AMC-072: Protective Effect of Quadrivalent Vaccine in Young HIV-Positive Males Who Have Sex With Males
Phase: PHASE2
Conditions: Anal Cancer, Nonneoplastic Condition, Penile Cancer, Precancerous Condition
Sponsor: AIDS Malignancy Consortium

 
AMC #072 (Version 5.0) 05/02/2014 
 
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NCI Version Date 05/02/2014 
 
 
SUMMARY OF CHANGES 
 
Protective Effect of Quadrivalent Vaccine in Young HIV-positive 
Males who have Sex with Males 
(Version 5.0) 
 
NCI Protocol #:  AMC-072 
Local Protocol #:  AMC-072 
 
NCI Version Date: 05/02/2014 
Update Date: 05/02/2014 
 
# 
Section 
Change Description 
1. 
Cover Page 
Changed from: 
Version 4.0 
NCI Version Date: January 31, 2012 
Changed to: 
Version 5.0 
NCI Version Date: May 2, 2014 
Update Date: May 2, 2014 
2. 
Footer 
Changed from:  
AMC # 072 (Version 4.0) 01/31/2012 
NCI Version Date 01/31/2012 
Changed to: 
AMC # 072 (Version 5.0) 05/02/2014 
NCI Version Date 05/02/2014 
3. 
Global 
Changed from: 
AdEERS 
Changed to: 
References to the “Adverse Event Expedited Reporting System (AdEERS)” have been 
changed to “CTEP Adverse Event Reporting System (CTEP-AERS)” throughout the 
protocol. 
4. 
Abbreviations 
Changed from: 
Intravenous immunoglobin 
Changed to: 
Intravenous immunoglobulin 

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5. 
2.2.1 
Changed from: 
To determine the protective effect of the HPV-6, -11, -16, -18 vaccine in preventing 
penile/scrotal condyloma and HPV-6, -11, -16, -18- associated perinal/anal disease in 
HIV-positive males who have sex with males (MSM) age 13-26 years by comparing the 
incidence of these lesions among those naïve to the relevant HPV type(s) at baseline to 
those who are not naïve at baseline.. 
Changed to: 
To determine the protective effect of the HPV-6, -11, -16, -18 vaccine in preventing 
penile/scrotal condyloma and HPV-6, -11, -16, -18- associated perianal/anal disease in 
HIV-positive males who have sex with males (MSM) age 13-26 years by comparing the 
incidence of these lesions among those naïve to the relevant HPV type(s) at baseline to 
those who are not naïve at baseline. 
6. 
3.1.2 
Changed from: 
HIV-1 infection as documented by any federally approved, licensed HIV test performed 
in conjunction with screening (ELISA,Western blot or other approved test). 
Alternatively, this documentation may include a record that another physician has 
documented that the patient has HIV based on prior ELISA and western blot, or other 
approved diagnostic tests.  
Changed to: 
HIV-1 infection as documented by any federally approved, licensed HIV test performed 
in conjunction with screening (ELISA, Western blot or other approved test). 
Alternatively, this documentation may include a record that another physician has 
documented that the patient has HIV based on prior ELISA and western blot, or other 
approved diagnostic tests. If the participant’s HIV status is documented by an outside 
physician, the protocol team strongly recommends obtaining a copy of the HIV 
laboratory reports from this physician. All confirmatory tests and the physician’s note 
must be on file before the participant is enrolled. In the rare circumstance where only an 
outside physician’s note with no supporting laboratory documentation is available, the 
local site should have additional tests performed to verify the participant’s HIV status. 
One of the following additional tests should be performed: 
 
A rapid HIV test 
 
ELISA and Western blot 
 
Chemiluminescence immunoassay and Western blot 
 
HIV RNA > 2000 copies/mL 
 
HIV antigen test 
 
7. 
3.2.3 
Changed from: 
HGAIN (e.g., AIN 2 or 3, or perianal intraepithelial neoplasia grade 2 or 3), or invasive 
carcinoma at pre-entry on biopsy. 
Changed to: 
HGAIN (e.g., AIN 2 or 3, or perianal intraepithelial neoplasia grade 2 or 3) or invasive 
carcinoma at pre-entry on biopsy, or participant has a history of invasive carcinoma or 
any prior anal cytology result of HSIL or ASC-H. 

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8. 
5.2.1 
Changed from: 
Text added 
Changed to: 
The ACSR tissue biopsy may be collected at week 104 even if a baseline ACSR tissue 
biopsy donation was not collected. The ACSR tissue biopsy may only be collected with 
the participant’s consent, if there are suspected lesions observed during HRA (i.e., not 
from normal areas), and must be a separate specimen from the diagnostic biopsy. 
9. 
5.3.1 
Changed from: 
HIV-1 infection as documented by any federally approved, licensed HIV test performed 
in conjunction with screening (ELISA, Western blot or other approved test). 
Alternatively, this documentation may include a record that another physician has 
documented that the patient has HIV based on prior ELISA and western blot, or other 
approved diagnostic tests. 
Changed to: 
HIV-1 infection as documented by any federally approved, licensed HIV test performed 
in conjunction with screening (ELISA, Western blot or other approved test). 
Alternatively, this documentation may include a record that another physician has 
documented that the patient has HIV based on prior ELISA and western blot, or other 
approved diagnostic tests. If the participant’s HIV status is documented by an outside 
physician, the protocol team strongly recommends obtaining a copy of the HIV 
laboratory reports from this physician. All confirmatory tests and the physician’s note 
must be on file before the participant is enrolled. In the rare circumstance where only an 
outside physician’s note with no supporting laboratory documentation is available, the 
local site should have additional tests performed to verify the participant’s HIV status. 
One of the following additional tests should be performed: 
 
A rapid HIV test 
 
ELISA and Western blot 
 
Chemiluminescence immunoassay and Western blot 
 
HIV RNA > 2000 copies/mL 
 
HIV antigen test 
10. 
4.3.2 
Changed from: 
The Investigator, or a responsible party designated by the Investigator, must maintain a 
careful record of the inventory and disposition of all drugs received using the NCI Drug 
Accountability Record Form (DARF) (available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the Pharmaceutical Management Branch at 301-
496-5725) or a site-specific form that captures the same elements as the NCI DARF. 
Changed to: 
The Investigator, or a responsible party designated by the Investigator, must maintain a 
careful record of the inventory and disposition of all drugs received using the NCI Drug 
Accountability Record Form (DARF) (available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the Pharmaceutical Management Branch at 240-
276-6575) or a site-specific form that captures the same elements as the NCI DARF. 

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11. 
5.3.7 
Changed from: 
The penis, scrotum and perianal area will be examined for signs of HPV-related lesions. 
The presence or absence of penile/scrotal/perianal condyloma will be recorded on the 
CRFs. Anal cytology and HRA with biopsy of visible disease will be performed to assess 
anal HPV-associated disease.  Sampling of the penis/scrotum, perianal area and the anal 
canal for HPV DNA and other sexually transmitted agents will be performed.   
Changed to:  
The penis, scrotum and perianal area will be examined for signs of HPV-related lesions. 
The presence or absence of penile/scrotal/perianal condyloma will be recorded on the 
CRFs. Anal cytology and HRA with biopsy of visible disease will be performed to 
assess anal HPV-associated disease.  Sampling of the penis/scrotum, perianal area and 
the anal canal for HPV DNA and other sexually transmitted agents will be performed. 
HRA and anal cytology are required assessments at baseline and Weeks 28, 52, 78, and 
104. Only visual inspection of the penis, scrotum, and perianal area are required at Week 
8 and Week 24.   
12. 
5.3.7 
Changed from: 
Record all diagnoses identified by the CTCAE criteria (see Section 7.0 for details) for 
clinical events and other diseases. Furthermore, any diagnosis of a cellulitis, abscess or 
other infection at the vaccination site should be recorded. 
Changed to: 
Record all diagnoses identified by the CTCAE Version 4.0 criteria (see Section 7.0 for 
details) for clinical events and other diseases. Furthermore, any diagnosis of a cellulitis, 
abscess or other infection at the vaccination site should be recorded. 
13. 
5.3.9 
Changed from: 
Immunologic Studies 
To document eligibility for those subjects who are not on antiretroviral therapy, CD4+ 
level must be equal or greater than ≥350 cells/mm 3 within 90 days of study entry from a 
laboratory that possesses a CLIA certification or equivalent.  CD4+/CD8+ will be 
obtained from all subjects within 90 days of study entry and at Week 28. 
Changed to: 
Immunologic Studies 
To document eligibility for those subjects who are not on antiretroviral therapy, CD4+ 
level must be equal or greater than ≥350 cells/mm3 within 90 days prior to study entry 
from a laboratory that possesses a CLIA certification or equivalent. CD4+/CD8+ will be 
obtained from all subjects within 90 days prior to study entry and at Week 28. 
14. 
5.3.10 
Changed from: 
Plasma HIV-1 RNA 
On-study plasma HIV-1 RNAs will be done in real time. Plasma HIV viral load will be 
obtained within 90 days of study entry and at Week 28.   
Changed to: 
Plasma HIV-1 RNA 
On-study plasma HIV-1 RNAs will be done in real time. Plasma HIV viral load will be 

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obtained within 90 days prior to study entry and at Week 28. 
15. 
7.3.1 
Changed from: 
In the rare occurrence when internet connectivity is lost, an AE report may be submitted 
using CTEP’s Adverse Event Expedited Report-Single Agent or Multiple Agent paper 
template (available at http://ctep.cancer.gov) and faxed to the AMC Operations Center at 
240-238-2842. Once Internet connectivity is restored, an AE report submitted on a paper 
template must be entered electronically into CTEP-AERS by the original submitter at 
the site. 
Changed to: 
A 24-hour notification is to be made to the AMC ODMC by telephone at 301-251-1161, 
only when Internet connectivity is disrupted. Once Internet connectivity is restored, an 
AE report submitted on a paper template must be entered electronically into CTEP-
AERS by the original submitter at the site. 
16. 
7.3.1 
Changed from: 
Expedited Reporting Timelines for Investigational Agents 
Changed to: 
Expedited Reporting Timelines for Adverse Events that occur within 8 Weeks1 of 
the Last Dose of the Investigational Agent on Phase 2 and 3 Studies 
The title of this table was revised to add the appropriate reference to footnote 1 for the 
legacy expedited AE reporting table. 
17. 
7.3.2 
Changed from: 
All AE reports submitted through AdEERS will be forwarded to designated Merck 
personnel by the AMC Operations Center. 
Changed to: 
All SAE reports submitted through CTEP-AERS that are at least possibly attributed to 
study vaccine administration will be forwarded to designated Merck personnel by the 
AMC Operations Center. 
18. 
8.1 
Changed from: 
If we assume hypothetically that the incidence of persistent HPV infection w/o vaccine 
is 10 per 100 PY and the the expected incidence of HPV-associated disease is 5 per 100 
PY, then the attached table shows the effect size and associated lower rate of infection 
that can be detected with the anticipated numbers of patients for a “per protocol” 
population for each HPV type. 
Changed to: 
If we assume hypothetically that the incidence of persistent HPV infection w/o vaccine 
is 10 per 100 PY and the expected incidence of HPV-associated disease is 5 per 100 PY, 
then the attached table shows the effect size and associated lower rate of infection that 
can be detected with the anticipated numbers of patients for a “per protocol” population 
for each HPV type. 

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Section 
Change Description 
19. 
Appendix I 
Changed from: 
Footnote added (Clinical assessments at Week 8 and 24). 
Changed to: 
2 HRA and anal cytology are not required assessments at Week 8 and Week 24. Visual 
inspection of the penis, scrotum, and perianal area should be done at Week 8 and Week 
24. 
20. 
Appendix I 
Changed from/to: 
Footnote reference for HRA at baseline changed from footnote 2 to footnote 4. 
21. 
Appendix I 
Changed from: 
Text moved 
Changed to: 
Moved the following required procedures: Swab for anal HPV DNA PCR, swab for 
penile/scrotal HPV PCR, serum HPV antibody testing, urine testing for GC/Chlamydia, 
oral HPV PCR testing and exam from column Screening/Pre-Entry to column Entry 
Injection 1. 
22. 
Appendix I 
Footnote 5 
Changed from: 
Footnote reference for anal biopsy changed from footnote 4 to footnote 5. 
Changed to: 
Anal biopsies (if lesion suspected). 
23. 
Appendix I 
Changed from: 
ACSR Donation (Optional if patient consents)  
Changed to: 
The ACSR donation is now listed in two rows, one for each sample type: ACSR Biopsy 
Donation (Optional if patient consents) and ASCR Blood Donation (Optional if patient 
consents). Within both rows, the optional ACSR donation schedule was moved from the 
column for Entry/Visit 1 to the column Screening/Pre-Entry. The donation remains 
scheduled for Week 104 for both specimen types. 
Added footnote 6 to the row for ACSR Biopsy Donation: 
6 Anal biopsies for ACSR donation may be obtained with the subject’s consent from 
suspected lesions. The tissue biopsy for ACSR donation must be separate from the 
diagnostic biopsy. 
24. 
Appendix V 
Changed from: 
All cytological specimens should be processed and examined locally. Cytological 
slides from subjects who enter the trial should be available for central review upon 
request. 
Changed to: 
All cytological specimens should be processed and examined locally. If insufficient 
or inadequate cytology results are obtained, the cytology assessment should be repeated 
if possible. Cytological slides from subjects who enter the trial should be available for 

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central review upon request. 
25. 
Appendix VI 
Changed from: 
Text added 
Changed to: 
High resolution anoscopy is performed at screening and weeks 28, 52, 78 and 104. 
Biopsies are obtained if a lesion is suspected. One of the study outcomes is any incident 
AIN or anal/perianal condyloma associated with HPV 16, 18, 6 or 11 DNA as determined 
by PCR analysis of the anal tissue biopsy. Biopsies are fixed in formalin and sent to the 
local pathology lab for interpretation. We are requesting that the cassettes containing the 
biopsy be sent to the Palefsky lab. After the procedures described below are performed, 
the Palefsky lab will ship the remaining specimens back to the pathology lab that sent 
them. 
Specimens may be shipped to the Palefsky lab quarterly and will be returned to the 
pathology lab within 1 month. 
26. 
Appendix VI 
Sample 
labeling 
Changed from: 
Specimen Type:   “Penile/Scrotal Swab”, “Perianal Swab” or "Anal Swab”  
Changed to: 
Specimen Type:   “Penile/Scrotal Swab”, “Perianal Swab” or "Anal Swab” or “Anal 
biopsy” 
27. 
Appendix VII 
Changed from: 
Biopsy any areas clinically suspicious for AIN. 
Changed to: 
Biopsy area if a lesion is suspected. 
28. 
Appendix VII 
Changed from: 
Biopsies will be processed and read locally at the institution. 
The tissue block, along with a copy of the surgical pathology report should be available 
for central review upon request. If the block is not available, a representative H & E 
stained section and six unstained slides should be submitted. All materials will be 
retained unless return is specifically requested. Tissue will be evaluated for histology as 
demonstrated by H & E staining. 
Changed to:  
Biopsies will be processed and read locally at the institution. 
The tissue block, along with a copy of the surgical pathology report should be available 
for central review upon request. If the block is not available, a representative H & E 
stained section and six stained slides should be submitted. All materials will be retained 
unless return is specifically requested. Tissue will be evaluated for histology as 
demonstrated by H & E staining. 
 
All slides should be sent to the following address for central pathology review: 
 
Teresa M. Darragh, MD 

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UCSF/Mt. Zion Medical Center 
Dept. of Pathology, Box 1785 
1600 Divisadero Street, Room B217 
San Francisco, CA  94115 
Tel: 415-353-7861 
Fax: 415-353-7676 
 
Slides from UCSF that are read by local pathologist Dr. Teresa Darragh will be reviewed 
by Dr. Mieke van Zante for central review. 
 
When affixing the specimen label, do not wrap the label around the slide as any 
protrusion at the bottom will result in the slide not sitting flat on the microscope stage.  In 
addition, do not cover the slide’s accession number.  In some cases, the label may need to 
be trimmed to allow the barcode and 9-digit portion of the label to be affixed at the top of 
the slide.) 
 
Shipping Instructions 
1. Place the labeled slides into a specimen container or a slide box if available. Place 
the container or slide box in bubble wrap or other adequate cushioning.  Use sturdy 
outer packaging to prevent breakage. 
2. Affix the FED-EX airbill on blank side of the shipper. 
3. Mark “OTHER” in the airbill under “Packaging”. 
4. Under 
airbill 
section 
“special 
Handling” 
indicate 
“YES-SHIPPERS 
DECLARATION NOT REQUIRED”. 
5. Enter FED-EX account #: 
 
6. Place “From/To” information onto areas provided on the shipper. Specimens are 
accepted MONDAY through THURSDAY only. All specimens should be shipped 
by FedEx 2-day service to Dr. Darragh at the address listed above: 
7. Make certain that shipper is visibly labeled “Exempt human specimen.” 
8. RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
9. Place the box in the FedEx pickup area at your site or call to request a package 
pickup. 
 
Record of Specimens 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTraceSM shipment manifest must accompany all 
specimens. 
29. 
Appendix IX 
Changed from: 
Serum shipments to Merck (PPD) should be sent routinely on the first Monday or 
Tuesday of the month (or as requested by the Clinical team) to the following address: 
Changed to: 
Serum shipments to Merck (PPD) should be sent quarterly on the first Monday or 
Tuesday of the month (or as requested by the Clinical team) to the following address: 
30. 
Appendix X 
Changed from:  
AMC DATA SAFETY AND MONITORING PLAN 
(Version 4.0  September 13, 2010) 
Changed to: 

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AMC DATA SAFETY AND MONITORING PLAN 
(Version 5.0  January 28, 2014) 
Revisions to Version 5.0 of the DSMP are limited to the CTEP-AERS change described in 
Item #3. 
31. 
Appendix XII 
Changed  from: 
1) How often do you currently smoke cigarettes?  (Choose one) 
__  Not at all (skip to question 4) 
 
__  Some days 
__  Every day 
__  I prefer not to answer (skip to question #3) 
Changed to:  
1)  How often do you currently smoke cigarettes?  (Choose one) 
__  Not at all (skip to question #3) 
__  Some days 
__  Every day 
__  I prefer not to answer (skip to question #3) 
 

 
AMC #072 (Version 5.0) 05/02/2014 
 
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AIDS MALIGNANCY 
CLINICAL TRIALS CONSORTIUM 
 
 
 
AMC PROTOCOL #072: 
Protective Effect of Quadrivalent Vaccine in Young HIV-positive 
Males who have Sex with Males 
 
A Multi-Center Trial of the AIDS Malignancy 
Clinical Trials Consortium (AMC) and the Adolescent Medicine 
Trials Network (ATN) for HIV/AIDS Interventions 
 
 
Sponsored by: 
National Cancer Institute 
Office of HIV AIDS and Malignancy (OHAM) 
and 
The Eunice Kennedy Shriver National Institutes of 
Child Health and Human Development Pediatric, 
Adolescent and Maternal AIDS Branch 
 
 
Pharmaceutical Support 
and Vaccine Provided by: 
 
Merck & Co., Inc. 
 
Study Vaccine: 
Quadrivalent Human Papillomavirus (Types 6, 11, 
16 and 18) Recombinant Vaccine, NSC 745201 
 
 
Protocol Chair: 
Joel Palefsky, MD 
 
 
Protocol Co-chairs: 
Bret Rudy, MD 
Jessica Kahn MD, MPH 
 
 
Version 5.0, May 2, 2014 
NCI Version Date May 2, 2014 
 

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AMC PROTOCOL SIGNATURE PAGE 
 
I,                           , Principal Investigator at site            , agree to conduct and follow this protocol: 
Protective Effect of quadrivalent vaccine in young HIV-positive males who have sex with males 
(Version 5.0, 05/02/2014), as written according to AMC, NCI and FDA guidelines. I understand that 
no deviations from the above protocol may be made without written permission from the Protocol 
Chair(s). 
 
 
_________________________________ 
_____________________ 
 
Signature 
Date (mm/dd/yyyy) 

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TABLE OF CONTENTS 
 
SUMMARY OF CHANGES ................................................................................................................ i 
AMC PROTOCOL SIGNATURE PAGE ......................................................................................... 2 
TABLE OF CONTENTS .................................................................................................................... 3 
ABBREVIATIONS .............................................................................................................................. 6 
SITES PARTICIPATING IN THE STUDY ..................................................................................... 9 
PROTOCOL ROSTER ..................................................................................................................... 10 
SCHEMA ............................................................................................................................................ 11 
1.0 
BACKGROUND AND RATIONALE ................................................................................. 13 
1.1 
Background ................................................................................................................. 13 
1.2 
Rationale ..................................................................................................................... 17 
1.3 
Study Design ............................................................................................................... 18 
2.0 
HYPOTHESIS AND STUDY OBJECTIVES ..................................................................... 19 
2.1 
Hypothesis ................................................................................................................... 19 
2.2 
Primary Objectives ...................................................................................................... 19 
2.3 
Secondary Objectives .................................................................................................. 19 
2.4 
Tertiary Objectives ...................................................................................................... 19 
3.0 
SUBJECT SELECTION ....................................................................................................... 21 
3.1 
Inclusion Criteria ........................................................................................................ 21 
3.2 
Exclusion Criteria ....................................................................................................... 21 
3.3 
Number of Subjects to be Enrolled ............................................................................. 22 
3.4 
Study Enrollment Procedures ..................................................................................... 23 
4.0 
STUDY TREATMENT PLAN/PHARMACEUTICAL AGENT...................................... 24 
4.1 
Drug Regimen, Administration, and Duration ............................................................ 24 
4.2 
Study Vaccine Formulation and Preparation .............................................................. 25 
4.3 
Pharmacy: Study Vaccine Supply, Distribution, and Accountability ......................... 25 
4.4 
Concomitant Medications ........................................................................................... 26 
5.0 
CLINICAL AND LABORATORY EVALUATIONS ....................................................... 27 
5.1 
Schedule of Evaluations .............................................................................................. 27 
5.2 
Timing of Evaluations ................................................................................................. 27 
5.3 
Special Instructions and Definitions of Evaluations ................................................... 28 
5.4 
Dose Modification/Toxicity Management .................................................................. 33 
6.0 
CRITERIA FOR DISCONTINUATION ............................................................................ 35 

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6.1 
Permanent Treatment Discontinuation........................................................................ 35 
6.2 
Premature Study Discontinuation ............................................................................... 35 
7.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................. 36 
7.1 
Classification of AEs by Severity and Relationship to Study Vaccine Administration36 
7.2 
Routine Reporting of AEs with Investigational Agents/VAERS ............................... 37 
7.3 
Expedited AE Reporting ............................................................................................. 37 
8.0 
STATISTICAL CONSIDERATIONS ................................................................................. 39 
8.1 
General Design Issues ................................................................................................. 39 
8.2 
Endpoints .................................................................................................................... 39 
8.3 
Sample Size and Accrual ............................................................................................ 40 
8.4 
Safety Analysis ........................................................................................................... 42 
8.5 
Monitoring .................................................................................................................. 42 
8.6 
Primary, Secondary and Tertiary Analyses ................................................................. 42 
9.0 
DATA COLLECTION AND MONITORING ................................................................... 46 
9.1 
Records to Be Kept ..................................................................................................... 46 
9.2 
Role of Data Management .......................................................................................... 46 
9.3 
Clinical Site Monitoring and Record Availability ...................................................... 46 
10.0 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................. 47 
10.1 
Institutional Review Board (IRB) Review and Informed Consent ............................. 47 
10.2 
Subject Confidentiality ............................................................................................... 47 
10.3 
Study Discontinuation ................................................................................................. 47 
10.4 
Women and Minorities ............................................................................................... 47 
11.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................... 48 
12.0 
BIOHAZARD CONTAINMENT ......................................................................................... 49 
13.0 
REFERENCES ...................................................................................................................... 50 
APPENDIX I: SCHEDULE OF EVENTS....................................................................................... 52 
APPENDIX II: KARNOFSKY PERFORMANCE SCALE .......................................................... 54 
APPENDIX III: MERCK GARDASIL® PRODUCT INFORMATION ..................................... 55 
APPENDIX IV: PENILE/SCROTAL SCRAPING PROCEDURES ........................................... 56 
APPENDIX V: ANAL CYTOLOGY SAMPLING PROCEDURES ............................................ 57 
APPENDIX VI:  HPV DNA PCR SPECIMEN COLLECTION AND SHIPPING ..................... 58 
APPENDIX VII:  HIGH RESOLUTION ANOSCOPY (HRA) .................................................... 61 
APPENDIX VIII:  ORAL EXAMINATION/TESTING STORAGE AND SHIPMENT ........... 63 
APPENDIX IX:  SERUM HPV ANTIBODY TESTING ............................................................... 65 

