be considered and studied, 
such as the natural history of the underlying diseases, concomitant treatment, other risk factors and 
the temporal relationship of the event with the investigational product. In addition, the technical data 
sheet of the products will be consulted.   
  
In order to analyse the possible cause-effect relationship, the temporal relationship between the 
administration of the drug and the AA, possible alternative causes, the evolution (complete remission, 


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
21 
partial recovery, death, sequelae, persistence), persistence or not after the suspension of 
administration, reappearance with the readministration of the product or the prior knowledge of said 
event coinciding with the known or expected response pattern of the drug under study will be 
considered.   
  
The causal relationship of an AA with the medication under study will be established according to the 
following definitions:  
  
Unlikely relationship: The adverse event does not occur after a plausible chronological 
sequence related to the administration of the product under study and/or is reasonably explainable by 
other factors, such as the patient's clinical status or other concomitant therapeutic, toxic, or 
environmental interventions. In addition, it does not match the known or expected response pattern of 
the drug.  
  
Possible relationship: the adverse event occurs after a plausible chronological sequence 
related to the administration of the product under study, but can also be explained by the patient's 
clinical status or other concomitant therapeutic, toxic, or environmental interventions. It also matches 
the known or expected response pattern of the drug.  
  
Probable relationship: The adverse event occurs after a plausible chronological sequence 
related to the administration of the product under study, cannot be reasonably explained by the 
patient's clinical status or other concomitant therapeutic, toxic, or environmental interventions, and 
after withdrawal or reduction of the dose of the suspect drug the event follows a logical clinical 
sequence. It also matches the known or expected response pattern of the drug.  
  
Very likely relationship: the adverse event occurs after a plausible chronological sequence 
related to the administration of the product under study, cannot be reasonably explained by the clinical 
status of the patient or other concomitant therapeutic, toxic or environmental interventions, after 
withdrawal or reduction of the dose of the suspect drug the event follows a logical clinical sequence 
and it is necessary that after the readministration of the suspicious drug the adverse event reappears. 
It also matches the known or expected response pattern of the drug.  
  
Unrelated: Adverse event clearly due to causes unrelated to the medication under study and 
the criteria for another causal relationship are not met.  
Non-assessable relationship: any notification that suggests an adverse effect, which cannot 
be judged because the information is insufficient or contradictory and which cannot be supplemented 
or verified.  
10.2. Notification   
  
The investigator or designee must notify all AAGs, regardless of whether or not they are 
considered 
drug-related 
or 
planned, 
to 
the 
CTU 
manager. 
Dr. 
Anna 
Cruceta 
(acruceta@clinic.ub.es) tel 2275400 ext 4380 and fax 932279877 in order to notify local and national 
health authorities within one working day of becoming aware of the event., so that the contact of 
the designated promoter can prepare the corresponding written report. AAGs occurring will be reported 
at any time from the subject's inclusion in the study and up to 30 days after the study has been 
completed or discontinued. In the specific case of selection failure, the AAGs will be recorded from the 
moment the consent is signed until the subject is considered a selection failure.  
  
Regardless of the classification of adverse effects, the Investigator must collect all the AEs in the 
corresponding section of the study data collection notebook (CRD) and fill in all the information 
pertaining to them.  
  
The sponsor must notify in an EXPEDITIOUS manner all relevant SAFETY INFORMATION, i.e. that 
could modify the risk/benefit ratio of the investigational medicinal product, or determine changes in its 
administration schedule or in the conduct of the trial, for example:  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
22 
- 
a qualitative change or an increase in the percentage of occurrence of expected RAGs, which 
is considered clinically important.  
- 
RAGIs that occur after the completion of a clinical trial and that are notified by the investigator 
to the sponsor.  
 -New developments related to the conduct of the trial or the development of the investigational 
medicinal product and likely to affect the safety of the subjects, such as:  
• 
Serious adverse events that may be associated with the trial procedures and may modify the 
conduct of the trial  
• 
A significant risk to subjects such as the lack of efficacy of an investigational drug used for 
the treatment of a life-threatening disease.  
• 
Important new safety findings from new animal studies (such as cardiogenicity).  
• 
Any premature termination or temporary halt of a clinical trial with the same investigational 
medicinal product for safety reasons, carried out in another country and by the same sponsor.  
• 
GRAs related only to an MNI that are considered relevant as they are not subject to RAGI's 
general rules of expedited reporting of individual cases.  
- 
Any recommendations from the data monitoring committee, which are relevant to the safety of 
the subjects.  
  
