Conditions: HIV Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
This study is a prospective, open-label, randomized, three-arm, dose-escalation exploratory pilot clinical trial involving HIV-1 infected participants treated with suppressive combination antiretroviral combination therapy (cART). The study will test whether combined treatment with the histone deacetylase inhibitor panobinostat and the immunomodulatory cytokine Interferon-alpha2a can reduce the residual reservoir of HIV-1 infected cells that persist during treatment with currently available antiretroviral drugs.

Detailed description:
This study is a prospective, triple-arm, randomized, open-label, dose-escalation exploratory clinical trial involving HIV-1 infected participants treated with suppressive combination antiretroviral combination therapy (cART). The primary objective of this study is to evaluate a new strategy for reducing the residual reservoir of HIV-1 infected cells that persists despite treatment with current HIV drugs. The clinical trial is conducted in the Infectious Diseases Clinical Trials Unit (CTU) at the Massachusetts General Hospital.

The study medication includes two agents: panobinostat is an oral tablet that can reverse HIV-1 latency and awaken HIV from a "sleeping" condition during which it is protected from the human immune system. The second drug is pegylated interferon-alpha2a (IFN-alpha2a), an injectable cytokine that activates the immune system. The combined use of both agents may lead to immune-mediated elimination of HIV-1 infected cells in which viral latency has been reversed by panobinostat.

Participants will be randomized to receive a treatment course with panobinostat alone (Arm A, 4 participants total), panobinostat in combination with pegylated IFN-alpha2a (Arm B, 9 participants total), or pegylated IFN-alpha2a alone (Arm C, 4 participants total). Participants receiving panobinostat will undergo one week of treatment (15mg, dosed every second day on Monday, Wednesday, Friday), followed by three weeks off-treatment. Subcutaneous injections with pegylated IFN-alpha2a will be administered at the start of the week-long treatment course (simultaneously with the first dose of panobinostat for Arm B). ART will be continued during the entire treatment duration in all study participants.

Participants will undergo close monitoring for side effects during the entire time of study participation. The total study duration will be 2 months.

Arms:
arm 1: Participants in Arm A will receive panobinostat as an oral tablet on days 0, 2, and 4 of the treatment week. The dose of panobinostat will be a 15 mg tablet. arm 2: Participants in Arm B will receive one subcutaneous injection of pegylated interferon-alpha2a on day 0. The dose of pegylated IFN-alpha2a will be 180 mcg. Simultaneously with interferon-alpha2a, a 15 mg tablet of panobinostat will be administered on day 0. Participants will also receive panobinostat as an oral tablet on days 2 and 4 of the treatment week. arm 3: Participants in Arm C will receive one subcutaneous injection of pegylated interferon-alpha2a on day 0.The dose of pegylated IFN-alpha2a will be 180 mcg.

Interventions: intervention 1: Panobinostat intervention 2: Pegylated Interferon-alpha2a
Intervention descriptions: intervention 1: Panobinostat will be administered orally. intervention 2: Pegylated Interferon-alpha2a will be administered subcutaneously in one shot.

Protocol document:
Prot_SAP_000.pdf: 
 
1 
 
 
 
A Phase I-II Pilot Study to Assess the Safety and Efficacy of Combined Administration 
with Pegylated Interferon-2a and the Histone Deacetylase Inhibitor (HDACi) 
Panobinostat for Reducing the Residual Reservoir of HIV-1 Infected Cells in cART-
Treated HIV-1 Positive Individuals 
 
 
Clinical Trial Sponsored by:  
Massachusetts General Hospital, Boston, MA, USA 
 
Investigational Products Provided by:  
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA 
Genentech Inc./Roche, South San Francisco, CA, USA 
 
IND #: 123446 
Local IRB protocol Number: 2015P000858 
DAIDS-ES ID: 12049  
Funding Mechanism: U01 AI117841 (NIH/NIAID) 
 
Study Co-chairs: 
Mathias Lichterfeld, M.D., Ph.D. 
Daniel R. Kuritzkes, M.D. 
 
 
Version 7.0, August 19th, 2018 
 


 
2 
 
Panobinostat/INF U01 
 
A Phase I-II Pilot Study to Assess the Safety and Efficacy of Combined Administration with 
Pegylated lnterferon-alpha2a and the Histone Deacetylase Inhibitor (HDACi) Panobinostat 
for Reducing the Residual Reservoir of HIV-1 Infected Cells in cART-Treated HIV-1 
Positive Individuals  
 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization Guideline 
for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee determinations; all 
applicable in-country, state, and local laws and regulations; and other applicable requirements 
(e.g., US National Institutes of Health, Division of AIDS) and institutional policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________ Date: ________________ 
Name/Title 
 
 
 


 
3 
 
TABLE OF CONTENTS 
 
PAGE 
1.0 
LIST OF ABBREVIATIONS ........................................................................................... 65 
2.0 
PROTOCOL TEAM ROSTER ......................................................................................... 98 
3.0 
SCHEMA ........................................................................................................................ 109 
4.0 
STUDY OBJECTIVES ................................................................................................. 1211 
4.1 
Primary Objectives............................................................................................ 1211 
4.2 
Secondary Objectives........................................................................................ 1211 
5.0 
INTRODUCTION ........................................................................................................ 1211 
5.1 
HIV-1 Eradication and Cure ............................................................................. 1211 
5.2 
Targeting Latently HIV-1 Infected CD4 T Cells with HDACi ........................ 1312 
5.3 
Panobinostat ...................................................................................................... 1312 
5.4 
Clinical Trials with HDACi in cART-treated HIV-1-Positive Individuals .......... 15 
5.5 
Pegylated Interferon-α2a ................................................................................... 1716 
5.6 
Rationale and Hypotheses for this Study .......................................................... 1817 
6.0 
STUDY DESIGN.......................................................................................................... 1918 
7.0 
SELECTION, ENROLLMENT AND RANDOMIZATION OF PARTICIPANTS .... 2019 
7.1 
Inclusion Criteria .............................................................................................. 2019 
7.2 
Exclusion Criteria ............................................................................................. 2321 
7.3 
Participant Recruitment, Information and Consent .......................................... 2523 
7.4 
Study participant replacement........................................................................... 2524 
7.5 
Randomization .................................................................................................. 2524 
8.0 
STUDY TREATMENT ................................................................................................ 2524 
8.1 
Panobinostat ...................................................................................................... 2524 
8.2 
Peginterferon alfa-2a, (Pegylated interferon -2a, Pegasys) ........................ 2625 
8.3 
Accountability of study medication .................................................................. 2625 
8.4 
Dosing schedule for investigational drugs: ....................................................... 2625 
8.5 
Monitoring for adherence to investigational drugs ........................................... 2725 
8.6 
Concomitant Medication ................................................................................... 2725 
9.0 
CLINICAL AND LABORATORY EVALUATIONS ................................................. 2826 
9.1 
Study Conduct ................................................................................................... 2826 
9.2 
Definition of clinical evaluations ...................................................................... 2827 
9.3 
Schedule of Events ............................................................................................ 2928 


 
4 
 
9.4 
Long-term follow-up ......................................................................................... 3433 
9.5 
Early termination visit....................................................................................... 3433 
9.6 
Pregnancy .......................................................................................................... 3433 
10.0 
STUDY MONITORING .............................................................................................. 3433 
10.1 
Internal Safety Review Committee (ISRC) ...................................................... 3433 
10.2 
Safety Monitoring Committee (SMC) .............................................................. 3534 
10.3 
Definitions of Adverse Reactions ..................................................................... 3534 
10.4 
Monitoring for Adverse Events ........................................................................ 3635 
10.5 
Reporting of Adverse Events ............................................................................ 3736 
10.6 
Reporting to FDA ............................................................................................. 4039 
10.7 
Follow-up of Adverse Events ........................................................................... 4140 
10.8 
Contraindications to further administration of study drugs .............................. 4140 
10.9 
Criteria for Study Continuation to stage 2 and 3 .............................................. 4140 
11.0 
TOXICITY MANAGEMENT ...................................................................................... 4241 
11.1 
Early or delayed hypersensitivity reactions ...................................................... 4241 
11.2 
Grade 2 adverse events ..................................................................................... 4241 
11.3 
Grade 3 and Grade 4 adverse events ................................................................. 4241 
11.4 
Specific management of panobinostat and PEG-IFN-α2a toxicity ................... 4342 
11.5 
Abnormal CD4 T cell counts ............................................................................ 4443 
11.6 
Adverse reactions due to ART .......................................................................... 4544 
11.7 
Other abnormal laboratory or clinical findings ................................................. 4544 
11.8 
Antiretroviral treatment failure ......................................................................... 4544 
12.0 
TERMINATION RULES ............................................................................................. 4645 
12.1 
Termination rules for individual participants ................................................... 4645 
12.2 
Temporary suspension of all study drug administration in all study participants
 
474643 
12.3 
Permanent suspension of all study medication in all study participants ........... 4746 
13.0 
SAMPLE HANDLING AND ANALYSIS .................................................................. 4746 
13.1 
Treatment and Storage of biological samples ................................................... 4746 
13.2 
Standard laboratory assays ................................................................................ 4847 
13.3 
Virologic assays for HIV-1 reservoir quantification ........................................ 4847 
13.4 
Immunologic Assays ......................................................................................... 4948 
13.5 
Gene Expression Profiling ................................................................................ 4948 


 
5 
 
13.6 
Immunogenetic Studies ..................................................................................... 4948 
13.7 
Exploratory Analyses ........................................................................................ 5049 
14.0 
DATA EVALUATION AND STATISTICAL ANALYSIS ........................................ 5049 
14.1 
Co-primary Endpoints ....................................................................................... 5049 
14.2 
Secondary Endpoints ........................................................................................ 5049 
14.3 
Sample Size Considerations .............................................................................. 5049 
14.4 
Final Analyses ................................................................................................... 5150 
15.0 
DATA MANAGEMENT.............................................................................................. 5251 
15.1 
Data Management ............................................................................................. 5251 
15.2 
Confidentiality ...................................................................................................... 52 
16.0 
PUBLICATION OF RESEARCH FINDINGS ............................................................ 5352 
17.0 
BIOHAZARD CONTAINMENT ................................................................................. 5352 
18.0 
PROTOCOL REGISTRATION ................................................................................... 5352 
18.1 
Introduction ....................................................................................................... 5352 
18.2 
Initial Registration ............................................................................................ 5352 
18.3 
Amendment Registration .................................................................................. 5352 
19.0 
REFERENCES ............................................................................................................. 5453 
20.0 
APPENDIX: .................................................................................................................. 5756 
20.1 
Genentech Safety Reporting Fax Cover Sheet .................................................. 5756 
20.2 
Novartis Safety Reporting Fax Cover Sheet ..................................................... 5857 
20.3 
DAIDS Expedited Adverse Event Reporting Form (EAE form) ...................... 6160 
 
 
 
 
 
 
 
 
 
 
 
 


 
6 
 
1.0 
LIST OF ABBREVIATIONS 
AE 
 
 
 
 
adverse event 
ALT 
 
 
 
 
alanine aminotransferase  
ANC   
 
 
 
absolute neutrophil count 
AST 
 
 
 
 
aspartate aminotransferase  
ATI 
 
 
 
 
analytical treatment interruption 
AUC 
 
 
 
 
area under the curve 
bpm 
 
 
 
 
beats per minute  
β-HCG  
 
 
 
β-human chorionic gonadotropin 
cART   
 
 
 
combination antiretroviral therapy 
CDC 
 
 
 
 
Centers for Disease Control and Prevention  
CFR 
 
 
 
 
Code of Federal Regulations 
CMV  
 
 
 
cytomegalovirus  
CP 
 
 
 
 
clinical pharmacology  
CRF 
 
 
 
 
Case report form 
CTU 
 
 
 
 
Clinical trial unit 
CyTOF  
 
 
 
cytometry-by-time-of-flight assays  
DAIDS  
 
 
 
Division of AIDS 
DNA 
 
 
 
 
Deoxyribonucleic acid 
EAE 
 
 
 
 
Expedited Adverse Event 
ECG 
 
 
 
 
Electrocardiogram 
FDA 
 
 
 
 
Food and Drug Administration  
GCP 
 
 
 
 
Good Clinical Practice  
eGFR  
 
 
 
estimated glomerular filtration rate 
GT 
 
 
 
 
genotype  
HBV 
 
 
 
 
Hepatitis B Virus 
HCV 
 
 
 
 
Hepatitis C Virus 
HGB 
 
 
 
 
Hemoglobin 
HIV-1  
 
 
 
Human Immunodeficiency Virus-1 
HDAC  
 
 
 
Histone deacetylase 
HDACi  
 
 
 
Histone deacetylase inhibitor 
HLA 
 
 
 
 
human leukocyte antigen  
HR 
 
 
 
 
heart rate  
IC50 
 
 
 
 
Inhibitory Concentration at which 50% of viruses are inhibited 
ICH 
 
 
 
 
International Council on Harmonization  


 
7 
 
IFA 
 
 
 
 
immunofluorescent antibody  
IFN 
 
 
 
 
Interferon 
IND 
 
 
 
 
Investigational New Drug  
IRB 
 
 
 
 
Institutional Review Board  
ISRC  
 
 
 
Internal Safety Review Committee 
ISG 
 
 
 
 
Interferon-stimulated gene 
IUPM  
 
 
 
infectious viral units per million  
i.v. 
 
 
 
 
intravenous 
KIR 
 
 
 
 
killer cell immunoglobulin-like receptor  
LLN 
 
 
 
 
lower limit of normal 
LTR 
 
 
 
 
long terminal repeat 
MMRM 
 
 
 
mixed models with repeated measures  
NK 
 
 
 
 
Natural killer 
NRTI  
 
 
 
Nucleoside Reverse Transcriptase Inhibitor 
NNRTI  
 
 
 
Non-Nucleoside Reverse Transcriptase Inhibitor 
PBMC  
 
 
 
peripheral blood mononuclear cells  
PBT 
 
 
 
 
panobinostat  
PCR 
 
 
 
 
Polymerase Chain Reaction 
PEG 
 
 
 
 
pegylated 
pDC 
 
 
 
 
plasmacytoid dendritic cells 
PK 
 
 
 
 
pharmacokinetics 
PI 
 
 
 
 
Protease Inhibitor 
p.o. 
 
 
 
 
per os (by mouth) 
PLT 
 
 
 
 
platelets 
PPD 
 
 
 
 
purified protein derivative  
PTT 
 
 
 
 
partial Thromboplastin time 
QOW  
 
 
 
every second week 
QOD 
 
 
 
 
every second day 
RNA 
 
 
 
 
Ribonucleic acid 
SAE 
 
 
 
 
severe adverse event 
s.c.  
 
 
 
 
subcutaneous 
SCA 
 
 
 
 
single copy assay  
SMC 
 
 
 
 
Safety monitoring committee 
SNP 
 
 
 
 
single nucleotide polymorphisms  
TCP 
 
 
 
 
Thrombocytopenia 


 
8 
 
TSH 
 
 
 
 
Thyroid stimulating hormone 
TIW 
 
 
 
 
Three time per week 
TILDA  
 
 
 
Tat/rev Induced Limiting Dilution Assay  
ULN 
 
 
 
 
upper limit of normal 
 


 
9 
 
2.0 
PROTOCOL TEAM ROSTER 
 
Protocol Co-Chair and Clinican: 
 
Protocol Immunologist: 
Mathias Lichterfeld, M. D., Ph. D.  
 
 
Xu Yu, M. D.   
Assistant Professor of Medicine  
 
 
Associate Professor of Medicine 
 
Massachusetts General Hospital  
 
 
Ragon Institute of MGH, MIT and Harvard 
55 Fruit Street, Boston, MA 02114 
 
 
400 Technology Square, Cambridge, MA 02129  
Phone: 617-724-7516 
 
 
 
 
Phone: 857-268-7004 
Fax: 617-726-5411 
 
 
 
 
Fax: 857-268-7142 
E-mail: mlichterfeld@partners.org 
 
 
E-mail: xyu@partners.org 
 
Protocol Co-Chair: 
 
 
 
 
Statistician: 
Daniel R. Kuritzkes, M. D.  
 
 
 
Lu (Summer) Zheng, Ph. D.  
Professor of Medicine  
 
 
 
Research Scientist 
Chief, Infectious Disease Division 
 
 
Center for Biostatistics in AIDS Research 
Brigham and Women’s Hospital  
 
 
Harvard School of Public Health 
75 Francis Street, Boston, MA 02115 
 
 
FXB Building, 613, Boston, MA 02115 
Phone: 617-732-8881 
 
 
 
 
Phone: 617-432-3021 
Fax: 617-768-8738 
 
 
 
 
Fax: (617) 432-1355 
E-mail: dkuritzkes@partners.org 
 
 
szheng@sdac.harvard.edu 
 
Protocol Clinician:  
 
 
 
 
Pharmaceutical Company Representative 
Rajesh T. Gandhi, M. D.  
 
