Conditions: Severe Sepsis With Septic Shock
Keywords: sepsis lymphocytopenia IL-7 immune reconstitution
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
A multicenter, randomized, double-blinded, placebo-controlled study of two dosing frequencies of recombinant Interleukin-7 (CYT107) treatment to restore absolute lymphocyte counts in sepsis patients; IRIS-7B (Immune Reconstitution of Immunosuppressed Sepsis patients).

A parallel study will be performed in France to allow a common statistical analysis of the primary end points and analysis for the enrolled patient population.

Detailed description:
Sepsis is the leading cause of death in critically ill patients in most intensive care units in Europe and the US. Recently, evidence has accumulated that sepsis progresses from a state of hyper-inflammation to a state of immunosuppression. This immunosuppressive phase is characterized by increased incidence of secondary infections often with relatively avirulent opportunistic type pathogens. Currently, new therapeutic approaches to sepsis are occurring using immuno-adjuvants that boost host immunity. One of the most promising agents Interleukin-7 is an essential, non-redundant, pluripotent cytokine produced mainly by bone marrow and thymic stromal cells that is required for T-cell survival.In addition to its anti-apoptotic properties, IL-7 induces potent proliferation of naïve and memory T-cells potentially supporting replenishment of the peripheral T-cell pool which is severely depleted during sepsis. These effects were confirmed in clinical trials at the National Cancer Institute and in HIV+ patients.

This clinical study will test the ability of IL-7 to restore the absolute lymphocyte counts in septic patients who have markedly reduced levels of circulating lymphocytes. An effect already confirmed in preclinical models of sepsis.

Arms:
arm 1: Patients will receive Interleukin-7 (CYT107 liquid solution) at 10µg/kg twice a week for 4 weeks arm 2: Patients will receive Interleukin-7 (CYT107 liquid solution) at 10µg/kg twice a week for the first week, followed by CYT107 and Placebo once a week for the three following weeks arm 3: Patients will receive Placebo (NaCl 0.9%) twice a week for 4 weeks

Interventions: intervention 1: Interleukin-7 intervention 2: Placebo
Intervention descriptions: intervention 1: IM (intra-muscular) administration of CYT107 recombinant glycosylated human IL-7 (SC administration for patients with INR (International Normalized Ratio) \>2.5 or platelet count \< 35,000 intervention 2: IM administration of Placebo (SC administration for patients with INR\>2.5 or platelet count \< 35,000

Protocol document:
Prot_000.pdf: 
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A multicenter, randomized, double-blinded, placebo-controlled study of 
CYT107 to restore absolute lymphocyte counts in sepsis patients 
 
IRIS-7B 
(Immune Reconstitution of Immunosuppressed Sepsis patients) 
 
PROTOCOL VERSION 1.4 
 
 
 
 
 
 
Trial codification: 
NCT02640807 
Active ingredient tested: 
 recombinant glycosylated human CYT107 
(CYT107) 
Development phase: 
Phase II 
 
 
Study chairmen 
Dr. Edward Sherwood M.D., PhD 
Vanderbilt University School of Medicine 
Sponsor: 
RevImmune 
Date: 
12/14/2015 
Information contained in this protocol is the property of Vanderbilt University and Revimmune and is confidential. 
Information may not be disclosed to any third party without written authorization from Revimmune. This material 
may be disclosed and used by staff and associates, as necessary. These persons should be told that this information 
is confidential. This document may not be reproduced or stored in any form (i.e. electronic, printed, etc.), except as 
required by regulatory authorities, without permission from Vanderbilt University and Revimmune.   


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 A multicenter, randomized, double-blinded, placebo-controlled study of 
CYT107 to restore absolute lymphocyte counts in sepsis patients 
IRIS-7B 
(Immune Reconstitution of Immunosuppressed Sepsis patients) 
 
INVESTIGATORS AGREEMENT 
I,……………………………………………………….the undersigned, understand that the study 
will not start without the prior written approval of a properly constituted Ethics Committee. No 
changes will be made to the study protocol without the prior written approval of the sponsor and 
the Ethics Committee.  
I have read, understood, and agreed to abide by all the conditions and instructions contained in 
this protocol. I agree to comply with the National regulations and ICH Harmonized Tripartite 
Guideline for Good Clinical Practice for conducting clinical trials and local regulations and will 
conduct the above study under these standards. 
 
 
____________________________  
Principal Investigator  (print name) 
 
____________________________  
 
___________________________ 
Principal Investigator  (signature) 
 
 
Date (day/month/year) 
 
____________________________ 
Sponsor Representative (print name) 
 
____________________________  
 
___________________________  
Sponsor Representative (signature)  
 
Date (day/month/year) 


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TABLE OF CONTENTS 
1. 
Protocol Synopsis................................................................................................................. 8 
2.1 
Sepsis ............................................................................................................................... 21 
2.1.1 
Epidemiology of Sepsis ................................................................................................. 21 
2.1.2 
Pathogenesis of Sepsis, critical immune paralysis ......................................................... 21 
2.1.2.1 
Low ALC is associated with increased incidence of bacteremia and mortality .......... 21 
2.2 
Current treatments and their limitations ......................................................................... 22 
2.3 
Study product: glycosylated recombinant human CYT107 “CYT107” ............................ 22 
2.3.1 
Quantitative and functional effects of CYT107 ............................................................. 23 
2.3.1.1 
Inverse correlation between CD4+ T cells lymphopenia and circulating IL-7............ 24 
2.3.1.2 
Experimental effects of CYT107 in HIV/SIV infection .............................................. 24 
2.3.1.3 
Results of trials with CYT107 and ongoing trials with CYT107 ................................ 24 
2.4.2 
Study Population .......................................................................................................... 32 
3.2 
Secondary Objectives ....................................................................................................... 34 
3.2.1 
To characterize CYT107 pharmacokinetics (PK) in this patient population ..................... 34 
3.2.2 
To characterize CYT107 Pharmacodynamics - To determine if CYT107 can restore 
depressed functional activity of immune effector cells in patients with sepsis. .............................. 35 
3.2.3 
To assess the impact on number and type of secondary infections:.................................. 35 
4.3.1   Primary Biological Activity & Safety Study Endpoints ..................................................... 38 
4.3.2 
Secondary Biological Activity Study Endpoints ............................................................ 38 
5.1 
Inclusion Criteria:............................................................................................................ 39 
5.3 
Study ID Numbers ........................................................................................................... 41 
6.2 
Randomization ................................................................................................................. 41 
6.3.1.2 
Post CYT107 administration Day 1 Week 1 ........................................................... 42 
6.3.2 
Procedure for Days 4, 8, 15, 22, 29, 42 ......................................................................... 43 
6.3.2.1 
Additional procedure for day 11 ............................................................................ 43 
6.3.2.2 
Additional procedure for day 22 ............................................................................ 43 


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6.3.2.3 
Additional Procedure for Day 42............................................................................... 43 
(See Appendix 2 Flow Chart for complete lists of clinical and laboratory studies.)........................ 43 
7.2 
CYT107 Pharmacokinetics............................................................................................... 44 
7.3 
CYT107 Immunogenicity ................................................................................................. 44 
7.4  
CYT107 Pharmacodynamics/Immunology....................................................................... 45 
8.1 
CYT107............................................................................................................................ 45 
8.1.1 
Description ................................................................................................................. 45 
8.1.2 
Source ........................................................................................................................ 45 
8.1.3 
Formulation ................................................................................................................ 45 
8.1.4 
Stability...................................................................................................................... 45 
8.1.5 
Special Handling ......................................................................................................... 45 
8.1.6 
CYT107 Preparation ................................................................................................... 45 
8.1.7 
Drugs interactions ....................................................................................................... 46 
8.2 
CYT107 Presentation and Packaging ............................................................................... 46 
8.3 
CYT107 Storage Accountability and Return of Unused Product...................................... 46 
8.4 
Study Drug Administration.............................................................................................. 46 
8.5 
Duration of treatment ...................................................................................................... 47 
8.5.1 
Dose Adjustment According to Patient’s Weight ........................................................... 47 
8.5.1.1 
Obese Persons ...................................................................................................... 47 
8.6 
CYT107 Administration Permanently Discontinued ........................................................ 47 
8.6.1 
Reasons for CYT107 administration permanently discontinued ...................................... 47 
8.6.2 
Procedure in case of CYT107 administration permanently discontinued ......................... 47 
8.7 
BLINDING ...................................................................................................................... 48 
8.7.1 
Organization of Blinding ............................................................................................. 48 
8.7.2 
Unblinding ................................................................................................................. 48 
8.7.3 
Final Unblinding ......................................................................................................... 48 
8.8 
Concomitant treatments................................................................................................... 48 