This information must be notified as soon as possible and no later than 15 days after the promoter has 
become aware of it. In addition, if additional information that is relevant is obtained, it must be notified 
as quickly as possible.  
  
10.3 Evaluation of toxicity parameters  
  
The classification system for drug toxicity is set out in the DAIDS Table for Grading the Intensity of 
Adverse Events in Adults and Children, which can be found on the DAIDS RSC website: http://rsc.tech-
res.com/safetyandpharmacovigilance/.  
   
Treatment of PEG-IFN Side Effects  
  
Side effects of PEG-IFN usually include flu-like symptoms such as myalgia, arthralgias, headache, 
chills, low-grade fever, nausea, vomiting, and tiredness, as well as erythema, pain, and edema at the 
injection site. Less common are side effects of the central nervous system (CNS), such as depression, 
insomnia, anxiety, and irritability. Abnormalities of thyroid function have been described, as well as 
neutropenia, thrombocytopenia, and alopecia. The decrease in neutrophil and platelet count is usually 
dose-dependent and usually reaches nadir by week 4. Reductions in the total number of white blood 
cells may also occur, although usually not below normal levels. In week 2, dose-related decreases 
have been observed for other analytical parameters, such as albumin, globulin, total proteins, 
potassium and calcium; however, most parameters normalize by week 4 of treatment. Inflammation at 
the injection site occurs intermittently throughout treatment, but usually does not limit it. In general, all 
these effects are reversed by decreasing or interrupting the dose; patients cannot continue to take 
RBV and BOC if PEG-IFN is permanently discontinued.  
  
Treatment of IFN-associated neutropenia  
Patients who develop neutropenia during treatment may receive G-CSF (not provided by the study) at 
the discretion of the center investigator.  
 
Table 1.  
Treatment of toxicity: neutropenia  
  
Parameter  
Downward dose adjustment of PEG-IFN  
RAN  
(cells/mm3)  
  
Grade 1 (1,000- 
1.300)  
None  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
23 
Grade 2 (750999)  
No dose adjustment is necessary; G-CSF at the discretion of the centre's researcher  
Grade 3 (500749)  
Immediately reduce the dose by UN* one level and administer G-CSF at the discretion 
of the center investigator. If neutropenia disappears, the dose may be increased at the 
discretion of the center investigator.  
Grade 4 (<500)  
Study weeks 1 and 2: defer or discontinue administration until grade 2 is reached, then 
resume administration with dose reduction of DOS* levels. Study weeks 3 to 48: defer 
or discontinue administration until grade 2 is reached, then resume administration with a 
dose reduction of ONE level. Administer G-CSF at the discretion of the centre's 
investigator. If neutropenia disappears, the dose may be increased at the discretion of 
the center investigator.  
  
* 
The dose reduction levels of PEG-IFN are indicated in the label.  
  
Treatment of IFN-associated thrombocytopenia  
  
Table 2.  
Treatment of toxicity: decreased platelet count  
  
Platelet count (cells/mm3)  
MEASURE  
Grade 2 (50,000-99,999)  
No  
Grade 3 (25,000-49,999)  
Halving the dose of interferon   
Grade 4 (<25,000)  
Suspend the PEG-IFN definitively.  
* 
The dose reduction levels of PEG-IFN are indicated in the label.  
  
Dose reduction of PEG-IFN  
  
Dose reductions should be uniform between participating centers and patients. For this purpose, the 
following reductions shall be used:  
Table 3. Guidelines for Recommended Dose Reduction of PEG-IFN 1.5 μg/kg  
  
  
Reduction of one level 
(decrease to 1.0 μg/kg)  
Two-level reduction (decrease to 
0.5 μg/kg)  
  