 
 
Richard Colvin, M. D., Ph. D.  
Associate Professor of Medicine 
 
 
Director, Translational Medicine, 
Massachusetts General Hospital  
 
 
Infectious Diseases 
55 Fruit Street  
 
 
 
 
Novartis Institute for Biomedical Research 
Boston, MA 02114 
 
 
 
 
220 Massachusetts Avenue, 330F 
Phone: 617-726-8403 
 
 
 
 
Cambridge, MA 02139 
Fax: 617-726-7653 
 
 
 
 
Phone: +1 617 871 4987 
E-mail: rgandhi@partners.org 
 
 
 
E-mail: richard.colvin@novartis.com 
 
Study Coordinator: 
 
 
 
 
Research Pharmacist:  
Theresa (Teri) Flynn, MSN, ANP 
 
 
John Vetrano, RPh. 
Clinical Trials Unit 
 
 
 
 
Chief Research Pharmacist 
Massachusetts General Hospital  
 
 
Massachusetts General Hospital 
55 Fruit Street,  Boston, MA 02114 
 
 
55 Fruit Street, Boston, MA 02114 
Phone: 617-724-0072 
 
 
 
 
Phone : 617-726-2515 
Fax: 617-726-7416 
 
 
 
 
Fax : 617-724-5013 
E-mail: tflynn@partners.org 
 
 
 
E-mail: jvetrano@partners.org 
 
Study Cardiologist: 
Rajeev Malhotra, M. D.  
Instructor in Medicine 
Massachusetts General Hospital 
55 Fruit Street, Boston, MA 02114 
Phone: 617-726-2677 
E-mail: rmalhotra@partners.org 


 
10 
 
3.0 
SCHEMA 
 
A Phase I-II pilot study to assess the safety and efficacy of combined administration with pegylated 
IFN-α2a and the histone deacetylase inhibitor (HDACi) panobinostat for reducing the reservoir of 
HIV-1 infected cells in cART-treated HIV-1 positive individuals. 
DESIGN: 
This study is a prospective, open-label, randomized, two-arm, dose-escalation 
exploratory pilot clinical trial involving HIV-1 infected participants treated with 
suppressive combination antiretroviral therapy (cART).  
DURATION: 
One month of pre-treatment observation, one week of treatment, three weeks of post-
treatment observation. The total duration per patient will be 2 months.   
SAMPLE SIZE: n=8 participants for stage 1 and stage 2; n=18 in stage 3 (total of 34 individuals) 
POPULATION: Participants (18-65 years of age) with HIV-1 infection who have received antiretroviral 
therapy (ART) with HIV RNA levels <50 copies/mL for at least two years and a CD4 T 
cell count >400 cells/mm3. Patients who started antiretroviral treatment in early HIV-1 
infection (within <12 months of HIV-1 transmission), and patients who started 
antiretroviral treatment in chronic infection (≥12 months after HIV-1 transmission) are 
eligible for this study.  
REGIMEN: 
All study patients will receive the histone deacetylase (HDAC) inhibitor panobinostat 
administered as an oral tablet three times every other day (TIW) during the treatment 
week.  
 
In stage 1, each panobinostat dose will be 5 mg; in stage 2, each panobinostat dose will 
be 10 mg; in stage 3, each panobinostat dose will be 15 mg.  
In each stage, participants will be randomized to one of the following regimens: 
 
Arm A:  Treatment with panobinostat alone at stage-specific dose (n=2 participants in 
stages 1 and 2; n=4 participants in stage 3). 
Arm B: Combined treatment with panobinostat (at the stage-specific dose) and pegylated 
IFN-2a (Pegasys, 180 micrograms, administered by s.c. injection simultaneously with 
the first dose of panobinostat during the treatment week (n=6 participants in stages 1 and 
2; n=10 participants in stage 3).   
Arm C: Treatment with pegylated IFN-2a only (Pegasys, 180 micrograms, 
administered by s. c. injection; n=0 in stage 1/2, n=4 in stage 3) 
Progression to stages 2 and 3 will depend on satisfactory safety reviews of data from the 
preceding stage.  
ART will be continued throughout the entire treatment course in the entire study 
population.  
OBJECTIVES: 
The primary objectives of this study are (i) to evaluate the safety and tolerability of 
combined treatment with panobinostat and pegylated IFN-2a in individuals with well-
controlled HIV-1 infection on suppressive cART, and (ii) to evaluate effects of combined 
treatment with panobinostat and pegylated IFN-2a on the reservoir of HIV-1 infected 
cells in comparison to effects of treatment with panobinostat only or with Interferon-2a 
only.   
ENDPOINTS: 
The two co-primary study endpoints will be (i) the cumulative frequency and intensity 
of any (grade ≥ 1) adverse event and serious adverse event during the one week treatment 


 
11 
 
period (primary safety endpoint) and (ii) change from baseline in the number of latently 
infected CD4 T cells, as assessed by CD4 T cell-associated proviral HIV-1 DNA levels, 
after completion of study treatment (primary efficacy endpoint) in arm B vs. arm A or C. 


 
12 
 
4.0 
STUDY OBJECTIVES 
4.1 
Primary Objectives 
4.1.1 
To evaluate the safety and tolerability of combined treatment with panobinostat and PEG-IFN-α2a 
in individuals with well-controlled HIV-1 infection on suppressive cART. 
4.1.2 
To evaluate effects of combined treatment with panobinostat and PEG-IFN-2a on the reservoir of 
HIV-1 infected cells in comparison to effects of treatment with panobinostat alone.  For this 
primary efficacy objective, the reservoir measurements will be CD4 T cell-associated proviral HIV-
1 DNA levels.  
4.2 
Secondary Objectives 
4.2.1 
To evaluate levels of CD4 T cells harboring replication-competent HIV-1 during treatment with 
the study medication in the different treatment arms.  
4.2.2 
To evaluate acetylation of histone proteins in CD4 T cells during treatment with the study 
medication in the different treatment arms.  
4.2.3 
To evaluate levels of CD4 T cell-associated HIV-1 RNA during treatment with the study 
medication in the different treatment arms.  
4.2.4 
To analyze levels of plasma HIV-1 RNA by standard and single-copy assay (SCA) during treatment 
with the study medication in the different treatment arms.  
4.2.5 
To evaluate effects of the study medication on chromosomally integrated proviral HIV-1 DNA and 
2-LTR HIV-1 DNA in CD4 T cells in the different treatment arms.  
4.2.6 
To assess effects of the study medication on levels of proviral HIV-1 DNA in CD4 T cell subsets 
(naïve, T memory stem cells, central-memory, effector-memory, terminally-differentiated) in the 
different treatment arms.  
4.2.7 
To identify expression patterns of interferon-stimulated genes (ISG) that are associated with 
changes in viral reservoir size during treatment with the study medication in the different treatment 
arms.  
4.2.8 
To identify innate and adaptive immune responses that are associated with a change in the reservoir 
of HIV-1 infected cells during treatment with the study medication in the different treatment arms.  
4.2.9 
To analyze changes in cellular and soluble immune activation markers in response to the study 
treatment in the different treatment arms.  
5.0 
INTRODUCTION 
5.1 
HIV-1 Eradication and Cure 
Current combination antiretroviral therapy (cART) is extremely effective at suppressing HIV-1 viremia, 
and substantially reduces HIV-1 associated morbidity and mortality1. The major weakness of current ART 
is its inability to fully eliminate HIV-1. This failure is mainly due to the fact that HIV-1 persists in specific 
cells in a transcriptionally silent, latent form that is not susceptible to antiretroviral effects of HIV-1 drugs2,3. 
Once treatment is stopped, latently infected cells can become activated and produce new viral virions that 
fuel rebound viremia, which typically leads to pre-treatment levels of HIV-1 replication within a short time4-
6. Therefore, ART currently has to be given life-long, which is associated with drug-related adverse 
reactions, high costs, and the possibility for selecting drug-resistant viruses7,8. Moreover, it is now well 
recognized that despite treatment with ART, abnormal immune activation is detectable in the majority of 
individuals9,10, which may be related to HIV-1 persistence and seems to be responsible for increased 
cardiovascular co-morbidities, accelerated aging and cognitive deficits that can be encountered in 


 
13 
 
individuals undergoing long-term antiretroviral therapy11,12. As such, the development of clinical strategies 
that can reduce or eradicate the reservoir of latently-infected CD4 T cells and induce a long-term drug-free 
remission of HIV-1 infection is a high priority for HIV-1 clinicians and scientists and would be of great 
benefit to infected patients13.  
Hope for successful reduction or elimination of the reservoir of HIV-1 infected cells in ART-treated patients 
was primarily galvanized by the recent identification of selected patients who appear to have achieved long-
term ART-free remission of HIV-1 infection. Such patients include the “Berlin” patient, an HIV-1 infected 
patient with AML who received an allogeneic hematopoietic stem cell transplant from a CCR532-
homozygous donor14, a group of patients who maintained a drug-free remission of HIV-1 infection after 
initiation of treatment in early HIV-1 infection15, and a baby with intrauterine HIV-1 infection who was 
started on ART within 30 hours after birth and maintained undetectable HIV-1 RNA for two years despite 
interrupting ART16.  
5.2 
Targeting Latently HIV-1 Infected CD4 T Cells with HDACi 
HIV preferentially infects activated CD4 T cells, which do not survive for more than a few days thereafter.  
On rare occasions, however, the virus infects a CD4 T cell as it transitions to a resting memory T-cell state. 
The result is stably integrated proviral HIV-DNA in a cell with a very long life span capable of resuming 
viral replication upon subsequent activation17-19. The molecular mechanisms by which HIV establishes 
latency are manifold and complex and include enzymatic processes that affect the chromatin organization 
of the HIV-promoter region, one of the key determinants of transcriptional activity20. Histone deacetylation 
by histone deacetylases (HDACs) leads to conformational changes that constrict the chromatin and block 
transcription. There are 18 known HDACs which are grouped into 4 classes. Of these, the class I HDACs 
1, 2, and 3 may be particularly important to maintaining HIV latency21-23. Pharmacological HDAC 
inhibitors (HDACi) have shown the ability to reactivate and induce expression of HIV-1 from latently 
infected cells24. The use of HDACi for pharmacological reactivation of HIV-1 was first tested in a clinical 
study using the weak HDAC inhibitor valproic acid.25 Reduction of the latent viral reservoir was seen in 3 
of 4 participants, but further studies gave mixed results and the effect could not be confirmed. Newer and 
more potent HDAC inhibitors include suberoylanilide hydroxamic acid [SAHA] (vorinostat, Merck), 
PXD101 (belinostat, TopoTarget), ITF2357 (givinostat, Italfarmaco), romidepsin (Celgene) and LBH589 
(panobinostat, Novartis). These compounds can induce expression of HIV-1 in chronically infected cell 
lines and ex vivo in resting CD4 T cells from aviremic ART treated HIV-1 patients26.  
5.3 
Panobinostat  
LBH589 (panobinostat, Novartis) is a novel HDAC inhibitor that exhibits potent HDAC inhibition 
including powerful activity against HDAC3, the enzyme that appears to be particularly important to 
disrupting HIV latency. Panobinostat is formulated as an oral capsule and a solution for intravenous (i.v.) 
injection. Both the oral and i.v. formulations are currently being investigated in on-going phase I-III studies 
for various oncologic indications. Panobinostat was approved by the US FDA on February 23rd, 2015 for 
the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including 
bortezomib and an immunomodulatory agent.  
5.3.1 
Clinical Experience  
In clinical studies, both oral and intravenous (i.v.) formulations of panobinostat have been explored for a 
variety of indications. As of December 31st, 2013, 36 clinical studies, including clinical pharmacology (CP), 
Phase I and Phase II trials, as well as two randomized Phase III studies have either been completed or are 
ongoing. A total of 2428 participants were enrolled, 235 for i.v. and 2193 for oral, who received at least 
one dose of panobinostat either as a single agent or in combination with other agents. 
5.3.2 
Pharmacokinetics (PK)  
Panobinostat is rapidly absorbed with a median Cmax reached within 1 h after oral administration. The 
absolute oral bioavailability of panobinostat is approximately 30%. The compound can be administered 


 
14 
 
regardless of food intake as the variability and overall systemic exposure remained unchanged in 
participants taking panobinostat with or without food. AUC increased linearly and proportionally with 
doses up to 50 mg. The inter-individual variability (CV%) in systemic exposure is 60%. The plasma protein 
binding of panobinostat (mainly to albumin) is moderate (89.6% at 37°C) and independent of concentration. 
Elimination half-lives averaged 15 hours. Steady state is achieved by the third dose following days 1, 3, 
and 5 (TIW) weekly (QW) dosing. The metabolism of panobinostat involves several metabolic pathways 
including reduction, hydrolysis, oxidation, and glucuronidation processes. It is a substrate of cytochrome 
P450 3A4 (CYP3A4) with minor involvement of CYP2D6 and 2C19 as well as a weak inhibitor of CYP2D6 
in vivo. Panobinostat and its metabolites (~at least 40 metabolites in circulating plasma) were nearly equally 
excreted in urine and bile/feces of participants. Dose adjustments are not necessary in patients with severe 
renal impairment. 
5.3.3 
Safety Profile  
As of December 31st, 2013, a total of 2428 participants (235 for i.v. & 2193 for oral) were enrolled into the 
panobinostat clinical development program. A total of 762 (31.3%) participants treated with single agent 
oral panobinostat with available safety data were included in the pooled safety population described in the 
Investigator’s Brochure. Across all these single agent studies conducted to date, the most common adverse 
events of all grades are thrombocytopenia (TCP), neutropenia, fatigue, nausea/vomiting and diarrhea. Most 
common grade 3/4 events reported are TCP, neutropenia and fatigue. TCP appears to be dose-dependent 
and was identified as the leading cause of dose-reduction/interruption or discontinuation with single agent 
dosing. Preliminary evidence suggests that switching from the QW to the QOW schedule may be more 
effective than other dose modifications for reducing the recurrence of TCP. The median time to the first 
event of grade 3-4 TCP at the dose 40 mg TIW QOW is >15 days. A trend to increased TSH levels from 
baseline and a slight compensatory decrease in T4 not associated with clinical signs or symptoms have been 
noted in on-going clinical studies of oral panobinostat. The clinical significance of these observations is 
unclear. A theoretical risk of HDAC inhibitors is that they will induce activation of other retroviruses, 
oncogenes and/or DNA viruses, including CMV, hepatitis B virus and JC viruses. To date there is no 
evidence that the clinical use of HDAC inhibitors is associated with reactivation of DNA viruses27,28, but 
the long-term impact is not fully known.  
5.3.4 
Mutagenicity 
Panobinostat demonstrated dose-dependent mutagenic potential in bacterial cells and in mouse lymphoma 
cells, but did not reveal clastogenic potential in a chromosome aberration test in human peripheral blood 
lymphocytes. However, the assays demonstrated an increased frequency of endoreduplicated cells after 
panobinostat exposure of human lymphocytes. Endoreduplication is a form of nuclear polyploidization that 
results in multiple, uniform copies of chromosomes. This physiologic process is common in plants and 
animals, especially in tissues with high metabolic activity, and it generally occurs in cells that are terminally 
differentiated. Increased induction of endoreduplicated cells is likely related to the pharmacologic 
mechanism of panobinostat and contributes to its effects against malignant cells. Evaluation of panobinostat 
in general toxicity studies in mice and dogs did not reveal any evidence for increased frequencies of 
malignant diseases during panobinostat treatment. Moreover, there was no evidence for increased risks for 
malignant diseases in human clinical trials conducted with panobinostat since the initiation of the 
panobinostat clinical development program in 2004. According to current classification criteria for 
mutagenicity, panobinostat is classified as a category 4 substance. Therefore, use of contraceptive methods 
for both female and male study participants is required during the entire study period; this is specified in 
the inclusion criteria.  
5.3.5 
QTc prolongation and cardiovascular toxicity 
As with other HDAC inhibitors, panobinostat, has the potential to prolong the QTc interval29,30. In the initial 
Phase I study utilizing the i.v. formulation of panobinostat administered on consecutive days, significant 
QTc interval abnormalities were noted, with one patient experiencing Torsades de pointes. Extensive ECG 


 
15 
 
monitoring has been conducted in all clinical studies of panobinostat. With the intermittent oral dosing 
(TIW QW and TIW QOW) used in clinical trials, QTc intervals >500 msec are uncommon and only noted 
with the TIW QW schedule. No cases of Torsades de pointes have been reported in clinical trials with 
intermittent i.v. or oral dosing regimens29,31. Other ECG abnormalities reported from previous clinical 
studies of panobinostat are asymptomatic T-wave abnormalities and asymptomatic sinus tachycardia. These 
have been noted frequently, but were generally not associated with clinical symptoms and their clinical 
significance is unclear. Ischemic heart disease, regardless of causality, was observed in 12 out of 666 study 
patients (1.8%) who received oral panobinostat as a single agent in the panobinostat development program. 
3 of these patients had severe (Grade 3/4) events. In the panobinostat licensing study (a randomized phase 
III study in which panobinostat was tested in combination with dexamethasone and bortezomib vs. 
dexamethasone and bortezomib alone in 758 individuals with refractory multiple myeloma), cardiac 
ischemic events occurred in 4% of the subjects assigned to the panobinostat arm vs 1% of patients assigned 
to the control arm.  
5.3.6 
Interactions with other drugs  
Based on in vitro data, panobinostat is a CYP3A4 and CYP2D6 substrate and a CYP2D6 inhibitor (IC50 
0.17 μM). Thus, two clinical DDI studies were conducted using ketoconazole as a potent CYP3A inhibitor 
[CLBH589B2110] and panobinostat as CYP2D6 inhibitor with dextromethorphan as CYP2D6 substrate 
[CLBH589B2109]. Study [CLBH589B2110] was conducted in 14 participants with advanced cancer. 
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of panobinostat by 1.6- and 1.7-fold, 
respectively, but with no change in Tmax32. The less than 2-fold increase in panobinostat AUC upon co-
administration suggests that CYP3A contribution to the total clearance is low. The observed effect of 
ketoconazole on panobinostat CYP3A mediated metabolic pathways is considered weak and not clinically 
relevant, as doses at least 2-fold greater than 20 mg (i.e. 40 mg and 60 mg) have been safely administered 
in participants. Clinical monitoring of signs of possibly panobinostat related adverse events is 
recommended when long-term (≥1 week) concomitant administration of potent CYP3A inhibitors and 
panobinostat at doses >20 mg is medically indicated. Study [CLBH589B2109] was conducted in 17 
participants with advance cancer. Multiple panobinostat doses at 20 mg (TIW) increased Cmax and AUC 
of dextromethorphan by a mean of 1.8- and 1.6-fold, respectively, but with no change in Tmax. An 
approximately 2-fold increase in dextromethorphan AUC upon co-administration with panobinostat 
indicated that in vivo CYP2D6 inhibition of panobinostat is weak. As the study was conducted using a 
sensitive CYP2D6 substrate resulting in a weak inhibition, drugs with a large therapeutic index such as 
anti-emetics, antihypertensives, and anti-depressants are generally considered safe to be co-administered 
with panobinostat. Caution is to be exercised when panobinostat is co-administered with medications that 
are exclusively metabolized by CYP2D6 and have a narrow therapeutic window (e.g. tamoxifen, anti-
arrhythmics). There are known interactions with the following anti-retroviral drugs of the protease inhibitor 
class: Indinavir/ritonavir, Lopinavir/ritonavir Saquinavir/ritonavir, Tipranavir/ritonavir, Ritonavir. In 
addition, there are interactions with antiretroviral regimens containing cobicistat. Use of any protease 
inhibitor or cobicistat will not be permitted during participation in this study. NNRTIs can induce CYP3A, 
but there was no clinical or laboratory evidence for significant pharmacokinetic interactions between 
NNRTIs (Efavirenz, Rilpivirine) or Integrase Inhibitors (Raltegravir) with panobinostat in a prior clinical 
trial with panobinostat in cART-treated HIV-1 participants33.  
5.4 
Clinical Trials with HDACi in cART-treated HIV-1-Positive Individuals 
So far, three different HDACi (vorinostat, romidepsin, panobinostat) have been or are being tested for 
reactivation of HIV-1 in ART-treated participants. Major findings from these studies are summarized 
below.  
5.4.1 
Clinical Trials with Vorinostat 
Effects of vorinostat on HIV-1 reactivation have so far been tested in two clinical trials, one conducted at 
the University of North Carolina at Chapel Hill (UNC)26,34 and one at the University of Melbourne, 