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APPENDIX X: AMC DATA SAFETY MONITORING PLAN .................................................... 69 
APPENDIX XI: VACCINATION REPORT CARD ...................................................................... 72 
APPENDIX XII:  SMOKING STATUS/RECENT SEXUAL HISTORY/RISK PERCEPTION 
AND KNOWLEDGE QUESTIONNAIRE ......................................................................... 78 
APPENDIX XIII:  ACSR INFORMED CONSENT FORM – AMC-072 ..................................... 85 
APPENDIX XIV:  ACSR ASSENT FORM – AMC 072 ................................................................ 90 
APPENDIX XV:  AIDS AND CANCER SPECIMEN RESOURCE (ACSR) – SPECIMEN 
PREPARATION AND SHIPPING INSTRUCTIONS ...................................................... 95 
 

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ABBREVIATIONS 
 
ACIP 
Advisory Committee on Immunization Practices 
ACSR 
AIDS Cancer Specimen Resource 
ACTG 
AIDS Clinical Trials Group 
CTEP-AERS 
Adverse Event Expedited Reporting System 
AdvantageEDCSM 
AMC Internet Data Entry System 
AE 
Adverse Event 
AIN 
Anal intraepithelial neoplasia 
ALT 
Alanine transaminase 
AMC 
AIDS Malignancy Consortium Clinical Trials 
ANC 
Absolute neutrophil count 
ART 
Antiretroviral therapy 
ASC-H 
Atypical squamous cells suggestive of HSIL 
ASCUS 
Atypical squamous cells of undetermined significance 
AST 
aspartate aminotransferase 
ATN 
Adolescent Medicine Trials Network 
BUN 
Blood urea nitrogen 
CDC 
Centers for Disease Control 
CDUS 
Clinical Data Update System 
CIN 
Cervical intraepithelial neoplasia 
CLIA 
Clinical Laboratory Improvement Act 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Event reporting 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trials Monitoring Service 
DARF 
Drug Accountability Record Form 
DSMC 
Data Safety and Monitoring Committee 
EC 
AIDS Malignancy Consortium Executive Committee 

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EGL 
External genital lesions 
ELISA 
Enzyme linked immunosorbent assay 
FDA 
Food and Drug Administration 
HAART 
Highly-active antiretroviral therapy 
HERS 
HIV Epidemiology Research Study 
HGAIN 
High-grade anal intraepithelial neoplasia 
HIV 
Human immunodeficiency virus 
HPV 
Human papillomavirus 
HRA 
High Resolution Anoscopy 
HSIL 
High-grade intraepithelial lesion(s) 
IATA 
International Air Transport Association 
IDB 
Investigational Drug Branch 
IM 
Intramuscular 
IND 
Investigational New Drug 
IRB 
Institutional review board 
IVIG 
Intravenous immunoglobulin 
LSIL 
Low grade intraepithelial lesion(s) 
LSM 
Lymphocyte Separation Medium 
mcg 
Microgram 
mg 
Milligram 
ml 
Milliliter 
MSM 
Males who have sex with males 
NCI 
National Cancer Institute 
NICHD 
National Institute of Child Health and Human Development 
OHAM 
Office of HIV and AIDS Malignancy 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase chain reaction 
PIO 
Protocol Information Office 
RNA 
Ribonucleic acid 

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SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
STI 
Sexually transmitted infection 
VAERS 
Vaccine Adverse Event Reporting System 
VaIN 
Vaginal Intraepithelial Neoplasia 
VIN 
Vulvar Intraepithelial Neoplasia 
VLP 
Virus-like particles 
 

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SITES PARTICIPATING IN THE STUDY 
 
This protocol will be open to all interested AMC and ATN sites approved by the AMC HPV 
Working Group. The approval will be based on the capacity to perform high resolution anoscopy 
(HRA). 
 

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PROTOCOL ROSTER 
 
AMC #072 
 
Protective Effect of quadrivalent vaccine in young HIV-positive males who have sex with males 
 
Protocol Chair: 
Statistician: 
Joel M. Palefsky, MD, CM, FRCPC 
Jeannette Y. Lee, PhD 
University of California at San Francisco  
AMC Statistical Center 
C-634D, Box 0100  
University of Arkansas for Medical Sciences 
3rd and Parnassus Avenue  
4301 W. Markham, #781 
San Francisco, CA  94143-0001 
Little Rock, Arkansas 72205-7199 
Phone: (415) 476-1574 
Phone: (501) 526-6712 
Fax: (415) 476-4204 
Fax: (501) 526-6729 
Email: joel.palefsky@ucsf.edu 
Email: jylee@uams.edu 
 
 
 
 
Protocol Co-chairs: 
Operations & Data Management: 
Bret Rudy, MD 
AMC Operations & Data Management Center 
New York University School of Medicine 
The EMMES Corporation 
550 First Avenue, NBV-8S4-11 
401 N. Washington St., Suite700 
New York, NY 10016 
Rockville, MD  20850 
Phone: (212) 263-6425 
Phone: (301) 251-1161 
Fax: (212) 263-8172 
Fax: (240) 238-2842 
Email: Bret.Rudy@nyumc.org 
Email: amcpm@emmes.com 
 
 
 
 
Jessica Kahn, MD, MPH 
Email Address for Protocol Questions: 
Division of Adolescent Medicine 
072protocolteam@emmes.com 
MLC 4000 
 
Cincinnati Children’s Hospital Medical Center 
 
3333 Burnet Avenue 
AMC Website for ATN Sites: 
Cincinnati, OH 45229 
https://web.emmes.com/study/amc/atn/atn.htm 
Phone: (513) 636-2970 
 
Fax: (513) 636-1129  
 
Email: jessica.kahn@cchmc.org  
 
 
 
 
 
 
 
 

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SCHEMA 
 
AMC-072: Protective Effect of Quadrivalent Vaccine in Young HIV-positive Males  
who have Sex with Males 
 
 
DESIGN: 
Open-label, phase 2, single-arm study 
DURATION: 
2 years 
SAMPLE SIZE: 
150 
POPULATION: 
HIV-positive males who have sex with males 13 to 26 years of age 
without AIN 
REGIMEN: 
All participants will be vaccinated with the Quadrivalent Human 
Papillomavirus Recombinant vaccine (0.5 mL Gardasil®) by 
intramuscular injection at Day 1, Weeks 8 and 24. 
 
PRIMARY OBJECTIVES: 
1) To determine the protective effect of the HPV-6, -11, -16, -18 
vaccine in preventing penile/scrotal condyloma and HPV-6, -11, 
-16, -18- associated perianal/anal disease in HIV-positive males 
who have sex with males (MSM) age 13-26 years by comparing 
the incidence of these lesions among those naïve to the relevant 
HPV type(s) at baseline to those who are not naïve at baseline. 
2) To determine the protective effect of the HPV-6, -11, -16, -18 
vaccine in preventing persistent anogenital infection with HPV-
6, -11, -16, or 18 in HIV-positive MSM age 13-26 years by 
comparing the incidence of persistent infection  among those 
naïve to the relevant HPV type(s) at baseline to those who are 
not naïve at baseline. 
3) To determine the protective effect of the HPV-6, -11, -16, -18 
vaccine in preventing anogenital lesions associated with HPV 6,-
11,-16, -18 and persistent infection with these types, in HIV-
positive MSM age 13-26 years by comparing the incidence of 
lesions and persistent infection among those naïve to the relevant 
types at baseline to incident lesions and infection among MSM 
naïve to these HPV types who participated in the Merck 020 
protocol and who received placebo as part of the protocol. 
 

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SECONDARY OBJECTIVES: 
1) To define the safety of the HPV-6, -11, -16, -18 vaccine in HIV-
positive MSM age 13-26 years  
2) To evaluate the levels and persistence of HPV 6, 11, 16 and 18 
Ab titers after the vaccination series among subjects who are 
seropositive and seronegative for those HPV types at baseline. 
3) To examine whether the protective effect and antibody titers 
vary as a function of the following at the time of initial 
vaccination: Subject age, HAART treatment status, HIV viral 
load, 
CD4 
+ 
T 
cell 
count, 
nadir 
CD4 
level. 
 
TERTIARY OBJECTIVES: 
1) To quantify anogenital HPV DNA viral load prior to and after 
receipt of the quadrivalent HPV vaccine. 
2) To identify and quantify HPV types in the oral cavity of HIV-
positive MSM prior to and after receipt of the quadrivalent HPV 
vaccine. 
3) To identify HPV strain variants among HIV-positive participants 
prior to and after receipt of the quadrivalent HPV vaccine. 
4) Assess the prevalence and incidence of urinary gonorrhea and 
Chlamydia trachomatis infection at baseline and their 
relationship with prevalent and incident anogenital HPV 
infection and anal condyloma or AIN. 
5) To characterize young men’s risk perceptions, sexual behaviors, 
and STI diagnosis after HPV vaccination. 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Background 
Human papillomavirus (HPV) is a DNA virus of which over 100 types have been identified. 
Approximately 30 types are sexually transmitted and infect the anogenital area of both men 
and women.(1) The lifetime risk for anogenital HPV infection among sexually active men and 
women is at least 50%. (2) 
 
Anal HPV, AIN and anal carcinoma 
Anal carcinoma is strongly related to infection with high-risk types of HPV, as has been seen 
for cervical, vaginal, vulvar, and penile cancer.(3) The incidence of anal cancer in men who 
have sex with men is estimated to be 35 cases/100,000 person-years.(4) This incidence is 
comparable to that observed for cervical cancer before the introduction of routine 
Papanicolaou screening. The rate of anal cancer is estimated to be twice as high in HIV-
positive as in HIV-negative men who have sex with men.(5) Several studies suggest that the 
incidence of anal cancer in HIV-positive men who have sex with men has increased in the era 
of highly-active antiretroviral therapy (HAART).(6,7) 
 
Similar to cervical cancer, anal cancer is preceded by high-grade anal intraepithelial 
neoplasia (HGAIN). AIN is readily detected by anal cytology, and abnormal cytological 
results should prompt high resolution anoscopy and biopsy of areas suspicious for AIN. 
Areas of HGAIN can be treated with ablative therapy in an attempt to reduce the incidence of 
invasive cancer. The prevalence of cytological abnormalities among HIV-1-infected MSM 
has been estimated at 65%, and the prevalence of high-risk HPV at 78%.(8) Approximately 
30% are positive by HPV DNA PCR for type 16, 20% for type 18, and 10% for both (Wilkin, 
personal communication). The majority of HIV-1-infected MSM have multiple types of high-
risk HPV detected by PCR. Among HIV-positive women, the prevalence of anal cytological 
abnormalities has been estimated at 26%, and the prevalence of HPV at 76%.(9) 
 
Response to recombinant protein vaccines in HIV-positive populations 
As the availability of potent antiretroviral regimens has increased the life expectancy and 
quality of life of HIV-positive patients, vaccinations for preventable infections have 
increased significance. Poor responses to standard vaccination series have been documented 
in HIV-positive patients.(10-14) Meta-analysis of eight studies designed to evaluate the efficacy 
of hepatitis A vaccination in HIV-positive patients using the standard vaccination series 
revealed a low response rate.(13) The overall response rate for HIV-positive patients was 64% 
in a combined total of 458 subjects. Individual studies have yielded a lower proportion of 
patients achieving adequate hepatitis A antibody titers. In a small retrospective analysis, the 
hepatitis A vaccination response rate was only 48% compared with reported rates of 100% in 
HIV-negative patients.(15) 
 
Compared with success rates of greater than 90% in immunocompetent hosts, HIV-positive 
patients respond to hepatitis B vaccination at rates of 17.5% – 56%(11, 14, 16, 17) Strategies to 
improve the vaccination response rate include increasing the amount of the dose, the use of a 
four-dose schedule, and the administration of booster vaccinations.(18, 19) In the HIV 
population, there is evidence to suggest that an adequate antibody response may not be 
sustained over time as expected. The use of a six-dose strategy that produced initial antibody 

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titers comparable to the immunocompetent population found that adequate hepatitis B 
antibody was maintained for only 59% of subjects one year after completion of the modified 
series.(20) 
 
Investigators have analyzed patient-specific predictors associated with responders to both 
hepatitis A and B vaccination. The presence of low-level viremia has been consistently 
associated with failure to respond to hepatitis vaccination. In a logistic regression model, 
Overton, et al. showed that only HIV RNA level below 400 copies/mL at the time of hepatitis 
B vaccination was associated with a protective antibody response, while CD4+ count at time 
of vaccination was not found to be statistically significant.(17) In HIV-positive children, an 
undetectable plasma HIV-1 RNA and CD4+ T-cell percent greater than 20% predicted 
response to hepatitis A vaccination.(21) Nadir CD4+ count has not been shown to predict the 
development of protective antibody in HIV patients for either hepatitis A or B vaccination in 
any study to date. 
 
Gardasil® 
Gardasil® (Merck & Co., Inc.) was approved by the FDA in June 2006 and is indicated in 
girls and women 9-26 years of age for the prevention of cervical cancer, genital warts, and 
genital precancerous or dysplastic lesions caused by human papillomavirus (HPV) types 6, 
11, 16, and 18. Gardasil protects recipients against 4 types of HPV, including the two types 
that cause most cervical cancers and the two types that cause most genital warts. It consists of 
virus-like particles generated by the expression of the major capsid protein L1 from HPV 
types 6, 11, 16, and 18 with an aluminum adjuvant. This vaccine targeting HPV types 6, 11, 
16, and 18 can substantially reduce the acquisition of infection and clinical disease caused by 
these types. The ACIP recommends that Gardasil be routinely given to girls when they are 11 
or 12 years of age, before people become sexually active (i.e., before women are exposed to 
the viruses). Gardasil can be administered as early as age 9 years, and can also be given to 
women 13 to 26 years old. Gardasil is to be given as a three dose series completed over 6 
months. 
 
For many viruses, an infection induces neutralizing antibodies that are a correlate of immune 
protection. HPV cannot be cultivated in tissue culture and true neutralization assays are not 
commercially available. Instead, capsid proteins of HPV produced in non-mammalian cells 
self-assemble into virus-like particles (VLP) and can be used as reagents in enzyme 
immunoassays.(22) These VLP-based immunoassays and the scales for these assays are highly 
type-specific and thus, comparison across types and to other assays are not possible. (See 
Appendix III, Merck Gardasil Product Information). 
 
Natural HPV infection induces a low level of antibody production that for most types does 
not seem to confer complete protection against subsequent type-specific HPV infection. 
Furthermore, it has not been possible to establish minimum antibody levels that protect 
against clinical disease. Viscidi, et al. evaluated the prevalence of serum antibodies to HPV 
types 16, 18, 31, 35, and 45 in 829 HIV-positive and 413 HIV-negative risk-matched women 
enrolled in HERS and analyzed the association of seropositivity with risk of detection of 
HPV DNA in the genital tract during follow up. The seroprevalence of HPV 16 antibodies 
was 51.8% in HIV-positive women compared with 45.5% in HIV-negative women, and that 
of HPV 18 was 52.0% and 35.6% in HIV-positive and -negative women respectively.(23) 
There was no statistically significant difference in the risk of a new infection with the 

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homologous HPV type between HPV-seropositive and HPV seronegative women.(23) This 
suggests that natural HPV infection does not confer complete immunoprotection for most 
HPV types.  
 
Almost all HIV-negative girls and women who received the Gardasil vaccine became HPV 6, 
11, 16, and 18 seropositive one month after the third vaccine dose (99.8%, 99.8%, 99.8%, 
and 99.5% respectively). The titers peaked at month 7 and stabilized through month 36 at 
levels above baseline. The aim of this study is to evaluate whether the new quadrivalent HPV 
vaccine induces detectable serum titers against the HPV types included in the vaccine among 
HIV-positive adult men and to establish its safety in this population.  
 
Immunogenicity and efficacy results for quadrivalent HPV vaccine in girls and women 
Immunogenicity results of Protocol 007 showed that administration of a 3-dose regimen (0, 
2, 6 Months) of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine 20/40/40/20 mcg 
(Gardasil) generates robust anti-HPV 6, 11, 16, and 18 responses 4 weeks after the 
completion of the vaccination regimen and durable anti-HPV 6, 11, 16, and 18 responses 2.5 
years following completion of the vaccination regimen. Efficacy results of Protocol 007 
showed that administration of a 3-dose regimen of Gardasil substantially reduced the risk for 
acquisition of persistent HPV 6-, 11-, 16-, or 18-related infection or HPV 6-, 11-, 16-, or 18-
related genital disease and substantially reduced the risk for development of a composite 
endpoint of HPV 6-, 11-, 16- or 18-related CIN or EGL. 
 
Immunogenicity results of the Protocol 016 adult/adolescent substudy showed that for each 
of the 4 HPV types, the vaccine induced numerically higher HPV 6, 11, 16, 18 geometric 
mean titers (GMTs) 4 weeks Postdose 2 (Month 3) and 4 weeks Postdose 3 (Month 7) in 10- 
to 15-year-old male and female subjects than in 16- to 23-year-old female subjects. 
Immunogenicity results of the Protocol 016 end expiry substudy showed that lower dose 
formulations of Gardasil induced anti-HPV responses at Month 7 that were statistically non-
inferior to those generated following administration of a 3-dose regimen. 
 
Immunogenicity results from Protocols 013 and 015 have been consistent with Protocols 007 
and 016 and have demonstrated ongoing vaccine immunogenicity for at least 24 Months 
post-vaccination that has correlated with demonstrable vaccine efficacy. 
 
In clinical trials, administration of a 3-dose regimen of Gardasil to women naïve to the 
relevant vaccine HPV types, at Day 1 and the through the completion of the vaccination 
regimen, was over 90% efficacious in preventing the development of: 
• 
HPV 16- and 18-related CIN 2/3 and adenocarcinoma in situ (obligate cervical cancer 
precursors); 
• 
HPV 16- and 18-related vulvar intraepithelial neoplasia (VIN) 2/3 and vaginal 
intraepithelial neoplasia (VaIN) 2/3 (obligate precursors to HPV-related vulvar and 
vaginal cancer, respectively; 
• 
HPV 6- and 11-related external genital lesions (including condyloma acuminata); 
• 
HPV 6-, 11-, 16-, and 18-related CIN; and 
• 
HPV 6-, 11-, 16-, and 18-related persistent infection 
 

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Efficacy studies of Gardasil in young HIV-negative men  
The FDA recently extended the approval of Gardasil for use in males ages 9 to 26 for the 
prevention of anal cancer caused by HPV types 16 and 18, genital warts (condyloma 
acuminata) caused by HPV types 6 and 11, and anal intraepithelial neoplasia (AIN) grades 1, 
2, and 3. However, data on the efficacy of Gardasil in young HIV-positive men is limited.  In 
bridging studies the antibody response in adolescent boys appears similar to that of 
adolescent girls. In a recent clinical trial of Gardasil in HIV-negative boys and men aged 16-
26 (Merck 020), unpublished data show that among those naïve to vaccine-specific HPV 
types, the vaccine was effective to prevent development of external genital condyloma 
acuminatum with an efficacy of 90%, and protection against persistent external genital 
infection with HPV 6, 11, 16 and 18 ranged from 79% to 96%.  Nearly 100% of boys and 
men seroconverted and the vaccine was well tolerated.   
Safety and tolerability results for quadrivalent HPV vaccine in women 
In clinical studies of GARDASIL™ about 25,900 people received at least one shot of 
GARDASIL™. About 2000 people received at least one shot of a similar vaccine at higher or 
lower doses than GARDASIL™. Fourteen studies are still ongoing. In these studies, 
GARDASIL™ has been generally well tolerated. Among the reported serious vaccine-related 
side effects: 
 
Eight (8) people had serious side effects judged by the study doctor to be related to 
GARDASIL™. 
• 
Wheezing and shortness of breath (1 subject) 
• 
Upset stomach with vomiting or diarrhea (1 subject) 
• 
Disease of the large bowel (called ulcerative colitis) starting 389 days after the third dose 
(1 subject) 
• 
Muscular weakness (1 subject) 
• 
Facial paralysis (1 subject) 
• 
Pain and joint stiffness (limiting movement) at the place where the study vaccine was 
injected (1 subject) 
• 
Vaginal bleeding that lasted on and off for up to 2 ½ months after each of two study 
vaccinations (1 subject) 
• 
Severe headache with high blood pressure on the day of a study vaccination that lasted 5 
days and 1 day, respectively (1 subject)  
 
Common side effects occur in 1 or more out of 100 subjects.  The side effects judged to be 
related to study vaccine or placebo and seen more commonly among subjects who received 
GARDASIL™ than subjects who received placebo include: 
• 
Fever 
• 
Nausea 
• 
Dizziness 
• 
Headache 
• 
Pain in extremity (pain in arm or leg) 
 
See section 4.1.3 for a comprehensive list of adverse events (AEs) or refer to the FDA-
approved package insert available at www.gardasil.com. 

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Safety and immunogenicity of the quadrivalent HPV vaccine in HIV-positive males and 
females  
A few studies have been performed of the safety and immunogenicity of the quadrivalent 
HPV vaccine in HIV-positive males and females.  The PACTG P1047 study has reported 
preliminary data indicating that the vaccine is well tolerated in adolescent HIV-positive boys 
and girls, with high HPV seroconversion rates, although the titers to HPV 6 and were lower 
than historical HIV-negative controls.  The vaccine has also been shown to be well-tolerated 
among HIV-positive MSM in AMC-052.   
 
1.2 
Rationale 
The men most likely to benefit from this vaccine are those who are seronegative to HPV 6, 
11, 16 and 18, and who do not have those types detected by HPV DNA PCR. In addition, 
men who are seropositive to those types and PCR negative may benefit by “boosting” the 
humoral response to those types and preventing re-infection. Prior studies in HIV-positive 
women suggest that the humoral response associated with natural infection was not protective 
against re-infection. There are few data on the seroprevalence to HPV types 6, 11, 16, and 18 
in HIV-positive MSM; none of which used the Merck assay. A study of 59 HIV-positive 
MSM found that 36% and 27% were seropositive for types 16 and 18, respectively.(24) A 
second study of 154 HIV-positive MSM found that 42% were seropositive for type 16.(25) In 
the AMC 052 study of HIV-positive MSM, most of whom were over the age of 30 years, at 
baseline, 29% were positive for HPV 16 antibodies, 19% were positive for HPV 18  
antibodies, 38% were positive for HPV 6 antibodies and 30% were positive for HPV 11  
antibodies.  Among HIV-positive women, approximately 50% were seropositive to type 16 
and 50% to type 18. Anal infection with high-risk HPV is extremely common among HIV-
positive MSM older than 20 years of age with a prevalence of 80%.   
 
Not surprisingly, the prevalence of anal HPV infection and disease was lower among younger 
HIV-positive MSM.  In one study of young HIV-positive MSM, (Moscicki AB AIDS. 
2003;17:311-20), 14% had anal HPV 16, none had HPV 18 DNA and 23% had HPV 6 and/or 
HPV11.   
 
Although the quadrivalent vaccine appears to be immunogenic and well tolerated in HIV-
positive individuals, no studies have been done yet on the protective effect of the vaccine in 
these populations regardless of their age.  The vaccine has been shown to be highly 
efficacious in HIV-negative populations to date, but the efficacy is restricted to those who are 
sero- or DNA-negative to a given HPV type.  Efficacy studies in HIV-positive individuals are 
hampered by the high prevalence of prior exposure to vaccine HPV types, and an efficacy 
study among HIV-positive individuals would be best performed in a HIV-positive population 
with relatively limited prior exposure to HPV, but with a high risk of incident infection and 
disease within the period of the study.  The optimal study population to determine the 
protective effect of the vaccine among HIV-positive individuals is young (age 13-26) HIV-
positive MSM, and this group is the focus of the present study.  This study will evaluate the 
protective effect of developing type 16-, 18- 6- or 11-associated AIN or anal condyloma, as 
well as persistent infection with these types.  Because the quadrivalent HPV vaccine was 
recently approved for use in boys by the FDA, a placebo control arm is not practical.  
Therefore in this study, all participants will be vaccinated, and the incidence of HPV 
infection and disease will be compared between those with and without exposure to HPV at 

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baseline prior to vaccination. 
 