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8.8.1 
Steroids ...................................................................................................................... 48 
8.8.2 
Prohibited Medications ................................................................................................ 48 
9.1 
Sample Size ...................................................................................................................... 49 
9.2 
Statistical Analysis ........................................................................................................... 49 
9.2.1 
Analysis Datasets ........................................................................................................ 49 
9.2.1.1 
Definition of protocol deviations ........................................................................... 49 
9.2.1.2 
Analysis datasets .................................................................................................. 50 
9.2.2 
Statistical Methods ...................................................................................................... 50 
9.2.3 
Analysis of the Primary Objective ................................................................................ 50 
9.2.4 
Analysis of Other Biological Activity Endpoints ........................................................... 51 
9.2.5 
Analysis of Safety Endpoints ....................................................................................... 51 
9.2.5.1 
Adverse Events .................................................................................................... 51 
9.2.5.2 
Safety laboratory tests........................................................................................... 51 
9.2.5.3 
Vital signs............................................................................................................ 52 
9.2.5.4 
Other safety variables ........................................................................................... 52 
9.2.6 
Concomitant Treatments .............................................................................................. 52 
9.3 
Statistical Analysis Plan ................................................................................................... 52 
10.1 
Steering Committee ...................................................................................................... 52 
10.2 
Data Safety Monitoring Board (DSMB)........................................................................ 53 
11.1 
Patient Replacement Policy .......................................................................................... 54 
11.2 
Patients Lost to Follow-up ............................................................................................ 54 
12.1 
Definitions .................................................................................................................... 54 
12.2 
Reporting of Adverse Events ........................................................................................ 55 
12.2.1 Clinical and Biological Adverse Events ........................................................................ 55 
12.2.1.1 
Nature and severity............................................................................................... 55 
12.2.2 Case of Routine Laboratory Measurements ................................................................... 57 
12.3 
Reporting Serious Adverse Events................................................................................ 58 


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12.4 
Assessment of SAE Expectedness and reference document........................................... 58 
12.5 
Reporting of Critical Events ......................................................................................... 58 
13.1 
Data Collection ............................................................................................................. 59 
13.2 
Source Data .................................................................................................................. 59 
13.3 
Trial Monitoring........................................................................................................... 59 
13.4 
Data Management/Statistics ......................................................................................... 59 
13.5 
Quality Assurance ........................................................................................................ 59 
14.1 
Informed Consent......................................................................................................... 60 
15.1 
Conditions for Conducting the Trial............................................................................. 61 
15.1.1  Study Initiation Requirements ..................................................................................... 61 
15.1.2 Study Personnel .......................................................................................................... 61 
15.2 
Protocol Amendments .................................................................................................. 61 
15.3 
Study Funding .............................................................................................................. 62 
16.1 
Confidentiality Agreement............................................................................................ 62 


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LIST OF FIGURES 
FIGURE 1 SEPTIC PATIENTS WITH PERSISTENTLY LOW ALC HAVE HIGHER MORTALITY ....... 22 
FIGURE 2 DOSE-DEPENDENT EFFECT OF CYT107 (CYT107) ON CD4+T CELLS..................... 27 
FIGURE 3 EXPANSION OF NAIVE (N) AND CENTRAL MEMORY (CM) T CELLS AFTER 
CYT107, 20 µG/KG ................................................................................................................. 27 
FIGURE 4 DECREASE OF EXHAUSTED (PD1+) CD4+ AND CD8+ T CELLS AFTER CYT107 ... 28 
FIGURE 5 INCREASE IN TREC RATIO, RECENT THYMIC EMIGRANTS AND NAÏVE T CELLS
 ............................................................................................................................................... 28 
FIGURE 6 LONG-TERM INCREASE OF CD4+ AFTER CYT107 ADMINISTRATION. ................. 29 
FIGURE 7 BENEFICIAL EFFECTS OF CYT107 IN SEPSIS .......................................................................... 31 
FIGURE 8 SCHEMATIC STUDY DESIGN OF CYT107 PROTOCOL ............................................................. 37 
 
LISTS OF TABLES 
TABLE 1 : MAIN IMMUNOLOGICAL PROPERTIES OF IL7 ...................................................................... 23 
TABLE 2  DIVISION OF AIDS TABLE (DAIDS 2.0) TOXICITY SCALE ....................................... 56 
 
LIST OF APPENDICES 
APPENDIX 1:  GOOD CLINICAL PRACTICE............................................................................................ 63 
APPENDIX 2: FLOW CHART............................................................................................................... 64 
APPENDIX 3: TABLE – CORRELATES  ................................................................................. 65 
APPENDIX 4: REFERENCES  ……………………………………………………………………..66 
 


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1. Protocol Synopsis 
 
TITLE  
A multicenter, randomized, double-blinded, placebo-controlled study of two 
dosing frequencies of glycosylated recombinant Interleukin-7 (CYT107) 
treatment to restore absolute lymphocyte counts in sepsis patients; 
IRIS-7B (Immune Reconstitution of Immunosuppressed Sepsis patients) 
Study 
chairman 
Edward Sherwood, PhD, MD; Vanderbilt University School of Medicine  
Clinical 
phase 
Phase II 
Sponsor(s) 
RevImmune 
Product 
 
CYT107  
Active 
Ingredient 
CYT107 – Glycosylated recombinant human CYT107 (CHO-S) 
Parallel 
study 
A parallel study will be performed in France to allow a common statistical analysis of 
the primary end points and analysis for the enrolled patient population. 


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Introduction 
Sepsis is the leading cause of death in critically ill patients in most intensive care units in 
Europe and the US. Despite advances in supportive treatment and encouraging findings in the 
laboratory, mortality has changed little in the past decades.(1)  Recently, evidence has 
accumulated that sepsis progresses from a state of hyper-inflammation to a state of 
immunosuppression.  This immunosuppressive phase is characterized by increased incidence 
of secondary infections often with relatively avirulent opportunistic type pathogens.(4),(5) 
Currently, new therapeutic approaches to sepsis are occurring using immuno-adjuvants that 
boost host immunity.  One of the most promising agents is interleukin-7 (IL-7, 
CYT107).(6),(7)  
 
IL-7 is an essential, non-redundant, pluripotent cytokine produced mainly by bone marrow 
and thymic stromal cells that is required for T-cell survival.(8)(9)(10)  In addition to its anti-
apoptotic properties, IL-7 induces potent proliferation of naïve and memory T-cells 
potentially supporting replenishment of the peripheral T-cell pool which is severely depleted 
during sepsis(8).  IL-7 also reverses T cell “exhaustion” and increases expression of cell 
adhesion molecules which improve the ability of T-cells to traffic to sites of 
infection.(11)(12)(13)   
 