 
16 
 
Australia35. The UNC study administered a single dose of vorinostat to ART-treated HIV-1 patients, which 
led to significant increase in HIV-1 RNA transcription within hours after drug administration in 8 study 
participants. Effects of a single dose of treatment on CD4 T cell-associated HIV-1 DNA (as a surrogate 
marker for the viral reservoir) were not expected in this study and not reported. No clinically significant 
toxicity was recorded. Repetitive dosing of vorinostat in a subsequent study did not show substantial 
increases of cell-associated HIV-1 RNA. In the study at the University of Melbourne, vorinostat was 
administered at 400 mg daily for 14 consecutive days to n=20 cART-treated HIV-1 patients. Enhanced 
HIV-1 transcription was observed at multiple timepoints during this study, but there were no significant 
effects on CD4 T cell-associated HIV-1 DNA. No significant toxicity of vorinostat treatment was reported 
in this study36. 
5.4.2 
Clinical Trials with Romidepsin 
A clinical trial evaluating effects of a single dose of romidepsin on HIV-1 reactivation in ART-treated HIV-
1 patients is being conducted by the AIDS Clinical Trials Group (ACTG). Data from this study are expected 
in early 2016. In a second clinical trial, romidepsin was administered once-weekly in three consecutive i. 
v. infusions in six cART-treated study participants at Aarhus University Hospital in Denmark. Results from 
the study demonstrate strong reactivation of CD4 T cell-associated HIV-1 RNA and HIV-1 plasma RNA 
in six study participants37.  
5.4.3 
Clinical Trials with Panobinostat 
The CLEAR study, conducted at the University of Aarhus in Denmark, was an investigator initiated, single-
group, non-randomized phase I/II trial designed to evaluate the safety and ability of oral panobinostat to 
activate HIV-transcription in latently infected CD4 T cells of HIV-infected patients on suppressive cART. 
None of the participants received protease inhibitors. The study enrolled 15 participants and included a 4-
week pre-treatment observation phase, an 8-week treatment course and a post-treatment follow-up 
observation period of 24 weeks. Each individual received oral panobinostat at a dose of 20mg three times 
a week (TIW) every other week (QOW) for a total of eight weeks (12 doses of panobinostat total). Major 
findings from this study have been published recently 33 and are summarized below.  
5.4.3.1 Safety analysis 
No serious adverse events related to the study medication were noted during the entire time of observation 
in the CLEAR study. A total of 15 adverse events were noted that were likely related to the study 
medication; all of these were Common Terminology Criteria for Adverse Events (CTCAE) grade 1 and 
included fatigue (7 AEs), diarrhea (2 AEs), nausea (2 AEs), subjective palpitations with an otherwise 
normal cardiac exam (1 AE), epigastric pain (1 AE), vomiting (1 AE), and insomnia (1 AE). 20 adverse 
events were recorded that were unlikely to be related to the study medication, 14 of these were CTCAE 
grade 1 and 6 were CTCAE grade 2. These events included a fracture due to accident (1 AE, grade 2), 
maxillary sinusitis (1 AE), subclinical TSH increase (1 AE), flu-like symptoms (fever, cough, myalgia, 1 
AE), skin excoriation after accident (1 AE, grade 2), identification of sigmoid polyp during colonoscopy (1 
AE, colonoscopy was part of study protocol), rash (1 AE), fungal skin infection (1 AE), pharyngitis (1 AE), 
aphthous stomatitis (1 AE), monosymptomatic fever (1 AE), headache (1 AE, grade 2), post-LP headache 
(5 AEs, 2 grade 1 and 3 grade 2; LP was part of study protocol), URI symptoms (1 AE). Thrombocyte and 
neutrophil levels remained within normal limits for all study participants during the entire time of 
observation.  
5.4.3.2 Virologic effects 
The degree of histone acetylation is a direct measure of the pharmacodynamic effect of an HDACi on cells. 
In the CLEAR study, mean histone H3 acetylation increased rapidly (2.5-fold, 95% CI: 1.9-3.4; p<0.0001) 
two hours after the first dose of panobinostat. Overall, panobinostat treatment resulted in significant 
changes in histone H3 acetylation with increases and decreases corresponding to the cyclic dosing pattern. 
To investigate changes in CD4 T cell-associated (CA) unspliced (US) HIV-1 RNA during panobinostat 


 
17 
 
treatment, we used a semi-nested real time quantitative PCR previously described by Pasternak et al38. The 
level of CA US HIV-1-RNA, which represented the primary outcome measure of the CLEAR trial, 
increased significantly during panobinostat treatment (p<0.0001) with statistically significant increases at 
all assayed time points on-panobinostat as compared to baseline. As with histone H3 acetylation, levels of 
CA US HIV-1-RNA increased rapidly with a mean 2.4-fold increase (95% CI: 1.8-3.3; p<0.0001) two hours 
after initiating panobinostat. The median maximal fold-increase in CA US HIV-RNA during panobinostat 
treatment was 3.5-fold (range 2.1–14.4). In conclusion, these data show that panobinostat treatment can 
lead to significant increases in histone H3 acetylation and HIV-1 transcription in CD4 T cells.  
T cell-associated HIV-1 DNA was measured in the CLEAR study as a surrogate marker for the viral 
reservoir size. Despite increased HIV-1 transcription and virion production during panobinostat dosing, our 
analyses did not detect cohort-wide reductions in HIV-1 DNA. However, on review of the dynamics of 
HIV-1 DNA changes in individual patients, we observed a significant and sustained 3-5 fold decline of total 
HIV-1 DNA in four out of the 15 study patients. This suggests that administration of panobinostat can, 
under specific circumstances, result in a reduction of the reservoir of HIV-1 infected CD4 T cells in cART-
treated patients. Interestingly, three of these four study patients participated in an analytical treatment 
interruption (ATI) and had delayed rebound kinetics in comparison to the six other study persons who 
participated in the ATI and for who no change of HIV-1 DNA was observed during panobinostat 
treatment33.  
5.4.3.3 Immunologic effects 
Immunological studies in the CLEAR study included assessments of HIV-1-specific T cells, NK cells, 
dendritic cells and B cells by flow cytometry. The immunological parameters most closely associated with 
decline of HIV-1 DNA during treatment with panobinostat were innate effector cell responses, in particular 
activated CD69+ NK cells. In addition, declining levels of HIV-1 DNA were correlated with proportions 
of plasmacytoid dendritic cells. Reductions of HIV-1 DNA were also associated with expression patterns 
of interferon-stimulated genes (ISGs). Together, these data suggest that innate immune activity is critical 
for a reduction of the viral reservoir during panobinostat treatment.  
5.4.3.4 Pharmacokinetics 
Plasma levels of panobinostat increased in all 15 participants of the CLEAR study with the highest levels 
measured two hours after dosing as compared to eight hours after the previous dose, consistent with a Cmax 
occurring approximately 1-2 hours after oral ingestion as described previously39. There was no clinical or 
laboratory evidence for relevant pharmacological interactions between panobinostat and the antiretroviral 
drugs used in this study (NRTIs, PIs, NNRTIs).  
5.5 
Pegylated Interferon-α2a 
Peginterferon-α2a (Pegasys, Hoffmann-La Roche) is a covalent conjugate of recombinant α-2a interferon 
(approximate molecular weight [MW] 20,000 daltons) with a single branched bis-monomethoxy 
polyethylene glycol (PEG) chain (approximate MW 40,000 daltons). The PEG moiety is linked at a single 
site to the interferon alpha moiety via a stable amide bond to lysine. Peginterferon-2a has an approximate 
molecular weight of 60,000 daltons. Interferon-2a is produced using recombinant DNA technology in 
which a cloned human leukocyte interferon gene is inserted into and expressed in Escherichia coli. A 
chemically modified IFN-2a has been developed in which a branched methoxy polyethylene glycol 
moiety has been covalently attached to IFN. PEG-IFN has a decreased systemic clearance and an 
approximately 10-fold increase in serum half-life compared with IFN-, leading to PEG-IFN circulating in 
the blood for a much longer time than the parent compound. The biological activity of PEG-IFN, as 
measured using serum 2’5’-oligoadenylate synthetase (OAS) activity, was similarly prolonged, resulting in 
a significantly improved pharmacodynamic response of PEG-IFN compared with IFN.   


 
18 
 
5.5.1 
Clinical experience with pegylated IFN-2a 
Pegasys was registered by the US Food and Drug Administration on October 16th, 2002. It is licensed for 
treatment of Hepatitis C and B infection. In addition, IFN-2a has an orphan drug status for treatment of 
chronic myeloid leukemia, renal cancer and melanoma. It has been safely administered to >10,000 patients 
since approval.  
5.5.2 
Safety and Toxicity 
Side effects of pegylated IFN-α2a are usually mild to moderate and include flu-like symptoms such as 
fatigue, muscle aches, headaches, chills/fever, nausea, vomiting, or diarrhea and injection site irritation. 
Depression, irritability, insomnia, and anxiety have been seen in a moderate percentage (40%) of 
participants, but are usually mild.  Other reported events include neutropenia and thrombocytopenia, 
alopecia, and infrequently an abnormal (increased or decreased) thyroid function. A decrease in leukocytes 
has been reported but is usually within normal range. All of these are usually manageable and reversible 
upon discontinuation of the drug or decrease in dosage. 
5.5.3 
Effects of IFN-α on active HIV-1 replication 
A number of studies in the pre-HAART era have assessed effects of IFN-α on plasma levels of HIV-1 RNA 
in otherwise untreated patients. These studies demonstrated that IFN-α leads to a 0.5- to 1-log reduction of 
plasma HIV-1 RNA40-42. This effect occurs within several weeks of IFN-α administration and was most 
pronounced at week 10-15 of therapy. Similar observations were made in SIV-infected rhesus macaques 
treated with recombinant IFN-α or IFN-α receptor agonists43. Antiviral effects of IFN-α likely result from 
an IFN-α-dependent upregulation of antiviral molecules in HIV-1 target cells44,45. In addition, IFN-α can 
directly activate innate and adaptive effector immune cells46-48, reduce the expression of inhibitory 
molecules (PD-1) on antigen-specific T cells, and reduce the frequency of regulatory T cells49, all of which 
are assumed to contribute to antiviral effects of IFN-α.   
5.5.4 
Effects of IFN-α on the reservoir of HIV-1 infected cells in ART-treated patients 
Effects of IFN-α on the reservoir of HIV-1 infected cells in HIV-1 patients receiving suppressive 
antiretroviral therapy have been investigated in two prior studies. In a prospective clinical trial, treatment 
with IFN-α led to moderate, approximately 2-fold reduction of integrated HIV-1 DNA in CD4 T cells in a 
subset of participants50. A retrospective analysis of ART-treated HIV/HCV-co-infected participants 
receiving treatment with PEG-IFN-α and ribavirin confirmed a moderate, approximately 2-fold decrease of 
HIV-1 DNA levels; this effect was sustained after treatment discontinuation51. Together, these studies 
suggest that IFN-α is effective in reducing the reservoir of HIV-1 infected cells in ART-treated patients. 
Given that IFN-2a can by itself influence viral reservoir dynamics, a control arm of patients receiving 
IFN-2a only will be recruited in stage 3 of this study to allow comparisons in reservoir size between 
patients receiving the combination of IFN-2a and panobinostat, and those receiving IFN-2a only. 
5.6 
Rationale and Hypotheses for this Study 
Findings from the CLEAR study suggest that the HDACi panobinostat can increase HIV-1 gene expression 
in CD4 T cells from cART-treated patients in vivo, and that this increased virus production leads to transient 
increases in residual HIV-1 plasma viremia, indicating that panobinostat can be effective in reactivating 
HIV-1 gene expression from latently infected cells in vivo. However, these effects were insufficient to 
substantially reduce the total reservoir of HIV-1-infected cells that persist despite treatment. The immune 
correlates most strongly associated with a decrease of HIV-1 DNA in participants during panobinostat 
treatment were the proportion of activated CD69+ NK cells, the proportion of CD57+ NK cells with 
increased cytotoxic activities, and the proportion of plasmacytoid dendritic cells.  
Interestingly, prior studies have shown that treatment with PEG-IFN-α rapidly activates NK cells within 
hours of administration and induces the exact CD69+ NK cell phenotype that was associated with declining 
HIV-1 DNA in CD4 T cells during the CLEAR study46,47. Treatment with PEG-IFN- also increases the 


 
19 
 
frequency of plasmacytoid dendritic cells52, the second innate immune effector cell population associated 
with decreasing levels of HIV-1 DNA during panobinostat treatment in the CLEAR study. Moreover, in 
vitro studies suggest that treatment with IFN-α can support cell-autonomous pro-apoptotic immune 
recognition of HIV-1 RNA that is reactivated by treatment with panobinostat, and selectively sensitizes 
CD4 T cells with viral reactivation to NK cell-mediated killing by increasing the expression ligands to 
activating NK receptors. Therefore, IFN-α2a may be able to induce innate and cell-autonomous immune 
activity against CD4 T cells in which HIV-1 is effectively reactivated with panobinostat, and in this way 
act synergistically with panobinostat in eliminating the reservoir of HIV-1 infected cells.  
The following hypotheses will be tested in this clinical trial:  
Hypothesis 1: Combined treatment with panobinostat and PEG-IFN-α2a is safe and well-tolerated in 
participants with HIV-1 infection who have virological suppression (HIV RNA <50 copies/mL) and CD4 
T cell counts >400 cell/mm3 while receiving combination ART.  
Hypothesis 2: Combined treatment with panobinostat and PEG-IFN-α2a in ART-treated HIV-1 patients 
will be significantly more effective in reducing the reservoir of HIV-1-infected cells than treatment with 
panobinostat alone, or IFN-2a alone. During the combined treatment, panobinostat will reactivate active 
viral gene expression in latently infected CD4 T cells, while PEG-IFN-α2a will activate innate effector cells 
and increase cell-autonomous immune activity against CD4 T cells in which viral reactivation occurs.   
6.0 
STUDY DESIGN 
This study will be a prospective, randomized, open-label, dose-escalation exploratory clinical trial with the 
primary objective to evaluate the safety of combined treatment with the HDACi panobinostat and pegylated 
Interferon-2a, and to assess the efficacy of the combined treatment regimen to reduce the reservoir of 
HIV-1 infected cells in comparison to treatment with panobinostat as a single agent. Sequential cohorts 
with increasing doses of panobinostat will be enrolled. The first two dosing cohorts (stages 1 and 2) will 
serve primarily to assess the safety of panobinostat administration together with pegylated IFN-2a; the 
third dose cohort (stage 3) has a larger sample size to allow for comparison of the effects of panobinostat 
plus pegylated IFN-2a versus panobinostat or pegylated IFN-2a alone on the HIV reservoir. The clinical 
trial will involve a collaboration of three institutions: the Division of Infectious Diseases at Massachusetts 
General Hospital in Boston, MA, the Division of Infectious Diseases at the Brigham and Women’s Hospital 
in Boston, and the Novartis Institute of Biomedical Research in Cambridge. The clinical trial will be 
conducted in the Infectious Diseases Clinical Trials Unit (CTU) at the Massachusetts General Hospital. 
Participants must have HIV-1 RNA levels <50 copies/mL for at least two years, must have been on 
suppressive antiretroviral therapy for at least 2 years, must have a CD4 T cell count >400 cells/mm3 at study 
screening, and must have been on a stable and acceptable ART regimen for at least 12 weeks prior to 
screening. An acceptable regimen includes 2 NRTIs with either one NNRTI (efavirenz or rilpivirine) or a 
non-boosted integrase inhibitor (raltegravir or dolutegravir). Patients who started treatment during early 
disease (within <12 months after transmission) and patients who started treatment in chronic infection (≥
12 months after HIV-1 transmission) are eligible to participate.  
After obtaining informed consent, all study participants will have a history and physical exam performed 
and have laboratory tests to confirm they meet all inclusion and exclusion entry criteria. Women of 
childbearing potential will have a urine pregnancy test before treatment and after treatment during study 
participation. All participants will receive treatment comprising one week of panobinostat (dosed every 
second day on e.g. Monday, Wednesday, Friday), followed by three weeks off-treatment for observation. 
In stage 1, participants will receive panobinostat at a dose of 5 mg TIW; this dose will be escalated to 10 
mg TIW (stage 2) and 15 mg TIW (stage 3), if the safety review of each preceding step is acceptable. 
Participants will be randomized to receive panobinostat alone (Arm A, n=2 participants in stages 1 and 2; 
n=4 participants in stage 3), or in combination with pegylated IFN-2a (Arm B, n=6 participants in stages 