1.3 
Study Design 
A Phase II open-label, single arm study of the safety and immunogenicity of HPV 
vaccination directed against types 6, 11, 16 and 18 in HIV-positive MSM aged 13 to 26 
years. Individuals will be screened with a liquid-based anal cytology and HPV DNA PCR. 
Eligible subjects must have no history of anal cancer or high-grade anal intraepithelial 
neoplasia.  Subjects are excluded if they have an anal cytology showing high-grade squamous 
intraepithelial lesion(s) (HSIL), atypical squamous cells cannot rule out HSIL (ASC-H) or 
cytology suggestive of carcinoma. At study entry, subjects will give samples for HPV DNA 
PCR, and HPV type-specific serologies. Subjects will receive the HPV vaccine on Day 1, 
Week 8 and Week 24. Subsequently, subjects will be seen for study visits through 24 months 
after entry (18 months after vaccination). HPV DNA PCR, liquid based anal cytology, high 
resolution anoscopy with biopsy and HPV serologies (types 6, 11, 16 and 18) will be 
obtained during study follow-up. 
 
Safety will be assessed by the occurrence of grade 3 or 4 events (Section 7.0). Routine liver 
function tests and chemistries will be obtained at screening and at Week 28, 4 weeks after 
completion of the vaccination series. Plasma HIV-1 RNA, CD4 cell count will be obtained at 
Baseline (study entry) and at Week 28. The immunogenicity will be assessed by comparing 
antibody titers to the four types at screening, 7 months, 12, 18 and 24 months post-
vaccination. 

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2.0 
HYPOTHESIS AND STUDY OBJECTIVES 
2.1 
Hypothesis 
The protective effect of the HPV -6, -11, -16, -18 vaccine in preventing anogenital disease 
associated with vaccine types will be significantly higher in HPV-seronegative and DNA-
negative HIV-positive MSM age 13 to 26 years vs. men who have evidence of prior exposure 
to vaccine HPV types, i.e. who are HPV-seropositive and/or DNA-positive for those types.   
 
2.2 
Primary Objectives 
2.2.1 
To determine the protective effect of the HPV-6, -11, -16, -18 vaccine in preventing 
penile/scrotal condyloma and HPV-6, -11, -16, -18- associated perianal/anal disease 
in HIV-positive males who have sex with males (MSM) age 13-26 years by 
comparing the incidence of these lesions among those naïve to the relevant HPV 
type(s) at baseline to those who are not naïve at baseline. 
 
2.2.2 
To determine the protective effect of the HPV-6, -11, -16, -18 vaccine in preventing  
persistent anogenital infection with HPV-6, -11, -16, or 18 in HIV-positive MSM age 
13-26 years by comparing the incidence of persistent infection  among those naïve to 
the relevant HPV type(s) at baseline to those who are not naïve at baseline.. 
 
2.2.3 
To determine the protective effect of the HPV-6, -11, -16, -18 vaccine in preventing 
anogenital lesions associated with HPV 6,-11,-16, -18 and persistent infection with 
these types, in HIV-positive MSM age 13-26 years by comparing the incidence of 
lesions and persistent infection among those naïve to the relevant types at baseline to 
incident lesions and infection among MSM naïve to these HPV types who 
participated in the Merck 020 protocol and who received placebo as part of the 
protocol. 
 
 
2.3 
Secondary Objectives 
2.3.1 
To define the safety of the HPV-6, -11, -16, -18 vaccine in HIV-positive MSM age 
13-26 years. 
 
2.3.2 
To evaluate the levels and persistence of HPV 6, 11, 16 and 18 Ab titers after the 
vaccination series among subjects who are seropositive and seronegative at baseline. 
 
2.3.3 
To examine whether the protective effect and antibody titers vary as a function of the 
following at the time of initial vaccination: Subject age, HAART treatment status, 
HIV viral load, CD4 + T cell count, nadir CD4 level. 
 
2.4 
Tertiary Objectives 
2.4.1 
To quantify anogenital HPV DNA viral load prior to and after receipt of the 
quadrivalent HPV vaccine. 
 
2.4.2 
To identify and quantify HPV types in the oral cavity of HIV-positive MSM prior to 
and after receipt of the quadrivalent HPV vaccine. 
 

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2.4.3 
To identify HPV strain variants among HIV-positive participants prior to and after 
receipt of the quadrivalent HPV vaccine. 
 
2.4.4  Assess the prevalence and incidence of urinary gonorrhea and Chlamydia trachomatis 
infection at baseline and their relationship with prevalent and incident anogenital 
HPV infection and anal condyloma or AIN. 
 
2.4.5 
To characterize young men’s risk perceptions, sexual behaviors, and STI diagnosis 
after HPV vaccination. 
 

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3.0 
SUBJECT SELECTION 
3.1 
Inclusion Criteria 
3.1.1 
Men age 13 to 26 years with a history of at least one male sexual partner. “Men” is 
defined as those documented “male” at birth (including male-to-female transgendered 
persons). 
 
3.1.2 
HIV-1 infection as documented by any federally approved, licensed HIV test 
performed in conjunction with screening (ELISA, Western blot or other approved 
test). Alternatively, this documentation may include a record that another physician 
has documented that the patient has HIV based on prior ELISA and western blot, or 
other approved diagnostic tests. If the participant’s HIV status is documented by an 
outside physician, the protocol team strongly recommends obtaining a copy of the 
HIV laboratory reports from this physician. All confirmatory tests and the physician’s 
note must be on file before the participant is enrolled. In the rare circumstance where 
only an outside physician’s note with no supporting laboratory documentation is 
available, the local site should have additional tests performed to verify the 
participant’s HIV status. One of the following additional tests should be performed: 
 
A rapid HIV test 
 
ELISA and Western blot 
 
Chemiluminescence immunoassay and Western blot 
 
HIV RNA > 2000 copies/mL 
 
HIV antigen test 
 
3.1.3 
If receiving antiretroviral therapy: 
 
Receipt of antiretroviral therapy for at least 3 months prior to entry 
 
No change in antiretroviral therapy within 30 days prior to entry 
 
3.1.4 
If not receiving antiretroviral therapy: 
 
CD4 cell count ≥350 cells/mm3 within 90 days prior to study entry 
 
No plans to start antiretroviral therapy prior to Week 28 
 
3.1.5 
Normal anal cytological result, LSIL/condyloma or ASCUS result within 90 days 
prior to entry, and no HGAIN on biopsy.  
 
3.1.6 
Absolute neutrophil count (ANC) >750 cells/mm3; hemoglobin ≥ 9.0 g/dL; platelet 
count ≥100,000/mm3; AST (SGOT), ALT (SGPT) ≤ 3 X ULN; Total or conjugated 
(direct) bilirubin ≤ 2.5 X ULN within 45 days prior to entry, with the exception of 
isolated hyperbilirubinemia that is considered due to atazanavir. 
 
3.1.7 
Calculated creatinine clearance ≥60 mL/min (Cockcroft-Gault Formula). 
 
3.1.8 
Karnofsky performance score ≥ 70 within 45 days prior to entry (See Appendix II.) 
 
3.2 
Exclusion Criteria 
3.2.1 
Current or history of anal or peri-anal carcinoma 
 
3.2.2 
Anal cytological result of HSIL, atypical squamous cells suggestive of HSIL (ASC-

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H), or suggestive of invasive carcinoma at screening; or history of these results. 
 
3.2.3 
HGAIN (e.g., AIN 2 or 3, or perianal intraepithelial neoplasia grade 2 or 3) or 
invasive carcinoma at pre-entry on biopsy, or participant has a history of invasive 
carcinoma or any prior anal cytology result of HSIL or ASC-H. 
3.2.4 
Use of any systemic antineoplastic or immunomodulatory treatment, systemic 
corticosteroids for greater than 14 days, investigational vaccines, interleukins, 
interferons, growth factors, or IVIG within 45 days prior to study entry. 
 
3.2.5  It is encouraged that standard of care vaccinations are not offered during the 2 weeks 
preceding plasma HIV-1 RNA measurements, and that standard of care vaccinations 
are not administered at the same time as the study vaccine. Routine vaccinations other 
than influenza vaccine that are administered after enrollment in the study should be 
given 1 month before or after HPV vaccination (or any visit where antibody titers are 
measured) during the study period. Influenza vaccination may be given within 1 week 
before or after HPV vaccination visits.  
  
3.2.6 
Expected use of any systemic antineoplastic or immunomodulatory treatment, 
systemic corticosteroids used for greater than 14 days, investigational vaccines, 
interleukins, interferons, growth factors, or IVIG during study followup.  Hepatitis C 
co-infected subjects should not enroll in this study if they expect to initiate treatment 
for hepatitis C (e.g., interferons) during this trial. 
 
3.2.7 
Active drug or alcohol use or dependence that, in the opinion of the site Investigator, 
would interfere with adherence to study requirements. 
 
3.2.8 
Serious illness requiring systemic treatment and/or hospitalization within 45 days 
prior to entry. 
 
3.2.9 
Serious medical or psychiatric illness that in the opinion of the site Investigator will 
interfere with the ability of the subject to give informed consent or adhere to the 
protocol. 
 
3.2.10 Subject is currently receiving anticoagulation therapy other than acetylsalicylic acid. 
 
3.2.11 Inability to provide informed consent (and assent, if subject is under the age of 18). 
 
3.2.12 Allergy to yeast or any of the components of Gardasil. 
 
3.2.13 Prior splenectomy. 
 
3.2.14 Hemophilia. 
 
3.2.15 Prior receipt of Gardasil or other HPV vaccine. 
 
3.3 
Number of Subjects to be Enrolled 
This study will enroll 150 subjects. A table of the accrual targets by ethnic and racial 
categories is found below. 

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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
0 
+ 
30 
= 
30 
Not Hispanic or Latino 
0 
+ 
120 
= 
120 
Ethnic Category: Total of all subjects 
0 (A1) 
+ 
150 (B1) 
= 
150 (C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
1 
= 
1 
Asian 
0 
+ 
2 
= 
2 
Black or African American 
0 
+ 
45 
= 
45 
Native Hawaiian or other Pacific Islander 
0 
+ 
2 
= 
2 
White 
0 
+ 
100 
= 
100 
Racial Category: Total of all subjects 
0 (A2) 
+ 
150 (B2) 
= 
150 (C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
3.4 
Study Enrollment Procedures 
Prior to implementation of this protocol, sites must have the protocol and protocol informed 
consent form(s) approved by their local institutional review board (IRB). 
 
This study will be available for enrollment at all interested AMC and ATN sites that have 
been approved by the HPV Working Group. Approval will be based on the capacity to 
perform HRA. Sites must be registered with the AMC Operations and Data Management 
Center (ODMC) before they may enroll subjects. 
 
3.4.1 
Registration for Screening 
After an informed consent form has been signed by the subject, the subject must be 
registered for screening (AMC-072, Segment A) on-line via the AMC 
AdvantageEDCSM Internet Data Entry System. After successful registration into 
screening, the subject will receive a nine-digit subject ID and will then enter the 
screening process (Screening and Pre-entry visits). 
 
3.4.2 
Enrollment 
After the screening evaluations have been obtained and the subject is determined to 
be eligible, the participating site will complete the protocol-specific eligibility 
checklist and enroll the subject into AMC-072 Segment B (on-line via the AMC 
Internet Data Entry System). Enrollment should occur no more than 72 hours prior to 
the initiation of vaccination. (Enrollment 1 day prior to or on the day of treatment is 
strongly encouraged). Once the eligibility checklist is submitted, a system generated 
confirmation email will be sent to the enroller upon successful completion of the 
subject enrollment. If the on-line system is inaccessible, the site should notify the 
AMC ODMC (via email at amcpm@emmes.com or via phone at 301-251-1161) for 
further instructions.  
 
Subjects must be enrolled into AMC-072 Segment B prior to receiving the first 
vaccination. 

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4.0 
STUDY TREATMENT PLAN/PHARMACEUTICAL AGENT 
4.1 
Drug Regimen, Administration, and Duration 
The vaccination schedule with quadrivalent HPV vaccine (0.5 mL vaccine by intramuscular 
[IM] injection) is at Day 1, Week 8, and Week 24. 
 
4.1.1 
Regimen 
Day 1, Week 8 and Week 24  
Quadrivalent HPV (Types 6, 11, 16, 18) recombinant vaccine, 0.5 mL, 
intramuscularly in the deltoid region of the upper arm or the higher anterolateral area 
of the thigh. 
 
4.1.2 
Study Product Administration 
Quadrivalent HPV (Types 6, 11, 16, 18) recombinant vaccine will be administered as 
three separate 0.5 mL doses according to the visit schedule. The vaccine will be 
administered in the clinic by study personnel using aseptic technique during 
preparation and administration. 
 
The vaccine is to be used as supplied; no dilution or reconstitution is necessary. 
Thorough agitation is required immediately prior to administration to maintain 
suspension of the vaccine. It is necessary to shake well before use. After thorough 
agitation, the suspension is a white, cloudy liquid. Inspect the suspension visually for 
particulate matter and discoloration prior to administration. Do not use the vaccine if 
particulates are present or it appears discolored. 
 
The vaccine will be supplied as a 0.5 mL single-dose vial. Withdraw the 0.5-mL dose 
of vaccine from the single-dose vial using a sterile needle and syringe. Once the 
single-dose vial has been penetrated, use the withdrawn vaccine promptly, and 
discard the vial. 
 
All injections should preferably be given in the non-dominant arm (or thigh), 
however, if this is not feasible, the dominant arm (or thigh) may be used. The vaccine 
must not be injected intravascularly, subcutaneously or intradermally. 
 
Syncope may follow vaccination. Observe that subject for approximately 15 minutes 
after administration of the vaccine. 
 
4.1.3 
Expected Adverse Events 
Please refer to the FDA-approved package insert for a comprehensive list of AEs. 
This package insert is available at www.gardasil.com. 
 
Local reactions include pain, swelling, erythema, itching and bruising. Systemic 
reactions include syncope, fever, nausea and vomiting, dizziness, fatigue, headache, 
and chills. Other rare, but serious side effects reported with this vaccine that may be 
associated with this vaccine include hypersensitivity reactions and Guillain-Barre 
Syndrome. 

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4.2 
Study Vaccine Formulation and Preparation 
Store vials of Quadrivalent HPV (Types 6, 11, 16, 18) recombinant vaccine under 
refrigeration at 2° to 8° C (36° to 46°F). Do not freeze. Protect from light. 
 
Each 0.5 mL dose contains approximately: 
HPV 6 L1 protein 
20 mcg 
HPV 11 L1 protein 
40 mcg 
HPV 16 L1 protein 
40 mcg 
HPV 18 L1 protein 
20 mcg 
Amorphous aluminum hydroxyphosphate sulfate adjuvant 
225 mcg 
Sodium chloride 
9.56 mg 
L-histidine 
0.78 mg 
Polysorbate 80 
50 mcg 
Sodium borate 
35 mcg 
Yeast protein 
< 7 mcg 
Water 
qs 
 
4.3 
Pharmacy: Study Vaccine Supply, Distribution, and Accountability 
Quadrivalent HPV (Types 6, 11, 16, 18) recombinant vaccine will be supplied by Merck & 
Co., Inc. Gardasil is a commercial agent. 
 
4.3.1 
Study Vaccine Acquisition 
Participating sites are to refer to the study drug request form located on the AMC 
ODMC web site (www.amcoperations.com). 
 
4.3.2 
Study Vaccine Accountability 
The Investigator, or a responsible party designated by the Investigator, must maintain 
a careful record of the inventory and disposition of all drugs received using the NCI 
Drug Accountability Record Form (DARF) (available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the Pharmaceutical Management Branch at 240-
276-6575) or a site-specific form that captures the same elements as the NCI DARF. 
 
4.3.3 
Study Vaccine Transfers 
Vaccine may not be transferred from one subject to another subject, from one center 
to another center, or from one protocol to another protocol. 
 

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4.3.4 
Study Vaccine Return 
Please refer to the agent return form for procedures regarding Gardasil return and 
disposal. 
The 
form 
is 
located 
on 
the 
AMC 
ODMC 
web 
site 
(www.amcoperations.com). 
 
4.4 
Concomitant Medications 
To avoid adverse events (AEs) caused by drug interactions, sites must refer to the most recent 
package inserts for the study vaccine and concomitant agents whenever a concomitant 
medication is initiated or a dose is changed. 
 
Sites must also refer to the most recent study product’s package insert to access additional 
current information on prohibited and precautionary medications. 
 
4.4.1 
Required Medications 
There are no required medications for subjects taking part in this study. 
 
4.4.2 
Prohibited Medications 
Systemic antineoplastic or immunomodulatory treatment, systemic corticosteroids (of 
greater than 14 days duration), investigational vaccines, interleukins, interferons, 
growth factors, or IVIG. 
 
Site staff must contact the Protocol Chair(s) for guidance if a subject requires a 
restricted medication prior to a study vaccine visit or a visit that is measuring HPV 
antibody titers (i.e., screening and Weeks 28, 52, 78 and 104). 
 
Note:  If a prohibited medication is taken after completion of all HPV vaccination 
visits, contact the Protocol Chair(s) first to discuss premature discontinuation. 
 
4.4.3 
Precautionary Medications 
It is encouraged that standard of care vaccinations are not offered during the 2 weeks 
preceding plasma HIV-1 RNA measurements, and that standard of care vaccinations 
are not administered at the same time as the study vaccine. Routine vaccinations other 
than influenza vaccine that are administered after enrollment in the study should be 
given 1 month before or after HPV vaccination (or any visit where antibody titers are 
measured) during the study period. Influenza vaccination may be given within 1 week 
before or after HPV vaccination visits. 
 
Initiation of antiretroviral therapy is not prohibited in this protocol for subjects who 
are not receiving antiretroviral therapy at study entry. Subjects should not be enrolled 
if they have known plans to initiate antiretroviral therapy prior to Week 28. 

 
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5.0 
CLINICAL AND LABORATORY EVALUATIONS 
5.1 
Schedule of Evaluations 
Please see Appendix I, Schedule of Evaluations. 
 
5.2 
Timing of Evaluations 
5.2.1 
Screening and Pre-Entry 
Screening evaluations must occur prior to the subject starting any study medications, 
treatments, or interventions. 
 
Screening and pre-entry evaluations to determine eligibility must be completed 
within 45 days prior to study entry unless otherwise specified. The screening and pre-
entry visit may be combined. 
 
In addition to data being collected on subjects who enroll into the study, 
demographic, clinical, and laboratory data on screening failures (that are available) 
will be captured in a screening log.  
 
ACSR Samples 
Although it is optional, blood and fresh-frozen tissue obtained before the start of 
therapy and at Week 104 will be requested whenever possible for research purposes. 
This should be sent to the AIDS and Cancer Specimen Resource (ACSR) for 
donation (Appendix XV) and REQUIRES a separate consent form (and assent, if 
applicable). (See Appendix XIII and Appendix XIV for ACSR consent and ACSR 
assent forms).  
 
The ACSR tissue biopsy may be collected at week 104 even if a baseline ACSR 
tissue biopsy donation was not collected. The ACSR tissue biopsy may only be 
collected with the participant’s consent, if there are suspected lesions observed during 
HRA (i.e., not from normal areas), and must be a separate specimen from the 
diagnostic biopsy. 
 
It is expected that anal tissue donated to ACSR may be evaluated for HPV detection 
and typing, gene expression by microarray analysis and potentially other research 
assays as additional correlative science studies are developed. These evaluations will 
not be done in real time. 
 
5.2.2 
On-Study Evaluations 
Evaluations must occur after subject registration. Study visits must be scheduled on 
the weeks indicated in the Schedule of Evaluations (Appendix I) ±7 days through 
Week 8. Study visits scheduled for Weeks 24 and 28 must be scheduled ±10 days. 
Study visits scheduled for Weeks 52, 78 and 104 must be scheduled ±28 days. 
Telephone follow-up (Section 5.3.11) must occur within 24-48 hours post vaccination 
at Day 1, Week 8, and Week 24. 
 

 
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Effort should be made to keep subjects on the proper vaccination schedule (Day 1, 
Week 8 ±7 days, and Week 24 ±10 days). If subjects cannot be seen within the 
protocol specified windows, then these visits may be conducted outside the window 
and the subsequent vaccination visit should be adjusted. For example, if vaccine dose 
#2 is delayed from Week 8 to Week 10, all subsequent visits should be delayed by 2 
weeks so that vaccine dose #3 will occur at Week 26 (Week 24 + 2 weeks). The 
Protocol Chair(s) and AMC ODMC should be notified of these protocol deviations 
and the site must complete a Protocol Deviation Form documenting all protocol 
deviations. 
 
The Week 28 visit will collect samples for the primary immunogenicity endpoint. 
This visit should be conducted 30 days (+/- 10 days) after the third vaccination. If a 
subject’s third vaccine (i.e., Week 24 visit) was delayed until Week 27, then the 
Week 28 visit should be conducted 30 days after the third vaccine (approximately 
Week 31 in this example). All subsequent visits after the primary immunogenicity 
endpoint (Weeks 52, 78 and 104) should occur according to the original planned 
schedule. 
 
Study Entry 
Entry evaluations must occur at least 24 hours after screening evaluations and within 
45 days of screening evaluations. Evaluations must be done prior to the subject taking 
any study treatment. Subjects must begin study treatment within 72 hours after 
registration. 
 
5.2.3 
Evaluations for Subjects Who Do Not Start Study Treatment 
Registered subjects who withdraw from the study prior to starting study treatment 
should have screening, study entry, and off-study forms completed and keyed. No 
further follow-up is required for these subjects. 
 
5.2.4 
Premature Treatment Discontinuation Evaluations 
Subjects who prematurely discontinue study treatment will be asked to continue in 
the study in an off-treatment/on-study status and receive all study evaluations per the 
schedule of evaluations through to completion of the study. No extra evaluations are 
required at the time of the treatment discontinuation. The Off-Treatment Form should 
be completed. 
 
5.2.5 
Premature Study Discontinuation Evaluations 
Subjects who prematurely discontinue from the study will have the premature study 
discontinuation evaluations indicated in the schedule of evaluations performed prior 
to being taken off the study. The Off-Treatment and Off-Study Forms should be 
completed. 
 
5.3 
Special Instructions and Definitions of Evaluations 
All clinical and laboratory information required by this protocol is to be present in the source 
documents. All data requested by the study should be recorded in the source documents. All 

 
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stated evaluations will be entered on the appropriate CRF via the AdvantageEDCSM Internet 
Data Entry System unless otherwise specified. Quality assurance of data should follow the 
standards prescribed by the network under which the site is enrolling subjects (AMC or 
ATN). 
 
5.3.1 
Documentation of HIV-1 
HIV-1 infection as documented by any federally approved, licensed HIV test 
performed in conjunction with screening (ELISA, Western blot or other approved 
test). Alternatively, this documentation may include a record that another physician 
has documented that the patient has HIV based on prior ELISA and western blot, or 
other approved diagnostic tests. If the participant’s HIV status is documented by an 
outside physician, the protocol team strongly recommends obtaining a copy of the 
HIV laboratory reports from this physician. All confirmatory tests and the physician’s 
note must be on file before the participant is enrolled. In the rare circumstance where 
only an outside physician’s note with no supporting laboratory documentation is 
available, the local site should have additional tests performed to verify the 
participant’s HIV status. One of the following additional tests should be performed: 
 
A rapid HIV test 
 
ELISA and Western blot 
 
Chemiluminescence immunoassay and Western blot 
 
HIV RNA > 2000 copies/mL 
 
HIV antigen test 
 
5.3.2 
Medical/Medication History 
Medical History 
The following must be in the CRF: 
• 
History of receptive anal intercourse ever 
• 
History of genital or anal condyloma 
• 
History of prior anal cytologies or anal biopsies  
• 
History of systemic cytotoxic chemotherapy and/or radiation 
• 
History of splenectomy or hemophilia 
• 
Presence of chronic hepatitis b or c 
 
Other aspects of the medical history including allergies to any medications should be 
in the source documents only. 
 