In clinical trials at the National Cancer Institute, IL-7 caused a doubling of circulating CD4 
and CD8 T cells and an increase in size of spleen and peripheral lymph nodes by ~ 
50%.(14),(15)  Similarly, a recent trial of IL-7 in HIV-1 infected patients who had persistently 
low CD4 T cells despite effective viral suppression demonstrated that Il-7 induced a 2-3 fold 
increase in circulating CD4 and CD8 T cells (12).  Thus, IL-7 reverses a major pathologic 
abnormality in sepsis, i.e., profound lymphopenia.(16) IL-7 has many additional actions that 
are highly beneficial in sepsis (Fig.3).  Il-7 increases the ability of T cells to become activated, 
potentially restoring functional capacity of hypo-responsive or “exhausted” T cells which 
typify sepsis. (8), (12)  Additionally, IL-7 increases expression of cell adhesion molecules 
which enhance trafficking of T-cells to sites of infection. (16)  Finally, IL-7 increases T cell 
receptor diversity leading to more potent immunity against pathogens. (12),(13) 
 
IL-7 has shown efficacy both clinically and in animal infectious models.  Multiple recent case 
reports of  patients with idiopathic low CD4 T cells suffering from progressive focal 
leukoencephalopathy (PML) have shown that IL-7 caused rapid increases in circulating 
lymphocytes, markedly decreased circulating JC virus (often to undetectable levels), and led 
to disease resolution.(17)  
Our collaborators  (Drs. Hotchkiss, Sherwood, and Crouser) demonstrated that IL-7 restored 
the delayed type hypersensitivity response, decreased sepsis-induced lymphocyte apoptosis, 
reversed sepsis-induced depression of interferon gamma (IFN-γ), a cytokine that is essential 
for macrophage activation, and improved survival in murine polymicrobial sepsis. (16).  This 
group also reported that IL-7 is beneficial in a fungal sepsis model that reproduces the delayed 
secondary infections typical of ICU patients.(18)  Importantly, as demonstrated in Figure 1, 
data in septic patients shows a highly significant correlation between the absolute lymphocyte 
count and survival in patients with sepsis.   
 
This proposal will test the ability of glycosylated recombinant IL-7 (CYT107) to restore the 
absolute lymphocyte counts in septic patients who have markedly reduced levels of 
circulating lymphocytes.  


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Objectives 
 
Primary Objective  
To study the biological activity and safety of two dosing regimens of CYT107 at 10 µg/kg  
twice a week for the first week, followed by: 
• Once a week for the low frequency regimen 
• Twice a week for the high frequency regimen 
• Control group: will receive placebo (NaCl 0.9%) twice a week  
 
Activity 
The primary objective is to demonstrate that treatment of lymphopenic septic patients with 
CYT107 will reverse their low absolute lymphocyte count (ALC) which is a marker of 
immunosuppression and which correlates with mortality. This primary end point, increased, 
ALC by >50% in septic patients with lymphopenia, will be measured in the control (placebo) 
and two “dosing frequency” groups at approximately day 42 following randomization and 
initiation of study drug treatment. 
Safety 
To characterize the short term safety in a context of a single cycle of CYT107 (4 weeks) 
administered according to these two dosing regimens in lymphopenic sepsis patients. 
Based on the data collected from previous CYT107 studies in Oncology and HIV 
infection,(12)(13)(14)(15) treatment of lymphopenic sepsis patients with CYT107 is expected 
to increase the absolute lymphocyte count (ALC) by greater than 50% from baseline by day 
42 after therapy is initiated.  
 
To date, CYT107 has not been tested in patients with sepsis. Septic patients frequently have 
decreased kidney and liver function, changes in circulating blood volume, and loss of vascular 
integrity with leakage of proteins into the interstitial space.(2) These alterations might impact 
the pharmacokinetics and pharmacodynamics of CYT107. Thus, we will administer CYT107 
using a protocol that is highly similar to a previous protocol that was effective in improving 
the ALC in patients with cancer, HIV, and hepatitis C and was well tolerated with a low 
incidence of serious adverse effects.(12)(13)(14)(15)(17). 
 
The incidence, type and severity of adverse events occurring during the 6 weeks study period 
will be analyzed for the control arm and two “dosing frequency” groups.  
 
Secondary Objectives 
To characterize CYT107 pharmacokinetics (PK) in  patients with sepsis 
To characterize CYT107 immunogenicity by detection and quantification of binding 
antibodies and detection of neutralizing antibodies in positive samples 
To characterize CTY107 pharmacodynamics, specifically to determine if CYT107 can restore 
depressed functional activity of immune effector cells in patients with sepsis  
To determine if CYT107 decreases the incidence of secondary infections in septic patients    
 


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Study Design 
This is a phase II, double-blinded, randomized, placebo-controlled study aimed at comparing, 
two dosing frequencies in lymphopenic patients with sepsis. 
 
The study will be performed in the US.  A twin study will be performed in France using the 
same study design so that a common statistical analysis could be performed at the end of the 
two studies. 
 
Patients will be randomized to three arms;  CYT107 High Frequency Arm, CYT107  Low 
Frequency Arm, and Control (standard of care), with a ratio of 1:1:1 
BLINDING: Patients and care-providers will be blinded as well as outcome assessors. 
Sample Size 
A total of 30 evaluable septic patients from US and French sites will be randomized 1:1:1 to 
receive study drug treatment over 4 weeks:  
 
• High frequency: intramuscular (IM) administration of CYT107 at 10µg/kg x2/week x 
4 wks (total of 8 doses of CYT107) 
 
• Low frequency: IM administration of CYT107 at 10µg/kg x2/ the first week followed 
by CYT107 and Placebo weekly for 3 wks(total of 5 doses of CYT107 + 3 doses of 
Placebo) 
 
• Control: Will receive 8 administrations of Placebo (twice a week for 4 wks) 
 
 


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Selection 
Criteria 
 
Inclusion Criteria:  
1) Patients of age ≥ 18 yrs to 80 yrs 
 
2) Patients with persistent suspected sepsis at 48-120 hrs after admission  
  
3) Two or more criteria for the systemic inflammatory response syndrome (SIRS) (see 
reference #19 for SIRS criteria) and a clinically or microbiologically suspected infection.  
 
4) At least one organ failure as defined by a SOFA score of ≥2 at any time point during the 
48-120 hrs after admission to the ICU 
  
5) Requirement of vasopressor treatment as follows: i) epinephrine or norepinephrine at ≥ 
0.05 µg/kg/min ideal body weight; ii) vasopressin, or iii) dopamine at ≥ 4-5 μg/kg/min 
ideal body weight, continuously for 4 hrs or more, provided that at least 20 ml/kg of ideal 
body weight of crystalloid or an equivalent volume of colloid was administered during the 
24-hour interval surrounding the start of vasopressor treatment,  to maintain  systolic 
pressure ≥ 90 mmHg or a mean arterial pressure ≥ 60 mmHg at any time point during 
their sepsis course preceding enrollment into the CYT107 study.   
  
6) Lymphopenia with an absolute lymphocyte count ≤ 900 cells/mm3 at either the day of 
consent or the day prior to consent during their ICU stay. 
  
7) Predicted length of stay in the ICU of up to two weeks  after starting drug therapy 
treatment in the trial 
8) Ability to obtain a signed informed consent from patient or LAR consent. 
 