 
20 
 
1 and 2, n=10 participants in stage 3); in stage 3, patients will also be randomized to a control arm of n=4 
study subjects receiving Interferon-2a only (Arm C). Subcutaneous injections with pegylated Interferon-
2a will be administered at the start of the week-long treatment course. ART will be continued during the 
entire study period in all study participants. Participants will undergo close monitoring for side effects 
during the entire time of study participation. The total study duration will be 2 months. Blood samples will 
be obtained for immunological and virological assays at study baseline and at selected time points during 
the treatment and observation periods as described below.  The study design is summarized in Figure 1. 
7.0 
SELECTION, ENROLLMENT AND RANDOMIZATION OF PARTICIPANTS 
7.1 
Inclusion Criteria 
The study will include participants who meet all of the following criteria: 
7.1.1 
Between 18 to 65 years of age at the time of study screening. 
7.1.2 
Written informed consent signed prior to all study procedures. 
7.1.3 
HIV-1 infection as documented by any licensed ELISA test kit and confirmed by Western blot, 
HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, immunofluorescent antibody test (IFA), or a 
second antibody test by a method other than ELISA. Tests from any time prior to entry are 
acceptable.   
7.1.4 
Receiving suppressive antiretroviral therapy for a minimum of 24 consecutive months prior to 
screening with no interruption of therapy. Participants must have been on the same ART regimen 
for at least 12 weeks prior to screening. Participants must not have a history of antiretroviral 
treatment failure.  
7.1.5 
Participants must take an acceptable ART regimen at the time of study screening. Acceptable 
regimens include 2 NRTIs in combination with either an NNRTI (efavirenz or rilpivirine) or a non-
boosted integrase inhibitor (raltegravir or dolutegravir or bictegravir). FDA-approved dual drug 
regimens such as the rilpivirine/dolutegravir combination (Juluca) are also acceptable. Triple NRTI 
regimens, protease inhibitor- or cobicistat-containing regimens are not permitted.  
7.1.6 
Patients who started antiretroviral treatment in early HIV-1 infection (within <12 months of HIV-
1 transmission), and patients who started antiretroviral treatment in chronic infection (≥12 months 
after HIV-1 transmission) are eligible for this study.  
7.1.7 
Investigator anticipates that a fully active, alternative antiretroviral regimen can be constructed in 
the event of virological failure of the current ART regimen.   
7.1.8 
Documented suppressed HIV-1 RNA. Participants must have plasma HIV-1 RNA values <50 
copies/ml on at least three consecutive measurements during the 24 months prior to the study entry, 
except for a single blip of <400 copies/mL (that is, if a study candidate has a single HIV-1 RNA 
that is >50 copies/mL but <400 copies/mL with subsequent HIV-1 RNA values <50 copies/mL, 
then he or she will not be excluded).  Three consecutive HIV-1 plasma RNA levels below the 
detection threshold of commercial PCR assays with other threshold levels (e.g.<75 copies/mL) are 
also acceptable. 
7.1.9 
CD4 T cell count >400 cells/mm3 at screening visit.  
7.1.10 Laboratory values at screening visit that meet the following criteria: 
a. Hemoglobin > 12.0 g/dL for men and > 11.0 g/dL for women   
b. Absolute neutrophil count > 1500 cells/mm3 
c. Platelet count > 150,000/mm3 


 
21 
 
d. Prothrombin time (PT) < 1.1 x upper limit of normal (ULN) and partial thromboplastin time 
(PTT) < 1.1 x ULN 
e. Creatinine level < 1.1 x ULN 
f. Total serum bilirubin < 1.1 x ULN 
g. AST (SGOT) and ALT (SGPT) < 1.1 x ULN 
7.1.11 Normal TSH. If K and Mg levels are below the limits of normal, participants will be 
provided with supplements and their levels will be rechecked. Supplementations will 
continue until electrolyte levels are normalized.  
7.1.12 Negative serologic test for HBsAg.  
7.1.13 Negative serologic test for antibodies to HCV or negative HCV PCR if anti-HCV antibodies are 
positive. 
7.1.14 QTc interval in an ECG performed at the screening visit must be <450msec for men and <470msec 
for women. 
7.1.15 A negative T spot TB test or a negative PPD skin test within the last 24 months. Participants with 
positive assays may participate if they have completed a recommended treatment course for latent 
TB in the past.  
7.1.16 Participants should have received vaccination for pneumococcal disease within the last 5 years. 
Participants may still be enrolled in case there is a medical or personal contraindication against 
pneumococcal vaccination.  
7.1.17 No evidence of clinical coronary heart disease, as determined by a stress echocardiogram, 
conducted within 2 years prior to study initiation. Data from a non-imaging exercise stress test or 
a nuclear imaging stress test conducted within two years prior to study initiation are also acceptable. 
However, when stress tests without imaging were done, a resting echocardiogram should be 
performed prior to enrollment to assess the cardiac ejection fraction. Patients who are unable, or 
predicted to be unable, to achieve >85% of their maximal predicted heart rate will undergo a 
dobutamine stress echocardiography instead of an exercise stress echocardiography since an 
exercise stress test would be insufficiently sensitive in this case. The stress test will be conducted 
at the Massachusetts General Hospital Cardiology division. Dr. Rajeev Malhotra, the protocol 
cardiologist, will facilitate short-term scheduling of patients.    
Patients with no history of coronary artery disease (CAD) or clinical symptoms suggestive of CAD, 
who have excellent exercise capacity and achieve >70% but less than 85% of the maximum age-
predicted heart rate during stress echocardiography and under these conditions have no clinical, 
EKG, or echocardiographic evidence of cardiac ischemia, can be considered for participation in 
this study.  The eligibility of these subjects should be assessed on a case-by-case basis with 
consultation from experts. 
No evidence for coronary artery disease can also be documented by a negative coronary 
angiography or by a negative stress magnetic resonance imaging study.  The procedural report of 
these tests should also include documentation of cardiac function (e.g. left-ventricular ejection 


 
22 
 
fraction).  If this information is not included in the procedural report, a resting echocardiography 
should also be performed. 
7.1.18 No clinically significant eye disease, as determined by a baseline fundoscopic eye exam. 
The eye exam will be performed with an opthalmoscope (Welch Allyn, PanOptic 
Ophthalmoscope), and electronic retinal photographs will be taken of each eye.  
7.1.19 For females of reproductive potential, urine pregnancy test (latter with a sensitivity of 15-25 
mIU/mL) at the screening visit within 30 days prior to treatment by any US laboratory that has a 
CLIA certification or its equivalent. 
Reproductive potential is defined as: 
▪ 
Girls who have reached menarche or 
▪ 
Women who have had menses within the past 12 months and who do not have an FSH > 40 
IU/L or 
▪ 
Women who have had menses within the past 24 consecutive months if an FSH measurement 
is not available or  
▪ 
Women who have not undergone surgical sterilization (e.g. hysterectomy, or bilateral 
oophorectomy, or bilateral salpingectomy).  
 
Confirmation of the lack of reproductive potential is required.  
 
Written documentation or oral communication from a clinician or clinician’s staff documented in 
source documents of one of the following must be provided: physician report/letter, operative report 
or other source documentation in the patient record, discharge summary, laboratory report of 
azoospermia (required to document successful vasectomy of the male partner), FSH measurement 
elevated into the menopausal range (as established by the reporting laboratory). 
 
If the female participant cannot provide written proof of a male partner’s vasectomy status, the 
verbal report of her partner’s status should be written into the source documents. 
7.1.20 Female participants of reproductive potential must refrain from participating in active attempts to 
become pregnant, and, if participating in sexual activity that could lead to pregnancy, the participant 
must agree to use at least two reliable forms of contraception that are non-estrogen based. All 
participants of reproductive potential must continue to use contraceptives for 90 days after 
completing panobinostat/IFN-2a treatment.  
Acceptable forms of contraception include: 
• Condoms (male or female) with or without spermicidal agent 
• Diaphragm or cervical cap with spermicide 
• Non-hormonal intrauterine device (IUD) 
• Tubal ligation 
• Non-estrogen containing formulations of hormonal birth control drugs, given by pills, shots, or 
placed on or under the skin, for at least 90 days prior to study entry 
 
Providers and participants should be advised that not all contraceptive choices listed above can 
prevent HIV transmission and that some may actually increase the risk of HIV acquisition. Study 
participants who are sexually active with HIV negative or unknown HIV serostatus partners should 
be advised that they need to consider effective strategies for reducing the risk of HIV transmission, 
as well as meeting the requirement for effective contraception during their participation in the 
study. Study participants should discuss contraceptive choices and HIV risk reduction methods 
with their healthcare provider. 


 
23 
 
7.1.21 Female participants who are not of reproductive potential are not required to practice contraception.  
7.1.22 Male study participants must use a condom during intercourse while taking panobinostat and for 
five half-lives (5x16h, total of 80 hours) after stopping treatment and should not father a child in 
this period. A condom is required to be used also by vasectomized men in order to prevent delivery 
of the drug via seminal fluid. The partners of patients should also use contraception to avoid 
pregnancy. 
7.2 
Exclusion Criteria 
7.2.1 
Confirmed HIV-1 RNA >50 copies/mL within 24 months of screening, except for a single blip of 
<400 copies/mL during the 24 months prior to screening.   
7.2.2 
Participants with moderate or severe, uncontrolled psychiatric disease, a history of a previous 
suicide attempt or a history of prior hospitalization for mental illness will not be enrolled.  
7.2.3 
Any past evidence of medical conditions associated with chronic liver disease (e.g. genetic 
hemochromatosis, autoimmune hepatitis, alcoholic liver disease). 
7.2.4 
Any evidence of active, immunologically mediated disease (e.g. inflammatory bowel disease, 
systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis, 
rheumatoid arthritis). 
7.2.5 
Severe retinopathy due to diabetes, hypertension, cytomegalovirus or macular degeneration.   
7.2.6 
Evidence of cardiac disease such as: congestive heart failure, clinically significant coronary artery 
disease, ECG changes consistent with myocardial ischemia or bifascicular hemiblock (right bundle 
branch block and left anterior hemiblock), ventricular tachyarrhythmia, moderate or severe 
hypertension, ventricular fibrillation or Torsade de Pointes, bradycardia defined as HR < 50 bpm. 
Patients with pacemakers are eligible if HR ≥ 50 bpm.  
7.2.7 
Known history of active thyroid disease requiring medication that is not under control. Patients are 
permitted to receive thyroid hormone supplements to treat underlying hypothyroidism. 
7.2.8 
Breastfeeding. 
7.2.9 
Presence of an active bacterial, fungal, viral or protozoal infection requiring systemic anti-infective 
therapy (other than HIV infection or chronic herpes simplex virus infection requiring suppressive 
therapy). 
7.2.10 Uncontrolled seizure disorder. 
7.2.11 History or other evidence of severe illness or other conditions that would make the participant, in 
the opinion of the investigator, unsuitable for the study (e.g. conditions that could potentially be 
exacerbated by the study drugs). 
7.2.12 History of malignancy of any organ system (other than localized basal cell or squamous cell 
carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases. 
7.2.13 Female participants who are pregnant or nursing a child. Pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
7.2.14 History of solid organ transplantation with an existing functional graft. 
7.2.15 Use of any immunomodulatory agents within 30 days prior to study enrollment or planned use 
during the trial. Influenza vaccination or other routine vaccines will be permitted 30 days or more 
prior to administration of study medication 


 
24 
 
7.2.16 Active drug or alcohol use or dependence that, in the opinion of the sponsor, would interfere with 
adherence to study requirements. 
7.2.17 Any surgical or medical condition which might significantly alter the absorption, distribution, 
metabolism, or excretion of drugs, or which may jeopardize the participant in the study. The 
Investigator should make this determination in consideration of the participant’s medical history 
and/or clinical or laboratory evidence of any of the following: 
• 
Inflammatory bowel disease 
• 
Major gastrointestinal tract surgery such as gastrectomy or gastroenterostomy 
• 
Pancreatic insufficiency 
7.2.18 Use of HIV protease inhibitor or other strong or moderately strong CYP3A4 inhibitors: 
Strong inhibitors of CYP3A4 include: boceprevir clarithromycin, cobicistat, conivaptan, indinavir, 
itraconazole, ketoconazole, fluconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, aprepitant, grapefruit 
juice.  
Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, darunavir/ritonavir, 
diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil. 
Co-medication with weak inhibitors of CYP3A4 will be permitted. Weak inhibitors of CYP3A4 
include: alprazolam, amlodipine, atorvastatin and other statins, bicalutamide, cilostazol, 
cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, nilotinib, oral 
contraceptives, ranitidine, ranolazine, zileuton.  
Note: Use of azithromycin, regular orange juice and dihydropyridine calcium channel blockers (e.g. 
amlodipine, felodipine, nicardipine, nifedipine) are allowed. 
7.2.19 Since panobinostat is a weak inhibitor of CYP2D6, participants using pharmaceuticals that are 
CYP2D6 substrates with a narrow therapeutic window are not permitted. Such agents are: 
thioridazine, tamoxifen, and the antiarrhythmics mexiletin, propafenone and flecainide. Drugs that 
are CYP2D6 substrates with a large therapeutic index such as certain anti-emetics, anti-
hypertensives, and anti-depressants are generally safe to be co-administered with panobinostat.  
7.2.20 Participant has a history of anaphylaxis, allergy or serious adverse reactions to Interferon-
2a/Interferon-2b or panobinostat.  
7.2.21 Participant taking any of the following medications at the time of study entry: systemic steroids 
(inhaled or nasal steroid therapy or low dose oral steroid treatment up to no more than 7.5mg of 
Prednisone per day or the equivalent dose of alternative corticosteroids are permitted), interleukins, 
systemic interferons or systemic chemotherapy.  
7.2.22 Regular use of concomitant medication with a known potential to lead to QTc prolongation or 
Torsades de pointes. These drugs include: quinidine, procainamide, disopyramide or any other class 
IA antiarrhythmic drug, sotalol, cisapride, amiodarone, bretylium, disopryramide, dofetilide, 
ibutilide or any other class III antiarrhythmic drug, macrolide antibiotics (clarithromycin, 
erythromycin. telithromycin), thioridazine, mesoridazine, chlorpromazine, pimozide, halofantrine, 
chloroquine, pentamidine, astemizole, arsenic trioxide, bepridil, domperidone, methadone, 
droperidol, levomethady. This list of medications was developed in collaboration with an external 
cardiology consultant, and represents those medications which are deemed to have an unacceptable 
risk of co-administration with panobinostat. 
Note: azithromycin, ciprofloxacin, levofloxacin and moxifloxacin are allowed. 


 
25 
 
7.3 
Participant Recruitment, Information and Consent  
Written information and advertisements approved by the IRB may be used for recruitment purposes. 
Individuals treated at MGH, BWH, other Harvard University CFAR-associated institutions, and other 
hospitals in the Boston area, such as Fenway Health, Tufts Medical Center, and the Boston Medical Center, 
are permitted to participate; all possible candidates will be referred to MGH for evaluation and possible 
study participation. Eligible study participants may receive an invitation to participate in the study if the 
participant has previously agreed to be contacted in such matters. Invitation may also be provided as part 
of routine medical visits to the Department of Infectious Diseases at MGH, the MGH Clinical Trials Unit 
or BWH, or to other hospitals. Interested participants can contact the primary Investigator or study nurse to 
receive written information and schedule an appointment for further information, possibly attended with a 
companion. If the participant then wishes more time to consider participation in the study, presence of a 
companion, or repetition of information, a new appointment will be scheduled for this. 
Individuals from investigators’ own clinics are also potentially eligible for this study. Patients of the 
investigators will be informed of the study by participant summary sheets or one of the co-investigators 
(who do not serve as the patient’s primary physician). A study co-investigator distinct from the 
patient’s primary physician will conduct the informed consent process with interested patients from 
the investigators’ clinics.  
Individuals who participated in stage 1 or 2 are permitted to take part in stage 3 if they have not 
experienced a (clinical or laboratory) grade 3 or 4 adverse events during stage 1 or 2.  
7.4 
Study participant replacement 
 
In stage 1 and 2, up to two participants dropping out of the study prior to study completion will be replaced 
by a new study subject. If, however, the subjects discontinue the study due to safety or tolerability concerns, 
the subjects will not be replaced. In stage 1, 2 and 3, all participants dropping out of the study prior to 
initiation of the first dose of the study medication will be replaced.  
7.5 
Randomization 
Participants will be randomized to treatment Arm A or treatment Arm B or treatment Arm C (in stage 3 
only). Participants in treatment Arm A (n=2 participants in stage 1 and 2; n=4 participants in stage 3) will 
receive treatment with panobinostat only, and participants in treatment Arm B (n=6 participants in stage 1 
and 2; n=10 participants in stage 3) will receive combined treatment with panobinostat and pegylated IFN-
2a. Participants in Arm C (n=4 in stage 3) will receive treatment with pegylated IFN-2a only.  
Randomization will occur on day 0 of the study, prior to administration of the first dose of the study 
medication. Participants will be informed about the randomization decision, and open-label study 
medication will be administered.  
8.0 
STUDY TREATMENT 
8.1 
Panobinostat 
8.1.1 
Formulation 
Panobinostat is a highly potent class I/II HDAC inhibitor belonging to the hydroxamic acid class of 
compounds. The drug product provided is an immediate-release solid oral dosage form tablet containing 5 
mg panobinostat for stage 1, 10 mg panobinostat for stage 2, and 15 mg panobinostat for stage 3. For further 
details on physical, chemical and pharmaceutical properties refer to the Investigator’s Brochure. The drug 
will be packed and labeled as investigational product in accordance with current guidelines and applicable 
regulatory requirements.  
 