Volume  
Volume  
Weight at Sit Up*  
Pen Size  
Injection 
(ml) 
Dosage 
(μg)  
Pen Size  
Injection 
(ml)  
Dosage 
(μg)  
40 to 50 kg  
88 to 110 lbs  
Redipen 50  
0,45  
45  
Redipen 50  
0,30  
30  
>50 to 60 kg  
>110 to 132 
lbs  
Redipen 80  
0,35  
56  
Redipen 50  
0,30  
30  
>60 to 65 kg  
>132 to 143 
lbs  
Redipen 80  
0,40  
64  
Redipen 50  
0,35  
35  
>65 to 75 kg  
>143 to 165 
lbs  
Redipen 80  
0,45  
72  
Redipen 50  
0,35  
35  
>75 to 80 kg  
>165 to 176 
lbs  
Redipen 80  
0,5  
80  
Redipen 50  
0,40  
40  
>80 to 85 kg  
>176 to 187 
lbs  
Redipen 120  
0,35  
84  
Redipen 50  
0,40  
40  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
24 
>85 to 95 kg  
>187 to 209 
lbs  
Redipen 120  
0,40  
96  
Redipen 50  
0,50  
50  
>95 to 105 kg  
>209 to 231 
lbs  
Redipen 150  
0,35  
105  
Redipen 50  
0,50  
50  
>105 to 125 kg  >231 to 275 
lbs  
Redipen 150  
0,35  
105  
Redipen 50  
0,50  
50  
* 
Use the usual rounding methods: values between 0.1 and 0.4 kg should be rounded down and those between 
0.5 and 0.9 kg should be rounded up.  
  
Missed or deferred doses of PEG-IFN  
  
If a dose of PEG-IFN is delayed but is finally administered, the following guidelines are recommended 
for the following scheduled doses:  
  
● 
Dose delay of 1 or 2 days: administer on the usual day of administration of the week (for example, 
if Monday is the usual day of administration and the dose is delayed to Wednesday, the next dose 
will be administered as usual, on Monday).  
● 
Dose delay of 3 to 5 days: Giving subsequent doses every 5 to 6 days until the patient gets back 
to their original schedule (for example, if Monday is the usual day of administration and the dose 
is delayed until Saturday, the next dose will be given on Thursday, the next dose on Tuesday, and 
the next dose on Monday).  
● 
6-day dose delay: discontinue that week's dose and continue with the usual schedule the following 
week (e.g. if Monday is the usual day of administration but the dose is delayed until the following 
Sunday, the dose is considered to have been interrupted and the next injection will coincide with 
the following week's dose,  on Monday).  
● 
Dose delay of 7 or more days: The investigator may resume administration of the study drug at 
any time up to 28 days after the last dose and, if necessary, administer the dose every 5 or 6 days 
until the weekly dose is received on the patient's usual scheduled day.  
Treating the Side Effects of RBV  
  
The most common AA in RBV treatment is anemia, which may be due to hemolysis or decreased 
release of red blood cells from the bone marrow. Anemia usually appears 1 to 2 weeks after you start 
receiving RBV and usually goes away within 4 to 8 weeks of withdrawal or reduction of the drug's 
dose. In patients with anemia secondary to RBV-induced hemolysis, an elevation of indirect bilirubin 
is common. BOC may increase the incidence or severity of anemia. In case of anaemia during 
treatment with BOC and RBV, the dose adjustment of RBV, as described below, takes precedence 
over BOC.  
  
NOTE: A serious side effect of RBV is its teratogenicity; therefore, it is recommended not to administer 
RVB to pregnant or breastfeeding women and to men whose partner is pregnant. Women who become 
pregnant during the study will be required to discontinue study treatment and undergo withdrawal 
assessments.  
  
The dose of RBV in this study will depend on weight at study entry (see section 5). The following table 
shows the recommendations for dose reduction in case of anemia. The administration of epoetin 
(EPO) will be at the discretion of the centre's researcher. If the administration of RBV is temporarily or 
permanently stopped, patients may continue to receive PEG-IFN and BOC.  
  
Board. Recommended RBV dose reduction in anaemia  
  
  
Starting dose  
Measure  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
25 
Hemoglobin <10 g/dL, ≥8.0 g/dL.  
1,400 mg/day 1,200 mg/day  
Decrease RBV to  
1,000 mg/day  
  
1,000 mg/day  
Decrease RBV to 800 
mg/day 
  
800 mg/day  
Decrease RBV to 600 
mg/day 
  
600 mg/day  
Decrease 
RBV 
to 
400 
mg/day  
(Initiate treatment with EPO 
at the discretion of the 
center's investigator)  
Hemoglobin <8.0 g/dl  
All doses  
Temporarily discontinue the 
RBV  
Symptomatic decrease in haemoglobin will be treated at the discretion of the centre's investigator.  
  