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Selection 
Criteria 
(Con’t) 
Exclusion Criteria:  
 
1) Cancer with current chemotherapy or radiotherapy and/or .receipt of 
chemotherapy or radiotherapy within the last 6 weeks. All patients with 
current, or history of, hematologic malignancy (including, but not limited to, 
ALL, AML, CLL, CML, etc.) or lymphoma will be excluded, regardless of 
receipt of recent chemotherapy. 
2) Cardiopulmonary resuscitation within the previous 4 weeks without objective 
evidence of full neurologic recovery) or patients who have minimal chance of 
survival and are not expected to live > 3-5 days as defined by an APACHE II 
score of ≥ 35 at time of consideration for study eligibility 
3) Patients with a history of or who currently have evidence of autoimmune 
disease including for example: myasthenia gravis, Guillain Barre syndrome, 
systemic lupus erythematosis, multiple sclerosis, scleroderma, ulcerative 
colitis, Crohn’s disease, autoimmune hepatitis, Wegener’s etc. 
4) Patients who have received solid organ transplant or bone marrow transplant 
5) Patients with active or a history of acute or chronic lymphocytic leukemia 
6) AIDS-defining illness (category C) diagnosed within the last 12 months prior 
to study entry  
7) History of splenectomy 
8) Any hematologic disease associated with hypersplenism, such as thalassemia, 
hereditary spherocytosis, Gaucher’s Disease, and autoimmune hemolytic 
anemia  
9) Pregnant or lactating women 
10) Participation in another investigational interventional study within the last 6 
months prior to study entry, with the exception of studies aimed at testing 
sedation products belonging to standard of care such as Propofol, 
Dexmedetomidine, Midazolam. 
11) Patients receiving immunosuppressive drugs, e.g., TNF-alpha inhibitors, for 
rheumatoid arthritis, inflammatory bowel disease or any other reason, or 
systemic corticosteroids other  than hydrocortisone at a dose of ≤ 300 mg/day 
12) Patients receiving concurrent immunotherapy or biologic agents including: 
growth factors, cytokines and interleukins, (other than the study medication); 
for example IL-2,growth factors, interferons, HIV vaccines, 
immunosuppressive drugs, hydroxyurea, immunoglobulins, adoptive cell 
therapy 
 
13) Prisoners 
 


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Study 
Treatment 
Each dose of CYT107 will be administered in the ICU or hospital setting. If the patients are 
discharged from the hospital at which treatment was begun, they will not receive additional 
treatment with CYT107. 
 
CYT107 will be administered by the intramuscular route at the dose of 10µg/kg based on the 
patient’s ideal body weight, twice a week for the first week, followed by: 
• Once a week for the low frequency regimen 
• Twice a week for the high frequency regimen 
• *Control is a placebo (denoted by “P”) and is the saline diluent.   To maintain 
blinding, all 3 combinations, i.e., low and high frequency CYT107 and placebo are 
administered at the same frequency.  
 
 
Week 1 
Week 2 Week 3 Week 4 
days 
1 
4 
8 
11 15 18 22 25 
CYT107 - High 
X 
X 
X 
X 
X 
X 
X 
X 
CYT107 -  Low 
X 
X 
X 
 P 
X 
 P 
X 
 P 
Placebo 
 
P 
P 
P 
P 
P 
P 
P 
P 
 
Primary 
Biological 
Activity & 
Safety Study 
Endpoints  
 
1)  Weekly measures of ALC to determine the kinetic of restoration of adequate absolute 
lymphocyte count and to validate that CYT107 therapy can increase the ALC by >50% from 
baseline.  The main indicators to be determined are: 
i) the relative increase in ALC at day 42 expressed as a percentage of baseline value 
determined at the time point that CYT107 was first administered (day 1) 
  
2)  assessment of the clinical, biological and immunological tolerance of CYT107 
administration in each group: incidence and scoring of all adverse events (AE)  
i) biological effects and tolerance (see Appendix Flowchart #3 for all biological/laboratory 
tests that are to be assessed for CYT107 effects) 
ii) adverse events (AEs) and serious adverse effects (SAEs) during the duration of the 
study period will be recorded, ending day 42 +/- 3 
 


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Secondary 
Biological 
Activity Study 
Endpoints 
 
1) To determine pharmacokinetics (PK) including Cmax, area under the curve,(AUC) and T1/2 
life of CYT107 in patients with severe sepsis and multiple organ failure who are treated with 
10 μgs/kg ideal body weight using 2 different dosing regimens   
2) Assessment of CYT107 immunogenicity by detection and quantification of binding 
antibodies and detection of neutralizing antibodies in positive samples  
3) To determine pharmacodynamics (PD) including effects of CYT107 therapy to: 
 i) improve absolute numbers and function of immune effector cells 
ii) changes in the absolute numbers of CD4+ and CD8+ T cells over the study period, 
standardized on the duration in the study. 
iii) Changes in the expression of the CYT107 receptor (CD127) on the surface of CD4+ 
and CD8+ T cells.  
iv) Effects of CYT107 on circulating monocyte HLA-DR expression  
v) Effects of CYT107 on whole blood LPS-stimulated TNF-α  
vi) Effects of CYT107 on anti-CD3/anti-CD28 stimulated peripheral blood mononuclear 
cells to produce IFN-γ.  
4) To determine effect of CYT107 to decrease the incidence of secondary infections. 
CYT107 has been highly effective in clinically relevant bacterial and fungal animal models of 
sepsis.(16)(18)  We will compare the effect of CYT107 to reduce hospital-acquired secondary 
infections in CYT107 treated septic patients versus a control group of septic patients who 
receive placebo. The rate of hospital-acquired secondary infections at 42 days is roughly 35-
40%.(20) We speculate that CYT107 will reduce the rate of secondary infections from 35-
40% % to 25%.  
 


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Clinical and 
biological 
assessment 
Medical History: A complete medical history of the patient will be obtained either by patient 
self-report, discussion with family if the patient is unable to provide a history, and review of 
the electronic medical records (EMR) of the patient.  
Physical Examination:  The physical exam findings will be obtained by examination of the 
electronic medical records (History & Physical). 
Laboratory Studies: Results from standard of care laboratory tests as necessary to evaluate 
safety and efficacy of CYT107 will be obtained either by the EMR or Principal Investigator 
(PI) orders for research labs as detailed in Appendix 2- Flow Chart.   
• 
APACHE II and SOFA scores will be obtained by review of EMR and/or by the CYT107 
Clinical Research Nurse Coordinator 
• 
Respiratory: oxygen saturation and inspired oxygen concentration 
• 
Imaging: ECG and spleen ultrasound  
• 
Hematology: hemoglobin, hematocrit, red blood cells, mean corpuscular volume,  white 
blood count and differential, platelets, Prothrombin Time (PT) and partial thromboplastin 
time (PTT) 
• 
Chemistry: electrolytes (i.e., sodium, potassium, chloride, bicarbonate, calcium, and 
phosphorus), creatinine, glucose, albumin, liver function tests (total bilirubin, AST, ALT, 
Alkaline Phosphatase), and CRP (C-reactive protein). 
• 
Urinalysis: red blood cells  
• 
Pregnancy Tests in women of childbearing age without known contraceptive method 
(Serum or urine) 
• 
CYT107 Pharmacokinetics. Plasma levels of CYT107 will be assayed at various time 
points as specified (see Section 4.3.2 for details of timing of blood draws for PK studies.   
• 
Specific CYT107 binding and neutralizing antibody (at specialized labs only) 
 


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Statistical 
methods and 
analysis 
Descriptive statistics will include:  
Quantitative variables: n, mean, standard deviation, minimum, maximum, 95% confidence 
intervals, median and quartiles will be presented when considered relevant 
Qualitative variables: n and percent, and 95% confidence intervals when relevant 
Inferential analyses 
Categorical variables: The Fisher exact test or Pearson Chi-2 test (and Cochran-Mantel 
Haenszel procedure for adjusted inferences) as appropriate, will be used to compare rates of 
categorical variables between the two dosing frequency levels. 
Continuous variables: parametric ANOVA (alternatives: non parametric ANOVA or 
transformation of the data / ANOVA for adjusted inferences) will be used to compare 
continuous variables between the two dosing frequency levels. 
 
Primary Analysis of the Primary Objective  
Primary endpoint: increase in absolute lymphocyte count (ALC) by 50% at Day 42 
Duration of 
Patient 
participation 
Patients are treated with CYT107 or control for 4 weeks and laboratory studies obtained for 
an additional 2 weeks up to approximately 42 days (Appendix 2, Flow Chart).   
Patient outcomes will be followed at approximately 29, 42, 60, 90, 180 and 365 days to record 
data including incidence of new secondary infections, patient disposition, (i.e., discharged to 
home, skilled care facility, or long term health care facility), and readmissions to hospital, 
ICU days, and mortality.  
  