 
26 
 
The Massachusetts General Hospital Pharmacy will be responsible for the import, labeling and storage of 
the investigational drug. The study Investigators or the study nurse will request the appropriate quantity of 
the investigational drug from the MGH Pharmacy prior to dispensing to study participants. The 
investigational drug will then be delivered with the required labeling containing batch number, 
manufacturing date and time, project name, contact person and drug ID number.  
Note: Refer to the Investigator’s Brochure for further information about panobinostat and its components. 
8.1.2 
Administration 
Panobinostat will be orally administered as a 5 mg tablet (stage 1), a 10 mg tablet (stage 2, two 5 mg tablets 
can also be used) and a 15 mg tablet (stage 3, three 5 mg tablets can also be used) every second day during 
the treatment week (total of three oral doses). The first dose of panobinostat will be administered 
concomitantly to the corresponding subcutaneous injection of PEG-IFN-2a in Arm B.  
The MGH Pharmacy will be responsible for secure and correct storage of the investigational drug until 
reception at the MGH Clinical Trials Unit, after which the Investigators will be responsible. The 
investigational drug will be clearly marked and stored in a locked medicine storage room at the MGH 
Pharmacy. Lists of received, used and remaining quantities of the investigational drug will be kept. Any 
discrepancies must be resolved.  
8.1.3 
Storage 
Panobinostat will be clearly marked and stored in a locked medicine storage room at room temperature.  
8.2 
Peginterferon alfa-2a, (Pegylated interferon -2a, Pegasys) 
8.2.1 
Formulation  
PEG-IFN-α2a will be used in single-use vials for this study. Other excipients include benzyl alcohol, 
sodium chloride, sodium acetate trihydrate, acetic acid, polysorbate 80, and water. For further information 
about this product, refer to the FDA-approved package insert. PEG-IFN-α2a will be obtained from Roche 
Laboratories by the MGH pharmacy in syringes containing 180mcg of the drug in 1ml.  PEG-IFN-α2a 
supplied by Roche in a single-use syringes containing 180mcg of the drug in 0.5ml is also acceptable.    
Commercially available PEG-IFN-α2a, manufactured by Roche and provided as syringes containing 180mc 
of the drug, can also be used. 
8.2.2 
Administration 
180mcg of PEG-IFN-α2a will be administered by subcutaneous injection once at the beginning of the 
treatment week in Arm B. One dose of IFN-α2a will be given. Injection of IFN-α2a will be given 
simultaneously with the first dose of panobinostat.   
8.2.3 
Storage 
PEG-IFN-α2a will be stored and refrigerated at 2 to 8 C (36 to 46 F) prior to dispensing. 
8.3 
Accountability of study medication 
The study participants in Arm B will receive PEG-IFN-α2a injections by study staff during their study visits. 
Panobinostat doses will be taken by participants in the clinic on day 0. The remaining tablets will be 
dispensed to participants and self-administered by participants at the scheduled time points.  
8.4 
Dosing schedule for investigational drugs: 
The investigational drugs will be administered as summarized in Figure 1 and Table 1.  


 
27 
 
8.5 
Monitoring for adherence to investigational drugs 
The first dose of the panobinostat (in study arm A and B) and pegylated IFN-2a (in study arm B or C 
only) will be administered during admission to the hospital under direct observation by study nurses or 
physicians. Subsequent doses of panobinostat can be self-administered by patients at home, at pre-defined 
time points. Internet-based scheduling tools will be used to remind patients of taking panobinostat as 
scheduled, if patients agree to this procedure.  
For each participant, received and remaining tablets of the investigational drugs will be accounted for 
during follow-up visits; results will be noted in the CRF. If non-adherence is suspected based on these 
evaluations, study staff will inform the protocol chairs and review the importance of adherence to all study 
medications with the participant and ongoing adherence support will be provided. The study chair may 
exclude a participant from continuing the study if there is evidence for a level of non-compliance with study 
medication that, in the investigators’ judgments, may compromise study results.  
8.6 
Concomitant Medication  
8.6.1 
Prohibited Medications 
Participants will be excluded from the study if they are taking any of these medications during the course 
of this clinical trial: 
• 
Systemic steroids up to 7.5 mg of Prednisone per day (or equivalent dose of alternative steroids); 
inhaled or nasal steroid therapy is also permitted  
• 
Interleukins 
• 
Systemic interferons other than the study medications  
• 
Systemic chemotherapy 
• 
Ritonavir, cobicistat or other similarly potent inhibitor of CYP3A4  
• 
Grapefruit juice is a moderate to strong CYP3A inhibitor and may increase absorption and exposure 
to panobinostat. Therefore, participants will be instructed not to consume grapefruit juice during 
the study 
• 
Pharmaceuticals that are strong or moderately strong CYP3A4 inhibitors, or CYP2D6 substrates 
with a narrow therapeutic window (see section 7.2.18 and 7.2.19) 
• 
Drugs with a known potential to lead to QTc prolongation (see section 7.2.22) 
8.6.2 
Required Medication 
Participants are required to maintain a fully suppressive ART regimen (defined above) throughout entire 
study period. These medications will not be provided by the study. ART that includes a protease inhibitor 
or cobicistat is not permitted. 
8.6.3 
Changes in cART Therapy  
Changes in ART will be allowed for toxicity so long as a protease inhibitor or cobicistat is not included in 
the new regimen. These changes should be discussed with the study co-chairs. See Section 11.8 for 
procedures to be followed in case of virological failure.  
8.6.4 
Other concomitant medication 
Any other current medical therapy either recorded at study entry or initiated during the study will be 
recorded in the CRF. Initiation of medical therapy that requires use of a drug specified in the exclusion 
criteria will result in withdrawal from the investigational drug. Medication entries should be specific to 


 
28 
 
trade name, the single dose and unit, the frequency and route of administration, the start and discontinuation 
date, and the reason for therapy. 
9.0 
CLINICAL AND LABORATORY EVALUATIONS 
9.1 
Study Conduct 
9.1.1 
Ethics and Regulatory Considerations 
 
The study will be conducted according to Good Clinical Practice (GCP) as specified in the ICH guidelines. 
The Sponsor will ensure that this study is conducted in agreement with all applicable laws, regulations and 
relevant ethics of Massachusetts General Hospital, Harvard Medical School, the City of Boston, the 
Commonwealth of Massachusetts and the United States.  
9.1.2 
Informed Consent 
Informed consent will be obtained prior to the performance of any study procedures (including blood tests). 
The responsible investigator physician will review the consent with the patient. Consent will be documented 
by dated signatures of the patient, and the person obtaining consent. The informed consent will include all 
standard elements including, at a minimum, description of the study goals, entry criteria, details of the 
study, known risks of the therapy, participant’s rights and criteria for record review by outside agencies 
(FDA for example). No elements of the informed consent will be waived. Only a fully IRB-approved 
consent will be used.  
9.2 
Definition of clinical evaluations 
9.2.1 
Medical history 
A medical history will be taken at the screening visit and should summarize all previous diagnoses, any 
allergies and a detailed medication history, including the start and stop dates of any antiretroviral 
medication (estimated if the exact dates cannot be obtained), and any immune-based therapies. A complete 
list of all prescription, non-prescription and alternative medications taken within 30 days prior to study 
entry with start and stop dates will also be recorded. 
9.2.2 
Clinical assessment and complete physical exam 
Complete physical exam is required at baseline and includes examination of the eye (with retinal 
photographs), skin, head, mouth, neck; auscultation of the chest, cardiac exam; abdominal exam and exam 
of extremities. The clinical assessment will also include signs and symptoms, diagnoses, height, weight and 
vital signs (temperature, blood pressure, pulse).  
9.2.3 
Targeted Physical exam 
A targeted physical examination will be driven by any signs and symptoms previously identified or new 
that the participant has experienced since the last visit. If indicated based on the participant’s symptoms 
and history, evaluation for suicidal ideation will be performed using the Columbia Suicide Severity Rating 
Scale (available at http://www.cssrs.columbia.edu/).  
9.2.4 
Pre-treatment assessments 
Pre-treatment assessments will be performed on the first day of the treatment week, prior to administration 
of the investigational drugs. Pre-treatment assessments on these days will include:  
• 
ECG: QTc time must be <450msec for men and <470mesc for women.  
• 
Vital signs: Systolic blood pressure must be between 90-150 mm Hg, diastolic blood pressure must 
be between 65-100 mm Hg, heart rate must be between 50-100 bpm. Oral temperature measured 
according to standard procedures must be lower than 100.5F.  


 
29 
 
• 
Pregnancy test (urine HCG test, only in women of childbearing potential): Results must be 
negative.  
• 
Lab tests: Most recent safety lab tests must be within the following limits: 
a. Hemoglobin > 12.0 g/dL for men and > 11.0 g/dL for women   
b. Absolute neutrophil count > 1500 cells/mm3 
c. Platelet count  > 150,000/mm3 
d. Creatinine level < 1.1 x ULN 
e. Total serum bilirubin < 1.1 x ULN 
f. AST (SGOT) and ALT (SGPT) < 1.1 x ULN 
g. Mg, K > LLN. If the value is < LLN, then the patient’s potassium or magnesium should be 
supplemented following the availability of that laboratory result. Patients must then undergo a 
repeat biochemistry test to demonstrate values ≥ LLN. These values must be ≥ LLN before the 
patient is dosed with oral panobinostat. 
• 
Targeted physical exam: Targeted physical must not reveal new signs of organ dysfunction or acute 
illness.  
• 
Eye exams will be performed using an ophthalmoscope (Welch Allyn, PanOptic Opthalmoscope) 
and retinal photographs will be taken from each eye and electronically documented. These 
fundoscopic exams will be non-mydriatic.  
If any of these criteria are not met, study medication must not be given. Delay of the study drug 
administration for up to two weeks until all criteria are met is possible if permitted by the study chairs.  
9.3 
Schedule of Events 
9.3.1 
Overview 
The study will comprise three phases:  
1. A pre-treatment screening/observation phase  
2. A treatment phase of 1 week with panobinostat only (Arm A), pegylated IFN-2a only (Arm C) or the 
combination of panobinostat and pegylated IFN-2a (Arm B).  
3. A post-treatment observation period of three weeks.  
A graphical overview of the study is given in Figure 1. A summary of all study procedures at each visit is 
provided in Table 1. Time windows and blood draws for each study visit are also listed in Table 1.  
9.3.2 
Screening/pre-entry phase 
Once a candidate for study entry has been identified, the patient will be scheduled to meet with a study 
representative to discuss the study. If the patient decides to participate, s/he will sign the IRB-approved 
consent form. Subsequently, the participant will have a screening visit; this visit can occur immediately 
after signing the consent form.  
During this screening visit (V1), the patient will be questioned regarding their medical history and will have 
laboratory testing performed to determine eligibility for the study. The following procedures will be 
performed: 


 
30 
 
• 
Obtain a medical history, including all information relevant to inclusion and exclusion criteria  
• 
Review concomitant medications 
• 
Perform a complete physical exam, including a non-mydriatic fundoscopic eye exam  
• 
Perform a 12-lead ECG to calculate QTc intervals  
• 
Schedule patient for a cardiac stress echocardiogram test (unless data already available) 
• 
Obtain samples for screening laboratory tests: 
o Plasma HIV-1 RNA testing by Roche Taqman Version 2.0 assay. 
o CD4 T cell counts. 
o HIV antibody (if not previously documented). 
o TSH levels. 
o Urine HCG pregnancy test for female participants of childbearing potential. 
o PPD skin test or T spot TB test (unless data already available).  
o Hematology parameters and chemistry parameters as per Table 1.  
If the candidate is eligible for the trial, he or she will return for one pre-entry visit. At this visit (V2), the 
following procedures will be performed:  
• Pregnancy test (women of childbearing age). 
• Other lab tests as indicated in Table 1.  
• Collection of blood/serum for virological and immunological and gene expression assays. 
• Immunogenetic studies for HLA class I and IL-28B genotyping.  
• Record baseline level of diarrhea, nausea and vomiting that patients experience with their regular 
antiretroviral regimen.  


 
 
 
 
 
 
 
 
 
 
28 
 
Screening/Pre-Entry 
Treatment Phase 
Post-Treatment Observation 
Time 
≤-30dǂ 
≤-10dǂ 
D0 (0h) 
D0 (6h) 
D2 
*D4 (6h) 
D10 
D28 
Windows 
 
 
 
 
 
+1 
+/- 2 
+/- 2 
Amount Collected from Blood Draws (cc) 
49 
91 
60 
57 
 
87 
99 
87 
IFN-α2a injection (Arm B and C only) 
 
 
X 
 
 
 
 
 
Panobinostat (Arm A and B only) 
 
 
X 
 
X 
X 
 
 
Visit numbers 
V1 
V2 
V3 
 
V4 
V5 
V6 
Phone call for evaluation of AEs 
 
 
 
 
X 
 
 
 
CBC1 
X 
X 
X 
 
 
X 
X 
X 
HLA, KIR, IL-28b GT 
 
X 
 
 
 
 
 
 
Liver function tests2 
X 
 
 
 
 
X 
 
X 
Chemistry3 
X 
X 
 
 
 
X 
X 
X 
TSH 
X 
 
 
 
 
 
 
 
Pregnancy testing4 
X 
X 
X 
 
 
 
 
X 
Hep B/C serologies, PPD/TB Spot PT, PTT 
X 
 
 
 
 
 
 
 
Eye exam 
X 
 
X 
 
 
 
 
 
Stress echocardiogram/dobutamine stress test 
X 
 
 
 
 
 
 
 
HIV antibody  
X 
 
 
 
 
 
 
 
Differential blood count and CD4/CD8 
T cell counts 
X 
X 
X 
 
 
X 
X 
X 
Plasma HIV-1 RNA 
X 
 
X 
X 
 
X 
X 
X 
Complete/targeted physical exam 
X 
X 
X 
 
 
X 
X 
X 
Panobinostat PK 
 
 
X 
X 
 
X 
X 
 
ECG 
X 
 
X 
X 
 
X 
 
 
Histone acetylation levels 
 
X 
X 
X 
 
X 
X 
X 
HIV-1 DNA 
 
X 
X 
 
 
X 
X 
X 
Viral outgrowth assays 
 
X 
 
 
 
 
X 
 
CD4 T cell -associated 
HIV-1 RNA 
 
X 
X 
X 
 
X 
X 
X 
HIV-1 DNA in CD4 T cell subsets 
 
X 
 
 
 
 
X 
 
Immune phenotyping 
 
X 
X 
X 
 
X 
X 
X 
Functional immune assays 
 
X 
 
X 
 
X 
X 
 
Gene expression profiling 
 
X 
 
 
 
 
X 
 


 
 
 
 
 
 
 
 
 
 
28 
Immune activation markers 
 
X 
 
X 
 
X 
X 
 
Table 1: Schedule of events during the study. (*blood draws on this day will occur 6h after administration of study drug). 1CBC includes WBC, RBC, PLT, Hgb, Hct, MCV, MCH, RDW, MCHC, MPV. 2Liver function 
tests include AST/ALT, TBili, DBili, Albumin. 3Chemistry levels include Na, K, Cl, HCO3, BUN, Crea, Glucose, Mg. 4Women of childbearing potential only. ǂNumber reflects time interval during which study visit 
should occur from Study Entry. 


Protocol  
 
33 
 
 
 
 
Figure 1: Study overview. PBT refers to panobinostat.  
 
9.3.3 
Treatment phase 
 
Study entry will be defined as the day on which the first dose of study drug is administered (day=0, visit 
V3).  
On this day, participants will have the following procedures performed:  
• 
Perform a pregnancy test, ECG and vital signs/physical exam (including eye exam), as described in 
pre-treatment assessment (9.2.4). 
• 
Review concomitant medications. 
• 
Collect blood for baseline immunologic and virologic assays.  
• 
Perform randomization to treatment Arm A or B or C. 
• 
After the above procedures are completed, administer one s.c. dose of PEG-IFN-2a in patients 
randomized to treatment Arm B and C.   
• 
Immediately after the first administration of PEG-IFN-2a, participants will be asked to take the first 
pill of panobinostat p.o., at the stage-specific dose if randomized to arm A or B. 
• 
At 6h after administration of panobinostat, blood samples will be collected for virological, 
immunological and pharmacokinetic assays. 
• 
4-6 hours after administration of panobinostat, at the time of Cmax for panobinostat, a 12-lead ECG 
will be performed.  
• 
On discharge, participants randomized to stage A or B will receive two more stage-specific 
panobinostat doses and will be instructed to take them in the mornings of study day 2 and day 4.  
On Day 2, participants will be called by phone by one of the study investigators to discuss possible side 
effects. Participants will return on Day 4, six hours after administration of the third dose of panobinostat 
(visit V4), for collection of blood samples for virological, immunological and gene expression studies, as 
described in Table 1, and for an ECG. The full volume of blood to be collected on day 4 will only be 
collected if the most recently available hemoglobin level is ≥ 12.0 g/dL for men and hemoglobin ≥ 11.0 
g/dL for women. 
Treatment Cycle I
-60d        -30d       -10d          0d         6h                   2d
4d   6h            10d                   28d
PEG-IFN2a
PBT
Study day
PBT
PBT
Visit number
1
2
4
7
5
Blood draws
Screening
Baseline assessments
3
6
Randomization
Arm B and C
Arm A and B


Protocol  
 
34 
 
 
9.3.4 
Post-treatment observation period 
Participants will return for additional collection of blood samples for virological and immunological 
analyses on day 10 (visit V5) and 28 (visit V6) (see Table 1). Preceding each blood collection, the 
hemoglobin levels determined from the visit before (visit V4 and V5, respectively) will be used to assess 
the participant’s ability to give blood. A minimum requirement of hemoglobin ≥ 12.0 g/dL for men and 
hemoglobin ≥ 11.0 g/dL for women will be used.  
9.4 
Long-term follow-up 
All participants will be encouraged to follow-up with their primary HIV care providers after completion of 
this study, and to actively participate in age-appropriate screening exams recommended by the US 
Preventative Services Task Force (USPSTF, http://www.uspreventiveservicestaskforce.org). All 
participants will be entered into a study registry where they will be contacted once a year (by phone or in 
person) for 10 years after completion of their study participation to determine if any diseases that may be 
attributable to the study medication have occurred. 
9.5 
Early termination visit 
Any participant who discontinues study treatment prematurely should be encouraged to continue to 
participate in all scheduled visits.  
A participant may voluntarily discontinue participation in this study at any time. The investigator may also, 
at his or her discretion, discontinue the participant from participating in this study at any time. If a 
participant is prematurely discontinued from participation in the study for any reason, the investigator must 
make every effort to perform the following evaluations: 
• 
Perform clinical evaluation.  
• 
Review adverse events and concomitant medications. 
• 
Obtain samples for laboratory tests:  
o Hematology (CBC/differential), Chemistry testing. 
o HIV RNA testing by Roche Taqman Version 2.0 assay. 
o CD4 T cell counts. 
o Collection of blood samples for virological and immunological assays. 
9.6 
Pregnancy 
Women of childbearing potential will be required to have a negative urine pregnancy test prior to first study 
drug administration. Any woman who becomes pregnant during the study period will not receive any further 
study medication and will be followed for safety until the end of the study or until the outcome of the 
pregnancy, whichever is longer. The participant will be advised to have her infant undergo regular doctor’s 
visits for 6 months following birth in order to assess and record any abnormal health outcomes. 
In addition, if the participant continues her pregnancy, the patient is encouraged to prospectively register 
her pregnancy in the "Antiretroviral Pregnancy Registry” (In US and Canada: 1-800-258-4263, 
international: 910-256-0238). 
10.0 
STUDY MONITORING  
10.1 
Internal Safety Review Committee (ISRC) 
 
This committee will consist of the following four individuals: Dr. Mathias Lichterfeld, Dr. Daniel Kuritzkes 
(study co-chairs), Dr. Rajesh Gandhi (protocol clinician) and Dr. Lu Zheng (protocol statistician).  