Reintroduction of RBV  
  
In the event that RBV is temporarily stopped due to anaemia, haemoglobin values should be checked 
again after two weeks and then at two-week intervals until stabilised. If hemoglobin returns to an 
acceptable level, RBV should be reintroduced at doses of 600 mg/day (with a regimen of 200 mg in 
the morning and 400 mg in the evening). The dose may be increased by 200 mg/day every two weeks 
until the initial dose is reached.  
  
Treatment of anemia with EPO is recommended, but this is not provided in the study. On the other 
hand, it is not advisable to administer EPO with hemoglobin values ≥10 g/dl. If necessary, at the 
discretion of the centre investigator, the dose of RBV may be reduced by a haemoglobin value ≥10 
g/dl.  
  
Increasing the dose of RBV  
  
Once haemoglobin has returned to an acceptable level, patients who have had their RBV dose reduced 
without discontinuing their administration may, at the discretion of the centre investigator, increase the 
dose by 200 mg/day every two weeks until the initial dose is reached.  
  
Missed doses: If a patient misses a dose of RBV, they should take it as soon as possible, along with 
food, during the same day. If a full day has passed, you should skip the missed dose and continue 
with the normal schedule of administration. In no case should the dose be doubled to "compensate" 
for the missed dose.  
  
Treatment of Adverse Events Related to PEG-IFN alfa-2a and Ribavirin (PEGASYS™ PCR)  
  
Dose adjustment in case of adverse reaction  
  
  
Reduce 
ribavirin to  
600 mg  
Suspend  
ribavirin  
Reduce Pegasys to 
135/90/45 
micrograms  
Suspend 
Pegasys  
Suspended 
r la  
combination  
Absolute 
neutrophil count  
  
  
<750/mm3  
<500/mm3  
  
Platelet count  
  
  
<50,000/mm3 
>25.0 00/mm3  
  
<25,000/m 
m3  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
26 
Hemoglobin  
-  absence of 
heart disease  
<10 g/dl , and  
≥8.5 g/dl   
<8.5 g/dl  
  
  
  
Hemoglobin  
-  stable heart 
disease  
Decrease 
≥2 g/dL for 
any 4 weeks  
< 12 g/dL 
despite 4 
weeks at a 
reduced 
dose  
  
  
  
  
Treating BOC Side Effects  
  
The safety profile represented by nearly 1,500 patients treated with the combination of boceprevir with 
peginterferon alfa-2b and ribavirin is derived from pooled safety data from two clinical trials in 
treatment-naïve patients and one clinical trial in treatment-failed patients.  
  
The most frequently reported adverse events in the BOC/PEG/RVB groups were largely the reflection 
of events that are associated with the treatment spine (PEG/RBV).  
  
The most frequent adverse reactions were fatigue, anemia, nausea, headache and dysgeusia. Only 
two adverse events, anaemia and dysgeusia, are 20% more common in boceprevir-containing 
treatments and will be discussed as events of particular interest.  
  
Boceprevir monotherapy did not cause a decrease in hemoglobin in either the animal studies or a 
phase I monotherapy study. In healthy adult males who received boceprevir for up to 57 days, no 
effects on red blood cell formation, survival, and destruction or on markers of anaemia were detected. 
However, boceprevir added to PEG and RVB therapy results in a gradual decrease in hemoglobin of 
approximately 1 g/dL.  
  
Treatment of anemia in patients receiving boceprevir polytherapy is identical to that of anemia in 
patients treated with peginterferon plus ribavirin. The incidence of discontinuation of treatment due to 
anemia is just as low, close to 1%, both in the control group with PEGIFN plus RBV and in the 
experimental groups treated with boceprevir.  
  
Anemia in patients treated with boceprevir is transient, as baseline hemoglobin values recover after 
treatment.  
  
Based on the above data, BOC is usually well tolerated and has an AA profile similar to that of the 
standard of care (PEG-IFN + RBV) with the exception of dysgeusia, which is more common in patients 
treated with BOC. The anemia appears to be mainly due to exposure to RBV.  
  
Rules for processing  
  
The dose of BOC cannot be reduced in the study.  
  