Medication History 
The following must be in the CRF:  
• 
Actual or estimated start date of each agent that is part of the current HAART 
therapy. 
 
A medication history must be present in source documents, including:  
• 
HIV treatment history in the 6 months prior to study entry, including any 
antiretroviral medication. 
• 
Any vaccines received by the participant 45 days prior to study entry. 

 
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• 
Treatment history of any prescription medications, immune modulating herbal 
supplements, and over the counter medication taken within 45 days prior to study 
entry, including actual or estimated start and stop dates. 
• 
History of Gardasil or other HPV vaccine use. 
 
5.3.3 
Concomitant Medications/Antiretroviral Medication Modifications 
Concomitant Medications 
Use of any systemic antineoplastic or immunomodulatory treatment, systemic 
corticosteroids, investigational vaccines, interleukins, interferons, growth factors, or 
IVIG should be documented in the CRFs. 
 
Any prescription medications that have been initiated since the last report should be 
documented in the source documents only.  
 
Antiretroviral Medications 
Any modifications to antiretroviral medications since the last report will be entered 
on the CRFs. Modifications would include more than 7 consecutive days of missed 
antiretroviral medications. Modifications do not include change in current 
antiretroviral medication dose or formulations. 
 
5.3.4 
Study Treatment Record 
All modifications to study vaccine including initial doses and permanent 
discontinuation of treatment will be entered on the CRFs. 
 
5.3.5 
Nadir CD4+ Cell Count 
The subject’s prior nadir CD4+ cell count (absolute value and date) should be 
documented, when possible, with a copy of the nadir CD4+ cell count report and 
entered on the CRF. If this documentation is not available, then subject recollection 
will suffice. For subjects who do not know the exact nadir value and for whom there 
is no source documentation, then recall of the categorical nadir (e.g., <50, <100, <200 
cells/mm3) will suffice. 
 
5.3.6 
Complete Physical Exam 
This should be documented in the source documents only. This examination includes 
at a minimum an examination of the skin, head, mouth, and neck; auscultation of the 
chest; cardiac exam; abdominal exam; examination of the lower extremities for 
edema; and Karnofsky performance test. The complete physical exam will also 
include signs and symptoms, height, weight, diagnoses, and vital signs (temperature, 
pulse, respiration rate, and blood pressure). 
 

 
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5.3.7 
Clinical Assessments 
Targeted Physical Exam 
This should be documented in the source documents only. A targeted physical 
examination is to include vital signs (temperature, pulse, respiration rate, and blood 
pressure) and is to be driven by any previously identified or new signs or symptoms 
including diagnoses that the subject has experienced since the last visit. The 
vaccination site should be examined for erythema, swelling, tenderness or lumps up 
to Week 28. Staff should inquire about symptoms and examine the relevant areas, as 
indicated. Staff should inquire specifically about signs and symptoms of muscle 
aches, skin rashes, pruritus or redness. 
 
The penis, scrotum and perianal area will be examined for signs of HPV-related 
lesions. The presence or absence of penile/scrotal/perianal condyloma will be 
recorded on the CRFs. Anal cytology and HRA with biopsy of visible disease will be 
performed to assess anal HPV-associated disease. Sampling of the penis/scrotum, 
perianal area and the anal canal for HPV DNA and other sexually transmitted agents 
will be performed. HRA and anal cytology are required assessments at baseline and 
Weeks 28, 52, 78, and 104. Only visual inspection of the penis, scrotum, and perianal 
area are required at Week 8 and Week 24. 
 
Staff should inquire about symptoms of sexually transmitted diseases such as genital 
ulcer, dysuria, penile discharge, rectal pain or discharge, rash or sore throat. Staff 
should provide subjects with counseling and condoms to avoid acquisition of sexually 
transmitted diseases or new strains of HIV, and to avoid spread of HIV infection at 
each visit. 
 
Signs and Symptoms 
All signs and symptoms that begin during or after the entry visit should be recorded 
in the CRF regardless of grade. Any signs and symptoms that began prior to the entry 
visit should be recorded only if there is a significant worsening of the sign or 
symptom. After Week 32, only signs or symptoms ≥ grade 3 or signs and symptoms 
that are possibly, probably or definitely related to study vaccine should be recorded. 
 
This study will utilize the CTCAE Version 4.0 (Common Terminology Criteria for 
Adverse Event reporting) for grading of clinical or laboratory events. (See Section 
7.0) 
 
Diagnoses 
Record all diagnoses identified by the CTCAE Version 4.0 criteria (see Section 7.0 
for details) for clinical events and other diseases. Furthermore, any diagnosis of a 
cellulitis, abscess, or other infection at the vaccination site should be recorded. 
 
Vaccine Report Card 
Subjects should be given a Vaccine Report Card (Appendix XI) to take home and fill 
out after each vaccination. The subject should record an oral temperature 4 hours 

 
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after vaccination and then daily for 4 more days.  They should indicate whether 
redness, swelling, or pain or tenderness has occurred 4 hours after vaccination and 
then daily for 4 more days. They should record any adverse event for up to 15 days 
after vaccination to include local and systemic reactions. They should be instructed to 
contact the study nurse for any fever or moderate/severe symptoms. The nurse will 
call them within 24-48 hours of vaccination. The subject should be instructed to 
return the Vaccine Report Card at the next visit following each vaccination (Weeks 8, 
24 and 28). 
 
5.3.8 
Laboratory Evaluations (See Appendix I for timing of evaluations.) 
This study will utilize the CTCAE Version 4.0 for Common Terminology Criteria for 
Adverse Event reporting. Record all Grade ≥ 2 laboratory values (except for CD4 cell 
counts) as AEs. All laboratory toxicities that led to a change in treatment, regardless 
of grade, must be recorded. 
• 
Hematology - CBC with differential 
• 
Liver Function Tests - AST (SGOT), ALT (SGPT), and total bilirubin 
• 
Anal cytology (See Appendix V, Anal Cytology Sampling Procedures) 
• 
Anal HPV DNA PCR (See Appendix VI, HPV DNA PCR Specimen Collection 
and Shipping) 
• 
HPV strain variant analysis among those who are positive for these types in more 
than one sample at any visit or over time.  
• 
HPV 16, 18, 31, 6 or 11 DNA quantitation using quantitative PCR before and 
after vaccination among those who are HPV-positive at baseline. 
• 
High resolution anoscopy (HRA) (See Appendix VII) 
• 
Oral testing for HPV DNA (See Appendix VIII) 
• 
Urine specimens for GC and Chlamydia using nucleic acid amplification test 
(NAAT) (performed locally at sites)  
• 
Penile, scrotal and perianal area sampling for HPV DNA PCR 
• 
AIN or condyloma biopsies diagnosed during the study will be analyzed for the 
presence of HPV DNA using PCR. 
 
5.3.9 
Immunologic Studies 
To document eligibility for those subjects who are not on antiretroviral therapy, 
CD4+ level must be equal or greater than 
≥350 cells/mm
3 within 90 days prior to 
study entry from a laboratory that possesses a CLIA certification or equivalent. 
CD4+/CD8+ will be obtained from all subjects within 90 days prior to study entry 
and at Week 28. 
 
Serum HPV antibody testing 
A serum sample will be drawn for HPV antibody testing as well as storage for future 
testing. The HPV antibody test will be performed by the Merck Research Laboratory. 
Please refer to Appendix IX for information regarding HPV antibody specimen 
collection and shipping procedures.  
 

 
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5.3.10 Virologic Studies 
Plasma HIV-1 RNA 
On-study plasma HIV-1 RNAs will be done in real time. Plasma HIV viral load will 
be obtained within 90 days prior to study entry and at Week 28. 
 
5.3.11 Telephone Follow-Up 
Each subject (or legal guardian) will be contacted by the study nurse by telephone 24 
to 48 hours following each vaccination to determine if any side effects have occurred. 
Information from the telephone contact will be recorded. If a subject experiences any 
side effects (including fever) that are grade 3 or 4, or if he has edema (swelling), 
erythema (redness), or induration of grade ≥ 2, the subject should be scheduled to 
come into the clinic as soon as possible, for an evaluation that includes a targeted 
physical examination focused on the area involved. 
 
5.3.12 Smoking Status/Recent Sexual History /Risk Perception And Knowledge 
Questionnaire 
Each subject will be given a Questionnaire to determine their smoking status, recent 
sexual history and risk perceptions about HPV after receiving each vaccination (Day 
1, Week 8 and Week 24) and at Weeks 52, 78 and 104 (See Appendix I). Sites should 
ensure that the Questionnaire includes the subject’s 9-digit study number prior to 
giving the Questionnaire to the subject. Subjects will fill out the Questionnaire, place 
the completed Questionnaire in an envelope and seal it. Site should mail completed 
Questionnaires to: 
ATTN:  AMC Operations and Data Management Center 
The EMMES Corporation 
401 N. Washington Street, Suite 700 
Rockville, MD  20850 
 
5.4 
Dose Modification/Toxicity Management 
5.4.1 
Management of Injection Site and Allergic Reactions 
 
Local and systemic reactions will be graded according to the CTCAE Version 4.0 for 
Common Terminology Criteria for Adverse Event reporting. 
 
5.4.1.1 Injection Site Reactions 
• 
Swelling or redness at the injection site 
• 
Pain or tenderness, or other reactions at the injection site 
 
For injection site reactions judged to be severe, the safety review team should 
be notified within 24 hours and further vaccines should not be given to that 
subject prior to consultation with Protocol Chair/Co-chairs. 
 
For injection site reactions judged to be life-threatening, the safety review 
team should be notified within 24 hours and no additional vaccinations shall 
be given to that subject. 

 
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5.4.1.2 Systemic Reactions occurring within 48 hours after vaccination 
• 
Fever or chills  
• 
Malaise or fatigue  
• 
Headache or pain (e.g., myalgias or arthalgias)  
• 
Nausea or vomiting 
• 
Allergic reactions 
 
The safety review team should be contacted within 24 hours for any systemic 
grade 3 or 4 reactions (e.g., elevated temperatures following vaccination) 
thought definitely, possibly, or probably related to vaccination. Further 
vaccines should not be given to that subject prior to consultation with the 
Protocol Chair/Co-chairs. 
 
Subjects who are allergic to yeast or to any component of the vaccine 
should not receive quadrivalent HPV vaccine. 
 
Clinically significant adverse reactions and other problems related to vaccines 
will be reported to the Vaccine Adverse Event Reporting System (VAERS), 
which is maintained by the FDA and CDC (http://vaers.hhs.gov/). 
 
5.4.2 
Other Adverse Events 
For toxicities not specifically addressed above, the following guidelines should be 
used for the management of AEs: 
 
Grade 1 or 2 Toxicity/AE 
Subjects who develop a grade 1 or 2 AE may continue study vaccine. For instructions 
regarding subjects experiencing grade 1 or 2 AEs who choose to permanently 
discontinue study treatment or study participation, see Sections 5.2.4 and 5.2.5. 
 
Grade 3 or 4 Toxicity/AE 
Subjects who develop a grade 3 or 4 AE should be reevaluated for that toxicity until 
the AE returns to grade ≤ 2. The study vaccine may be given at the discretion of the 
site investigator. If the same grade 3 or 4 AE recurs and is considered by the 
investigator to be possibly related to the study vaccine, the study vaccine must be 
permanently discontinued. If, in the investigator’s opinion, the AE has NOT been 
caused by the study vaccine or if the event is an asymptomatic laboratory 
abnormality, study treatment may continue. 
 
For instructions regarding subjects experiencing grade 3 or 4 AEs that result in 
permanent discontinuation of study vaccine or study participation, see Sections 5.2.4 
and 5.2.5. These subjects should be followed weekly until resolution of the AE. 

 
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6.0 
CRITERIA FOR DISCONTINUATION 
6.1 
Permanent Treatment Discontinuation 
• 
Drug-related toxicity (see Section 5.4 for details of toxicities requiring treatment 
discontinuation). 
• 
Development of an allergy or systemic sensitivity to study medication. 
• 
Completion of treatment as defined in the protocol. 
• 
Request by subject to terminate treatment. 
 
6.2 
Premature Study Discontinuation 
• 
Request by the subject to withdraw. 
• 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the subject. 
• 
The subject is judged by the Investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results. 
• 
At the discretion of the AMC, ATN, IRB, Office for Human Research Protections 
(OHRP), NCI, NICHD, investigator, or pharmaceutical supporter.  
• 
Clinical reasons believed life-threatening by the site Investigator, even if not addressed in 
the toxicity section of the protocol. 
 

 
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7.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
The CTEP Version 4.0 of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be utilized for AE reporting. The CTEP Version 4.0 of the CTCAE is 
identified 
and 
located 
on 
the 
CTEP 
website 
at 
http://ctep.cancer.gov/protocol 
Development/electronic_applications/ctc.htm. All appropriate treatment areas should have 
access to a copy of the CTEP Version 4.0 of CTCAE. 
 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31, and October 31. 
 
7.1 
Classification of AEs by Severity and Relationship to Study Vaccine Administration 
Adverse Event 
Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom 
or disease temporally associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probable, or definite). 
 
Life-Threatening Adverse Event 
Any AE that places the patient or subject, in view of the investigator, at immediate risk of 
death from the reaction. 
 
Serious Adverse Event (SAE) 
Any AE occurring at any dose that results in any of the following outcomes: Death, a life-
threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, in the Investigator’s opinion, or a congenital 
anomaly/birth defect. 
 
Please note for hospitalization – All hospitalizations (or prolongation of existing 
hospitalization) for medical events equivalent to CTCAE Grade 3, 4, 5 must be reported 
regardless of the requirements for Phase of study, expected or unexpected, and attribution. 
For example, do not report an admission for pharmacokinetic sampling, but do report an 
admission for a myocardial infarction.  
 
Toxicity 
Toxicity is a term NOT clearly defined by regulatory organizations. Toxicity has been 
described as an AE that has an attribution of possibly, probably or definitely related to 
investigational treatment. To minimize confusion the NCI would recommend that the term 
toxicity NOT be utilized for AE reporting purposes. The CTCAE continues to use the term 
‘toxicity’ because of familiarity. 
 
Unexpected Adverse Event 
Any AE that is not listed in the package insert, protocol, or informed consent form. 
 

 
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CTEP Adverse Event Reporting System(CTEP-AERS)  
An electronic system for expedited submission of AE reports. 
 
Attribution 
The determination of whether an AE is related to a medical treatment or procedure. 
Attribution categories: 
Definite 
The AE is clearly related to the investigational agent(s). 
Probable 
The AE is likely related to the investigational agent(s). 
Possible 
The AE may be related to the investigational agent(s). 
Unlikely 
The AE is doubtfully related to the investigational agent(s). 
Unrelated 
The AE is clearly NOT related to the investigational agent(s). 
 
7.2 
Routine Reporting of AEs with Investigational Agents/VAERS 
An investigational agent is one being studied under an Investigational New Drug Application 
(IND). In some instances, a commercial agent may also be considered investigational when 
used under an IND. 
 
All AEs, regardless of severity, and whether or not ascribed to the study vaccine 
administration, will be recorded in the appropriate section of the CRF. After Week 32, only 
SAEs and AEs or symptoms > grade 3 or symptoms that are possibly, probably, or definitely 
related to the study vaccine should be recorded. Subjects withdrawn from the study due to 
AEs will be followed by the Investigator until the outcome is determined and, when 
appropriate, additional written reports and documentation will be provided. 
 
AEs reported through CTEP-AERS must also be reported in routine study data submissions. 
 
Clinically significant adverse reactions and other problems related to vaccines will be 
reported to the Vaccine Adverse Event Reporting System (VAERS), which is maintained by 
the FDA and CDC (http://vaers.hhs.gov/). 
 
7.3 
Expedited AE Reporting 
7.3.1 
Expedited AE Reporting through CTEP-AERS 
Expedited AE reporting for this study will occur via CTEP-AERS (Adverse Event 
Reporting System) accessed via the Cancer Therapy Evaluation Program (CTEP) 
home page. (http://ctep.cancer.gov). Expedited reporting requirements are outlined in 
the table below. CTEP-AERS is programmed for automatic electronic distribution of 
reports to the following individuals: Protocol Study Chair, Principal Investigator at 
the local AMC treating institution, and AMC Operations Center. CTEP-AERS 
provides a copy feature for other e-mail recipients. All reported SAEs will be 
reviewed by the Protocol Chair to determine if further action is necessary. 
 
A 24-hour notification is to be made to the AMC ODMC by telephone at 301-251-
1161, only when Internet connectivity is disrupted.  Once Internet connectivity is 
restored, an AE report submitted on a paper template must be entered electronically 
into CTEP-AERS by the original submitter at the site. 

 
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Expedited Reporting Timelines for Adverse Events that occur within 8 Weeks1 of the Last Dose of 
the Investigational Agent on Phase 2 and 3 Studies 
 
1 
2 
2 
3 
3 
4 & 5 
4 & 52 
Unexpected 
and  
Expected 
Unexpected Expected 
Unexpected 
Expected 
Unexpected Expected 
with  
Hospitalization 
without 
Hospitalization 
with 
Hospitalization 
without 
Hospitalization 
Unrelated 
Unlikely 
Not  
Required 
Not  
Required 
Not  
Required 
10 Calendar 
Days 
Not  
Required 
10 Calendar 
Days 
Not  
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not  
Required 
10 
Calendar 
Days 
Not  
Required 
24-Hour;  
5 Calendar 
Days 
24-Hour;  
5 Calendar  
Days 
24-Hour;  
5 Calendar 
Days 
24-Hour;  
5 Calendar 
Days 
24-Hour;  
5 Calendar 
Days 
10 
Calendar 
Days 
1Adverse events with attribution of possible, probable, or definite that occur greater than 8 weeks after the last dose of treatment 
require reporting as follows: 
24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 3 events at least possibly related to treatment 
• 
Grade 4 and Grade 5 unexpected events 
Complete SAE report within 10 calendar days: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2Although 24-hour notification is not required for death clearly related to progressive disease a full report is required as outlined in the 
table. 
 
December 15, 2004 
 
7.3.2 
Expedited AE Reporting to Merck 
All SAE reports submitted through CTEP-AERS that are at least possibly attributed 
to study vaccine administration will be forwarded to designated Merck personnel by 
the AMC Operations Center. 

 
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8.0 
STATISTICAL CONSIDERATIONS  
8.1 
General Design Issues 
The sample size considerations are based on estimation of the incidence of HPV 
infection/anogenital disease. This is an open-label trial in which the beneficial effects of the 
vaccine are expected to be limited to those who are naive to one or more of the HPV vaccine 
types.  Analyses will be conducted for HPV 6, 11, 16 and 18 separately. The study will 
evaluate the impact of vaccination on anogenital disease associated with vaccine HPV types: 
anogenital disease is defined as intra-anal and external ano-genital lesions further defined as 
low-grade 
(condyloma/intraepithelial 
neoplasia 
grade 
1) 
and 
high-grade 
lesions 
(intraepithelial lesions grades 2-3) 
 
The incidence of HPV infection/anogenital disease will be estimated in four groups based on 
all four types combined and on a type-specific basis: 
1) Seronegative/DNA negative 
2) Seronegative/DNA positive 
3) Seropositive/DNA negative 
4) Seropositive/DNA positive 
 
Our plan is to administer the vaccine to all study participants. The power estimates are based 
on an anticipated incidence of HPV-associated disease without vaccine and determining 
whether we can detect a lower rate with the vaccine. If we assume hypothetically that the 
incidence of persistent HPV infection w/o vaccine is 10 per 100 PY and the expected 
incidence of HPV-associated disease is 5 per 100 PY, then the attached table shows the effect 
size and associated lower rate of infection that can be detected with the anticipated numbers 
of patients for a “per protocol” population for each HPV type. No adjustments were made for 
the fact that we are looking at four distinct HPV types. 
 
8.2 
Endpoints 
8.2.1 
Primary Endpoints 
• 
Any incident AIN or anal/perianal condyloma associated with HPV 16, 18, 6 or 
11 DNA (as determined by PCR analysis of the anal tissue biopsy). No biopsies 
will be taken of penile/scrotal lesions and incident penile/scrotal condyloma will 
be considered an endpoint if associated with a positive penile/scrotal sample for 
HPV 6, 11, 16 or 18 DNA at the same visit.  
• 
Diagnosis of HGAIN related to vaccine HPV types at any time during the study is 
also a study endpoint.  Subjects with HGAIN should be treated but should remain 
in follow-up during the study per the routine study calendar.  
• 
Any persistent anogenital infection with HPV 16, 18, 6 or 11 DNA, defined as 
having positive PCR results with a specific HPV type at 2 or more consecutive 
visits. Persistent HPV DNA positivity is defined as detection of the same HPV 
type in any of the samples at a given visit over at least 2 consecutive visits.  To be 
considered eligible for analysis at least one of the specimens at a given visit must 
be positive for beta-globin DNA.  
 
8.2.2 
Secondary Endpoints 

 
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• 
Occurrence of grade ≥ 3 AEs that are possibly, probably or definitely related to 
the vaccine. 
• 
Longitudinal changes in plasma HIV-1 RNA and CD4+ cell count from Baseline. 
• 
Level of HPV antibodies to types 6, 11, 16 and 18, at Baseline, one month after 
the completion of HPV vaccination series and Weeks 52, 76 and 104. 
 
8.2.3 
Tertiary Endpoints 
• 
Level of HPV DNA before and after vaccination. 
• 
Type and level of HPV DNA in the oral cavity 
• 
HPV strain variation before and after receipt of the quadrivalent HPV vaccine. 
• 
Baseline prevalence and incidence of penile gonorrhea and Chlamydia infection.  
• 
Change in young men’s risk perceptions, sexual behaviors, and STI diagnosis 
after HPV vaccination. 
 
8.3 
Sample Size and Accrual 
Based on the existing literature among young HIV-positive MSM (Moscicki AB AIDS. 
2003;17:311-20) it was assumed that the baseline prevalence of HPV 16 DNA would be 14% 
DNA-positive, and an additional 14% was estimated to be seropositive.  Therefore 72% 
would be eligible for PPE analysis.  For HPV18, we assumed 0% to be DNA-positive and 
10% to be seropositive, therefore 90% would be eligible for PPE analysis.  HPV 6 and HPV 
11 were presented combined in the paper at a total of 23%.  We can assume for our purposes 
that each was found at 16% for 6 and 8% for HPV 11.  Assuming another 16% and 8% to be 
seropositive for 6 and 11, respectively, therefore we assume that 68% would be available for 
PPE analyses for HPV 6 and 84% for HPV 11.  
 
Data on incidence HPV infection or disease are available on the placebo group from the 
Merck 020 study. The vaccine will be considered to have a preventive effect if it reduces the 
anticipated incidence of HPV infection/anogenital disease by 75% overall in the study 
population.  
 
It is anticipated that 150 patients will be recruited and followed for two years for a total of 
300 person-years.  The ITT Merck placebo rates were used to determine the number of events 
(HPV-type specific AIN or persistent infection) that are expected with 200 person-years.  If 
the vaccine has a 75% efficacy rate, then the number of events expected on the vaccine 
would be 25% of that expected using the Merck rates.  Using the normal approximation to 
the Poisson distribution with the standard deviation based on the Merck rate (conservative 
approach), there will be 99% power to detect the following differences at the one-sided 0.10 
significance level with 150 patients followed for 2 years. 
 

 
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HPV-related AIN 
 
Merck Placebo data 
Vaccine Group 
Standard 
deviation 
Effect Size 
 
AIN-rate per 
100 PY 
Expected 
AIN events 
(300 PY) 
AIN-rate 
per 100 PY 
Expected 
AIN events 
(300 PY) 
HPV-6 
7.30 
21.90 
1.83 
5.48 
4.68 
3.51 
HPV-11 
3.80 
11.40 
0.95 
2.85 
3.38 
2.53 
HPV-16 
2.70 
8.10 
0.68 
2.03 
2.84 
2.14 
HPV-18 
1.60 
4.80 
0.40 
1.20 
2.19 
1.64 
 
 
HPV-related Persistent Infection 
 
Merck Placebo data 
Vaccine Group 
Standard 
deviation 
Effect Size 
 
Persistent 
infection rate 
per 100 PY 
Expected 
Persistent 
infection 
events 
(300 PY) 
Persistent 
infection 
rate per 100 
PY 
Expected 
Persistent 
infection 
events 
(300 PY) 
HPV-6 
10.70 
32.10 
2.68 
8.03 
5370 
4.22 
HPV-11 
4.30 
12.90 
1.08 
3.24 
3.59 
2.70 
HPV-16 
5.60 
16.80 
1.40 
4.20 
4.10 
3.07 
HPV-18 
3.80 
11.40 
0.95 
2.85 
3.38 
2.53 
 
It is anticipated that there will be 100 HPV-type naïve patients for each HPV type.  If the 
vaccine has a 75% protective effect, then the following table shows the upper the estimated 
upper bound of the 90% confidence interval for the incidence of HPV-specific AIN and 
persistent infection. 
 