Protocol  
 
35 
 
 
 
The committee will meet by conference call every month during the trial or at an appropriate interval based 
on the pace of enrollment. A quorum of three Committee members is required for each scheduled meeting, 
teleconference or unscheduled meeting. A project manager will be responsible for tabulating all adverse 
events, distributing these tables to the members of the Internal Safety Review Committee and organizing 
the meetings.  
 
The committee will review all adverse events that occur during the trial. The Internal Safety Review 
Committee will be responsible for forwarding the following reports to the Safety Monitoring Committee 
for immediate review: 
a. Serious adverse events. 
b. Grade 3 and 4 adverse events that are related to the study medication.  
c. CD4 T cell count decline to <50% of relative CD4 cell count compared to baseline (average of the 
screening and pre-entry visits) that is not attributable to non-adherence with antiretroviral medication. 
10.2 
Safety Monitoring Committee (SMC) 
 
This committee will consist of the following three individuals: Dr. Martin Hirsch (chair), Dr. Joseph Eron 
(member) and Dr. Rebecca Gelman (statistician).  
 
A quorum of all three Committee members is required at scheduled meetings, teleconferences or 
unscheduled meetings. All members will have signed a Confidentiality Agreement. In addition, members 
will treat the reports, meeting discussions, minutes and recommendations of the SMC as confidential. 
 
The committee will meet to review safety information at scheduled meetings two times per year during the 
study. Unscheduled meetings will be convened in case of serious adverse events or grade 4 toxicity events 
that are attributable to the study medication.  
10.3 
Definitions of Adverse Reactions 
10.3.1 Adverse event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation participant that occurs after 
providing written informed consent for participation in a study. Therefore, an AE may or may not be 
temporally or causally associated with the use of a medicinal (investigational) product or other protocol-
imposed intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product or other protocol-imposed intervention, regardless of attribution.   
An AE does include: 
• 
Exacerbation of a pre-existing illness. 
• 
An increase in frequency or intensity of a pre-existing episodic event or condition. 
• 
A condition detected or diagnosed after study drug administration even though it may have been 
present prior to the start of the study. 
• 
Continuous, persistent disease or symptoms present at baseline that worsen following the start of 
the study. 
• 
Overdose of either study drug or concurrent medication, even when not associated with any signs 
or symptoms. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g. invasive procedures 
such as cardiac catheterizations). 


Protocol  
 
36 
 
 
An AE does not include: 
• 
Pregnancy 
• 
A medical or surgical procedure (e.g. surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure may be an AE. 
• 
A pre-existing disease or condition present or detected at the start of the study that does not worsen. 
• 
Situations where an untoward medical occurrence has not occurred (e.g. hospitalizations for 
cosmetic elective surgery, social and/or convenience admissions). 
 
• 
The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition. 
 
AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (e.g. 
invasive procedures, modification of participant’s previous therapeutic regimen). Intercurrent illnesses that 
occur after screening but before starting treatment, and that are not the result of protocol-mandated 
procedures, do not need to be captured as AEs. 
10.3.2 Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening. Any adverse event that places the participant, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred (i.e. it does not include a reaction that, had 
it occurred in a more serious form, might have caused death). 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is an event that required intervention to prevent permanent impairment or damage. 
• 
Important medical events that do not result in death, are not life-threatening, or do not require 
hospitalization may be considered serious adverse events when, if based upon appropriate medical 
judgment, might jeopardize the participant and might require medical or surgical intervention to 
prevent one of the outcomes listed above. 
10.4 
Monitoring for Adverse Events 
10.4.1 Recording of Adverse Events 
The occurrence of adverse events should be sought by non-directive questioning of the participant at each 
visit during the study. Adverse events also may be detected when they are volunteered by the participant 
during or between visits or through physical examination, laboratory test, or other assessments. 
Each reported AE or SAE will be described by its duration (i.e. start and end dates), suspected relationship 
to the study drugs, and grade of seriousness. 
At each visit, the participant will have an opportunity to spontaneously mention any new medical problems. 
The investigator should inquire about adverse events by asking one of the following standard questions: 
“Have you had any (other) medical problems since the last visit?” 


Protocol  
 
37 
 
 
“How have you felt since your last clinical visit?” 
The investigators are responsible for the detection and documentation of events meeting the definition of 
an adverse event (AE) or serious adverse event (SAE) as provided in this protocol. 
10.4.2 Attribution of Adverse Events 
Investigators must determine if there is a reasonable possibility that the study drugs caused or contributed 
to an AE or SAE. The relationship assessment should consider the following aspects:  
• 
A temporal relationship between the event and the administration of the study drug 
• 
A plausible biological mechanism for the event to cause the AE 
• 
Another possible etiology for the AE 
• 
Previous reports of similar AE associated with the study drug or other agents in the same drug class  
• 
Recurrence of the AE after re-challenge or resolution after de-challenge, if applicable 
The terms used to assess the relationship between an event and the study agents are:  
• 
Related:  
There is a plausible temporal relationship between the onset of the AE and administration of the study 
drug(s) and the AE cannot be readily explained by the subject’s clinical state, intercurrent illness, or 
concomitant therapies; and/or the AE follows a known pattern of response to the study drug(s); and/or 
the AE abates or resolves upon discontinuation of the study drug or dose reduction and, if applicable, 
reappears upon re-challenge. 
• 
Not Related:  
Evidence exists that the AE has an etiology other than the study drug (e.g. preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no 
plausible temporal relationship to study drug administration (e.g. cancer diagnosed 2 days after first 
dose of study drug). 
When an AE is assessed as “not related” to the study agents, an alternative etiology, diagnosis or 
explanation should be provided. When new information becomes available, the relationship assessment of 
any AE should be reviewed again and updated as required.  
Expected adverse events are those adverse events that are listed or characterized in the Package Inserts or 
current Investigators’ Brochures of the study drugs.  
Unexpected adverse events are those not listed in the Package Insert or current Investigator’s Brochure or 
are not identified. This includes adverse events for which the specificity or severity is not consistent with 
the description in the Package Inserts or Investigators’ Brochures. 
10.4.3 Grading of Adverse Events 
The intensity of adverse events will be graded according to the NIH Division of AIDS “System for Grading 
the Severity of Adult Adverse Events” in its most updated version (Version 2.0, November 2014). 
(http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_GRADING_TABLE_v2_NOV2014.pdf).  
10.5 
Reporting of Adverse Events 
10.5.1 General Reporting Procedures 
Any adverse event occurring during the study must be documented in the participant’s study records, and 
on the AE or SAE pages of the case report form (CRF). The investigators will record all adverse events. A 


Protocol  
 
38 
 
 
causal relationship to study drug is not necessarily implied. The investigators are responsible for ensuring 
that all AEs and SAEs that are observed or reported during the study are collected and reported to the 
medical officer of DAIDS, Dr. Larry Fox (LFOX@niaid.nih.gov), the FDA, appropriate IRB(s), and the 
companies providing the study drugs (Novartis and Genentech Inc.).  
All SAEs will be reported to these institutions within 24h after the investigators are made aware of the 
event.  
10.5.2 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent is obtained 
and study treatment is initiated and ends 30 days following the last administration of study treatment or 
study discontinuation/termination, whichever is earlier. After this period, investigators should only report 
SAEs that are attributed prior to study treatment. 
10.5.3 Reporting of Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and symptoms. 
However, if a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, it is alright to report the information that is currently 
available. If a diagnosis is subsequently established, it should be reported as follow-up information. 
10.5.4 Reporting of Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study. Such conditions should be 
reported as medical and surgical history. A pre-existing medical condition should be re-assessed throughout 
the trial and reported as an AE or SAE only if the frequency, severity, or character of the condition worsens 
during the study. When reporting such events, it is important to convey the concept that the pre-existing 
condition has changed by including applicable descriptors (e.g. “more frequent headaches”). 
10.5.5 Reporting of Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as 
an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a result of an AE, the 
event responsible for the procedure, not the procedure itself, should be reported as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for pre-
existing conditions or 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the study. 
10.5.6 Reporting of SAEs 
All SAEs occurring between study entry and the end of study in each participant must be reported promptly 
once the investigator determines that the event meets the protocol definition of an SAE.  
The initial notification should include, as a minimum, sufficient information to permit identification of: 
• 
The reporter 
• 
The participant 
• 
Adverse event(s) 
• 
Date of onset 
The investigators will inform the local IRB, regulatory authorities (FDA), the Medical and Program officers 
assigned to the protocol at the Division of AIDS (DAIDS) at NIH, the Safety Monitoring Committee (SMC) 
and the medication suppliers (Novartis and Genentech Inc.) of any SAE within a maximum of 24 hours 


Protocol  
 
39 
 
 
after the investigators are made aware of the event using a dedicated SAE form. Facsimile transmission is 
the preferred method to transmit this information. In the event of a death or a serious adverse event 
determined by the investigator to be related to the study medication, receipt of the fax must be confirmed 
by a telephone call.   
A separate set of SAE CRF pages should be used for each SAE. However, if at the time of initial reporting 
multiple SAEs are present that are temporally and/or clinically related, they may be reported on the same 
SAE CRF page. 
The investigators should attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis should be documented as the AE and/or SAE and 
not the individual signs/symptoms. New or updated information should be recorded on the originally 
completed SAE CRF pages with all changes signed and dated by the investigators.   
Primary Study Contact for Reporting of Serious Adverse Events: 
Massachusetts General Hospital, Infectious Disease Unit  
Dr. Rajesh Gandhi, MGH pager # 36298 
Dr. Mathias Lichterfeld, MGH pager #12897 
Phone:  617-726-3819 (24h/24h)  
10.5.7 Reporting of Deaths 
All deaths that occur during the study period, regardless of attribution, will be reported to the appropriate 
parties as an SAE. When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be reported as the single medical concept. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, “Unexplained Death” will be reported. A copy of any post-mortem 
findings, including histopathology, should be provided on an updated SAE CRF page. 
10.5.8 Reporting of Pregnancy  
If a participant becomes pregnant during the study, treatment will be discontinued (i.e. no additional dose 
of study medication will be given) and the Early Termination Visit procedures will be performed. The 
outcome of any pregnancy occurring during the study period (at a minimum, up to and including one month 
[minimum 30 days] after receiving the last treatment dose) in a participant treated with study medication 
must be reported. Although not considered an SAE, pregnancy should be reported similarly. Abortion, 
whether accidental, therapeutic, or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female subject 
exposed to the study drugs should be reported as an SAE. 
Any reports of pregnancy following the start of administration with the study drugs will be transmitted to 
the pharmaceutical companies supplying the study drugs within thirty (30) calendar days of the Awareness 
Date.  
10.5.9 Reporting of Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior study drug exposure. If the investigator should become 
aware of the development of cancer or a congenital anomaly in a subsequently conceived offspring of a 
female subject who participated in the study, this should be reported as an SAE.  
10.5.10 Contact information for Reporting of adverse events 
For reporting of serious adverse events to the NIH DAIDS, the DAIDS Expedited Adverse Event Reporting 
Form (EAE form) should be used. This form can be found at the website of the DAIDS safety office 
(http://rsc.tech-res.com/safetyandpharmacovigilance) and is included in the appendix. This form will 
be emailed to Dr. Larry Fox, the assigned medical officer at DAIDS (LFOX@niaid.nih.gov).  


Protocol  
 
40 
 
 
For adverse event reporting to Genentech Inc., reports should be faxed to Genentech Drug Safety at the 
following numbers: (650) 225-4682 or (650) 225-5288. A cover sheet for fax transmission is included in 
the appendix of this protocol. Occasionally, Genentech may contact the reporter for additional information, 
clarification, or current status of the patient for whom an adverse event was reported. Relevant follow-up 
information should be submitted to Genentech Drug Safety as soon as it becomes available and/or upon 
request. For questions regarding SAE reporting to Genentech, the Genentech Drug Safety Office should be 
contacted at (888) 835-2555.  
For adverse event reporting to Novartis, reports should be faxed to the Local Novartis Drug Safety and 
Epidemiology Safety Desk using the fax number (877) 778-9739. A cover sheet for fax transmission is 
included in the appendix of this protocol. 
10.5.11 Reconciliation 
In all safety reporting, the Sponsor agrees to conduct reconciliation for the product. Genentech, Novartis 
and the Sponsor will agree to the reconciliation periodicity and format, but agree at minimum to exchange 
monthly line listings of cases received by the other party. If discrepancies are identified, the Sponsor and 
Genentech will cooperate in resolving the discrepancies. The responsible individuals for each party shall 
handle the matter on a case-by-case basis until satisfactory resolution. 
10.6 
Reporting to FDA 
Since this is an Investigator-Sponsored IND Study, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 600.80. Events meeting the following criteria 
need to be submitted to the FDA as expedited IND Safety Reports according to the following guidance and 
timelines: 
• 7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the investigator to be possibly related to the use of panobinostat or pegylated 
IFN-2a. An unexpected adverse event is one that is not already described in the Investigators’ Brochures 
for the study drugs. Such reports are to be telephoned or faxed to the FDA and the collaborating 
pharmaceutical companies within 7 calendar days of first learning of the event. 
• 15 Calendar Day Written Report 
The Investigators are also required to notify the FDA and all participating investigators, in a written IND 
Safety Report, of any serious, unexpected AE that is considered reasonably or possibly related to the use of 
the study drugs. An unexpected adverse event is one that is not already described in the Investigators’ 
Brochures for the study drugs. 
Written IND Safety reports should include an Analysis of Similar Events in accordance with regulation 21 
CFR § 312.32. All safety reports previously filed by the investigator with the IND concerning similar events 
should be analyzed and the significance of the new report in light of the previous, similar reports commented 
on. 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, the 
collaborating pharmaceutical companies, and all participating investigators within 15 calendar days of first 
learning of the event. The FDA prefers these reports on a Medwatch 3500 form, but alternative formats are 
acceptable (e.g. summary letter). The FDA fax number for IND Safety Reports is: 1 (800) FDA-0178. 


Protocol  
 
41 
 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to Genentech 
Drug Safety (Fax: (650) 225-4682 or (650) 225-5288), to Novartis Drug Safety ((877) 778-9739) and to 
the IRB (phone: 617-424-4148).  
• IND Annual Reports 
IND annual reports will be submitted to the FDA by the Sponsor-Investigator. Copies of such reports should 
be faxed to Genentech Drug Safety (Fax: (650) 225-4682 or (650) 225-5288) and to Novartis Drug Safety 
((877) 778-9739).  
Any other study report submitted to the FDA by the Sponsor-Investigator should be copied to Genentech 
and Novartis. This includes the Clinical Study Report (final study report). Additionally, any literature 
articles that are a result of the study should be sent to Genentech and Novartis. Copies of such reports should 
be mailed to the assigned Genentech Clinical Operations contact for the study: pegasys-gsur@gene.com.  
10.7 
Follow-up of Adverse Events 
All AEs and SAEs must be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or the participant is lost to follow-up. The investigators are responsible to ensure that 
follow-up includes any supplemental investigations that may be indicated to elucidate as completely as 
practical the nature and/or causality of the AE or SAE. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals.   
10.8 
Contraindications to further administration of study drugs 
Clinical events listed below constitute absolute contraindications to further administration of the study 
medication; if any of these events occur during the study, the participant must not receive additional doses 
of the investigational product but may continue other study procedures at the discretion of the investigators. 
The participant must be followed until resolution of the event, as with any adverse event. 
• 
Early or delayed hypersensitivity reactions 
• 
Pregnancy 
The following adverse events constitute contraindications to administration of the study medication at 
that point in time; if any one of these adverse events occurs at the time scheduled for administration of the 
study drugs, administration of study drugs will be delayed for a maximum of one week or withdrawn from 
study participation at the discretion of the investigators. The participant must be followed until resolution 
of the event, as with any adverse event (see Section 10.7). 
• 
Acute disease, defined as the presence of a moderate or severe illness with or without fever. 
However, study medication can be administered to persons with a minor illness such as diarrhea, 
mild upper respiratory infection with or without low-grade febrile illness, i.e. oral temperature < 
100.5F.  
• 
Oral temperature of  100.5F  
10.9 
Criteria for Study Continuation to stage 2 and 3 
After completion of stage 1, all safety data will be reviewed by the internal safety review committee (ISRC), 
the external safety monitoring committee, the IRB and the FDA. The study can only proceed to stage 2 if 
all of these committees agree that the safety profile in stage 1 is acceptable. A similar interim review will 
occur after completion of stage 2 to determine study progression to stage 3.  
Dose escalation criteria are defined as: 
a) No more than one subject has experienced a ≥ Grade 3 toxicity event that is related to study treatment 
(as judged by the investigators) prior to or on Day 28 after the treatment administration; however, if 


Protocol  
 
42 
 
 
grade 3 toxicity events are limited to clinically insignificant laboratory abnormalities, the independent 
SMC may, after a detailed review of all safety events, allow progression of the study to the next stage.  
b) None of the subjects have experienced a serious or worse AE or toxicity that is Grade ≥ 4 and related 
to study treatment (as judged by the investigators) prior to or on Day 28 after the treatment 
administration.  
c) No patient has experienced a cardiac ischemic event or shown ECG evidence of myocardial ischemia 
during the study treatment.  
11.0 
TOXICITY MANAGEMENT 
It is possible that some participants will experience transient or prolonged adverse effects during the trial. 
The following guidelines should be followed for managing toxicity of the study medication.   
11.1 
Early or delayed hypersensitivity reactions 
 
Early or delayed hypersensitivity reactions constitute absolute contraindications to further 
administration of the study medication. If any of these adverse events occur during the study, the 
participant must not receive additional doses of the investigational products but may continue other study 
procedures at the discretion of the investigators. The participant must be followed until resolution of the 
event, as with any adverse event. 
11.2 
Grade 2 adverse events 
 
Participants experiencing grade 2 AE(s), which the patient believes is/are tolerable and in the Investigators’ 
judgment is/are acceptable, may continue treatment at the current dose and schedule. More frequent patient 
monitoring may be required, and participants must be informed to contact the Investigators immediately if 
there is any worsening of symptoms. If a patient experiences new (or treatment emergent) grade 2 AE(s) 
considered at least possibly related to the study medication, and which the patient finds intolerable or in the 
Investigators’ judgment is/are not acceptable, treatment must be held until the AE(s) resolves to grade ≤ 1. 
Study treatment may then be restarted at the same dose and schedule. If the same intolerable grade 2 AE(s) 
occurs again, the study treatment must again be temporarily discontinued until the toxicity resolves to grade 
≤ 1. At the discretion of the Investigators, participants with repeated grade 2 AEs of major organs (e.g. 
heart, lungs, CNS) may be discontinued from further study treatments. 
11.3 
Grade 3 and Grade 4 adverse events 
 
If a study participant develops a grade 3 or 4 adverse event that is assessed as being related to the study 
medication, the person must not receive additional doses of the study medication but may continue other 
study procedures at the discretion of the investigators. The participant must be followed until the resolution 
of the event. 