Anaemia should be treated initially by reducing the dose of ribavirin and an erythropoiesis stimulant 
whenever available and appropriate. For dysgeusia, attempts will be made to reduce symptoms (e.g., 
pills, plastic cutlery, etc.). Treatment of headache and nausea should also be symptomatic. Grade 1 
and 2 AEs require close follow-up but no change in treatment.  
  
All grade 3 toxicities will be treated by the facility investigator as appropriate. Any grade 4 toxicity that, 
in the opinion of the centre's investigator, is directly related to BOC, will be treated with the permanent 
suspension of the latter.  
  
In case of intolerance to the BOC, its administration will be suspended; The dose cannot be reduced. 
If BOC is temporarily or permanently stopped, patients may continue to receive PEG-IFN and RVB.  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
27 
  
NOTE: EPO with hemoglobin values greater than or equal to 10 g/dl is not recommended.  
  
10.4 COMMUNICATION TO RESEARCHERS  
  
The sponsor shall communicate to investigators any information that may affect the safety of the trial 
subjects as soon as possible.  
  
It is advisable when deemed appropriate that information on serious and unexpected adverse reactions 
(RAGI) be presented in a list together with a brief analysis of the data provided.  
  
Researchers must also be informed of the safety aspects that impact the conduct of the clinical trial or 
the development of the product. Including disruption of the development program or security-related 
protocol modifications.  
  
Follow-up of subjects after adverse events will be performed by clinical and complementary 
examinations necessary for the duration of treatment and then on a monthly basis during follow-up 
and up to 30 days after the end of treatment. In the event of a possible pregnancy, the health status 
of both the mother and the newborn will be monitored during the trial, whether the person who has 
become pregnant is the one who is taking the investigational drug or if it has been taken by her partner.  
  
No interim analyses are planned for the present study.  
  
11. Statistics  
  
11.1 Sample  
  
Phase III studies are usually randomized, often with one group receiving the current standard 
treatment. These studies may or may not be placebo-controlled. However, the population with co-
infection with HCV and HIV is difficult to treat and has very few treatment options. In this population, 
the use of a standard care group is difficult to justify ethically because response rates with such a 
regimen are low and because the toxicity of the current standard of care (i.e., PEGIFN + RBV) is 
considerable.   
  
In this regard, we could establish that SVR in the historical control group is between 10% (95% 
confidence interval [CI]: 5%-18%) in previously treated patients and 26% described in the placebo 
control group in the phase II study of patients infected with HCV and not previously treated with 
boceprevir.  
11.2 Sample size  
  
The primary objective of this study is to estimate SVR with response-guided therapy with boceprevir 
in patients with controlled HIV infection and chronic hepatitis C with genotype 1 virus in whom prior 
treatment with peginterferon/ribavirin has failed.  
  
Since no comparative analysis is to be performed, the sample size depends on the accuracy of the 
SVR calculation. SVR from double treatment with peginterferon and ribavirin ranges from 27% to 39%.  
  
The expected SVR with boceprevir triple therapy is 60%. If we define a margin of error (60% ± 8.5%) 
that encompasses the maximum SVR observed with dual therapy (39%), the required sample size 
based on a bilateral 95% confidence interval is 128 patients.  
  
The sample size calculation for the different RVM values was based on a bilateral 95% confidence 
interval for different levels of accuracy.  
  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
28 
Stratification  
Since this is a non-randomized study, no stratification is planned; however, for the purposes of data 
analysis, patients will be classified according to the type of failure of previous HCV treatment (no 
response, virologic rebound, and relapse).  
  
No response: HCV RNA positivity at week 12.  
  
1. Partial response. Patients who achieved at least a reduction in HCV RNA of two logarithmic units 
from baseline at week 12 but still had viremia at the end of treatment.  
2. Null response. Patients who did not achieve a reduction of two logarithmic units of HCV RNA at 
week 12.  
Rebound: negativity for HCV RNA at week 12, but positivity before week 48.  
  
Relapse: HCV RNA undetectable at the end of treatment and subsequently detectable during 24 weeks 
of follow-up.  
  
As this is an exploratory study, the inclusion of difficult-to-treat patients, such as those with 
no response (reduction in HCV RNA of less than two log units with prior HCV treatment) or with 
cirrhosis, will be limited to 30% of the study population.  
11.3 Analysis  
  
In this open study, all variables will be tabulated. Quantitative variables will be described by the number 
of available and omitted observations, the mean, the median, the standard deviation, the interval 
(minimum and maximum) and the first and third quartiles. Of the qualitative variables, the frequency 
and percentage will be presented. Omitted values will be tabulated with their frequency, but will not be 
included in the calculation of the percentages.  
  