 


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Abbreviations 
 
 
ADA 
AICD 
Anti-Drug Antibodies 
Activation induced cell death 
AE 
Adverse effects 
ARV 
Anti-retroviral 
CCR5 
CC chemokine receptor type 5  
CD 
Cluster of differentiation 
CHO 
Chinese hamster ovary 
CMV 
Cytomegalovirus 
CRF 
Case report form 
CRO 
Contract research organization 
CROI 
Conference on retroviruses and opportunistic Infections 
CRP 
C reactive protein 
CTL 
Cytotoxic T lymphocytes 
CXCR4 
CXC chemokine receptor type 4 
CYT107 
CHO recombinant-human-Interleukin-7 
CYT 99 007 
Escherichia Coli recombinant human-Interleukin-7 
D 
Day 
DAIDS 
Division of acquired immunodeficiency syndrome 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
EMR  
Electronic medical record 
FAS 
Full analysis activity dataset 
GCP 
Good clinical practice 
GI 
Gastro-intestinal 
HAART 
Highly active antiretroviral therapy 
HCT 
Hematopoietic cell transplantation 
HIV 
Human immunodeficiency virus 
ICH 
International conference on harmonization 
CYT107(R) 
Interleukin 7 (receptor) 


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INR 
Immune non responders 
IRIS 
Immune reconstitution inflammatory syndrome 
DSMB 
Independent safety monitoring committee 
IWRS 
Interactive web response system 
LPD 
Lymphoproliferative disorder 
LTi  
Lymphoid tissue inducer 
M 
NADA 
Month 
Neutralizing Anti-Drug Antibodies 
NK 
Natural killer 
NKT 
Natural killer thymic 
PBMC 
Pbo 
Peripheral blood mononuclear cells 
Placebo 
PD 
Pharmacodynamics 
PD-1 
Programmed death-1 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PP 
Per protocol activity data set 
QTc 
Corrected QT Interval 
r-hCYT107 
Recombinant human CYT107 
SAE  
Serious adverse effects 
SIV 
Simian immunodeficiency virus 
TCR 
T cells receptor 
TGF-β 
Tumor growth factor  
TREC 
T cells receptor rearrangement excision circles 
Treg 
Regulatory T cells 
TSH 
Thyroid-stimulating hormone 
W 
Week 
 


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Definitions 
 
Study entry: signature of informed consent 
Study period: time interval between study entry (enrollment) and end of study 


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2.0 
Background and Rationale 
2.1 
Sepsis 
2.1.1 Epidemiology of Sepsis 
In 2012, over 20 million patients world-wide are estimated to be afflicted by sepsis annually and 
recent epidemiological analyses showed that mortality from severe sepsis and septic shock is 
still elevated – around 30% both in Europe and US.(1) Both pro and anti-inflammatory 
responses are initially induced in septic shock patients with the secondary occurrence of sepsis-
induced immunosuppression.(2)  
 
2.1.2 Pathogenesis of Sepsis, critical immune paralysis 
In contrast to the theory that morbidity and mortality in sepsis are due to unrelenting 
inflammation, our group recently demonstrated that patients dying of sepsis have marked 
immunosuppression.3  In the first detailed immunologic study of organs from patients dying of 
sepsis, spleens and lungs were harvested in the ICU within 30-180 minutes after death in 40 
septic patients.  Stimulated cytokine secretion studies and immune phenotyping of cell surface 
receptor/ligand expression profiles were conducted.  Isolated splenocytes were stimulated with 
lipopolysaccharide (LPS) or anti-CD3/anti-CD28 and production of cytokines quantitated.  
Stimulated splenocytes from septic patients had profoundly decreased production of both pro- 
and anti-inflammatory cytokines, values which were often <10% of those from critically-ill non-
septic patients.  Similar findings were observed in immune effector cells isolated from lung 
(unpublished data).  Immune effectors cells from spleen and lung demonstrated upregulated 
expression of inhibitory receptors including PD-1, expansion of T regulatory cells and myeloid 
derived suppressor cells, and down-regulation of activation pathways.  Collectively, these 
results show that sepsis induces numerous overlapping mechanisms of immune suppression 
involving both innate and adaptive immunity.   
 
2.1.2.1 Low ALC is associated with increased incidence of bacteremia and mortality  
Sepsis induces widespread apoptosis of CD4 and CD8 T cells leading to a low ALC.  The 
absolute CD4 T cell count in many septic patients is as low as observed in patients with 
AIDS.(21)(22) Numerous investigators have shown that septic patients with the lowest ALC 
have the highest mortality in the disorder.(23)(24)  CYT107 induces proliferation of naïve and 
memory T cells thereby supporting replenishment of lymphocytes which are needed to combat 
infection.  
Recently, our group examined the relationship between the ALC in sepsis survivors versus 
patients dying of sepsis.  As shown in Figure 1. below, septic patients who died had a 
persistently low ALC compared to patients who survived sepsis.  


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Figure 1 Septic patients with persistently low ALC have higher mortality 
 
We prospectively monitored a group of patients with a diagnosis of severe sepsis.  We examined 
the ALC in patients who survived sepsis versus patients who died of sepsis. Both groups of 
septic patients tended to have an ALC which was lower than the lower limit of normal for our 
hospital, i.e., 1.2 cells/μL x 103. In Figure 1 (left hand panel), the Y axis equals the ALC in 
cells/μL x 103.  X axis equals the number of days septic; the number in parentheses is the 
number of patients who are septic on that particular day. Note that patients who survived sepsis 
had a gradual increase in the ALC count while those septic patients who died of sepsis tended to 
have a persistently low ALC. In Figure 1 (right hand panel), the averaged ALC over patient 
length-of-stay was divided into 4 quartiles.  Note that patients with the lowest averaged ALC 
had the highest mortality.  It is also important to note that mortality continued to increase from 
days 30 to 80 and was ~50% in the patients with the lowest ALC.  These data provide a strong 
rationale for use of CYT107 therapy in sepsis because it will increase the ALC and thereby 
improve patient host defenses. 
 
2.2 Current treatments and their limitations 
Current therapies have focused on agents which block the host immune response.  Over 30 trials 
of immune blockers have failed to improve survival in sepsis.(25) These failures have led to a 
reevaluation of the pathophysiology of sepsis and new therapies consisting of agents that boost 
host immunity.(2)  New trials with GM-CSF and IFN-γ, drugs which enhance immune function 
are underway in sepsis.(26)(27) 
 
2.3 Study product: glycosylated recombinant human CYT107 “CYT107” 
CYT107 has critical roles in T cell development and may restore at multiple levels the 
immunologic situation specifically by restoring adequate T cells count.(8)(9)(10).   CYT107 that 
will be employed in the present clinical trial is the current glycosylated form of recombinant 
human CYT107 and is produced in engineered CHO mammalian cells. This form shows less 
immunogenicity in primates and is expected to be less/non-immunogenic in humans. 
Furthermore, as discussed below, its pharmacokinetic and dynamic profile may allow for a 
greater interval between administrations. CYT107 has been assessed in humans and results of 


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toxicity studies performed in cynomolgus macaques after one cycle of treatment are summarized 
in section 4.3 of the investigator brochure.  
 
2.3.1 Quantitative and functional effects of CYT107 
The quantitative and functional effects of CYT107 are comprehensively reviewed in the 
Investigator’s Brochure and briefly summarized in the table below, demonstrating how 
administration of CYT107 may help to meet several of the unmet medical needs. 
 