Protocol  
 
43 
 
 
 
Participants who experience a grade 3 or grade 4 adverse event not attributable to the investigational 
products or are confined to asymptomatic laboratory abnormalities may be allowed to continue treatment 
at the investigators’ discretion, unless regulated otherwise in Tables 2-4. 
11.4 
Specific management of panobinostat and PEG-IFN-α2a toxicity 
11.4.1 Diarrhea 
Diarrhea is a recognized side effect of panobinostat, although the frequency of diarrhea with low-dose 
panobinostat is expected to be low. Each patient should be instructed to have loperamide readily available 
and to begin treatment for diarrhea at the first episode of poorly formed or loose stools or the earliest onset 
of bowel movements more frequent than normally expected for the patient. 
TOXICITY 
ACTION 
Diarrhea 
 
 
 
 
Grade 2: Persistent episodes of unformed to 
watery stools OR increase of 4-6 stools over 
baseline per 24h period.  
Use anti-diarrheal medication. Correct 
electrolytes. Dosing of study medication 
may continue at current level.  
Grade 3: Bloody diarrhea OR increase of >7 
stools per 24h period OR fluid replacement 
indicated 
Discontinue dosing permanently, unless 
diarrhea is attributed to alternative disease 
such as C. diff infection or Norovirus 
infection.  
Grade 4: Life threatening consequences (e. 
g. hypotensive shock) 
Nausea/Vomiting 
Grade 2: Persistent nausea resulting in 
decreased oral intake for 24-48h  
Discontinue dosing.  
 
Grade 3-4: per DAIDS/NIH criteria 
Total bilirubin  
Grade 2: 1.6x to < 2.6x ULN  
Discontinue dosing. 
 
Grade 3: 2.6x to < 5x ULN 
Grade 4: > 5x ULN 
AST/ALT 
Elevations 
Grade 2: up to 5x ULN 
Discontinue dosing.  
 
Grade 3: up to 10x ULN 
Grade 4: > 10x ULN 
Table 2: Management of  GI Toxicity 
TOXICITY 
ACTION 
Thrombocytopenia 
 
Grade 2 (PLT 50,000-99,999/ul) 
Discontinue dosing. 
 
Grade 3 (PLT<50,000/ul) 
Grade 4 (PLT <25,000/ul) or  
Neutropenia  
Grade 1 (ANC 800-1000/ul) 
none 
Grade 2 (ANC 600-799/ul) 
If ANC >750/ul, patient may continue study drugs 
If ANC <750/ul, discontinue dosing permanently 
Grade 3 (ANC 400-599/ul) 
Discontinue dosing permanently.  
Grade 4 (ANC <400) 


Protocol  
 
44 
 
 
 
Loperamide 4 mg should be taken at the first loose stool or more frequent than usual bowel movements, 
followed by 2 mg as needed, no more frequently than every 4 hours, not to exceed a total of 16 mg in 24 
hours. Participants with diarrhea grade ≥ 2 despite this loperamide regimen should be managed as described 
in Table 2. Additional treatment should be provided in accordance with institutional standard of care and/or 
local guidelines. Premedication with loperamide is not recommended. The use of drugs with laxative 
properties should be avoided because of the potential for exacerbation of diarrhea. Participants should be 
advised to contact their physician to discuss any laxative use. 
11.4.2  Nausea, Vomiting, liver toxicity 
Nausea, vomiting and liver toxicity should be managed according to Table 2.  
11.4.3 Hematologic toxicity  
Both PEG-IFNa2a and panobinostat can cause hematologic toxicity. Hematologic toxicity during the study 
should be managed per Table 3.  
11.4.4 QTc prolongation 
Panobinostat can cause prolongation of the QTc interval in ECGs, although clinically significant QTc 
prolongation is unlikely with low dose panobinostat.  
ECGs will be performed during the screening/pre-entry visits as well as during the treatment week. 
Guidelines for the management of QTc prolongation in the context of this study are provided in Table 4. 
All cardiac events should be treated as per the local standard of care and referred to a cardiologist if 
clinically indicated. Any final decisions concerning dose modifications or permanently discontinuing the 
patient from study drug due to QTc prolongation should be discussed with the study chairs.  
11.5 
Abnormal CD4 T cell counts 
 
For any CD4 T cell decline of 50% or greater, or if the CD4 T cell count is <200/mm3, the participant will 
be contacted and asked to return for a repeat test as soon as the participant is available. If repeated 
Anemia 
Grade 2 (Hgb 9 < 10g/dL)  
If clinically asymptomatic, no change in dosing. 
Phlebotomy-related blood loss should be considered 
when deciding to continue dosing.  
Grade 3 (Hgb 7 < 9g/dL)  
Discontinue dosing.  
Grade 4 (Hgb <7g/dL) 
Table 3: Management of hematologic toxicity  
QTc ABNORMALITY 
ACTION 
QTc ≥450 msec  (men) or 
>470msec (women) OR >60 
msec increase from baseline 
average 
Check and correct serum potassium and magnesium if indicated. 
Discontinue dosing.  
  
 
Average QTc ≥500 msec 
Table 4: Management of QTc interval prolongation during treatment  


Protocol  
 
45 
 
 
measurements of CD4 T cell counts confirm an absolute CD4 T cell decline of 50% or more relative to 
baseline (average of screening and pre-entry values) or an absolute CD4 T cell decline below 200/mm3 
cells, the results should be discussed with the study chairs. The chairs will discuss these results with the 
patient’s primary HIV clinician and may decide to continue the study medication with close monitoring of 
CD4 T cells if the relative CD4 T cell count is <5 percentage points lower from the baseline relative CD4 
T cell count. 
11.6 
Adverse reactions due to ART 
Any participant experiencing an AE that is attributable to background ART may have the event treated 
according to recommendations in the package insert(s) of the product(s) or current treatment guidelines.  
Irrespective of possible causality, all non-serious AEs and SAEs must be recorded in the CRF. All changes 
to a participant’s ART regimen should be discussed with the study co-chairs and must be accurately 
recorded on the CRF. 
11.7 
Other abnormal laboratory or clinical findings 
Abnormal laboratory tests and abnormal clinical findings will be categorized using a standard grading scale 
described before.  
Abnormal laboratory findings (e.g. clinical chemistry, hematology, urinalysis) or other abnormal 
assessments (e.g. ECGs, X-rays, vital signs) that are judged by the investigators as clinically significant 
will be recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section 10.3.1 
("Definition of an AE"), or SAE, as defined in Section 10.3.2 ("Definition of a SAE"). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are detected during the study or are present 
at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs.  
However, clinically significant abnormal laboratory findings or other abnormal assessments that are 
associated with the disease being studied, unless judged by the investigators as more severe than expected 
for the participant’s condition, or that are present or detected at the start of the study and do not worsen, 
will not be reported as AEs or SAEs. 
Participants with grade 3 and 4 asymptomatic and clinically insignificant laboratory abnormalities may 
continue to receive cART and remain on the treatment schedule at the investigators’ discretion, unless 
regulated otherwise in Tables 2 to 4. 
Any abnormal clinical finding will be reported as an SAE if it meets the criteria defined above. 
11.8 
Antiretroviral treatment failure 
HIV treatment failure is defined as a confirmed HIV-1 RNA increase to >400 copies/mL for more than 4 
weeks. This level is higher than typical in clinical trials, due to the fact that panobinostat can increase 
plasma HIV- RNA as a result of increased transcription (not replication).  
An increase in viral load to >1000 copies/mL among study participants should be confirmed with repeat 
testing on samples obtained at least 7 days apart. If there is a confirmed increase to >1000 copies/mL in 
plasma HIV-1 RNA viral loads in participants on ART, a plasma specimen should be obtained and sent for 
evaluation of antiretroviral drug resistance. Confirmed HIV-1 relapse specimens must have repeated 
detection of >1000 copies/mL for successful HIV-1 drug resistance testing.  
Clinical management of HIV-1 virologic breakthrough and treatment failure will be handled by the 
investigators according to current HIV treatment guidelines. 


Protocol  
 
46 
 
 
12.0 
TERMINATION RULES 
12.1 
Termination rules for individual participants 
12.1.1 Participant Withdrawal from Study  
Participant withdrawal from study is defined as any participant who does not complete the final follow-up 
visit or an early termination visit defined in this protocol. Reasons why a study participant does not complete 
final visits can include:  
 
• 
Participant request (withdrawal of consent)  
• 
Protocol violation  
• 
Adverse events or reactions  
• 
Any condition, interaction, or contraindication where continued participation in the study will 
result in an unacceptable risk for the participant, as assessed by the Investigators or advisers  
• 
Discontinuation of the study by the Sponsor  
• 
Lost to follow-up  
• 
Investigator determination in consultation with study co-chairs, e.g. for repeated non-adherence 
to study protocols 
Investigators will contact participants who fail to return for planned visits and if possible schedule a new 
visit. Information related to study withdrawal is documented in the CRF including the reason for 
withdrawal, date of withdrawal, and whether the participant or Investigators made this decision. Participants 
withdrawn from the study will contribute with data for the statistical analyses until the date of withdrawal. 
Participants withdrawn from the study will resume routine treatment following standard treatment 
guidelines.  
12.1.2 Withdrawal from the investigational drug 
Withdrawal from the investigational drug is defined as a participant who discontinues study treatment but 
agrees to continue follow-up until completion of the study. Any participant who withdraws from the 
investigational drug after having received at least one dose of study medications will be asked to return for 
all subsequent study visits. If withdrawal from the investigational drug is due to adverse events, this will 
be followed up as detailed under 10.7.  
 
Study participant will be withdrawn from the investigational drug in case of the following events:  
 
• 
Participant request (withdrawal of consent)  
• 
Pregnancy 
• 
Development of a grade 3 or 4 adverse event that is related to the investigational products. 
Participants with grade 3 or 4 adverse events limited to laboratory abnormalities without clinical 
signs and symptoms or are clearly attributable to other diseases may be allowed to continue  
• 
Early or delayed hypersensitivity reaction 
• 
Investigator determination in consultation with study co-chairs, e.g. for repeated non-adherence to 
study protocols 
• 
Termination of the study by the Protocol Safety Monitoring Committee, NIAID, FDA or the 
pharmaceutical companies providing the investigational agents 
• 
Any condition, interaction, or contraindication where continued participation in the study will 
result in an unacceptable risk for the participant, as assessed by the Investigators or advisers 


Protocol  
 
47 
 
 
Information related to withdrawal from the investigational drug is documented in the CRF including the 
reason for withdrawal, date of withdrawal, and whether the participant or Investigators made this decision. 
Participants withdrawn from the investigational drug will contribute with data for the statistical analyses 
until the date of withdrawal. Participants withdrawn from the investigational drug will resume routine 
treatment and control at the Department of Infectious Diseases following standard treatment guidelines. 
12.2 
Temporary suspension of all study drug administration in all study participants 
The following events will trigger a temporary suspension of all study drug administration: 
• 
Development of a grade 4 adverse event that is related to the study medication 
• 
At least two participants experience sustained antiretroviral treatment failure that is not attributable 
to non-adherence with antiretroviral medications. Sustained HIV rebound is defined as HIV RNA 
levels >400 copies/mL for longer than a 4-week period.  
• 
At least two participants experience a significant and sustained CD4 T cell count decline that is not 
attributable to non-adherence with antiretroviral medications. A significant and sustained CD4 T 
cell count decline is defined as two measurements taken at least two weeks apart of either a) CD4 
T cell counts that are <50% of the baseline relative CD4 T cell count (average of screening and 
pre-entry values) or b) CD4 T cell counts <200/mm3. 
The SMC will review these events to determine if any study procedures should be changed. After this 
review, the SMC may allow the study to continue. A quorum of three Committee members is required for 
the review of the event(s) and for providing recommendation. The FDA will be informed in the event that 
temporary suspension of study medication occurs.  
12.3 
Permanent suspension of all study medication in all study participants 
After review and confirmation by the SMC, permanent suspension of all study medications will be 
considered if: 
• 
Two or more participants who received study medication develop any grade 4 adverse event that is 
related to the study medication. 
• 
Two or more participants experience sustained antiretroviral treatment failure not attributable to 
non-adherence with antiretroviral medication. 
• 
Two or more participants experience a significant and sustained CD4 T cell count decline that is 
not attributable to non-adherence with antiretroviral medications. 
• 
At the request of the pharmaceutical companies providing the investigational agents (Novartis AG 
and Roche AG). 
The SMC will review the event to determine if any study procedures should be changed. After this review, 
the SMC may allow the study to continue. A quorum of three Committee members is required for evaluation 
of the event(s) and for providing recommendation. The final decision for study suspension remains with 
the Sponsor. The FDA will also be informed in the event that permanent suspension of study medication 
occurs.  
13.0 
SAMPLE HANDLING AND ANALYSIS 
13.1 
Treatment and Storage of biological samples 
Whole blood and serum will be collected in standard collection tubes containing EDTA or Heparin as 
anticoagulant. PBMC for virological and immunological assays will be extracted by Ficoll density 
centrifugation and cryopreserved according to standard procedures.  


Protocol  
 
48 
 
 
13.2 
Standard laboratory assays 
The following measurements will be performed when indicated in Table 1.  
13.2.1 Virology 
Screening HIV-1 RNA tests must be performed using the Roche Taqman version 2.0 assay by a laboratory 
that possesses CLIA certification or its equivalent. Eligibility will be determined based on the screening 
value.  
13.2.2 Chemistry 
Sodium, potassium, chloride, BUN, HCO3-, creatinine, ALT (SGPT), AST (SGOT), and total bilirubin will 
be measured in the clinical laboratory of the Massachusetts General Hospital according to standard 
procedures.  
13.2.3 Hematology 
Hemoglobin, mean corpuscular volume (MCV), white blood cell count (WBC), differential WBC, platelet 
count, partial thromboplastin time, prothrombin time will be measured in the clinical laboratory of the 
Massachusetts General Hospital according to standard procedures. 
13.2.4 Other laboratory studies 
TSH, HBsAg, HBV DNA PCR, HCV Ab and HCV RNA PCR will be done at the local clinical laboratories 
of MGH.  
13.3 
Virologic assays for HIV-1 reservoir quantification 
The following virological assays will be performed for measuring effects of the study medication on size 
of the viral reservoir. 
13.3.1 CD4 T cell-associated HIV-1 RNA 
Unspliced HIV-1 RNA in isolated CD4 T cells will be measured using established protocols to determine 
the influence of the study medication on HIV-1 RNA transcription.  
13.3.2 Proviral HIV-DNA in CD4 T cells 
Proviral HIV-1 DNA will be analyzed in isolated total CD4 T cells, using optimized protocols for 
quantitative analysis of HIV-1 DNA. Analysis of proviral HIV-1 DNA in sorted naive, central-memory, 
effector-memory, terminally-differentiated CD4 T cells and CD4 T memory stem cells will be performed 
if sufficient PBMC are available. 
13.3.3 Analysis of integrated HIV-1 DNA and HIV-1 2-LTR circles.  
If sufficient PBMC are available, chromosomally integrated HIV-1 DNA and viral 2-LTR circles will be 
analyzed using DNA extracted from CD4 T cells, according to established experimental protocols.  
13.3.4 HIV Reactivation Assay 
This assay is performed to assess changes in the functional HIV-1 reservoir after study treatment. The 
majority of the proviral HIV DNA sequences is defective virus not capable of completing replication cycles 
and therefore not able to drive viral rebound in the absence of cART. The HIV reactivation assay measures 
changes in the frequency of cells latently infected with replication competent virus, i.e. integrated HIV 
DNA capable of resuming viral replication once reactivated. As an alternative to HIV reactivation assays, 
the TILDA assay or full-genome HIV-1 sequencing assays will be considered.  