The primary endpoint will be assessed with a bilateral CI of 95% around the observed proportion of 
SVR. The analysis of the primary endpoint in SVR will be carried out in two ways. Patients who 
withdrew from the study within the first four weeks will be included in the main analysis, which will be 
counted as SVR failures. As a secondary analysis, an SVR analysis will also be performed, but 
restricted to patients who have not withdrawn from the study in the bitherapy period in the first four 
weeks. In both analyses, patients in whom SVR data are lacking due to premature withdrawal from 
the study at any time after the initial biterpia period of the first four weeks will be included and counted 
as SVR failures.  
  
Inferential analysis of boceprevir efficacy will be assessed by SVR at week 24 and the 95% confidence 
interval. A similar analysis will be applied to evaluate the secondary variables. For continuous 
quantitative variables, the mean or median and the 95% confidence interval or the interquartile interval 
shall be calculated.  
  
Descriptive analyses of treatment-occurring adverse events and treatment-occurring adverse events 
that are possibly or likely related to the study drug will be performed. With regard to the safety 
assessment in the AEs, the 95% CI of the percentage of grade 3 or higher adverse events and other 
serious adverse events reported by the centres shall be provided. The highest grade episode per 
person over time will be used. Descriptive tables will be provided summarizing the events and the 
number of people who have presented the events by grade.  
  
Variations in HIV-1 viral load or RNA and CD4+ T cell count at each post-enrollment visit will be 
summarized. The rates and reasons for premature discontinuation of treatment, including HCV 
treatment failures, will be summarized.  
  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
29 
In addition, a logistic regression analysis will be carried out taking SVR as a dependent variable. The 
importance of the previously identified prognostic factors will be confirmed by univariate logistic 
regression. The independence of these factors will then be evaluated using a stepwise method in 
which the factors that were significant in the univariate analyses will be used.  
  
All analyses will be bilateral and will have a significance level of 5%. The following variables will be 
analyzed:  
  
Efficacy: sustained virologic response, virologic response at weeks 4, 8, 12, and 24.  
  
Safety: All adverse events, whether or not related to the study medication.  
  
HCV resistance following BOC-containing treatment in patients with virologic failure.  
  
* Predictive factors of SVR: SVR will be analyzed by subgroups according to sex, age, degree of 
fibrosis at baseline, previous null response, CD4 lymphocyte count at baseline, greater or lesser 
decrease of one logarithmic unit of HCV RNA at week 4), undetectable HCV RNA at week 8, and 
pharmacogenetic markers  
   
11.4 Completion Criteria  
  
The study will be considered to have been completed on the date of the last visit of the last subject 
recruited into the study.  
11.5 Processing of lost data  
  
Missing data imputation techniques will not be used. Only the available data will be analyzed.  
  
11.6 Deviations from the statistical plan  
  
Any deviation from the planned statistical analyses will be justified and detailed in the reports derived 
from the processing of the data.  
   
11.7 Population under analysis  
  
The population analyzed in the study will consist of all patients included in the study as detailed in the 
protocol and without major deviations from the protocol.  
  
12. Direct Access to Source Data/Documents  
  
The sponsor shall ensure that it is specified in the protocol or other written agreement that the 
investigator or institution shall allow direct access to the source data or documents for monitoring, 
auditing and review by the IRB as well as inspection of the trial by the competent health authorities.  
 
13. Ethics  
  
General considerations: The trial will be carried out in accordance with the principles emanating from 
the Declaration of Helsinki (See Annex VIII) and according to the legal regulations in force (Royal 
Decree 223/2004) and will not begin until the approval of the reference CEIC, the approval of the 
Management of all the participating centres, and the authorisation of the Spanish Agency for Medicines 
and Health Products have been obtained.  
  
Information to the subjects: Patients will be informed orally and in writing and all relevant information 
adapted to their level of understanding will be communicated to the participants.  (See Attachment III: 
Patient Information Sheet/Written Consent Sheet)  
  


BOC-HIV Trial                                                                                                                                                
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
30 
14. Data Management and Archiving of Records  
  
The patient will be informed that their participation in the trial will be treated with the same 
confidentiality as their clinical documentation.  
  