HPV-related AIN 
 
Incidence on vaccine 
(per 100 PY) 
Upper 90% 
Confidence Limit 
(per 100 PY) 
HPV-6 
1.83 
2.00 
HPV-11 
0.95 
1.07 
HPV-16 
0.68 
0.75 
HPV-18 
0.40 
0.48 
 
HPV-related Persistent Infection 
 
Incidence on vaccine 
(per 100 PY) 
Upper 90% 
Confidence Limit 
(per 100 PY) 
HPV-6 
2.68 
2.88 
HPV-11 
1.08 
1.21 
HPV-16 
1.40 
1.55 
HPV-18 
0.95 
1.07 
 
To determine if there will be sufficient numbers of HPV-naïve patients for each type, the 
study team will review the distribution of HPV types after a total of 100 patients have 
enrolled in the study.  If it appears that for any of the HPV types, that there will be fewer than 
67% of the patients that are naïve to that type, an amendment may be submitted to increase 

 
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42 
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the number of patients to ensure that there are 100 naïve patients per type. At the time of the 
amendment the scientific rationale for the sample size increase (including the use of the 
Merck Placebo data as historical control) will be re-evaluated. 
 
8.4 
Safety Analysis 
Regarding safety, the adverse event rate will be assessed for the combined groups, and will 
include all subjects who receive at least one dose of study vaccine. We will report the adverse 
event rate as defined by 8.2.2 with a corresponding upper bound of a one-sided 95% 
confidence interval. With 100 evaluable patients, if no more than eight patients experienced 
an adverse event as defined by Section 8.2.2, the upper bound of the one-sided 95% 
confidence interval for the AE rate would be below 15%. There is 80% power to reject the 
null hypothesis that the AE rate is 6.5%. All safety endpoints will be reviewed by a team of 
AMC and ATN medical monitors. The final adjudication for the relationship to vaccine 
(unrelated, unlikely, possible, probable, or definite) will be made by this team. We will also 
report the adverse event rate and corresponding confidence interval for adverse events 
regardless of attribution to study vaccine.  
 
We will also report injection site reactions and systemic reactions specified in Section 5.4.1.1 
and 5.4.1.2 of all grade.   
 
8.5 
Monitoring  
The study will be reviewed at least quarterly by a team of AMC and ATN medical monitors. 
The study team will receive monthly reports on accrual and study conduct, and the NCI 
Clinical Representative will review a safety report every 3 months. 
The first AMC/ATN Medical Monitor team review will be after the first 30 subjects have 
reached Week 28. The AMC/ATN Medical Monitor team will be provided data on accrual, 
retention, and occurrence of adverse events as defined by the secondary endpoints.  
 
The occurrence of at least two adverse events as defined by Section 8.2.2 or a single grade 4 
or 5 adverse event that is at least possibly related to study vaccine will cause the study to halt 
enrollment and further vaccinations. The study will restart only after a review of available 
safety data and SAE reports by the safety review team.  If consensus about restarting the 
study is not reached among these members, then the decision will be made by the AMC 
Executive Committee. This process will be repeated after every 2 adverse events as defined 
by Section 8.2.2 or after each grade 4 or 5 adverse event that is at least possibly related to 
study vaccine. 
 
8.6 
Primary, Secondary and Tertiary Analyses 
8.6.1 
Primary 
The primary analysis of the study on incident AIN or condyloma will be performed 
among those who are naïve to a given HPV type and who complete the vaccination 
series per protocol, compared with subjects who are not naïve. Specifically, we will 
report the prevalence of anal condyloma or AIN at weeks 28, 52, 76 and 104. To be 
counted as a case, the anal biopsy must be positive for HPV 6, 11 16 or 18 DNA. No 
penile/scrotal biopsies will be taken and a case of incident penile/ scrotal condyloma 

 
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will be defined as clinical diagnosis of condyloma along with a positive HPV DNA 
result from the penile/scrotal specimen on the same day for one or more of the four 
HPV vaccine types. One set of primary analyses will be performed combining all 
cases positive for HPV 16, 18 and 6 or 11.  Another set of analyses will be done on 
HPV 16, HPV 18 and HPV 6- or 11-associated lesions individually.   
 
The primary analysis on prevention of persistent anal HPV infection will be 
performed among those who are naïve to a given HPV type and who complete the 
vaccination series per protocol, compared with subjects who are not naïve.  A 
combined endpoint of persistent HPV 16, 18, 6 or 11 will be analyzed, as will 
persistent anal HPV 16, HPV 18 and HPV 6 or 11 individually.   
 
We will obtain all available abnormal cytology and histology slides (pre-entry and 
post-entry) and 10% of normal cytology slides for central pathology review.  A 
revised rate of incident condyloma or AIN after vaccination will be reported 
excluding those subjects with pre-existing high grade AIN at pre-entry or week 28 as 
judged by central review. 
 
Using the incidence rates of HPV 6/11/16/18 - related AIN and anal cancers, 
persistent infection and DNA detection from the placebo group of a recently 
completed study (REF) in a Poisson distribution, the probability of detecting the 
results from the current trial will be estimated to determine if they are consistent with 
the previously reported placebo rates.  It is anticipated that these analyses will be 
done for each HPV type. For the analysis of AIN and anal cancers, analyses will also 
be performed by lesion type.  A one-sided significance level of 0.10 will be used for 
this analysis.  No adjustments for multiple testing are planned. 
 
8.6.2 
Secondary 
The safety analysis on the study AEs described in the primary endpoint will be 
performed according to section 8.4. For a safety analysis, the rate of AEs of grade 2 
or higher will be estimated with a one-sided 95% CI. In addition, the changes in HIV 
RNA and CD4+ count from baseline at the scheduled measurement times will be 
summarized for all the subjects. 
 
Detectable Ab response at Week 28 will be performed by HPV type (6, 11, 16 and 
18) on the subjects who are seronegative and HPV DNA PCR-negative for that type 
at baseline and complete the vaccination series per protocol. The type-specific Ab 
response rates will be estimated with one-sided 95% CI’s to specify the lower 
bounds. A secondary analysis will include only those subjects who are HPV DNA 
PCR negative at entry and Week 28. 
 
The antibody response will also be analyzed on all study subjects who are 
seronegative for that type at baseline, as an intent-to-treat analysis. In addition, the 
Ab titer (as a continuous measure) at the scheduled times will be summarized using 
descriptive statistics for the subjects who are seronegative at baseline, for each HPV 
type (6, 11, 16, 18). Also, the Ab titer changes from baseline will be summarized for 
each of the four HPV types, for the subjects who are seropositive for that type at  
 

 
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baseline. We will also describe the antibody response among subjects who are HPV 
DNA PCR positive at baseline. 
 
A logistic regression model will be developed to assess the effect of baseline and 
nadir CD4+ count, and age on Ab response to type 16 or 18 - depending on the 
baseline serostatus - using all study subjects. Note that subjects who initiate, 
discontinue, or modify antiretroviral therapy during the trial will not be excluded 
from these analyses. 
 
8.6.3 
Tertiary 
Incident infections will be defined as HPV infections found after Week 28 with no 
evidence for prior infection: the type was not present at screening, entry or Week 28; 
and subjects were seronegative for that type at entry. We will also report 
reactivations/reinfections defined as HPV infections found after Week 28 that were 
not present at Week 28 among subjects with a prior history of that HPV type: 
presence of that type at screening or entry; or seropositivity at entry. For each HPV 
type, the proportion of study participants were develop a new HPV infection and the 
proportion who report reactivations/reinfections will be estimated using the binomial 
proportion and its 95% confidence interval. We will also describe the cytological and 
histological abnormalities observed at baseline.  
 
In tertiary analyses, we will the use descriptive statistics to characterize changes in 
the level of anogenital and oral  HPV types 16, 18, 31, 6 and 11 at screening, entry 
and at all other time points at which DNA is collected. Significant changes will be 
defined as those more than one-half log difference from the previous specimen. 
 
We will also describe the ongoing sexual exposure to HPV in the study population. 
Specifically, we will report the total number of sex partners (male and/or female), 
receptive anal sex partners, and active oral sex partners at study entry and every 6 
months thereafter. In exploratory analyses, we will correlate these variables with 
incident HPV infections in the mouth and anus.   
 
We will perform HPV strain variant analysis of samples positive for HPV 16, 18 and 
31 at more than one visit to determine if the same variant is present in different 
anatomic locations and over time at the same location.   
 
We will assess the prevalence of urinary gonorrhea and Chlamydia trachomatis 
infection at baseline and at all visits where samples are collected for GC and 
Chlamydia, and their relationship with prevalent and incident anogenital HPV 
infection and anal condyloma or AIN. 
 
We will determine the effect of vaccination on young men’s risk perceptions, sexual 
behaviors, and STI diagnosis. Participants will fill in the risk perceptions and 
knowledge survey (Appendix XII).  Descriptive analyses will characterize subjects’ 
risk perceptions, knowledge about HPV, sexual behaviors (e.g., condom use with 
sexual intercourse, number of sexual partners over prior 3 months) at study entry 
(immediately after vaccine dose #1), Week 8 (after vaccine dose #2), Week 24 (after 
vaccine dose #3), Week 52, Week 78, and Week 104. 

 
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Univariate analyses will be conducted to determine whether subject characteristics 
and HPV knowledge are associated significantly with risk perceptions after vaccine 
dose #1, and also whether knowledge and risk perceptions immediately post-
vaccination are associated significantly with sexual behaviors or STI diagnosis at 
each of the follow-up visits. 
 
In order to determine whether attitudes immediately post-vaccination are associated 
with behaviors and STI diagnosis at the four follow-up time points, we will use 
correlated logistic regression or generalized estimating equation (GEE) models with 
attitudes as the independent variables and behaviors or STI diagnosis as the 
dependent variables.  GEE is a useful technique for dealing with repeated categorical 
data and is commonly used in situations where an identical measurement (behaviors 
or STI diagnosis) is repeatedly taken on the same subject.  Repeated measurements 
induce a variance/covariance structure that can be utilized in the analysis, for 
example, the most general (unstructured) variance/covariance structure.  Therefore, in 
addition to the odds ratios, the 10 variance/covariance parameters of the 4x4 
variance/covariance matrix (since we have 4 time points) will be estimated. 
 
If these parameters were found to be inestimable, then a Toeplitz structure (equi 
variance/covariance parameters along the diagonals), with four variance/covariance 
parameters, would be used. 
 
We will also use linear mixed models to examine trends in sexual behaviors over 
time, and to compare trends in sexual behaviors over time in subjects who hold 
specific attitudes immediately post-vaccination vs. those who do not, taking into 
account all time points after vaccination.  These models will also control for variables 
associated in univariate analyses with sexual behaviors or STI diagnosis.  Linear 
mixed models take into account the repeated measures which also induce a 
variance/covariance structure that can be utilized in the analysis.  Similar models will 
be used with STI diagnosis as the outcome variable. 
 
 
 

 
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9.0 
DATA COLLECTION AND MONITORING 
9.1 
Records to Be Kept 
CRFs will be provided for each subject via the AMC AdvantageEDCSM Internet Data Entry 
System upon enrollment. Subjects must not be identified by name on any study documents. 
Data will be recorded on the CRFs using the unique subject identification number assigned at 
registration. Sample CRFs will be available on the AMC ODMC web site 
(www.amcoperations.com). 
 
9.2 
Role of Data Management 
Instructions concerning the recording of study data on CRFs will be provided by the AMC 
ODMC. The AMC Internet Data Entry System User’s Guide can be found on the AMC 
ODMC web site (www.amcoperations.com). Each site is responsible for keying the data in 
and submitting the forms according to the target submission dates set forth by the 
AdvantageEDCSM system. 
 
It is the responsibility of the AMC ODMC to assure the quality of computerized data for each 
AMC study. This role extends from protocol development to generation of the final study 
databases. 
 
9.3 
Clinical Site Monitoring and Record Availability 
This protocol will follow the AMC Data Safety Monitoring Plan (see Appendix X). 

 
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10.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
10.1 
Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent documents and any subsequent modifications will be 
reviewed and approved by the IRB or ethics committee responsible for oversight of the study. 
A signed consent form will be obtained from the subject (or parent, legal guardian, or person 
with power of attorney for subjects who cannot consent for themselves, such as those below 
the legal age of consent). 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 subject, parent, or legal guardian, and this fact will be documented 
in the subject’s record. A signed assent form will be obtained from all subjects < 18 years of 
age. 
 
10.2 
Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will 
be identified by coded number only to maintain subject 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 subject, 
except as necessary for monitoring by the IRB, the NCI, the NICHD, the OHRP, or the 
pharmaceutical supporter(s) or designee.  
 
10.3 
Study Discontinuation 
The study may be discontinued at any time by the IRB, the NCI, the NICHD, the 
pharmaceutical supporter(s), the OHRP, or other government agencies as part of their duties 
to ensure that research subjects are protected. 
 
10.4 
Women and Minorities 
This study is being conducted by the NCI-sponsored AIDS Malignancy Clinical Trials 
Consortium (AMC) and the NICHD-sponsored Adolescent Trials Network (ATN). As part of 
their contractual obligations, each participating site within the AMC/ATN and the 
AMC/ATN as a whole is required to assure that the participation of minority subjects reflects 
the percentage representation of these populations in their geographic region and, for the 
AMC/ATN, the United States as a whole. As such, it is expected that the representation of 
subjects on this trial will reflect the constitution of the respective populations. Women are not 
being studied in this protocol. The safety and immunogenicity of Gardasil in HIV-positive 
women is being studied in ACTG 5240, AMC-060 and ATN 064. 
 
 
 

 
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11.0 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by AMC and ATN policies. Any 
presentation, abstract, or manuscript will be made available for review by the pharmaceutical 
supporter(s) prior to submission.  

 
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12.0 
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 Centers for 
Disease Control and Prevention and the National Institutes of Health. 
 
All dangerous goods materials, including diagnostic specimens and infectious substances, 
must be transported according to the instructions detailed in the International Air Transport 
Association (IATA) Dangerous Goods Regulations. 
 

 
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13.0 
REFERENCES 
1. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 
2. Centers for Disease Control and Prevention. Rockville, Md: CDC National Prevention 
Information Network; 2004 
3. Zaki SR, Judd R, Coffield LM, Greer P, Rolston F, Evatt BL. Human papillomavirus 
infection and anal carcinoma: retrospective analysis by in situ hybridization and the 
polymerase chain reaction. Am J Pathol 1992; 140:1345–55. 
4. Daling JR, Weiss NS, Hislop TG, Maden C, Coates RJ, Sherman KJ, Ashley RL, Beagrie 
M, Ryan JA, Corey L. Sexual practices, sexually transmitted diseases, and the 
incidence of anal cancer. N Engl J Med 1987; 317:973–7. 
5. Goedert JJ, Cote TR, Virgo P, et al. Spectrum of AIDS-associated malignant disorders. 
Lancet 1998; 351:1833–9. 
6. Bower M, Powles T, Newsom-Davis T, Thirlwell C, Stebbing J, Mandalia, S, Nelson M, 
Gazzard B. HIV-associated anal cancer: has highly active antiretroviral therapy 
reduced the incidence or improved the outcome? J Acquir Immune Defic Syndr. 
2004. Dec 15;37(5):1563-5. 
7. Diamond C, Taylor TH, Aboumrad T, Bringman D, Anton-Culver H. Increased incidence 
of squamous cell anal cancer among men with AIDS in the era of highly active 
antiretroviral therapy. Sex Transm Dis. 2005 May;32(5):314-20. 
8. Wilkin TJ, Palmer S, Brudney KF, Chiasson MA, Wright TC. Anal intraepithelial 
neoplasia in heterosexual and homosexual HIV-positive men with access to 
antiretroviral therapy. J Infect Dis. 2004 Nov 1;190(9):1685-91. 
9. Palefsky JM, Holly EA, Ralston ML, Da Costa M, Greenblatt RM. Prevalence and risk 
factors for anal human papillomavirus infection in human immunodeficiency virus 
(HIV)-positive and high-risk HIV-negative women.  J Infect Dis. 2001 Feb 
1;183(3):383-91 
10. Bruguera M, Cremades M, Salinas R, Costa J, Grau M, J S. Impaired response to 
recombinant hepatitis B vaccine in HIV-positive persons. J Clin Gastroenterol 
1992;14(1):27-30. 
11. Keet IP, van Doornum G, Safary A, Coutinho RA. Insufficient response to hepatitis B 
vaccination in HIV-positive homosexual men. Aids 1992;6(5):509-10. 
12. Rimland D, Guest JL. Response to hepatitis A vaccine in HIV patients in the HAART 
era. Aids 2005;19(15):1702-4. 
13. Shire NJ, Welge JA, Sherman KE. Efficacy of inactivated hepatitis A vaccine in HIV-
positive patients: a hierarchical bayesian meta-analysis. Vaccine 2006;24(3):272-9. 
14. Tayal SC, Sankar KN. Impaired response to recombinant hepatitis B vaccine in 
asymptomatic HIV-positive individuals. Aids 1994;8(4):558-9. 
15. Weissman S, Feucht C, Moore BA. Response to hepatitis A vaccine in HIV-positive 
patients. J Viral Hepat 2006;13(2):81-6. 
 

 
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16. Bruguera M, Cremades M, Salinas R, Costa J, Grau M, Sans J. Impaired response to 
recombinant hepatitis B vaccine in HIV-positive persons. J Clin Gastroenterol 
1992;14(1):27-30. 
17. Overton ET, Sungkanuparph S, Powderly WG, Seyfried W, Groger RK, Aberg JA. 
Undetectable plasma HIV RNA load predicts success after hepatitis B vaccination in 
HIV-positive persons. Clin Infect Dis 2005;41(7):1045-8. 
18. Bruguera M, Rodicio JL, Alcazar JM, Oliver A, Del Rio G, Esteban-Mur R. Effects of 
different dose levels and vaccination schedules on immune response to a recombinant 
DNA hepatitis B vaccine in haemodialysis patients. Vaccine 1990;8 Suppl:S47-9; 
discussion S60-2. 
19. Idilman R, Colantoni A, De Maria N, Ustun C, Sam R, Ing TS, et al. Impaired antibody 
response rates after high dose short interval hepatitis B virus vaccination of 
immunosuppressed individuals. Hepatogastroenterology 2003;50(49):217-21. 
20. Rey D, Krantz V, Partisani M, Schmitt MP, Meyer P, Libbrecht E, et al. Increasing the 
number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-
positive patients. Effects on HIV-1 viral load. Vaccine 2000;18(13):1161-5. 
21. Weinberg A, Gona P, Nachman SA, Defechereux P, Yogev R, Hughes W, et al. Antibody 
responses to hepatitis A virus vaccine in HIV-positive children with evidence of 
immunologic reconstitution while receiving highly active antiretroviral therapy. J 
Infect Dis 2006;193(2):302-11. 
22. Schiller JT, Lowy DR. Papillomavirus-like particles and HPV vaccine development. 
Semin Cancer Biol 1996;7(6):373-82. 
23. Viscidi RP, Snyder B, Cu-Uvin S, Hogan JW, Clayman B, Klein RS, Sobel J, Shah KV. 
Human papillomavirus capsid antibody response to natural infection and risk of 
subsequent HPV infection in HIV-positive and HIV-negative women. Cancer 
Epidemiol Biomarkers Prev. 2005 Jan;14(1):283-8. 
24. Hopfl R, Petter A, Thaler P, Sarcletti M, Widschwendter A, Zangerle R. High prevalence 
of high risk human papillomavirus-capsid antibodies in human immunodeficiency 
virus-seropositive men: a serological study. BMC Infect Dis. 2003 Apr 30;3:6. 
25. Hagensee ME, Kiviat N, Critchlow CW, Hawes SE, Kuypers J, Holte S, Galloway DA. 
Seroprevalence of human papillomavirus types 6 and 16 capsid antibodies in 
homosexual men. J Infect Dis. 1997 Sep;176(3):625-31. 
 

 
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APPENDIX I: SCHEDULE OF EVENTS 
Evaluation 
Screening/ 
Pre-Entry 
(- 45 days) 
Entry 
(D1) 
Injection 
1 
24-48 
Hr 
Post  
Wk 8 
(± 7 days) 
Injection 
2 
24-48 
Hr 
Post 
Wk 24 
(± 10 days) 
Injection  
3 
24-48 
Hr 
Post  
Wk 28 
(± 10 
days) 
Primary 
Endpoint 
Wk 52 
(± 28 
days) 
Wk 78 
(± 28 
days) 
Wk 
104 
(± 28 
days) 
Early 
Study 
Discont.  
Documentation of HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history/Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications/treatment 
modifications 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Nadir CD4+ cell count 
X1 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessments 
 
X 
 
X2 
 
X2 
 
X 
X 
X 
X 
X 
Smoking status/sexual 
questionnaire/risk perception and 
knowledge survey 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
Vaccine/distribute vaccine report card 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Collect vaccine report card 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Telephone follow-up  
 
 
X 
 
X 
 
X 
 
 
 
 
 
CD4+/CD8+ 
 
X1 
 
 
 
 
 
X 
 
 
 
X 
Plasma HIV-1 RNA 
 
X1 
 
 
 
 
 
X 
 
 
 
X 
CBC with differential 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Liver function tests 
X 
 
 
 
 
 
 
X 
 
 
 
X 
BUN/creatinine 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Anal cytology 
X1 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Swab for perianal HPV DNA PCR 
X3 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Swab for anal HPV DNA PCR 
 
X3 
 
 
 
 
 
X 
X 
X 
X 
X 
Swab for penile/scrotal HPV PCR 
 
X3 
 
 
 
 
 
X 
X 
X 
X 
X 
Urine testing for GC/chlamydia 
 
X3 
 
 
 
 
 
X 
X 
X 
X 
 
High resolution anoscopy  
X4 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Anal biopsies5 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Serum HPV antibody testing 
 
X3 
 
 
 
 
 
X 
X 
X 
X 
X 
Oral HPV PCR testing and exam 
 
X3 
 
 
 
 
 
X 
X 
X 
X 
X 
ACSR Biopsy Donation (Optional if 
patient consents)5 
X 
 
 
 
 
 
 
 
 
 
X 
 
ACSR Blood donation (Optional if 
patient consents) 
X 
 
 
 
 
 
 
 
 
 
X 
 

 
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1 To be obtained within 90 days prior to study entry 
2 HRA and anal cytology are not required assessments at Week 8 and Week 24. Visual inspection of the penis, scrotum, and perianal area should be done at Week 8 and Week 24. 
3 Collect the swab, serum HPV, and oral specimens after the subject is deemed eligible for enrollment onto the study (segment B) and prior to the vaccination on Day 1.  
4 HRA to occur at pre-entry visit prior to enrolling into Segment B. 
5 Anal biopsies (if lesion is suspected). 
6 Anal biopsies for ACSR donation may be obtained with the subject’s consent from suspected lesions. The tissue biopsy for ACSR donation must be separate from the diagnostic biopsy. 
 

 
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APPENDIX II: KARNOFSKY PERFORMANCE SCALE 
 
 
Karnofsky Performance Scale 
 
 
ECOG Performance Status Scale 
Percent 
Description 
Grade 
Description 
100 
Normal, no complaints, no evidence 
of disease. 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up 
and about more than 50% of waking 
hours. 
50 
Requires considerable assistance 
and frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
0 
Dead. 
5 
Dead. 

 
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APPENDIX III: MERCK GARDASIL® PRODUCT INFORMATION 
www.gardasil.com 

 
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APPENDIX IV: PENILE/SCROTAL SCRAPING PROCEDURES 
 
To collect penile and scrotal cells for HPV testing, the foreskin will be retracted if present and the 
penile (shaft, glans and corona) skin and scrotal skin will be gently abraded with 600 grit emery 
paper followed by swabbing with a Dacron swab moistened with sterile saline.  The swab from the 
Digene Female Swab Specimen Collection Kit (Catalog #5123-1220, 1-800-426-8157) will be 
inserted into a tube containing 1 mL of Sample Transport Medium (Digene). The swab should be 
placed in the collection vial and the end snapped off at the pre-scored line.  Then the cap should then 
be replaced securely. 
 