Protocol  
 
49 
 
 
13.3.5 Residual HIV-1 plasma RNA 
Residual plasma viremia will be determined by single-copy assay (SCA).  This assay is a real-time PCR-
based method that can accurately quantify far lower levels of viremia than currently available commercial 
assays53.  
13.3.6 Phylogenetic studies 
Cell-associated and plasma HIV-1 RNA and cell-associated HIV-1 DNA will be subjected to viral 
sequencing studies to investigate phylogenetic associations between reactivated virus in CD4 T cells, 
plasma viral sequences and proviral HIV-1 DNA in total CD4 T cells and specific CD4 T cell subsets. 
13.4 
Immunologic Assays 
13.4.1 Immune phenotyping 
Phenotypic characteristics of different leukocellular subsets during treatment with study medication will be 
analyzed using standardized flow cytometry or cytometry-by-time-of-flight assays (CyTOF). Activation, 
maturation and differentiation markers of CD4 and CD8 T cells, B cells, NK cells, regulatory T cells, 
myeloid and plasmacytoid dendritic cells will be analyzed.  
13.4.2 Functional immunologic assays 
The functional assays described below will be considered:  
13.4.2.1 
Cytokine secretion assays 
Cytokine in CD4, CD8 T cells and NK cells will be measured using intracellular cytokine staining 
protocols, followed by flow cytometric/CyTOF analysis.  
13.4.2.2 
Cytotoxicity assays 
Cytotoxic activities of NK cells and cytotoxic T cells will be analyzed by flow cytometry- or CyTOF-based 
intracellular quantification of cytotoxic granules, and/or by cellular degranulation assays.  
13.4.2.3 
Proliferation assays 
Proliferative activities of HIV-1-specific CD8 T cells will be analyzed after CFSE staining, using in vitro 
tissue culture assays.  
13.4.2.4 
Elispot assays 
The magnitude and breadth of HIV-1-specific CD8 T cells will be analyzed by interferon- elispots, using 
established protocols.  
13.4.3 Analysis of immune activation 
Immune activation will be determined by proportions of CD38/HLA-DR positive CD4 and CD8 T cells. 
The following soluble markers of immune activation will be considered: 2D-Dimer, IL-6, hs-CRP, IP-10.   
13.5 
Gene Expression Profiling 
Gene expression intensities of interferon-stimulated genes will be analyzed using PCR or microarray-based 
assays.  
13.6 
Immunogenetic Studies 
HLA class I alleles and SNPs in the region of the IL-28B gene locus (rs12979860, rs8099917, rs12980275) 
will be typed in all study participants using standard protocols. 


Protocol  
 
50 
 
 
13.7 
Exploratory Analyses 
Other exploratory virological and immunological parameters may be analyzed, as new assays may become 
available. The PBMCs and serum collected for storage will be used for these exploratory assays. 
14.0 
DATA EVALUATION AND STATISTICAL ANALYSIS 
14.1 
Co-primary Endpoints 
• 
The cumulative frequency and severity of grade ≥ 1 adverse events, grade ≥ 1 laboratory 
abnormality, and other serious adverse events (SAEs) during the one week treatment period.  
• 
Changes from baseline in the reservoir of HIV-1 infected CD4 T cells, measured on a log scale 
using assays to evaluate CD4 T cell-associated proviral HIV-1 DNA, after completion of the 
combined treatment (on day 10 after study initiation) in treatment arm A vs. treatment arm B vs. 
treatment arm C.  
14.2 
Secondary Endpoints 
• 
Change from baseline in the levels of infectious viral units per million CD4 T cells (IUPM) as 
determined by viral outgrowth assays and TILDA assays after study completion. 
• 
Change from baseline in histone H3 acetylation in CD4 T cells during treatment with the study 
medication, as determined by changes in the acetylated H3 mean fluorescence intensity determined 
by flow cytometry. 
• 
Change from baseline in levels of CD4 T cell-associated HIV-1 RNA during treatment with study 
medication, determined by qRT-PCR. 
• 
Change from baseline in levels of plasma HIV-1 RNA during treatment with study medication, 
determined by single-copy assay or standard HIV-1 plasma assays.  
• 
Change from baseline in levels of CD4 T cell-associated HIV-1 2-LTR circles and chromosomally 
integrated proviral HIV-1 DNA during treatment with study medication.  
• 
Change from baseline in levels of HIV-1 DNA in different CD4 T cell subsets (naïve, T memory 
stem cells, central-memory, effector-memory, terminally-differentiated) during treatment with 
study medication. 
• 
Change from baseline in frequency and function of innate and adaptive immune effector cell 
responses during treatment with study medication, as determined using phenotypic and functional 
immunologic assays. 
• 
Change from baseline in levels of cellular and soluble immune activation markers during treatment 
with study medication, as determined by ELISA assays, luminex assays and flow cytometry. 
• 
Change from baseline in expression patterns of interferon-stimulated genes (ISG) during treatment 
with study medication.  
• 
Comparison of all immunological and virological parameters in study participants treated with IFN-
α and panobinostat stratified according to HLA class I and IL-28B genotypes.  
14.3 
Sample Size Considerations 
The primary efficacy analysis will compare changes from baseline to post-treatment HIV-1 DNA changes 
between the randomized treatment arms in stage 3. Allowing for one unevaluable participant in each arm 
due to lost to follow-up, ART discontinuation and/or other reasons, and under the assumption that a 
common standard deviation of change (measured as difference of log10 transformed HIV-1 DNA 
copies/million CD4 T cells) in all treatment arms is 0.436 (derived from baseline to end-of-study change in 


Protocol  
 
51 
 
 
the CLEAR study), the study with N=18 participants (9 evaluable participants treated with panobinostat 
and PEG-IFN-2a and 3 each treated with panobinostat or PEG-IFN-2a alone) will have 80% power to 
detect an effect size of 0.82 log10 (6.6-fold) in change of proviral CD4 T cell-associated HIV DNA level 
from baseline to day 10 in participants treated with panobinostat and PEG-IFN-2a compared to 
participants treated with panobinostat or PEG-IFN-2a only using a one-sided Wilcoxon rank sum test on 
a level of alpha=0.05, assuming a normal distribution. The above power estimation does not take into 
account of multiple comparisons for this pilot study. 
 
 
 
 
 
 
 
 
 
 
Regarding the assessment of safety, Table 7 and Table 8 display the probability of observing at least one or 
two participants with primary safety event with n=8 and 18 receiving study treatment. If the true probability 
is 10%, the study will have >57% probability of observing at least one participant with primary safety event 
in Stage 1 and 2 with 8 participants. The probability will be 85% for Stage 3 with N=18 participants.  
 
 
 
 
 
 
 
 
 
14.4 
Final Analyses 
14.4.1 Analysis of demographics 
 
Demographic characteristics (age, gender and race) and health status characteristics (baseline CD4 counts, 
nadir CD4 T cell counts, pre-ART HIV-1 RNA levels, cART duration) will be tabulated by randomized 
treatment. 
14.4.2 Analysis of safety 
For the safety analysis, AEs and SAEs will be recorded as described in this protocol and will be summarized 
in terms of frequency, severity and level of attribution to the study medication. Data will be reported as the 
 
N =8 
N =8 
True Probability 
Probability of at least 
 1 event 
Probability of at least 
2 events 
0.01 
0.08 
0.00 
0.05 
0.34 
0.06 
0.10 
0.57 
0.19 
0.12 
0.64 
0.25 
0.15 
0.73 
0.34 
0.20 
0.83 
0.50 
Table 7: Probability of safety endpoints in stage 1 and 2.  
 
N =18 
N =18 
True Probability 
Probability of at least 
 1 event 
Probability of at least 
2 events 
0.01 
0.17 
0.01 
0.05 
0.60 
0.23 
0.10 
0.85 
0.55 
0.12 
0.90 
0.65 
0.15 
0.95 
0.78 
0.20 
0.98 
0.90 
Table 8: Probability of safety endpoints in stage 3. 


Protocol  
 
52 
 
 
absolute and relative number of participants experiencing at least 1 event, the total number of events, the 
type of events, and the causality assessment. Due to the low expected safety event rates (based on the prior 
clinical study with panobinostat in HIV-1 participants), the study is not powered to do a formal statistical 
comparison between the randomized arms. AE rates will be presented for descriptive purposes.  
14.4.3 Statistical analysis of virological and immunological data 
The primary efficacy endpoint is the change from baseline to day 10 in the number of HIV-1 infected CD4 
T cells, as assessed by proviral CD4 T cell-associated HIV-1 DNA levels determined on a log-scale. The 
null hypothesis of no difference in the primary efficacy endpoint between the randomized treatments will 
be tested using a one-sided Wilcoxon rank sum test. The null hypothesis will be rejected with a p<0.05.  
Changes in the frequency of HIV-1-infected CD4 T cells (determined by levels of CD4 T cell-associated 
proviral HIV-1 DNA) from baseline to completion of the treatment phase will also be summarized as 
secondary efficacy endpoints and compared between the two randomized treatments. Mean and quartile 
plots will be used to summarize these efficacy endpoints at each visit. If feasible with the modest sample 
size, longitudinal data methods will also be used to evaluate and estimate treatment effects.  
Analysis for the primary efficacy endpoint will use a modified intent-to-treat analysis, limiting to 
participants who have received at least one dose of randomized treatment and have data at baseline and day 
10. Participants who go off ART, experience virologic failure or discontinue study participation for other 
reasons will be excluded from the efficacy analysis. For this analysis, mixed models with repeated measures 
will be considered (MMRM). Missing data will be managed using guidelines defined by the National 
Research Council54.  
Primary safety endpoints will be tabulated by Cohorts and randomized treatments. 
 
Analyses of secondary virologic and immunologic outcomes will parallel the primary analyses outline 
above.  
 
Baseline immunologic and virologic parameters will be assessed at multiple pre-entry timepoints (see Table 
1). For analysis of primary and secondary endpoints, the mean of multiple baseline assessments will be 
used.  
 
Secondary analyses of all immunologic and virologic parameters stratified by genetic polymorphisms (in 
HLA and IL-28B genes) will also be carried out. 
Associations between changes in the various virologic and immunologic measurements will be evaluated 
using scatterplots and correlation coefficients.  
15.0 
DATA MANAGEMENT 
15.1 
Data Management 
All study patient visits will be documented by the study nurses and physicians on case report forms provided 
by the sponsor. A study data manager will be responsible for storing these patient-related data in paper or 
electronic form at a central repository in the hospital.  
15.2 
Confidentiality 
Data on participants enrolled will be coded with a non-identifiable number. Access to confidential data such 
as participant identifiers and specific demographic data will be restricted to only those research team 
members for whom access is necessary, as defined by the study sponsor.  


Protocol  
 
53 
 
 
16.0 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by requirements for authorship promulgated by the 
International Committee of Medical Journal Editors (ICMJE), which have been adopted by many 
biomedical journals and are posted on its website at http://www.icmje.org.  Any presentation, abstract, or 
manuscript will be made available for review by the pharmaceutical companies and DAIDS providing the 
investigational drugs at least thirty (30) days [or, for abstracts, at least five (5) working days] prior to 
submission.   
17.0 
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 NIH. 
All infectious specimens will be transported using packaging mandated in the Code of Federal Regulations, 
CDC 42 CFR Part 72. Please also refer to individual carrier guidelines, e.g. FedEx, Airborne, for specific 
instructions. 
18.0 
PROTOCOL REGISTRATION 
18.1 
Introduction 
Prior to implementation of this protocol, and any subsequent full version amendments, the study site must 
have the protocol and the protocol informed consent form approved, as appropriate, by the local institutional 
review board (IRB)/ethics committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the DAIDS Protocol 
Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC).  The DAIDS PRO will review 
the submitted protocol registration packet to ensure that all of the required documents have been received.   
18.2 
Initial Registration 
Site-specific informed consent forms (ICFs) WILL NOT be reviewed or approved by the DAIDS PRO, and 
sites will receive an Initial Registration Notification when the DAIDS PRO receives a complete registration 
packet. Receipt of an Initial Registration Notification indicates successful completion of the protocol 
registration process. Sites will not receive any additional notifications from the DAIDS PRO for the initial 
protocol registration. A copy of the Initial Registration Notification should be retained in the site's 
regulatory files. 
18.3 
Amendment Registration 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, the study site 
should implement the amendment immediately. The study site is required to submit an amendment 
registration packet to the DAIDS PRO at the RSC. The DAIDS PRO will review the submitted protocol 
registration packet to ensure that all the required documents have been received. Site-specific ICF(s) WILL 
NOT be reviewed and approved by the DAIDS PRO and sites will receive an Amendment Registration 
Notification when the DAIDS PRO receives a complete registration packet. A copy of the Amendment 
Registration Notification should be retained in the site's regulatory files. 
For additional information on the protocol registration process and specific documents required for initial 
and amendment registrations, refer to the current version of the DAIDS Protocol Registration Manual. 


Protocol  
 
54 
 
 
19.0 
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panobinostat, an HDAC inhibitor, combined with erlotinib in patients with advanced aerodigestive tract 
tumors. Clin Cancer Res 2014; 20(6): 1644-55. 
31. Li X, Zhang J, Xie Y, Jiang Y, Yingjie Z, Xu W. Progress of HDAC inhibitor panobinostat in the 
treatment of cancer. Curr Drug Targets 2014; 15(6): 622-34. 
32. Hamberg P, Woo MM, Chen LC, et al. Effect of ketoconazole-mediated CYP3A4 inhibition on clinical 
pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor. Cancer 
Chemother Pharmacol 2011; 68(3): 805-13. 
33. Thomas A Rasmussen, Martin Tolstrup, Christel R Brinkmann, et al. Panobinostat, a histone deacetylase 
inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a 
phase 1/2, single group, clinical trial. Lancet HIV 2014; 1(1): e13-21. 
34. Archin NM, Bateson R, Tripathy MK, et al. HIV-1 Expression Within Resting CD4+ T Cells After 
Multiple Doses of Vorinostat. J Infect Dis 2014. 
35. Elliott JH, Solomon A, Wightman F, et al. The Safety and Effect of multiple doses of Vorinostat on HIV 
Transcription in HIV Patients receiving cART. In: Program and abstracts of the 19 Conference on 
Retroviruses and Opportunistic Infections, Atlanta, GA (abstract 50LB) 2014. 
36. Elliott JH, Wightman F, Solomon A, et al. Activation of HIV transcription with short-course vorinostat 
in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog 2014; 10(10): e1004473. 
37. Sogaard OS, Graversen ME, Leth S, et al. The Depsipeptide Romidepsin Reverses HIV-1 Latency In 
Vivo. PLoS Pathog 2015; 11(9): e1005142. 
38. Pasternak AO, Adema KW, Bakker M, et al. Highly sensitive methods based on seminested real-time 
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multiply spliced RNA and proviral DNA. J Clin Microbiol 2008; 46(7): 2206-11. 
39. Anne M, Sammartino D, Barginear MF, Budman D. Profile of panobinostat and its potential for 
treatment in solid tumors: an update. OncoTargets and therapy 2013; 6: 1613-24. 
40. Tavel JA, Huang CY, Shen J, et al. Interferon-alpha produces significant decreases in HIV load. J 
Interferon Cytokine Res 2010; 30(7): 461-4. 
41. Lane HC, Davey V, Kovacs JA, et al. Interferon-alpha in patients with asymptomatic human 
immunodeficiency virus (HIV) infection. A randomized, placebo-controlled trial. Ann Intern Med 1990; 
112(11): 805-11. 
42. Pillai SK, Abdel-Mohsen M, Guatelli J, et al. Role of retroviral restriction factors in the interferon-alpha-
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43. Vanderford TH, Slichter C, Rogers KA, et al. Treatment of SIV-infected sooty mangabeys with a type-
I IFN agonist results in decreased virus replication without inducing hyperimmune activation. Blood 
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44. Neil S, Bieniasz P. Human immunodeficiency virus, restriction factors, and interferon. J Interferon 
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inhibits HIV-1 and Ebola virus particle release but is counteracted by the HIV-1 Vpu protein. Cell Host 
Microbe 2007; 2(3): 193-203. 
46. Ahlenstiel G, Edlich B, Hogdal LJ, et al. Early changes in natural killer cell function indicate virologic 
response to interferon therapy for hepatitis C. Gastroenterology 2011; 141(4): 1231-9, 9 e1-2. 
47. Edlich B, Ahlenstiel G, Zabaleta Azpiroz A, et al. Early changes in interferon signaling define natural 
killer cell response and refractoriness to interferon-based therapy of hepatitis C patients. Hepatology 
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48. Micco L, Peppa D, Loggi E, et al. Differential boosting of innate and adaptive antiviral responses during 
pegylated-interferon-alpha therapy of chronic hepatitis B. J Hepatol 2013; 58(2): 225-33. 
49. Su SS, He H, Kong LB, et al. Regulatory Phenotype, PD-1 and TLR3 Expression in T Cells and 
Monocytes from HCV Patients Undergoing Antiviral Therapy: A Randomized Clinical Trial. PLoS One 
2014; 9(4): e93620. 
50. Azzoni L, Foulkes AS, Papasavvas E, et al. Pegylated Interferon alfa-2a monotherapy results in 
suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J Infect Dis 
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CD4 T-Cell-Associated HIV-1 DNA in HIV-1/Hepatitis C Virus-Coinfected Patients. J Infect Dis 2013. 
52. Kanto T, Inoue M, Oze T, et al. Dynamics of regulatory T cells and plasmacytoid dendritic cells as 
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54. National Research Council: The Prevention and Treatment of Missing Data in Clinical Trials: 
Washington, DC: The National Academies Press; 2010. 
 
 
 


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20.0 
APPENDIX: 
20.1 
Genentech Safety Reporting Fax Cover Sheet 
 
 


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SAFETY REPORTING FAX COVER SHEET 
 
GENENTECH SUPPORTED RESEARCH 
 
AE / SAE FAX No: (650) 225-4682 
 
Alternate Fax No: (650) 225-5288 
 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
Subject Initials 
(Enter a dash if patient has no middle 
name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET 
 
20.2 
Novartis Safety Reporting Fax Cover Sheet 


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Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk 
Fax Number:  877-778-9739 
 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
Relationship between study treatment and event(s) is: 
 
Suspected/Unknown 
 
  
This document contains important safety information. 
If fax is received in error, please forward to +44 1403 323500 
 
Version 1.0, 01_Jul_2010 


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Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk 
Fax Number:  877-778-9739 
 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
Relationship between study treatment and event(s) is: 
 
Not Suspected 
 
  
This document contains important safety information. 
If fax is received in error, please forward to +44 1403 323500 
 


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20.3 
DAIDS Expedited Adverse Event Reporting Form (EAE form) 
 


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