In the data collection notebook, the patient will be identified only by their inclusion code in the study.  
  
The patient's name will not appear in any publication or communication of the results of the study.  
  
The patient's participation in the trial will be reflected in their medical history.  
  
The investigator will complete a list that will include the names of the patients participating in the trial, 
their inclusion number in the trial and their medical history.  
  
Only researchers and data quality assurance and data analysis personnel will have access to the 
participant's clinical documentation. Eventually, persons duly authorised by the Sponsor and the 
Health Authorities and the Clinical Research Ethics Committee may audit or inspect the trial. Personal 
information will not be available to the public, in compliance with the provisions of Organic Law 
15/1999, of 13 December, on the Protection of Personal Data.  
  
Prior to the start of treatment, a clinical examination, electrocardiogram and blood and urine sample 
will be taken (SEE TABLE OF DAILY DETERMINATIONS).  
  
The data will be collected through an online electronic CRD.  
  
15. Financing and Insurance  
  
The promoter has taken out civil liability insurance in accordance with current regulations.  
  
  
16. Publication Policy    
  
The Promoter undertakes to publish the results, both positive and negative, of this study as stated in 
art. 39 of RD 223/2004.   
  
  
  
  


BOC-HIV Trial                                                                                                                                                 
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
31 
               
17. Table of examinations and treatment during follow-up   
  
Treatment Visit Schedule  
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluations  
Day 1  
ST 2a  
ST 4  
ST 6  
ST 8  
ST 10  
ST 12  
ST 16  
ST 20  
ST 24  
ST 30  
ST 36  
ST 42  
ST 
48/dFT  
Inclusion and exclusion criteria  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital signs  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Weight  
X  
  
  
  
  
  
  
  
  
X  
  
  
  
X  
Physical examination  
X  
  
X  
  
  
  
X  
  
  
X  
  
X  
  
X  
Adverse events  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Concomitant medications  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Confirmation of the use of 
contraceptive methods by the 
patient and his or her partner  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Simplified Compliance 
Questionnaire  
X  
X  
X  
  
X  
  
X  
  
X  
X  
  
X  
X  
X  
Haematology  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
TP/TTP  
X  
  
  
  
  
  
X  
  
  
X  
  
  
  
X  
Blood biochemistry  
(simplified, fasting)  
  
X  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
Blood biochemistry (complete, not 
fasting)  
X  
  
  
X  
  
  
  
X  
  
X  
  
X  
  
X  
Thyrotropin (TSH)  
X  
  
  
  
  
  
X  
  
  
X  
  
X  
  
X  
Serum pregnancy test (women 
only)  
X  
  
  
  
  
  
  
  
  
  
  
  
  
X  
Urine pregnancy test (women 
only)  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Samples for pharmacogenetics  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
HCV RNA CPR*  
X  
  
X  
  
X  
  
X  
  
  
X  
  
  
  
X  
               
 


BOC-HIV Trial                                                                                                                                                 
EudraCT number: 2012-003984-23  
Protocol version 1.0 of 18 September 2012   
 
32 
All laboratory specimens should be obtained prior to administration of the first dose of study medication.  
•  Samples will be obtained for a genotypic resistance test if the patient has >100 IU/mL at week 12 or later. A single blood sample will be 
obtained for genetic studies.  
  
Complete blood biochemistry: ALT, AST, creatinine, alkaline phosphatase, gammaglutamyl transferase (GGT), total bilirubin (direct and indirect), total proteins, albumin, uric 
acid, urea nitrogen, glucose, HbA1C (patients diagnosed with diabetes, either receiving pharmacological treatment or controlled with diet), amylase, lipase, sodium, potassium, 
chloride, phosphorus, calcium, triglycerides, and cholesterol.  
  
Simplified blood biochemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, alkaline phosphatase, total bilirubin (direct and indirect), urea 
nitrogen, total proteins, albumin, uric acid and glucose.  
  
Fibrosis evaluation: This will be done by liver biopsy or Fibroscan. In patients without cirrhosis on histology or Fibroscan, evaluation must have been performed no more than 18 
months prior. A result of 12 kilopascals or more on the Fibroscan test would allow the patient to be considered cirrhotic.  
  
Ultrasound: Patients with bridge fibrosis or cirrhosis must have an ultrasound performed within 6 months prior to inclusion in the study.