Sample Labeling 
Each sample should be labeled with the following information: 
• 
Nine (9) Digit Subject ID:  “072-XXX-XXX” 
• 
Date of Sample Collection 
• 
Specimen Type:  "Penile/Scrotal Swab” 
• 
Specimen Purpose:  “HPV DNA PCR” 
 
Please refer to Appendix VI for shipping instructions. 
 

 
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APPENDIX V: ANAL CYTOLOGY SAMPLING PROCEDURES 
All anal cytology specimens will be examined at the local institution. 
Procedure for obtaining an anal cytology: 
The subject should undress from the waist down, and either bend over the exam table or lay on his 
side in the fetal position. The examiner should use one hand to spread the buttocks and expose the 
anoderm. A Dacron swab moistened in sterile saline will then be inserted as far as is comfortable into 
the anus, a minimum of 2-3 inches. If there is difficulty inserting the swab, the subject should also 
retract their buttocks. With pressure on the distal end of the swab rotate it gently and slowly in a 
circular fashion as it is withdrawn over 15 to 30 seconds. Do not retract the buttocks when the swab 
is close to the verge to ensure that it is sampled as well. Immediately immerse the swab in a liquid-
cytology vial agitating vigorously over 10 to 15 seconds to disperse the cells and then discard the 
swab. 
All cytological specimens should be processed and examined locally. If insufficient or inadequate 
cytology results are obtained, the cytology assessment should be repeated if possible. Cytological 
slides from subjects who enter the trial should be available for central review upon request. 
 
After the first swab has been immersed in the liquid cytology vial, a second moistened Dacron swab 
will be inserted and sample collected for HPV DNA testing (same procedure described above). 
Please see Appendix VI for processing and shipping of the second sample collected for HPV 
DNA. 

 
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APPENDIX VI:  HPV DNA PCR SPECIMEN COLLECTION AND SHIPPING 
All HPV DNA PCR specimens (penile/scrotal, perianal, and anal) will be collected at the local 
institution and shipped to the Palefsky Laboratory. 
High resolution anoscopy is performed at screening and weeks 28, 52, 78 and 104. Biopsies are 
obtained if a lesion is suspected. One of the study outcomes is any incident AIN or anal/perianal 
condyloma associated with HPV 16, 18, 6 or 11 DNA as determined by PCR analysis of the anal 
tissue biopsy. Biopsies are fixed in formalin and sent to the local pathology lab for interpretation. We 
are requesting that the cassettes containing the biopsy be sent to the Palefsky lab. After the 
procedures described below are performed, the Palefsky lab will ship the remaining specimens back 
to the pathology lab that sent them. 
Specimens may be shipped to the Palefsky lab quarterly and will be returned to the pathology lab 
within 1 month. 
Procedure for obtaining perianal HPV DNA PCR sample 
The perianal skin will be will be gently scraped with 600 grit emery paper followed by swabbing 
with a Dacron swab moistened with sterile saline. The wetted swab will then be placed into a 
container of STM (Specimen Transport Medium, DIGENE, Gaithersburg MD). The swab should be 
placed in the collection vial and cut with sterile or single-use scissors to allow the swab to fit in the 
vial.  Then the cap should then be replaced securely. 
 
Procedure for obtaining intra-anal HPV DNA PCR sample: 
The procedure described above (in Appendix V) for collection of anal cytology should be repeated 
using a second Digene Female Swab Specimen Collection Kit (Catalog #5123-1220, 1-800-426-
8157). The swab will be inserted into a tube containing 1 mL of Sample Transport Medium (Digene). 
The swab should be placed in the collection vial and cut with sterile or single-use scissors to allow 
the swab to fit in the vial.  The cap should then be replaced securely. 
 
Note: Specimens will be processed for HPV DNA PCR, not Digene HCII. 
 
Specimens obtained for HPV testing (perianal, anal, and penile) should be stored at -80 C until 
shipment.  All specimens can be shipped in batches. Specimens should be shipped quarterly on dry 
ice to the laboratory.  Specimens should be shipped on Mondays and Tuesdays only. 
 
Sample Labeling 
Samples must be labeled with the bar-coded labels provided. Each sample should be labeled with the 
following information: 
• 
Nine (9) Digit Subject ID:  “072-XXX-XXX” 
• 
Specimen Type:   “Penile/Scrotal Swab”, “Perianal Swab” or "Anal Swab” or “Anal biopsy” 
• 
Specimen Purpose:  “HPV DNA PCR” 
• 
Date of Sample Collection 
 
 

 
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Preparation and disposition of thinsections of anal biopsy tissue 
 
The following procedures will be performed at the Palefsky Laboratory.  The procedures will be 
performed according to the laboratory's SOP. The histotechnologist will ensure that the microtome 
and work areas are clean and free of contaminants.  All Thinsection microtomy for PCR will be 
performed at a time when all other routine work has been completed, so potential contaminations can 
be minimized. Prior to sectioning each block, a new blade will be installed in the microtome. The 
blade will only be positioned so that it is at the left margin of the block surface. Technicians 
sectioning study blocks will utilize “biologically clean” gloves while handling the blocks (new 
gloves for each block). First, the technologist will face the block by removing two 4-micron sections 
from the face of the block. These sections will be discarded. Using sterile plastic forceps, the next 
two 4-micron paraffin sections are collected and floated in a water bath for the preparation of 1 H&E 
slide (Slide 1, with 2 sections). The forceps are discarded and a new blade is inserted into the 
microtome. Nine more 4-micron sections are cut and using the clean, central part of the microtome 
discarded after placing the cut section in each tube. Each tube is then placed inside a plastic sleeve 
and sealed. Slides and tubes should be labeled with subject’s allocation number.  
 
Two additional 4-micron sections are cut and 2 sections each are placed on 1 slide (Slide 2, with 2 
sections) for H&E staining. Both H&E slides (Slides 1 and 2) will have a histopathologic review by 
the central laboratory's pathologist. 
 
The microtome is cleaned in preparation for the next block and the process above is repeated. The 
microtome blade is replaced with a new blade and adjusted for each new biopsy block and the same 
procedure is to be followed. A new pair of clean gloves and a new pair of clean, disposable forceps 
will be used for each block being sectioned. The “used” blade may be retained for cutting non-PCR 
blocks. The total number of sections to be cut from each block is 13. A total of 2 slides and 9 tubes: 
 
Slides 1, 2 (H&E), with 2 sections each, stained. 
Tubes 1, 2, 3, 4, 5, 6, 7, 8, 9 (HPV PCR Analysis), 1 section per tube. 
 
HPV PCR will be performed to detect HPV vaccine types as well as non-vaccine types according to 
the Palefsky Laboratory SOP.    
 
Shipping 
Please note that the shipment of these samples requires certified training in IATA regulations. All 
shipping materials can be ordered from SAF-T-PAK at www.saftpak.com.  
1) Please use the Saf-T-Pak STP 340 shipper (each tube must be sealed with tape or parafilm under 
2011 IATA rules). Place securely fastened tubes in the clear biohazard bag with the absorbent 
strip. Seal bag. 
2) Place clear biohazard bag into the white Tyvek bag and seal bag. 
3) Place white Tyvek bag into inner box. 
4) Place the inner box into the STP 340 insulated box and cover with dry ice. 
5) Seal the box and place your FedEx airbill on the outside. 
6) Ship to the address below. AMC SITES: Please use the AMC ODMC FedEx account number to 
ship all HPV DNA PCR samples:  #
. ATN SITES: Please use your local Fed Ex 

 
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number to ship all HPV DNA PCR samples. 
 
7) Shipping address: 
Joel Palefsky Laboratory 
c/o Maria Da Costa 
University of California, San Francisco 
513 Parnassus Ave., Room S-420 
San Francisco, CA  94143 
Tel: 415-476-8885 
 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT DEVIATE FROM 
REQUESTED LABELING. Shipping frozen aliquots requires the use of packaging acceptable for 
dry ice and Class 9 label with weight of dry ice written on package. STP-340 will come pre-printed 
with: Biological Substance Category B Marking, Exempt Human/Animal Specimen Marking, 
UN3373 Marking, Orientation Arrows, Class 9 Label and UN1845 Dry Ice Marking 
 
Record of Specimens 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimen shipments. 

 
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APPENDIX VII:  HIGH RESOLUTION ANOSCOPY (HRA) 
 
Procedure for performing HRA: 
High resolution anoscopy should only be done after the anal cytology and HPV DNA PCR are 
collected. The patient should undress from the waist down and lay on his side on the exam table in 
the fetal position. A mixture of 2% lidocaine jelly and water-soluble lubricating jelly should be used 
as a lubricant. A compound pharmacist can make the 2% lidocaine jelly. A digital rectal exam should 
be performed noting any masses or areas of induration. The procedure for HRA is as follows: 
1. Insert the plastic disposable anoscope, remove stylet, place a cotton swab wrapped in gauze 
soaked in 3% acetic acid into anus, remove the anoscope over the swab and leave in place for 1 
to 2 minutes. 
2. Remove the swab and re-insert the anoscope. Carefully examine the anal canal with a 
colposcope. 
3. Re-apply acetic acid as necessary to ensure adequate detection of lesions. 
4. If acetowhitening is noted, note vascular characteristics, if present. 
5. Lugol’s solution (iodine) may be used as desired to identify areas of AIN near the 
squamocolumnar junction. 
6. Biopsy up to six of the most abnormal appearing areas. 
7. Apply acetic acid to perianal area and examine carefully with colposcope. 
8. If planning to biopsy an external lesion, infiltrate areas with 1% lidocaine with epinephrine using 
a 30-gauge needle, if possible. 
9. Biopsy  area if a lesion is suspected. 
10. A genital exam should be performed to note the presence of condyloma 
11. Subjects with signs or symptoms consistent proctitis or sexually transmitted infections other than 
HPV should be referred for appropriate diagnosis and treatment. 
 
Biopsies will be processed and read locally at the institution. 
The tissue block, along with a copy of the surgical pathology report should be available for central 
review upon request. If the block is not available, a representative H & E stained section and six 
stained slides should be submitted. All materials will be retained unless return is specifically 
requested. Tissue will be evaluated for histology as demonstrated by H & E staining. 
 
All slides should be sent to the following address for central pathology review: 
 
Teresa M. Darragh, MD 
UCSF/Mt. Zion Medical Center 
Dept. of Pathology, Box 1785 
1600 Divisadero Street, Room B217 
San Francisco, CA  94115 
Tel: 415-353-7861 
Fax: 415-353-7676 

 
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Slides from UCSF that are read by local pathologist Dr. Teresa Darragh will be reviewed by Dr. 
Mieke van Zante for central review. 
 
When affixing the specimen label, do not wrap the label around the slide as any protrusion at the 
bottom will result in the slide not sitting flat on the microscope stage.  In addition, do not cover the 
slide’s accession number.  In some cases, the label may need to be trimmed to allow the barcode and 
9-digit portion of the label to be affixed at the top of the slide.) 
 
Shipping Instructions 
1. Place the labeled slides into a specimen container or a slide box if available. Place the container 
or slide box in bubble wrap or other adequate cushioning. Use sturdy outer packaging to prevent 
breakage. 
2. Affix the FED-EX airbill on blank side of the shipper. 
3. Mark “OTHER” in the airbill under “Packaging”. 
4. Under airbill section “special Handling” indicate “YES-SHIPPERS DECLARATION NOT 
REQUIRED”. 
5. Enter FED-EX account #: 
 
6. Place “From/To” information onto areas provided on the shipper. Specimens are accepted 
MONDAY through THURSDAY only. All specimens should be shipped by FedEx 2-day 
service to Dr. Darragh at the address listed above: 
7. Make certain that shipper is visibly labeled “Exempt human specimen.” 
8. RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
9. Place the box in the FedEx pickup area at your site or call to request a package pickup. 
 
Record of Specimens 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimens. 

 
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APPENDIX VIII:  ORAL EXAMINATION/TESTING STORAGE AND SHIPMENT 
 
Please visit the AMC ODMC web site (www.amcoperations.com) for complete instructions related 
to Oral Examination & Diagnosis procedures and Oral Specimen Collection procedures. 
Storage for specimens: 
• 
Digene vials to be placed at -80 o C until shipping 
Note: Specimens will be processed for HPV DNA PCR, not Digene HCII. 
 
Storage for oral fluid samples: 
 
Whole saliva 
• 
Patient will have expectorated 5 ml into a sterile 30 ml conical tube 
• 
The saliva should then be stored at -80o 
 
Throatwash 
• 
A swish/gargle with 10 ml of Scope mouthwash will be housed in a sterile wide mouth 50 ml 
conical tube 
• 
Centrifuge to collect a cell pellet by centrifugation at 1200 g for 10 minutes 
• 
Pour supernatant into a 30 ml tube 
• 
Using a pipette, transfer the cell pellet to a Digene HCII DNA collection kit transport container  
• 
Label tubes with identifiers and as throatwash pellet or throatwash supernatant 
• 
Place supernatant tube at -80o C for storage and cell pellet at -80o C 
 
Saliva and throatwash specimens obtained should be stored locally at -80o C and shipped to the 
laboratory in batches. Specimens should be shipped quarterly on dry ice to the laboratory along 
with the anal and penile/scrotal swabs (see Appendix VI).  
 
Sample Labeling 
Samples must be labeled with the bar-coded labels provided. Each sample should be labeled using a 
Sharpie pen the following information: 
• 
Nine (9) Digit Subject ID:  “072-XXX-XXX” 
• 
Date and time of sample collection 
• 
Specimen Type: “Saliva”, “Throatwash pellet”. “Throatwash supernatant 
• 
Specimen Purpose:  “HPV DNA PCR” 
Specimen Shipping and Handling Instructions 
Please note that the shipment of these samples requires certified training in IATA regulations. All 
shipping materials can be ordered from SAF-T-PAK at www.saftpak.com. 
These samples will be shipped in the same box as the same box as the anal and penile/scrotal 
samples.  See protocol in Appendix VI. 
 
 

 
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Order form for Oral Specimen Collection Kits 
 
1 kit per patient visit includes: 
• 
One 50 ml conical tube containing 10 ml of Scope 
• 
Two 30 ml self-standing conical tubes 
o 1 for the 5 ml of saliva 
o 1 for Scope supernatant after spin 
• 
One screw cap tube containing 1 ml Specimen Transport medium (STM) for oral rinse cell 
pellet (Digene HCII DNA collection kit transport container) 
• 
2-3 strips emery paper in autoclave pouch 
o 1 strip each for penile/scrotal, peri-anal 
o 1 strip for demonstration on patient’s arm of emery paper abrasion – baseline visit 
only 
• 
2 un-scored swabs  
o 1 for liquid anal cytology 
o 1 for HPV DNA 
• 
Return FedEx Airbill – Please write in your site’s FedEx account number 
 
Kits can be ordered by emailing, calling or faxing an order request to the following (email is 
preferred): 
 
Joel Palefsky Laboratory 
c/o Maria Da Costa 
University of California, San Francisco 
513 Parnassus Ave., Room S-420 
San Francisco, CA  94143 
Tel: 415-476-8885 
Fax: 415-476-9364 
Email: maria.dacosta@ucsf.edu 
 
 
AMC/ATN site requesting oral kits__________________ 
 
# of kits needed _______ 
 
 
Kits to be sent to:_____________________________________ 
                            
                           ______________________________________ 
                
                          ______________________________________ 
   
                          _______________________________________ 
 
 
Please include either a phone number or email address in your contact information for questions. 
 

 
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APPENDIX IX:  SERUM HPV ANTIBODY TESTING 
 
Blood/Serum Collection 
• 
Collect at least 7 ml of blood for serum separation.  After blood is drawn, invert collection tube 5 
times and allow the blood to clot 30-60 minutes in the tube. All blood specimens should be 
collected in a red top collection tube (Not a serum-separator tube). 
• 
Red-top tubes for serum collection are provided by the investigative site. 
• 
Once clotted, the collection tube should not be allowed to sit at room temperature or refrigerated 
for more than 1 hour prior to centrifugation and separation of the serum from the clot. 
• 
Centrifuge the collection tube for 10 minutes at 1100-1300 g. 
• 
After separation, the serum should be aliquoted (1.5 mL for serum retention; remainder of serum 
for HPV serology testing) and frozen immediately. 
• 
Sera must be stored at -20°C or below. 
 
 
Serum Labels 
• 
All serum labels are provided by Merck/PPD. Please submit all requests for additional labels 
with sufficient lead time (generally 15 business days). 
• 
All sites will be provided with regular labels (per subject, per visit interval) and blank labels that 
can be used for any subject, any interval in the event of loss or damage to regular labels. 
• 
Serum specimens must be labeled with the bar-coded labels provided. Each sample should be 
labeled using indelible ink (Sanford Sharpie Industrial Extra Fine Point Super Permanent Ink- 
Item #13801) with the following information: 
o Nine (9) Digit Subject ID:  “072-XXX-XXX” 
o Date of Sample Collection (in the universal format dd-mon-yyyy) 
 
Blank Labels will need: 
o Merck assigned BN (allocation number) 
o Visit interval 
 
• 
Please use the following format for all documented dates: DD/MMM/YYYY (01-JAN-2008). 
• 
IMPORTANT:  Labels should be affixed to serum vial at the top of the vial when possible. 
• 
If bar-coded labels do not adhere to the serum vial for any reason, they should be affixed to the 
vial with a single strip of clear tape so that the bar-code is clear and legible. 
 
Serum Storage 
• 
All serum specimens should remain frozen at -20C until ready for shipment. 
• 
If applicable, retention sera should be held frozen at the site until notification that they can be 
destroyed or until requested by Merck (PPD). 
 
Serum Packing and Shipping Supplies 
• 
Complete the Inventory List of Samples form (located at the end of this appendix). Ensure that 
you print a copy of the completed form detailing the contents of each shipment. This must 
accompany all sample shipments. 

 
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• 
The completed Inventory List of Samples form should be faxed to PPD at  
215-652-5843 or 215-993-0706 prior to every shipment. A Fax Notification Cover Sheet 
(located at the end of this appendix) should also be completed and serves as the cover sheet for 
your fax. 
• 
After filling the cell box with serum vials in order according to the inventory sheet, place the cell 
box inside one of the large plastic bags with absorbent material and seal the bag. (Repeat as 
necessary, up to two (2) cell boxes per container). 
• 
Place the specimen bags (containing the cell boxes) at the bottom of the Styrofoam cooler (no 
dry ice should be placed directly underneath the specimens). 
• 
Place the original Inventory List of Samples form in a plastic bag and place it on top of the cell 
boxes.  (Please be sure to maintain a copy of the form on site.)  PPD cannot inventory the 
serum if they are not accompanied by a completed inventory form. 
• 
Use the cardboard spacer provided to cover the serum. (If needed, please fill the empty space in 
the box with cardboard or newspaper to stabilize the cell boxes during transit). 
• 
Fill the remaining space in the box with a minimum of 5 pounds (2.3 kilograms) of dry ice. 
After loading the dry ice on top of the spacer, place the lid on the Styrofoam box, close the flaps 
of the outer cardboard box, and seal with clear shipping tape.  
• 
Record the amount of dry ice on the UN1845 label. Affix the completed air bill. 
• 
AMC SITES:  Please use the AMC FedEx account number (#
) for shipment of all 
serum samples to Merck/PPD. ATN SITES:  Please use your local FedEx account number for 
shipment of all serum samples to Merck/PPD. 
 
Shipments to PPD 
• 
Serum shipments to Merck (PPD) should be sent quarterly on the first Monday or Tuesday of 
the month (or as requested by the Clinical team) to the following address: 
 
PPD, LLC Vaccine and Biologics 
Letitia Holt/Louis Bussells 
466 Devon Park Drive 
Wayne, PA 19087 USA 
Telephone: 610.989.5337 
Fax:  610.989.8353 
letitia.holt@ppdi.com 
 
• 
It is the responsibility of the Primary Investigator to ensure that all staff personnel who will be 
handling, packaging, and/or shipping clinical specimens act in conformance with International 
Air Transport Association (IATA) regulations (IATA Packing Instruction 650) relating to the 
handling and shipping of hazardous goods. (IATA Packing Instruction 650 is located on the 
AMC web site.) 
• 
A Shipper’s Declaration for Dangerous Goods is not required. However, for all dry ice 
shipments, the following information must be shown in sequence on the airway bill in the 
“Nature and Quality of Goods” box: Dry Ice, 9, UN1845, number of boxes being shipped, net 
weight of dry ice per box. 

 
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PPD Vaccine and Biologics 
 
 
TO: _____________________ 
FROM (Investigator): _____________________ 
 
PHONE: _____________________ 
(Study site contact): _____________________ 
 
Shipping questions-Letitia Holt (610.989.5337) 
CLINIC: _____________________ 
 
COMPANY:   PPD Vaccine and Biologics 
 
 
Sample Management  
 
 
Letitia Holt/ Lou Bussells 
 
466 Devon Park Drive 
 
 
Wayne, PA 19087, USA 
 
 
Country: _USA____________________ 
 
SENDER COMPANY: _____________________ 
 
STREET ADDRESS: _____________________ 
 
CITY & STATE: _____________________ 
 
 
 
SENDER PHONE NUMBER: _____________________ 
 
FAX NUMBERS: 610-989-8352  
 
SENDER FAX NUMBER: _____________________ 
DATE: _____________________ 
TOTAL # OF PAGES TO FOLLOW:  ________ 
 
 
 
 
NOTIFICATION OF SPECIMEN / SAMPLE SHIPMENTS: 
 
PROJECT NAME/ “V” or "MK" NUMBER 
 
STUDY NUMBER (Protocol # - Site #) 
 
DATE SPECIMENS/SAMPLES SHIPPED 
 
NUMBER OF SPECIMENS/SAMPLES SHIPPED 
 
SAMPLE TYPE (required–i.e., Serum, Plasma, PBMC, Thin 
section, Swabs, etc) 
 
NUMBER OF INNER PACKAGES (e.g., CELL BOXES) 
 
NUMBER OF SHIPPING BOXES SENT 
 
NAME OF COURIER (e.g., Fed-Ex, DHL, World Courier, etc.) 
 
SHIPMENT AIBILL, TRACKING OR JOB NUMBER 
 
 

 
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Inventory List of Samples Form  
 
Inventory List of Samples (page ___ of ___) 
INm 
Compound 
V501 
Merck Protocol 
 
Protocol 
AMC-072 
 
Human Papillomavirus Vaccine 
 
INVENTORY LIST OF SAMPLES 
 
Samples sent from:       
Name of Carrier:       
Date Samples Sent:       
Airway Bill Number:       
Shipment Prepared By:       
Estimated Date of Arrival:       
Preparator’s Telephone No.:       
Fax No.:       
Number of Samples on this Page:       
Number of Boxes:       
Total Number of Samples in Shipment:       
Date Samples Received at Merck:       
AMC-072 
SUBJ. ID 
ALLOCATION 
NUMBER 
STUDY 
INTERVAL 
(e.g., Day 1) 
SAMPLE 
DATE 
(DD-Mon-
YYYY) 
SERUM 
PENILE 
SWAB 
SCROTAL 
SWAB 
PERIANAL/ 
PERINEAL 
SWAB 
RECTAL 
SWAB 
COMMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If this worksheet is used as a source document, it must be initialed and dated by the individual 
making the observation/recording. 
Initials 
 
DD-Mon-YYYY 
 

 
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APPENDIX X: AMC DATA SAFETY MONITORING PLAN 
(Version 5.0  January. 28. 2014) 
 
Monitoring the Progress of Trials and the Safety of Participants 
 
All AMC protocols that collect safety data follow the National Cancer Institute (NCI), Cancer 
Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting Requirements 
(http://ctep.cancer.gov/guidelines/index.html).  All adverse events that meet the NCI’s expedited 
reporting requirements are reported to the Investigational Drug Branch (IDB) of the NCI via the 
CTEP Adverse Event Reporting System(CTEP-AERS) web application.  All expedited adverse event 
reports are also required to be submitted to the local Institutional Review Board (IRB) of the 
reporting institution.  If NCI holds the IND or no IND is required for a study, the AMC site reports 
serious adverse events directly to the AMC Operations and Data Management Center (ODMC) via 
CTEP-AERS.  In some instances, the AMC sites may report serious adverse events directly to a 
commercial sponsor holding the IND, who will then report the event to the AMC ODMC.  Most 
AMC protocols require sites to report all serious adverse events via CTEP-AERS and the AMC 
ODMC to forward a copy of the report to the sponsor.  The AMC ODMC also distributes all IND 
safety reports to all investigators upon receipt, and makes these reports available on the password-
protected section of the AMC Operations web site.  Unless an AMC protocol specifies an alternate 
plan for the review and submission of serious adverse events, all serious adverse events received by 
the AMC ODMC will be reviewed by the AMC Medical Monitor at the AMC ODMC prior to 
submission to NCI and the sponsor.  For protocols for which the IDB does not have an assigned drug 
monitor to review serious adverse event reports, in the event of disagreement between the reporting 
physician and the AMC Medical Monitor regarding the attribution of the event to the investigational 
agent(s) (i.e., determination of whether the relationship is unrelated, unlikely, possible, probable, or 
definite), the AMC Medical Monitor will provide the final determination of the relationship. 
 