Table 1 : Main immunological properties of IL7 
Quantitative impact 
• Development and expansion of CD4+ and CD8+ αβ T cells:  naive, and memory 
subpopulations 
• Development and expansion of γδ T cells and natural killer thymic ( NK T) cells 
 
Functional impact 
• Decrease frequency of “exhausted” PD-1 CD4+  and CD8+ T cells 
• Decrease apoptosis (increase of anti-apoptotic Bcl-2 protein, decrease of pro-apoptotic 
Bim protein) 
• Decrease frequency of regulatory T cells (Tregs) 
• Increase cytotoxicity of CD8+ T cells 
• Co stimulation of T cells: 
 Increase reactivity of T cells against weak immunogens / subdominant epitopes 
 Increase differentiation and survival of central memory T cell 
Pre-clinical studies 
The available preclinical and clinical results of CYT107 underscore its therapeutic potential to 
restore adequate CD4+ T cells counts and improve immune protection. 
IL-7 plays a key role in thymopoiesis 
IL-7 has critical and non-redundant roles in T cells development, hematopoiesis, and post-
developmental immune functions as a prototypic homeostatic cytokine.(8-10)  IL-7 also 
supports T cells survival by up-regulating members of the anti-apoptotic Bcl-2 family, and by 
down-regulation of the pro-apoptotic activity In contrast to IL-2, CYT107 therapy in humans 
induces robust and functional CD4+ T cells expansion without selective expansion of Treg 
cells.(10) In addition, CYT107 therapy increases T cells receptor (TCR) repertoire diversity and 
increases circulating TCR rearrangement excision circles (TRECs) numbers, which have been 
used as an indirect measure of thymic output because they reflect TCR gene recombination 
events and are enriched within the RTE fraction (13).  CYT107 signals through the CYT107 
receptor, which is composed of the CYT107Rα (CD127) and the common gamma (γ) chains. 
 
 


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2.3.1.1 Inverse correlation between CD4+ T cells lymphopenia and circulating IL-7 
An inverse correlation between CD4+ T cells lymphopenia and circulating IL-7 has been 
consistently documented after any infectious or iatrogenic lymphopenia, implicating 
endogenous IL-7 in the regulation of T cell homeostasis(28).  In HIV-infected patients, elevated 
CYT107 levels gradually decline as CD4+ T cells recovery occurs following effective anti-
retroviral therapy. Importantly, several studies suggest that IL-7 drives CD4+ T cells restoration 
subsequent to the suppression of HIV replication. (12)  IL-7 circulating levels are particularly 
high in patients benefiting from an exceptionally successful and fast immune restoration.28  
 
2.3.1.2 Experimental effects of CYT107 in HIV/SIV infection 
a) Expansion of CD4+ T cells 
A sustained increase in CD4+ T cells and a parallel expansion of CD8+ T cells has been 
consistently demonstrated in SIV-infected monkeys treated by CYT107,(29) before being 
confirmed in humans which were performed using CYT 99 007 (1st generation non-
glycosylated 
CYT107/ 
E.Coli 
r-hCYT107) 
and 
CYT107 
(glycosylated 
r-hCYT107 
CYT107).(30)(12). 
 
b) Enhancement of anti-HIV/SIV T cells responses 
The pleiotropic quantitative or functional effects of CYT107 converge to improve T cells 
response against HIV: 
• CYT107, because of its co-stimulatory effect, may increase the magnitude and breadth of 
anti HIV CD4+ and CD8+ T cells responses; 
• CYT107 increases cytotoxicity of specific anti-HIV CD8+ T cells, as shown ex vivo with 
T cells derived from HIV-infected donors;  
• CYT107 may foster the differentiation, of protective memory CD4+ and CD8+ T cells, 
which is typically blocked and/or outnumbered by the accumulation of exhausted 
CD127low effector memory T cells. Thus r-hCYT107 may alter the balance between 
CD127low exhausted and CD127high protective T cells in favor of the latter 
subpopulation. 
  
2.3.1.3 Results of trials with CYT107 and ongoing trials with CYT107  
(See section 5 of the Investigator brochure for exhaustive information of human experience with 
CYT107) 
CYT107 the glycosylated form of CYT107 being developed by Revimmune was tested in 
several indications (oncology, HCV, HIV, HCT). The safety profile and preliminary activity as 
measured in the ongoing clinical studies were satisfactory. The total number of patients treated 
with CYT107 today is 275 in 13 trials (12)(13)(31). In addition more than ten patients received 
CYT107 for compassionate use (17). 
Safety 
Most frequent adverse reactions reported in clinical trials with CYT107 (see section 5.2.2) are: 
• injection site reaction 


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• lymphadenopathy 
• pyrexia 
• rash 
• fatigue 
 
Most frequent severe adverse reactions that are reported in clinical trials with CYT107 are: (see 
section 5.2.2 Investigator Brochure)  
• Rashes: overall rashes related to CYT107 do not require systemic treatment except 
antihistaminic and some require topical corticosteroids. Secondary prophylaxis is 
recommended 
• ALT/AST elevations: most are mild to moderate. Two asymptomatic and isolated 
transient grades 3 and 4 transaminase elevations were reported. Rules for decreasing 
CYT107 dose in case of transaminases elevation in HIV studies with repeated cycles of 
CYT107 are in place. 
• Allergic reactions – four patients (out of over 300 patients) developed grade 3 allergic 
reactions of generalized urticarial without significant systemic reactions. Treatment 
consisted of antihistimines and corticosteroids and patients resolved symptoms without 
complications.  All reactions occurred on the second treatment cycle of CYT107.  
• Anaphylactoid reaction:  One patient out of over 300 patients had a grade 2 
anaphylactoid reaction consisting of itching and swelling of the left side of her tongue 
and uvula.  There was no accompanying bronchospasm. She was treated with 
intravenous corticosteroids and promethazine.  She was monitored for 4 hours and 
recovered uneventfully and was discharged.     
• Immunogenicity: as of January 2013 ADA were detected in 66/274 patients after one 
cycle of CYT107 and 6 had neutralizing antibodies. After a second cycle, ADA were 
detected in 59/77 patients and 27 had neutralizing anti-drug antibodies (NADA). 
Occurrence of NADA is higher in case of repeated cycles. Nevertheless, occurrence of 
NADA was not associated with an increase in the frequency or severity of AEs. 
The drug is well tolerated and the most frequent adverse events observed are local erythema at 
injection site. (12-14, 31) 
 
Activity 
Recent trials in HIV-infected patients have demonstrated a sustained dose-dependent increase in 
naïve and memory CD4+ and CD8+ T cells after administration of r-hCYT107 either with CYT 
99 007 or CYT107.(12,30,31) In a prospective randomized placebo-controlled study, a single 
subcutaneous (SC) dose of r-hCYT107 was well tolerated with biologic activity demonstrable at 
3 µg/kg and a maximum tolerated dose (i.e. without SAE or dose limiting toxicity) of 30 µg/kg. 
Single-dose of recombinant r-hCYT107 increased the numbers of circulating CD4+ and CD8+ T 
cells, predominantly of central memory phenotype. Levy et al.1 published recently the 
preliminary results of the CYTHERIS study. These results were based on 13 patients who 
received a total of 8 subcutaneous injections of 2 different doses of r-hCYT107 (CYT 99 007); 3 


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or 10 µg/kg, 3 times per week (w) over a 16-day period. R-hCYT107 was well tolerated and 
induced a sustained increase of naive and central memory CD4+and CD8+ T cells. (12) 
We have now confirmed and extended our initial results with the completion of the INSPIRE 
study conducted in USA, Canada, France, Italy, utilizing the current glycosylated version of r-
hCYT107 (CYT107) in HIV patients whose disease was well controlled by HAART but who 
remained immune non-responders with CD4+ T cells counts below 400/µL. 
Results from INSPIRE patients confirmed the ability of CYT107 to produce a high quality 
immune recovery as shown in figure 2. The increases of CD4+ T cells counts induced by the 
three dosages of CYT107 administrations (10, 20 and 30 µg/kg/week) were significant when 
compared to the levels observed in the placebo arm (12). 
 
 


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Figure 2 Dose-dependent effect of CYT107 (CYT107) on CD4+T cells 
 
 
At 20 µg/kg, CYT107 (CYT107) preferentially expanded Naïve (N) and Central memory (CM) 
CD4+ as shown in figure 3. 
 