The AMC ODMC provides listings of all reported adverse events and serious adverse events to the 
Protocol Chair and Co-chair(s) for review on a regular basis.  The AMC ODMC compiles these 
events in a tabular format and posts them on the password-protected section of the AMC web site 
where these reports are updated nightly.  The AMC web site is accessible to all AMC investigators, 
co-investigators, and their staff.  Email notification that this information is available on the web site 
will be sent to all site PIs.  It is the responsibility of each site to provide this information to their 
respective IRBs, if required by their IRB.  For blinded studies, the serious adverse events are 
reviewed and tabulated without treatment assignment.  The AMC Medical Monitor will review 
listings of all reported adverse events on a quarterly basis for safety concerns. 
 
Accrual summaries for each AMC trial are updated nightly on the password-protected section of the 
AMC web site.  The progress of each AMC trial is reviewed regularly by the Protocol Chair and also 
by the appropriate disease-oriented Working Group during scheduled conference calls.  For phase I 
dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in the protocol and 
the Protocol Chair, AMC Medical Monitor, and Group Statistician determine whether these criteria 
have been met.  For phase II trials, stopping the trial for toxicity or efficacy, or suspending 
enrollment pending observation of responses in a multi-stage phase II trial, is based on meeting 
criteria stated in the protocol, and the Protocol Chair, AMC Medical Monitor, and Group Statistician 
determine whether these criteria have been met. 
 

 
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For phase III trials, the AMC has formed an independent Data Safety and Monitoring Board 
(DSMB).  Voting members of the DSMB are physicians, a statistician, and a patient advocate.  All 
voting members are from outside the AMC.  Nonvoting members are the AMC Group Statistician, 
the Statistician listed on the protocol, an AMC Operations Center staff member, two representatives 
(normally a clinician or statistician) from the Office of HIV AIDS Malignancy (OHAM) or from the 
Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, of the National 
Cancer Institute (NCI).   The AMC Data Safety and Monitoring Board reviews AMC phase III 
studies in accordance with the National Cancer Institute’s Policy for Data Safety and Monitoring.  
Confidential reports of all phase III trials are prepared by the AMC Group Statistician with support 
from the AMC ODMC. A written report containing the current status of each trial monitored, and 
when appropriate, any toxicity and outcome data, are sent to DSMB members by the AMC ODMC 
within the timelines specified by the AMC DSMB Charter.  This report addresses specific toxicity 
concerns as well as concerns about the conduct of the trial.  The report may contain 
recommendations for consideration by the DSMB concerning whether to close the trial, report the 
results, or continue accrual or follow-up. 
 
The results of each DSMB meeting are summarized in a formal report sent by the DSMB Chair to the 
Group Chair and AMC ODMC. The DSMB report contains recommendations on whether to close 
each study reviewed, whether to report the results, and whether to continue accrual or follow-up. A 
primary recommendation (e.g., continue with no change; recommended or required modification; 
stop) must be included in the document. The Group Chair is then responsible for notifying the 
Protocol Chair and relevant Disease-oriented Working Group Chair before the recommendations of 
the DSMB are carried out. In the unlikely event that the Protocol Chair does not concur with the 
DSMB, then the NCI Division Director or designee must be informed of the reason for the 
disagreement.  The Study Chair, relevant Disease-oriented Working Group Chair, Group Chair, 
DSMB Chair, and NCI Division Director or designee will be responsible for reaching a mutually 
acceptable decision about the study.  CTEP approval of a formal amendment will be required prior to 
any implementation of a change to the study. 
 
Following a DSMB meeting, a summary of the serious adverse events reported to the DSMB is 
posted to the AMC web site.  It is each site’s responsibility for conveying this information to its IRB. 
 
Plans for Assuring Compliance with Requirements Regarding the Reporting of Adverse Events 
(AE) 
 
For trials monitored by the NCI’s Clinical Data Update System (CDUS), adverse event information 
is transmitted electronically to NCI on a quarterly basis.  For trials monitored by NCI’s Clinical 
Trials Monitoring Service (CTMS), adverse event information is transmitted electronically to NCI 
every two weeks. 
 
The Protocol Chair, AMC Group Chair, and the AMC ODMC share responsibility in assuring that 
participating investigators comply with the protocol requirements for adverse event reporting.  All 
AMC investigators certify compliance with NCI and FDA requirements for adverse event reporting 
by signing the AMC Adherence Statement for site membership, the protocol signature page for each 
protocol active at the site, and Form FDA-1572 for CTEP investigator registration and IND studies 
sponsored by AMC investigators.  Investigators are responsible for identifying and reporting all 
adverse events to the AMC ODMC, CTEP-AERS, and/or sponsors according to the protocol 
requirements, and assuring compliance with reporting to the local IRB.  Protocol compliance with 
adverse event reporting requirements is assessed by the AMC ODMC during routine site monitoring 

 
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visits by reviewing the site’s source documentation.   
 
The data entry system used for AMC studies, AdvantageEDCSM (a web-based data entry and 
enrollment system), is programmed to notify the site investigator, protocol chair, and AMC ODMC 
via email in the event that a site reports an adverse event that meets expedited reporting criteria to 
NCI and/or FDA.  If the site does not follow with a CTEP-AERS report, the AMC ODMC contacts 
sites to request an expedited report.  Additionally, the protocol chair, AMC ODMC, and the AMC 
Medical Monitor review reported adverse events on a routine basis to identify adverse events 
reported by sites that require expedited reporting via CTEP-AERS.  The Protocol Chair, AMC Group 
Chair, and IND sponsors have general oversight for assuring that routine and expedited adverse 
reporting requirements are met by the responsible parties. 
 
Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension of an 
NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director Responsible for the 
Grant 
 
In the event that termination of the trial or major modification to the protocol is under consideration, 
the Protocol Chair will convene the AMC Data Coordinator and Disease-oriented Working Group 
Chair by conference call to discuss the options.  For phase I and II trials, the Protocol Chair also has 
the option of asking the AMC DSMB to review the study.  The AMC ODMC will inform the CTEP 
Protocol Information Office (PIO) when studies are temporarily or permanently closed.  The Cancer 
Treatment and Evaluation Program (CTEP) of the National Cancer Institute (NCI) must approve all 
protocol amendments prior to distributing to the AMC sites. 
 
Plans for Assuring Data Accuracy and Protocol Compliance 
 
All study data for AMC clinical trials are entered directly by AMC site staff into AdvantageEDCSM.  
During data entry, the system performs validation checks on many fields and performs consistency 
checks between select fields.  Range checks are placed on each field to eliminate entry of out-of-
range values.  Edit check programs are run on the database on a set schedule to identify and resolve 
inconsistencies between forms or data collected at different points in time.  AMC ODMC staff 
routinely interacts with site staff to resolve any data problems. 
 
In accordance with NCI guidelines, the AMC ODMC conducts monitoring visits at the AMC sites to 
evaluate compliance with regulatory issues, and to review data for specific cases by checking source 
documents.  These reports are sent to the site Principal Investigator and to the NCI.  In the event that 
major violations are identified, sites are asked to provide a plan to correct deficiencies within 30 
days.  If needed, a repeat site visit is conducted.  In the event that a site does not correct deficiencies 
in a pre-determined time frame, the AMC Executive Committee has the option of taking action 
against the site.  Possible actions include, but are not limited to, suspending enrollment of new 
patients to AMC trials until deficiencies are corrected; recommending a decrease in funding to the 
site; and requiring specific training for site investigators or staff members. 
 
 

 
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APPENDIX XI: VACCINATION REPORT CARD 
 
 
 
Protective effect of quadrivalent vaccine in young HIV-positive males who 
have sex with males 
 
A Multi-Center Trial of the AIDS Malignancy  
Clinical Trials Consortium and the Adolescent Trials Network 
 
 
Vaccination Report Card 
 
 
 
Only the SUBJECT should complete this vaccination report card.  Corrections to the 
vaccination report card by the subject should be dated and initialed by the subject. 
 
The STUDY NURSE will enter the dates where needed. 
 
 
Complete this card for 5 days after vaccination (until ___/___/___) 
and return the card to the study site when it is complete. 
 
Subject’s Comments: 
 
 
 
 
 
 
Study Site Personnel Comments: 
 
 
 
 
 
 
 
 
Study Site 
Patient’s/Subject ID  
072-      -       
Visit 

 
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TEMPERATURE MEASUREMENT 
 
It is very important that you take your temperature every day, starting on the day of vaccination 
through Day 5. 
Take your temperature orally and record this temperature in the appropriate box below. 
Take your temperature in the evening whenever possible.  If you need to take your temperature more 
than once during the day, record the highest temperature taken that day. 
 
TAKE ORAL TEMPERATURE 
EACH DAY. 
DAY 
DATE 
(month/day/year) 
ORAL 
TEMPERATURE 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
 
NOTE:  Day 1 temperature should be taken 4 hours after the vaccination.  Afterwards, temperature is 
to be taken daily for 4 more days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date Completed: ___________________________ 
 
Study Site 
Patient’s/Subject ID  
072-      -       
Visit 

 
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INSTRUCTIONS FOR INJECTION SITE REACTIONS: 
 
On the following pages entitled “Injection Site Reactions”, please measure any swelling or redness 
AT THE INJECTION SITE. 
 
Estimate the size of the reaction at its largest from edge to edge.  Use the ruler marks along the 
bottom of the page. 
 
Mark the box that best describes the size of the reaction: 
1 if the greatest width is anywhere in the area marked 1 (Example A) 
2 if the greatest width is anywhere in the area marked 2 
3 if the greatest width is anywhere in the area marked 3 (Example B) 
Over 3 if the greatest width is in any area marked with a number over 3. 
Write in the number. (Example C) 
If the reaction is wider than the area marked 7, write 8. 
 
 
On the following pages entitled “Injection Site Reactions”, please estimate the severity of any pain 
or tenderness or other reactions AT THE INJECTION SITE. 
 
Mark the box that best describes the severity of the reaction using the following definitions: 
 
Mild is when you know it bothers you, but it doesn't bother you too much 
Moderate is when it bothers you enough that you have difficulty doing your usual activities, like 
schoolwork or work 
 Severe is when it bothers you so much that you can't do your usual activities at all, like 
schoolwork or work 
 
Complete one column each day, starting with Day 1 (the day of vaccination – 4 hours after injection).  
If the reaction continues past Day 5, please write in the last date it was present. 
 
If an injection site reaction begins after Day 5, please estimate severity of the reaction in the box at 
the bottom of the pages entitled “Injection Site Reaction”. 
 
 
 
 
 
 
 
 
Study Site 
Patient’s/Subject ID  
072-      -       
Visit 
1 
2 
3 
4 
5 
6 
7 
8 

 
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EXAMPLES FOR MEASURING THE SIZE OF REACTIONS: 
 
Example A:  This reaction falls in the area marked 1 at its largest, so you would 
check the box marked “1”. 
 
 
 
 
 
 
 
 
Example B:  This reaction falls in the area marked 3 at its largest, so you would 
check the box marked “3”. 
 
 
 
 
 
 
 
 
 
 
 
 
Example C:  This reaction falls in the area marked 4 at its largest, so you would 
check the box marked “Over 3” and write in a 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Site 
Patient’s/Subject ID  
072-      -       
Visit 
1 
2 
3 
4 
1
2
3
4
1
2
3
4

 
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INJECTION SITE REACTIONS 
Complete one copy of this page per injection site.  Indicate the injection site for this page by 
checking the box below. 
Injection Site (check one per page):  
  Right Arm 
 
  Left Arm  
Other ______ 
 
 
DAY 1 
Vaccination Day 
_ _/_ _/_ _ 
month/day/year 
DAY 2 
 
_ _/_ _/_ _ 
month/day/year 
DAY 3 
 
_ _/_ _/_ _ 
month/day/year 
DAY 4 
 
_ _/_ _/_ _ 
month/day/year 
DAY 5 
 
_ _/_ _/_ _ 
month/day/year 
LAST DATE 
REACTION 
PRESENT 
SWELLING 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
_ _/_ _/_ _ 
month/day/year 
REDNESS 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
_ _/_ _/_ _ 
month/day/year 
 
PAIN OR 
TENDERNESS 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
_ _/_ _/_ _ 
month/day/year 
OTHER 
INJECTION 
SITE 
REACTION 
(specify): 
 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
_ _/_ _/_ _ 
month/day/year 
OTHER 
INJECTION 
SITE 
REACTION 
(specify): 
 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
 None 
 1 
 2 
 3 
 over 3:_ 
_ _/_ _/_ _ 
month/day/year 
 
If an injection site reaction began 6 or more days after your vaccination, please record it below.  
Record the date it started and the last date it was present.  Mark the box that best describes the 
severity of the injection site reaction. 
INJECTION SITE REACTIONS 
BEGINNING 6 OR MORE DAYS AFTER 
VACCINATION 
DATE (month/day/year) 
SEVERITY 
Started 
Last Present 
 
 
 mild  
 moderate  
 severe 
 
 
 mild  
 moderate  
 severe 
 
 
 
Date Completed: ______________________________ 
 
Study Site 
Patient’s/Subject ID  
072-      -       
Visit 
1
2
3
4
5
6
7
8

 
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OTHER COMPLAINTS OR ILLNESSES 
 
Write down, in the boxes below, any other problems, complaints, or illnesses that either started or got 
worse during the 15 days after your shot. 
Write down the date it started and the date it ended 
Mark the box that best shows how much this complaint or illness bothered you, using one of the three 
words below:  
Mild is when you know it bothers you, but it doesn't bother you too much 
Moderate is when it bothers you enough that you have difficulty doing your usual activities, like 
schoolwork or work 
Severe is when it bothers you so much that you can't do your usual activities at all, like 
schoolwork or work 
 Do not record injection site complaints on this page.  Those complaints are recorded on the previous 
page in the table entitled “Injection Site Reactions”. 
List each complaint or illness separately. 
 
If during the 15 days after vaccination you did not have any other complaints or illnesses check the 
box here:    None 
OTHER COMPLAINTS OR ILLNESSE 
DATE (month/day/year) 
SEVERITY 
Started 
Last Present 
 
 
 
 mild  
 moderate  
 severe 
 
 
 
 mild  
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 mild  
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 mild  
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 severe 
 
 
 
 mild  
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 mild  
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Date Completed: _________________________ 
Study Site 
Patient’s/Subject ID  
072-      -       
Visit 

 
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APPENDIX XII:  SMOKING STATUS/RECENT SEXUAL HISTORY/RISK PERCEPTION 
AND KNOWLEDGE QUESTIONNAIRE 
 
 AMC-072 Smoking Status/Recent Sexual History  
 
Patient ID number: 
Date: 
Study Week number: 
NOTE TO STAFF: This questionnaire is to be administered following vaccination at protocol-
specified time points. Please complete the three form fields above, and then give the questionnaire 
to the subject. The questionnaire must be self-administered and placed in an envelope and sealed 
after completion. 
Thank you for taking this questionnaire. This form will ask about cigarette smoking. It will also 
ask about sex you may have had in the last 6 months.       
1)  How often do you currently smoke cigarettes?  (Choose one) 
__  Not at all (skip to question #3) 
 
__  Some days 
__  Every day 
__  I prefer not to answer (skip to question #3) 
 
 
 
2)  On average over the past 6 months, how many cigarettes have you smoked per day?  (1 pack 
equals 20 cigarettes) 
 
____ 
 
 
 
The next few questions will ask about men you may have had sex with in the past 6 months.  Let's 
review some words so that we agree on what we are talking about.  By "having sex" we mean oral 
sex, anal sex or rimming. 
ORAL SEX is when a man puts his penis in someone else's mouth or when a man has someone 
else's penis in his mouth. 
ANAL SEX is when a man puts his penis into someone's rectum, anus, or butt (also known as 
insertive anal sex or being a top) or when a man has someone else's penis in his rectum, anus, or 
butt (also known as receptive anal sex or being a bottom).  
RIMMING:  When a man puts his mouth or tongue to someone's anus or butt, or someone else 
does that to him. 
3)   Have you ever had sex with a man (even only once)? 
__   Yes 
__   No  (skip to question #12) 
__   I prefer not to answer   (skip to question #12) 

 
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4)  Have you ever had sex by having a penis inserted into your anus (even only once)? 
__   Yes 
__   No  (skip to question #6) 
__   I prefer not to answer   (skip to question #6)  
 
5)  When was the last time you had sex by having a penis inserted into your anus? 
__  Within the past week 
__  Within the past month  
__  Within the past six months 
__  Within the past year 
__  Over a year ago   
 
6)  Have you had sex of any kind with a man in the past 6 months? 
__ Yes 
__  No (Skip to question #12) 
__ I prefer not to answer (Skip to question #12) 
 
 
 
7)  How many men have you had sex with in the past 6 months?   
__  1 
__  2 to 5  
__  6 to 10  
__  more than 10  
 
8)  With how many men have you had receptive anal sex with in the past 6 months (i.e., have sex by 
putting their penis into your anus)?   
__  0  (Skip to question #10) 
__  1 
__  2 to 5  
__  6 to 10  
__  more than 10  
 
9) How often did your sex partner use a condom during receptive anal sex?  
__  Every time (100%) 
__ Mostly  
__  Half the time 
__  Occasionally 
__  Never (0%) 

 
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10) How many men did you perform oral sex on during the past 6 months (i.e. have sex by putting 
your mouth on their penis)?  
__  0  (skip to question #12) 
__  1 
__  2 to 5  
__  6 to 10  
__  more than 10  
 
11) How often did your sex partner use a condom during oral sex?  
__  Every time (100%) 
__ Mostly  
__  Half the time 
__  Occasionally 
__  Never (0%) 
 
 
 
The next few questions will ask about any women that you have had sex with in the past 6 months. 
Let's start with reviewing some words so that we agree on what we are talking about.  By "having 
sex" we mean vaginal sex, oral sex or anal sex. 
ORAL SEX  is when a man puts his penis in someone's mouth or when a man puts his mouth on a 
woman's vagina or clitoris. 
VAGINAL SEX is when a man puts his penis in a woman's vagina. 
ANAL SEX is when a man puts his penis into someone's rectum, anus, or butt.  
 
12) Have you had sex with a woman in the past six months?  
__ Yes 
__  No (skip question #13 and #14) 
 
__  I prefer not to answer (skip question #13 and #14) 
 
 
13) How many women have you had sex with in the past 6 months?  
__  0  
__  1  
__  2 to 5  
__  6 to 10  
__  more than 10 
 

 
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14) How many women did you perform oral sex on in the past 6 months (i.e., have sex by putting 
your mouth on her vagina or clitoris)? 
__  0  
__  1  
__  2 to 5  
__  6 to 10  
__  more than 10 
 
The next set of questions asks how you feel after getting vaccinated against HPV.  Please mark with an “X” or 
checkmark “”in one of the boxes to show how strongly you agree or disagree with the following statements 
(0=strongly disagree, 5=neither agree nor disagree, 10=strongly agree) 
 
AFTER GETTING VACCINATED AGAINST HPV … 
1. I am less worried about getting HPV. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4         5         6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
2. I am still just as concerned about getting HPV. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4         5         6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
3. I think getting HPV will be less of a problem. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
4. I am less worried that one of my sex partners could get HPV from me. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 

 
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AFTER GETTING VACCINATED AGAINST HPV … 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
5. There is less of a chance that I will get HPV than there used to be. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
6. I am less worried about getting an STI or STD (sexually transmitted infection or disease) other than HPV. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
7. I am still just as concerned about getting an STI or STD other than HPV. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
8. I think getting an STI or STD other than HPV will be less of a problem. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
9. I am less worried that one of my sex partners could get an STI or STD other than HPV from me. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 

 
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AFTER GETTING VACCINATED AGAINST HPV … 
10. There is less of a chance that I will get an STI or STD other than HPV than there used to be. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
11. I feel that condom use during sex is less necessary. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
12. I feel it is still just as important to have as few sexual partners as possible. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
13. I feel it is not as important to talk to my sex partners about safe sex. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
14. I think it is still just as important to use a condom every time I have sex. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 

 
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AFTER GETTING VACCINATED AGAINST HPV … 
15. I will be less worried about having unprotected sex. 
  □      □      □      □      □      □      □      □      □      □      □ 
0         1         2         3        4          5        6         7         8         9        10 
STRONGLY                                                    NEITHER 
STRONGLY 
DISAGREE                                                  AGREE NOR 
  AGREE 
                                                                        DISAGREE 
 
 
 
The next 5 questions ask about your HPV knowledge.  Please mark whether you think the answer is true, 
false, or if you don’t know. 
 
QUESTION 
RESPONSE 
16. If a man’s sexual partners use condoms, he is completely protected against HPV. 
  True 
  False 
  Don’t know 
17. A person may be infected with HPV and not know it. 
  True 
  False 
  Don’t know 
18. HPV can be spread from person to person just by skin to skin genital contact. 
  True 
  False 
  Don’t know 
19. Genital warts always go away permanently if a man gets the right treatment. 
  True 
  False 
  Don’t know 
20. HPV can sometimes be cured with antibiotics.  
  True 
  False 
  Don’t know 
 
 
Thank you for taking this questionnaire!! 

 
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Subject ID:   
Visit (Please Mark):  □ Baseline  □ Week 104 
APPENDIX XIII:  ACSR INFORMED CONSENT FORM – AMC-072 
 
RESEARCH STUDY 
AIDS AND CANCER SPECIMEN RESOURCE (ACSR) 
 
A. 
INTRODUCTION 
You are being asked to donate specimens (tissues and/or blood) for research.  Before you 
decide to be a part of this research study, you need to understand the risks and benefits so that 
you can make an informed decision.  This is known as informed consent. 
 
This consent form provides information about the research study, which has been explained, 
to you. Once you understand the study and the tests it requires, you will be asked to sign this 
form if you want to take part in the study. Your decision to take part in the study is voluntary.  
This means that you are free to choose if you will take part in the study. 
 
B. 
PURPOSE 
The National Cancer Institute has set up a Biorepository for tissues and biological fluids from 
HIV-positive and HIV-negative individuals in order to have specimens available for 
scientists studying cancers and pre-cancers associated with HIV disease.   
 
Biopsy Tissue and Blood Donation 
Individuals who are having high resolution anoscopy (HRA) as part of this research study are 
being asked for permission to donate an additional anal tissue specimen to the Biorepository. 
If it turns out that your physician needs more of your tissue for additional studies, the 
Biorepository will release all of your tissue back to your doctor.  
 
It is expected that the biopsy tissues may be evaluated for human papillomavirus (HPV) 
detection and typing, and potentially other research assays as additional science studies are 
developed. This may also involve genetic testing. These evaluations will not be done in real 
time and you will not receive the results of these tests. 
 
In addition, you are being asked permission to donate some of your blood (up to 20 
milliliters) to the Biorepository so that scientists can better understand factors that may affect 
your risk of developing human papillomavirus (HPV)-related anal pre-cancers or other 
diseases that may occur in HIV-positive men. These evaluations will not be done in real time 
and you will not receive the results of these tests. 
 
We will also ask you if you will let any leftover tissue or blood that is not used during the 
study be donated to ACSR at the end of the study. 
 
Donation of blood or biopsy specimens is not a requirement to participate in the study and 
you may withdraw your approval for the storage of these specimens at any time.  You may 
also choose to donate blood but not tissue, or vice-versa.   
 

 
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C. 
PROCEDURES 
You are being asked for consent to place additional tissue and a blood sample in the ACSR.  
If you agree to allow the ACSR to have some of your tissue and/or blood, the following 
procedures will occur: 
• 
Procedure for tissue donation:  At the time you are seen for high resolution anoscopy 
(HRA), a swab moistened with acetic acid (i.e. diluted vinegar) is placed in your anus. 
Vinegar helps pre-cancers and warts in the anus show up.  The doctor or nurse then re-
inserts the plastic speculum into your anus. A colposcope (a machine similar to a 
magnifying glass) is used to see the skin inside the anus. Then biopsies of any areas 
worrisome for pre-cancer or anal warts may be performed. To do a biopsy, a small bit of 
skin about the size of a sesame seed is cut off. Iodine may also be used to help make pre-
cancers show up, and an injection of lidocaine may be given to numb the skin before a 
biopsy. 
• 
Procedure for blood donation: Two tubes (up to 20 milliliters) of blood will be drawn. 
 
If you agree to make a tissue and/or blood donation to the ACSR, we would also like to 
confidentially obtain some clinical information from your medical records that could be 
useful to research investigators. The report of the information retrieved from your medical 
record that is given to research investigators will not have your name, or include any 
information which could personally identify you. 
It is possible that you may not qualify for the study, based on the results of your screening 
visit.  If you agree to donate tissue and/or blood, but do not qualify for the study, we would 
still be interested in sending the specimens to the Biorepository.  
 
You will be asked if you are willing to make a tissue and/or blood donation to the ACSR at 
two time points: at the first visit and again about 2 years later. You may agree to donate 
specimens at either or both visits. 
 
D. 
POSSIBLE RISKS 
Some anal bleeding occurs with every biopsy.  Serious bleeding is rare, about 1 in 1000 
biopsies. If serious bleeding occurs, a simple procedure may be necessary to stop the 
bleeding such as burning or cauterizing the area.  An injection of lidocaine may be given 
prior to a biopsy.  It is possible that you can experience pain or dizziness from the injection.  
Rarely, you can experience an allergic reaction such as itching or swelling.  Iodine may be 
used to help identify pre-cancerous areas of the anus. It is possible that you may have an 
allergic reaction. 
 
There is a possibility of a bruise and slight pain at the time the blood samples are taken.  
There is also the possibility of fainting and infection at the site of the blood draw.   
 
Risks of genetic testing include the possibility that the information will not remain private or 
confidential. All personnel who will have access to genetic information about you are 
ethically and legally obligated to maintain the confidence of that information. However, there 
can be no absolute guarantees. In rare cases where information has not remained private, this 
has caused problems for persons related to their employment and/or their life and/or health 

 
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insurance and other benefits or entitlements. 
 
E. 
POSSIBLE BENEFITS 
It may be that there will be no direct benefit to you by consenting to allow the ACSR to have 
your tissue and blood.  However, there may be possible benefits to medical knowledge and 
HIV-infected individuals in the future. 
 
F. 
COSTS 
There will not be any additional costs to you for consenting to participate in the AIDS and 
Cancer Specimen Resource. 
 
G. 
PAYMENT FOR INJURY OR HARM 
As the lists of risks shows, taking part in this research study may result in injury or harm to 
you. If you require immediate medical care, you should go to an emergency room.  
Otherwise, the doctor in charge of the study will take care of you or help you get the care you 
need.  You will be sent a bill for whatever medical care you receive.  No funds have been set 
aside to compensate you in the event of injury. However, you are not giving up your right to 
seek to collect compensation for injury related to malpractice, fault, or blame on the part of 
those involved in the research. 
 
[ATN SITES: PLEASE USE THE FOLLOWING LANGUAGE:] 
If you are injured as a result of being in this research study, you will receive immediate, 
short-term treatment as determined by [name of hospital] for the injury.  The cost of the 
treatment will be charged to you or your insurance company, as would normally be done for 
your medical care.  You will then be told where you could receive additional treatment for 
injuries.  Your insurance carrier may or may not pay for treatments for injuries that are 
caused by taking part in this study.  No monetary compensation (payment to you) or other 
forms of compensation for such injuries will be provided by the hospital or sponsoring 
agency. 
 
H. 
PRIVACY 
Your hospital medical records will be confidentially reviewed to obtain clinical information 
that could be useful to research investigators. However, the report of this information will not 
have your name or social security number anywhere on the report, so you will not be easily 
identified. The results of this research study will be given to the sponsor, the National Cancer 
Institute (NCI), AIDS Malignancy Consortium, and may be asked for by the Department of 
Health and Human Services, FDA and Pharmaceutical Collaborator. In addition, the 
Institutional Review Board may see your records. Except for these people, records from this 
study will be kept private unless you authorize their release or release is required by law (i.e. 
court subpoena). Any publications of this study will not use your name, identify you 
personally, or include any information that could personally identify you. 
 
I. 
QUESTIONS 
If you have any questions about this research study, you should contact Dr. (_____________) 

 
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at (Phone Number) (day) or (Phone Number) (night), or the person in charge of the study, 
(_____________), the study coordinator, at (Phone Number).  If you have any questions 
about your rights as a research subject, you should call (IRB Representative), in (Institution) 
Office of Human Research at (______________).  (IRB Representative) is your 
representative and is not employed by the individuals conducting the study. 
 
J. 
OPTIONAL DONATIONS 
 Yes, I agree to have an additional anal biopsy to donate for future research. I understand 
that I may not qualify for the research study based on the results of my screening visit 
and that this specimen will still be sent to ACSR. 
 No, I do not want to have an additional biopsy to donate for future research. 
 Yes, I agree to donate an additional blood specimen for future research. I understand that 
I may not qualify for the research study based on the results of my screening visit and 
that this specimen will still be sent to ACSR. 
 No, I do not want to donate an additional blood specimen for future research. 
 
 
K. 
SIGNATURES 
Statement of professional obtaining consent 
I have fully explained this research study to the subject or guardian of subject. In my 
judgment and the subject’s or guardian’s, there was sufficient access to information, 
including risks and benefits to make an informed decision. 
Date:  ___________ 
Physician’s Signature: ______________________________ 
Physician’s Name:                                                                         (Print) 
 
Patient’s/subject (or guardian’s) statement 
I have read the description of the clinical research study or have had it translated into a 
language I understand.  I have also talked it over with the doctor to my satisfaction.  I 
understand that my/the subject’s participation is voluntary.  I know enough about the 
purpose, methods, risks, and benefits of the research study to judge that I want (the 
patient/subject) to take part in it. 
 
Date: _____________  
Patient/Subject (or guardian’s) Signature:___________________ 
 
Patient’s/Subject’s Name: ______________________________________ 
 
 
 
(Print) 
 
______________________________  
_______________________ 
Patient  
 
 
 
 
Date 
 
 
 
 
 
 
 
______________________________  
_______________________ 

 
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Person obtaining consent 
 
 
Date 
 
______________________________  
_______________________ 
Witness 
 
 
 
 
Date 
 
L. 
LEFTOVER STUDY SPECIMENS 
If you agree, excess blood, oral specimens and anal swab specimens may be donated to the 
ACSR and made available for research by other investigators. Storage of leftover specimens 
will not require additional procedures than those already taking place in the research study. 
Storage of leftover specimens is not a requirement to participate in the study and you may 
withdraw your approval for the storage of your leftover specimens at any time. These 
specimens may be held for an indefinite length of time. You will not be told of the results of 
the research done on these samples. 
 
Please check one of the following boxes to indicate whether or not you wish to have your 
leftover specimens stored for AIDS-related research in the future. 
 
 Yes, I agree to have my leftover specimens stored for future research.  
 
 No, I do not want to have my leftover specimens stored for future research. 

 
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Subject ID:   
Visit (Please Mark):  □ Baseline  □ Week 104 
APPENDIX XIV:  ACSR ASSENT FORM – AMC 072 
 
RESEARCH STUDY 
AIDS AND CANCER SPECIMEN RESOURCE (ACSR) 
 
A. 
INTRODUCTION 
You are being asked to donate specimens (tissues and/or blood) for research.  Before you 
decide to be a part of this research study, you need to understand the risks and benefits so that 
you can make an informed decision.  This is known as informed consent. 
 
This consent form provides information about the research study, which has been explained, 
to you. Once you understand the study and the tests it requires, you will be asked to sign this 
form if you want to take part in the study. Your decision to take part in the study is voluntary.  
This means that you are free to choose if you will take part in the study. 
 
B. 
PURPOSE 
The National Cancer Institute has set up a place where tissues and blood are kept so that 
these specimens can be available for scientists studying cancers and pre-cancers associated 
with HIV disease in the future. This place is called the AIDS and Cancer Specimen Resource 
Biorepository (ACSR). 
 
Biopsy Tissue and Blood Donation 
You are having high resolution anoscopy (HRA) as part of this research study that involves 
taking an anal biopsy. Individuals in the study are being asked for permission to donate an 
additional anal tissue specimen to the Biorepository described above. In addition, you are 
also being asked permission to donate some of your blood to the Biorepository. We will also 
ask you if you will let any leftover tissue or blood that is not used during the study be 
donated to ACSR at the end of the study. 
 
Any tissue and blood collected may be tested for types of human papillomavirus (HPV) and 
other research tests might be performed so that scientists can better understand HPV-related 
anal pre-cancers and other diseases that may occur in HIV-positive men. These future tests 
may also involve genetic testing. These tests will not be done now, so you will not receive 
the results of these future tests. 
 
Donating tissue or blood specimens is not a requirement to participate in the study and you 
may withdraw your approval to store these specimens at any time.  You may also choose to 
donate blood but not tissue, or vice-versa.   
 
C. 
PROCEDURES 
You are being asked to place additional tissue and a blood sample in the Biorepository.  If 
you agree, the following procedures will occur: 
• 
Procedure for tissue donation:  At the time you are seen for high resolution anoscopy 
(HRA), a swab moistened with acetic acid (i.e. diluted vinegar) is placed in your 

 
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anus. Vinegar helps pre-cancers and warts in the anus show up.  The doctor or nurse 
then re-inserts the plastic speculum into your anus. A colposcope (a machine similar 
to a magnifying glass) is used to see the skin inside the anus. Then biopsies of any 
areas worrisome for pre-cancer or anal warts may be performed. To do a biopsy, a 
small bit of skin about the size of a sesame seed is cut off. Iodine may also be used to 
help make pre-cancers show up, and an injection of lidocaine may be given to numb 
the skin before a biopsy. 
• 
Procedure for blood donation: Two tubes (up to 2 tablespoons) of blood will be 
drawn. 
 
If you agree to make a tissue and/or blood donation to the Biorepository, we would also like 
to confidentially obtain some clinical information from your medical records that could be 
useful to research investigators. This report that is given to research doctors will be coded, 
that means it will not have your name, or include any information which could personally 
identify you. 
It is possible that you may not qualify for the study, based on the results of your screening 
visit.  If you agree to donate tissue and/or blood, but do not qualify for the study, we would 
still be interested in sending the specimens to the Biorepository.  
 
You will be asked if you are willing to make a tissue and/or blood donation at two different 
times: at the first visit and again about 2 years later. You may agree to donate specimens at 
either or both visits. 
 
D. 
POSSIBLE RISKS 
Some anal bleeding occurs with every biopsy and there is a risk of infection. An injection of 
lidocaine may be given prior to a biopsy to numb the area and it is possible that you can 
experience pain or dizziness from the injection, or an allergic reaction.  Iodine may be used to 
help identify pre-cancerous areas of the anus and it is possible that you may have an allergic 
reaction to iodine. 
 
There is a possibility of a bruise and slight pain at the time the blood samples are taken.  
There is also the possibility of fainting and infection at the site of the blood draw.   
 
Risks of genetic testing include the possibility that the information will not remain private or 
confidential, even though people who have this information are legally required to keep the 
information private.  If this information were released, there is a chance problems will occur 
in your job, or with your health insurance, or other benefits you might have. It is unlikely that 
this information would be released, but there can be no absolute guarantees.  
 
E. 
POSSIBLE BENEFITS 
There may be no direct benefit to you by consenting to allow the ACSR Biorepository to 
have your tissue and blood.  However, there may be possible benefits to medical knowledge 
and HIV-infected individuals in the future. 
 
 

 
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F. 
COSTS 
There will not be any additional costs to you for agreeing to participate in donating tissue or 
blood to the Biorepository. 
 
G. 
PAYMENT FOR INJURY OR HARM 
It is important that you tell your study doctor, if you feel that you have been hurt because of 
taking part in this study. As the lists of risks shows, taking part in this research study may 
result in injury or harm to you. You will be sent a bill for whatever medical care you receive.  
No funds have been set aside to compensate you in the event of injury. However, you are not 
giving up your right to seek to collect compensation for injury related to malpractice, fault, or 
blame on the part of those involved in the research. 
 
[ATN SITES: PLEASE USE THE FOLLOWING LANGUAGE:] 
If you are injured as a result of being in this research study, you will receive immediate, 
short-term treatment as determined by [name of hospital] for the injury.  The cost of the 
treatment will be charged to you or your insurance company, as would normally be done for 
your medical care.  You will then be told where you could receive additional treatment for 
injuries.  Your insurance carrier may or may not pay for treatments for injuries that are 
caused by taking part in this study.  No monetary compensation (payment to you) or other 
forms of compensation for such injuries will be provided by the hospital or sponsoring 
agency. 
 
H. 
PRIVACY 
We will do our best to make sure that the personal information in your medical record is kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at 
scientific meetings, your name and other personal information will not be used. 
 
I. 
QUESTIONS 
If you have any questions about this research study, you should contact Dr. (_____________) 
at (Phone Number) (day) or (Phone Number) (night), or the person in charge of the study, 
(_____________), the study coordinator, at (Phone Number).  If you have any questions 
about your rights as a research subject, you should call (IRB Representative), in (Institution) 
Office of Human Research at (______________).  (IRB Representative) is your 
representative and is not employed by the individuals conducting the study. 
 
J. 
OPTIONAL DONATIONS 
 
 Yes, I agree to have an additional anal biopsy to donate for future research. I understand 
that I may not qualify for the research study based on the results of my screening visit 
and that this specimen will still be sent to ACSR. 
 
 No, I do not want to have an additional biopsy to donate for future research. 
 

 
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 Yes, I agree to donate an additional blood specimen for future research. I understand that 
I may not qualify for the research study based on the results of my screening visit and 
that this specimen will still be sent to ACSR. 
 
 No, I do not want to donate an additional blood specimen for future research. 
 
 
K. 
SIGNATURES FOR ASSENT 
You have been given copies of this assent form and the Experimental Subject's Bill of Rights 
to keep. 
 
PARTICIPATION IN RESEARCH IS VOLUNTARY.  You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to 
which you are otherwise entitled. 
 
If you wish to participate in this study, you should sign below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
Participant's Signature for Assent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
Person Obtaining Assent 
 
Statement of professional obtaining assent 
I have fully explained this research study to the subject or guardian of subject. In my 
judgment and the subject’s or guardian’s, there was sufficient access to information, 
including risks and benefits to make an informed decision. 
Date:  ___________ 
Physician’s Signature: ______________________________ 
Physician’s Name:                                                                         (Print) 
 
 

 
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L. LEFTOVER STUDY SPECIMENS 
If you agree, excess blood, oral specimens and anal swab specimens taken during the study may 
be donated to the ACSR and made available for research by other investigators. Storage of 
leftover specimens will not require additional procedures than those already taking place in the 
research study. This is not a requirement to participate in the study and you may withdraw your 
approval for the storage of your leftover specimens at any time. These specimens may be held for 
an indefinite length of time. You will not be told of the results of the research done on these 
samples. 
Please check one of the following boxes to indicate whether or not you wish to have your leftover 
specimens stored for AIDS-related research in the future. 
 
  
Yes, I agree to have my leftover specimens stored for future research.  
 
  
No, I do not want to have my leftover specimens stored for future research 

 
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APPENDIX XV:  AIDS AND CANCER SPECIMEN RESOURCE (ACSR) – 
SPECIMEN PREPARATION AND SHIPPING INSTRUCTIONS 
A. 
GENERAL 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 cc.  
The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. These 
shippers may be ordered at the SAF-T-PAK website www.saftpak.com. The following 
instructions below are for use with the recommended STP-210 shipper. If using another 
federally approved diagnostic shipper, please follow instructions provided for that specific 
shipper. 
 
NOTE: SPECIMENS MUST BE SHIPPED MONDAYS THROUGH WEDNESDAY AS 
AN OVERNIGHT PRIORITY SHIPMENT. SPECIMENS ARE NOT ACCEPTED ON 
FRIDAYS, SATURDAYS, OR SUNDAYS IN THE ACSR. 
 
B. 
SPECIMEN PREPARATION, PACKAGING, AND SHIPMENT 
BLOOD SPECIMENS 
Draw two 8.5 cc (ml) yellow top [acid citrate dextrose (ACD) Solution A] tubes from study 
patient. With a black, water resistant, sharpie pen, label each specimen with the following 
information: 
• 
AMC Protocol #072  
• 
AMC Subject ID#  
• 
Date and time of collection  
• 
Specimen type, i.e., S=Serum, or Tissue 
• 
Specimen purpose: Donation 
 
Specimen Shipment 
• 
Seal the tops of the two 8.5 cc yellow tops with parafilm. 
• 
Place the two sealed tubes into bubble wrap (provided in STP-210 kit). 
• 
Tape around the bubble wrap so that the roll stays together and the tubes cannot fall out 
or break. 
• 
Place absorbent material sheet around the bubble wrapped tubes and slip into a biohazard 
poly-bag and “self-seal”. 
• 
Place poly-bag containing tubes into the white TYVEK bag and seal. 
• 
Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Seal the cardboard 
shipper with clear packing/shipping tape. 
• 
Affix the FED-EX airbill on blank side of the shipper making sure that it is marked 
“FED-EX PRIORITY OVERNIGHT”. 
• 
Mark “OTHER” in the airbill under “Packaging”. AMC SITES: Please use FedEx 
Account # 
. ATN SITES:  Please use your local FedEx account number for 
shipment of all ACSR samples.  
• 
Under airbill section “Special Handling” indicate “YES-SHIPPERS DECLARATION 
NOT REQUIRED”. 
• 
Place “From/To” information onto areas provided on the shipper. 
 

 
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Blood specimens should be shipped by overnight express at room temperature to: 
Dr. Sylvia Silver/Bank Technologist 
George Washington University Medical Center 
2300 I Street, NW 
Washington, DC  20037 
Phone: (202) 994-3422 
Fax: (202) 994-5056 
 
• 
Make certain that shipper is already either pre-labeled with ‘UN#3373’ stamp, or make a 
paper label with ‘UN#3373” and affix it to the shipper. 
• 
Make certain that the net volume of the specimen being shipped is written in the space 
provided on the shipper or make a separate label with the volume in ml and affix to the 
shipper. 
• 
Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. 
• 
RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
• 
Place the box in the FedEx pickup area at your site or call to request a package pickup. 
 
Please Note: The shippers will be mailed back to each AMC site. 
 
INSTRUCTIONS FOR BLOOD SPECIMENS COLLECTED ON FRIDAY 
 
Preparation of Plasma and Mononuclear Cells 
It is preferable that separation occurs as soon as possible. If necessary, whole blood in ACD 
(yellow top tubes) can be held at room temperature for no more than 24 hours. 
 
Materials 
• 
Lymphocyte Separation Medium (LSM Solution, Ficoll-Hypaque - sterile) 
• 
15 ml conical centrifuge tubes (sterile) 
• 
PBS (sterile) 
• 
1, 5 ml and 10 ml serologic pipettes (sterile) 
• 
NUNC tubes 
• 
Alcohol-saturated, control rate freezer container 
• 
DMSO freezing media: 
• 
50% Cryoprotective Medium, Cambrex (catalog no.:12-132A) 
• 
50% Heat Inactivated Fetal Bovine Serum 
 
Preparation of Plasma Samples 
• 
The 8.5 ml tubes of whole blood in ACD should be rotated gently two or three times 
before being centrifuged. Do not transfer before centrifugation. 
• 
The cells are separated by centrifugation at 500 g for 10 minutes. 
• 
0.5 ml aliquots of plasma are removed and put into separate 1.5 ml screw top tubes 
(NUNC) and transferred to liquid nitrogen storage. 
 

 
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PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) SEPARATION AND 
FREEZING 
• 
The cells and plasma remaining from the previous step are transferred into a 15 ml 
conical tube or 50 ml centrifuge tube depending on volume. 
• 
Sterile PBS should be added to the suspended cells whole blood cells in an equal volume 
and pipetted up and down to mix (1:1). 
• 
The whole blood-PBS mixture should be carefully overlaid onto 4-5 ml of room 
temperature LSM or Ficoll-Hypaque solution in a sterile 15 ml conical centrifuge tube. A 
sharp interface should exist between the LSM and the whole blood mixture. (If the layer 
of LSM gets mixed with the blood-PBS, the tube should be gently rotated to mix the 
blood, PBS, and LSM, and transfer to a 50 ml sterile conical tube. An equal volume of 
PBS is added, and the cells are separated at 600 g for 15 minutes. After removal of LSM-
PBS supernatant, return to Step b). 
• 
Centrifuge the 15 ml conical tube for 30 minutes at 900 g at room temperature. The 
mononuclear leukocytes (principally lymphocytes and monocytes) will band at 
plasma/LSM interface. 
• 
The fluffy white layer just below the plasma layer should be aspirated off and transferred 
to an appropriately labeled 15 ml sterile conical centrifuge tube. Be careful to remove 
only the interface and a minimum amount of the LSM or Ficoll-Hypaque. 
• 
Add three volumes of PBS to the cell suspension and or enough to fill conical and mix by 
pipetting up and down. 
• 
Centrifuge at 500 g for 10 minutes. 
• 
Aspirate off and discard supernatant, taking care not to disturb pellet. 
• 
Resuspend in 12 ml of PBS.  Take 10 µl of suspension for cell counting (dilute 
accordingly whether using a hemocytometer or automated cell counter). Centrifuge again 
for 10 minutes at 500g to wash cells. 
• 
Using a 1 ml pipette, the *DMSO freezing mixture should be added dropwise to the cell 
pellet suspension. Gently finger-tap between drops to resuspend cells. If the cell pellet is 
small, only 0.5 ml of freezing media is added (and only one aliquot of cells is frozen). If 
the cell pellet is large, up to 2 ml of freezing media can be added in a drop wise fashion. 
(Cell densities of 1 - 10 million PBMC/ml are best for cryopreservation. If a 
hemocytometer is available, the optimal concentration is 5 x 106 PBMC/ml). 
 
*Important: Do not put the DMSO containing media on the cell button all at once. 
 
• 
Freeze the cell suspension in 0.5 ml aliquots in sterile NUNC vials by placing the NUNC 
tubes in a room temperature, alcohol saturated, control rate freezer container and store in 
the -80°C freezer overnight. Transfer the cell suspension into the liquid nitrogen 
temperature freezer for long-term storage the next working day. 
 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT 
DEVIATE FROM REQUESTED LABELING. Shipping frozen aliquots requires 
the use of packaging acceptable for dry ice and Class 9 label with weight of dry ice 
written on package. 
 
 
PREPARATION OF TISSUE SAMPLES 
Tissue specimens to be fresh frozen should be placed in OCT and then on dry ice 

 
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immediately. The specimens may stay on dry ice until being transferred to a -80ºC freezer. 
 
Tissue specimens for donation may be batched for shipping after storage in -80ºC freezer. 
*NOTE: Specimens can only be accepted Monday through Thursday. Therefore, specimens 
can only be shipped Sunday-Wednesday for delivery the next day. Shipping frozen tissue 
requires the use of packaging acceptable for dry ice and Class 9 label with weight of dry ice 
written on package. 
 
TISSUE specimens should be shipped by overnight express to: 
Dr. Sylvia Silver/Bank Technologist 
George Washington University Medical Center 
2300 I Street, NW 
Washington, DC  20037 
Phone: (202) 994-3422 
Fax: (202) 994-5056 
 
C. 
RECORD OF SPECIMENS 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTraceSM shipment manifest must accompany all 
specimen shipments.