 
 
Figure 3 Expansion of Naive (N) and Central Memory (CM) T cells after CYT107, 20 µg/kg 
 
X axis is the ALC/μL.  Y axis represents Days (D) or Weeks (W).   
 
*Wilcoxon test: CYT107 vs. Placebo 
p = 0.006, CYT107 10 µg/Kg 
p = 0.004, CYT107 20 µg/Kg 
p = 0.008, CYT107 30 µg/Kg 


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This expansion was associated with a significant decrease of the “PD-1+” exhausted CD4+ and 
CD8+ T cells as shown in figure 4: 
 
Figure 4 Decrease of exhausted (PD1+) CD4+ and CD8+ T cells after CYT107  
 
In addition, a clear support of thymopoïetic production, was demonstrated by the increase in 
TREC ratio, recent thymic emigrants and naïve T cells (see figure 5) 
 
 
 
Figure 5 increase in TREC ratio, recent thymic emigrants and naïve T cells 
 


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Various results from the INSPIRE study demonstrated the quality of CYT107-induced T cells 
reconstitution in these “Immune Non Responding” patients: 
• CYT107 administration was clinically and biologically well tolerated 
 
• 20 µg/kg/week was the dose with the best efficacy/safety ratio 
 
• A single cycle (3 subcutaneous injections) induced a rapid and sustained increase of 
CD4+ and CD8+ T cells, with most patients (5/8) treated with 20 µg/kg of CYT107 
reaching CD4+ T cells counts > 500 cells/µL at W12 
 
• CYT107 induced a brisk expansion of T cells subsets – increasing RTE, naïve, central 
memory and effector T cells 
 
• The increase in CD4 and CD8 T cells is long lived and persists for a number of months 
(Figure 6) 
 
Figure 6 Long-term increase of CD4+ after CYT107 administration. 
 
These results demonstrate that the effect of CYT107 to increase the ALC persists for a number of 
weeks after cessation of therapy.  Given the high rate of recurrent infections that persist for up 
to one year in septic patients following hospital discharge (Journal of Intensive Care 29:87-95 
2014), this CYT107 induced increase in ALC may be highly beneficial.  
Going forward, RevImmune is currently considering various new studies with CYT107 (CYT107) 
in oncology as well as in sepsis.  
**Wilcoxon test W52 CYT107 vs.Placebo 
p = 0.01  CYT107  10 µg/Kg 
p = 0.01  CYT107  20 µg/Kg 


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2.4 
Rational for an CYT107 clinical trial in sepsis 
CYT107 is an essential, non-redundant, pluripotent cytokine produced mainly by bone marrow 
and thymic stromal cells that is required for T-cell survival.(8,9)  In addition to its anti-apoptotic 
properties, CYT107 induces potent proliferation of naïve and memory T-cells potentially 
supporting replenishment of the peripheral T-cell pool which is severely depleted during 
sepsis.(10)  CYT107 also reverses T cell “exhaustion” and increases expression of cell adhesion 
molecules which improve the ability of T-cells to traffic to sites of infection.’12)  Unlike other 
closely related common γ-chain cytokines such as IL-2, CYT107 does not induce a hyper-
inflammatory “cytokine storm” response and has been remarkably well-tolerated.(8)    
Because of CYT107’s ability to boost and restore CD4 and CD8 T cell function, key 
components of the adaptive immune system, it was hypothesized that CYT107 would be 
efficacious against invading pathogens.  Subsequent studies have proven this hypothesis to be 
correct. (16, 18)  CYT107 has shown efficacy in improving morbidity and mortality against 
diverse pathogens. (16,18)  CYT107 restored cytokine secretion, improved T cell trafficking to 
the site of infection, and decreased tissue viral load in a mouse model of lymphocytic 
choriomeningitis.(11)  CYT107 reversed lymphopenia and T cell exhaustion and improved T 
cell repertoire diversity in rhesus macaques with simian immunodeficiency virus.(29)  Several 
independent laboratories have shown that CYT107 improves survival in a clinically relevant 
bacterial peritonitis model.(16,32)  Most recently, CYT107 has been shown to improve survival 
in a clinically-relevant, two-hit model of fungal sepsis.(18) 
Importantly, there is increasing evidence that CYT107 will be highly effective in clinical 
infectious disease.  CYT107 reversed T cell exhaustion and restored T cell functionality in HIV 
patients who were non-responders to HAART.12,(32)  CYT107 increased T cell receptor 
diversity in HIV patients with lymphopenia and in patients who had lymphopenia following 
radiation or chemotherapy for treatment of acute myelogenous leukemia.(12,13)  In a subset of 
patients with hepatitis C who were non-responders to conventional therapy, CYT107 lead to 
complete clearing of virus from the blood (33). CYT107 also lead to clearing of the JC virus in a 
lymphopenic 
patient 
with 
progressive 
multifocal 
leukoencephalopathy 
(PML).(17)  
Subsequently, 10 additional patients with PML have been treated with CYT107 on a 
compassionate basis and have had beneficial responses including clearing of virus (personal 
communication Dr. Michel Morre – former CEO of Cytheris). 


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Figure 7 Beneficial Effects of CYT107 in Sepsis 
 
CYT107 has numerous and diverse effects to improve immune function in sepsis including: i) 
decreases in sepsis-induced apoptosis, ii) increased production of T cells with diverse T cell 
receptors (TCRs), iii) decreasing PD-1 expression with reversal of T cell exhaustion, iv) 
increased IFN-γ production, v) increased integrin expression leading to improved T cell 
trafficking to infected sites.6,7,16,18  Thus, CYT107 is ideally suited to treat patients with sepsis 
because it directly reverses key immunologic defects in the disorder. 
2.4.1 Rationale of the Clinical Study: the need to reconstitute adequate lymphocyte 
counts in sepsis In conclusion, CYT107 reverses a fundamental defect in sepsis, i.e., the 
massive loss of lymphocytes.  CYT107 has been highly effective in improving survival in 
clinically relevant animal models of sepsis.(16,18,34).  It offers great promise in the treatment of 
septic patients.  
 
Therapeutic immune reconstitution should be: 
• Strong and stable:  meaning to allow patients to recover peripheral CD4+ T cells counts 
to above the 500 cells /µL for the duration of the study period, 
• Deep:  meaning not only involving peripheral CD4+ T cells recovery but also inducing a 
T cells repopulation of lymph nodes and gut mucosa,  
• Diverse:  involving both CD4+ and CD8+ T cells, naïve and memory,  
• Functional:  limiting over-activation (CD38+HLADR+), exhaustion (PD1+), and 
production of Treg cells while preserving functionality (CD28+). 


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• Broad:  supporting thymic activity and facilitating the recovery of the peripheral TCR 
repertoire. 
 
2.4.2 Study Population 
Patients selected in this trial will have severe sepsis with documented lymphocytopenia 
consisting of an absolute lymphocyte count (ALC) of less than 900 cells per microliter.  (ALC 
<900/ µL).  Also see Inclusion criteria.  
 
2.4.3  Investigational Medicinal Product – glycosylated recombinant human IL-7 
(CYT107)  
2.4.3.1 Route 
CYT107 will be administered intra-muscularly or subcutaneously based on hemostasis results 
and whether patients are receiving anticoagulant and antifibrinolytic treatments. If the patient 
receives anticoagulant and/or antifibrinolytic therapy, intramuscular route is contraindicated. In 
that case, CYT107 will be administered subcutaneously.   
 
By subcutaneous route, according to the monkey studies results, CYT107 bioavailability is 
satisfactory (> 75%) with an extended kinetic profile which may favor prolonged CYT107 
activity.  But the sub-cutaneous route is known to favor recombinant proteins immunogenicity, 
accordingly following the recent example of beta interferon, these new CYT107 studies will be 
mainly performed by intra-muscular administration. Depending on haemostasis results (INR 
greater than 2.5 or a platelet count less than 35,000), CYT107 will be administrated 
subcutaneously.  This explains why the present study also includes the assessment of PK profile 
in these patients (35)(36)(37). 
 
2.4.3.2 Dose  
To date, CYT107 has not been tested in patients with sepsis.  Septic patients frequently have 
decreased kidney and liver function, changes in circulating blood volume, and loss of vascular 
integrity with leakage of proteins into the interstitial space.(2) These alterations might impact 
the pharmacokinetics and pharmacodynamics of CYT107. Thus, we will administer CYT107 
using a protocol that is highly similar to a previously protocol that was effective in improving 
the ALC in patients with cancer, HIV and HCV infections and was well tolerated with a low 
incidence of serious adverse effects. (12-14)  
The dose of 10 µg/kg, ideal body weight, administered either once or twice a week, will be 
evaluated in this study.  CYT107 at a dose of 10 and 20µg/kg once a week has shown an 
excellent safety profile and biological activity in previous studies in HIV and oncology patients. 
(12-14, 32) 
2.4.3.3 Dosing frequency: 
Specificities of CYT107/CYT107Rα pathway regulation and data gathered now in humans 
favor injections once a week and short therapeutic cycles. According to monkey and human 
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recovery of CYT107Rα expression (CD127) at the surface of T cells which responded to a 
previous dose of CYT107. Furthermore, a sustained response of T cells to CYT107 should be 
fully restored, as measured one week later by Ki-67 expression. A weekly interval was 
successfully tested in the HIV and post HSCT studies aimed at inducing an immune 
reconstitution- Short cycles, limited to 4 weeks, should avoid inducing exhaustion of T cells 
responsiveness to high doses of CYT107, which could occur despite the recovery of CD127 
expression. 
In the specific case of sepsis, there is a real urgency to allow the patients recovering an adequate 
number of T lymphocytes. Accordingly we will use a twice a week regimen for the very first 
week of treatment in both groups. Although the recovery of the CYT107 receptor at day 4 is not 
100%, it is sufficient to re-stimulate the pool of T cells available for expansion.  In the low 
frequency group we will use this twice a week regimen for the first week only, while it will be 
used for the full 4 weeks cycle in the high frequency group. 
A staggered approach to CYT107 treatment will be used in which treatment will not be initiated 
in a newly enrolled patient until 24 hours after the previously enrolled patient has received the 
second dose of CYT107 without evidence of serious adverse event (SAE) occurrence. In cases 
of a suspected adverse event, a scheduled dose will be postponed by 3 days to allow the adverse 
event to resolve. For any severe or serious adverse event during the treatment period (as judged 
by the Investigator), dosing will be suspended and the DSMB will be consulted for case review 
and advice as to termination of treatment. 
2.5 
Risk-Benefit Ratio 
Sepsis causes extensive apoptotic death of immune effector cells leading to an impaired immune 
system. CYT107 prevents sepsis induced cell death and improves survival in many clinically-
relevant animal models of sepsis.  We postulate that by improving host immunity, CYT107 will 
improve the ability of septic patients to eradicate their primary infection and decrease the 
incidence of new secondary infections.  Given the low risk of adverse effects in patients treated 
with CYT107 and the potential for benefit, we believe that the risk benefit ratio lies greatly 
toward use of CYT107 in patients who have a highly likelihood of dying from sepsis; the 
expected mortality in septic patients who meet the entry criteria for this CYT107 study is 
approximately 45% at 60 days.   
 
3.0 
Objectives of the Trial 
3.1 
Primary Objective 
To study the biological activity and safety of two dosing regimens of CYT107 at 10µg/kg over 
a treatment period of 4 consecutive weeks: 
Twice a week for the first week, followed by: 
• Once a week for the low frequency regimen (plus placebo once a week) 
• Twice a week for the high frequency regimen 
• Control group: will receive placebo (NaCl 0.9%) twice a week  


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Activity 
The primary objective is to demonstrate that treatment of lymphopenic septic patients with 
CYT107 will reverse the drop in absolute lymphocyte count (ALC) which is a marker of 
immunosuppression and which correlates with mortality (see Figure 1 and references 4, 21, 23).  
The effect of CYT107 on the kinetics of the recovery of ALC will be recorded. CYT107 has 
been demonstrated to increase ALC in a diverse array of patient populations including patients 
with HIV, patients who underwent bone marrow transplantation, and patients with cancer.  
Based on the data collected from previous CYT107 studies in Oncology and HIV infection, the 
treatment of lymphopenic sepsis patients by CYT107 is expected to produce: 
• Primary endpoint: increase of ALC by greater than 50% from baseline by day 42 after 
CYT107 therapy initiated. 
• We will also evaluate the number of patients who restore ALC to >1200 cells/mm3 (the 
lower limit of normal for ALC at most hospitals) by day 42 with the aim of observing 
this recovery in more than 50% of the patients 
These end points will be measured in the three treatment groups (2 dosing frequencies + 1 
placebo) at day 42 in both the French and US studies. All patients will undergo randomization 
for study drug treatment and undergo all study related tests and procedures. 
Safety 
To characterize the short term safety in a context of a single cycle of CYT107 (4 weeks) 
administered according to these two dosing regimens in lymphopenic sepsis patients. 
3.2  
Secondary Objectives 
3.2.1 To characterize CYT107 pharmacokinetics (PK) in this patient population 
Another secondary objective of the study is to examine the pharmacokinetics (PK) and 
pharmacodynamics (PD) of CYT107 in patients with sepsis.  Septic patients frequently have 
changes in circulating blood volume, impaired vasculature integrity with leakage of proteins into 
the interstitial space, and organ dysfunction.  Although the investigators expect that CYT107’s 
main PK parameters in septic patients will not be substantially affected by these alterations, it is 
important to define CYT107 AUC, Cmax and half-life in this patient population. This 
information can be used to guide the proper dosing of CYT107 in a larger trial.  
Up to now, CYT107 was administered by sub-cutaneous route to patients, but this route of 
administration is susceptible to increase the immunogenicity of the drug and patient’s edema 
which is frequent in sepsis patients might alter the bioavailability. In this study the CYT107 
product will be preferentially given by intra muscular administration. As exemplified for 
Interferon by Munafo et al(35)., FSH by Steinkampf (36) et al., Alefacept by Sweetser (37) et al. 
and Onercept by Trinchard-Lugan (38) et al.,  the IM route is  known to deliver pharmacokinetic 
profiles very similar to the S.C. route. Nevertheless the PK profile of CYT107 administered by 
I.M. will be determined during the study. Nevertheless, septic patients are susceptible to 
development of coagulopathy, which increases the risk of complications associated with 


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intramuscular drug administration. Thus, CYT107 will be administered via the subcutaneous 
route in coagulopathic (INR>2.5, platelet count less than 35,000/ul) patients. 
 
3.2.2  To characterize CYT107 Pharmacodynamics - To determine if CYT107 can restore 
depressed functional activity of immune effector cells in patients with sepsis. 
We will look at the ability of CYT107 to improve common markers of immune function that 
have been shown to correlate with outcome in patients with sepsis. Note that these tests are not 
standardized clinically available tests but rather tests that may be useful in the future to help 
guide administration of immunotherapeutic agents.   These tests will be performed in the 3 
investigators laboratories by their laboratory technicians.  
• Effects to increase monocyte HLA-DR expression 
• Effects to increase whole blood LPS-stimulated TNF-α 
• Effects on anti-CD3/anti-CD28 stimulated peripheral blood mononuclear cells to 
produce IFN-γ.  
• Effects to increase patient ALC to >1200 and to increase absolute CD4 and CD8 T cell 
counts.   
 
3.2.3 To assess the impact on number and type of secondary infections:  
CYT107 has been highly effective in improving survival in clinically relevant bacterial and 
fungal animal models of sepsis.(16,18,34)  In addition, CYT107 has been effective in boosting 
immunity and reducing viral loads in patients with HIV and JC virus induced progressive multi-
focal leukoencephalopathy.(18,12,32)  Most recently, CYT107 led to restoration of gut 
associated lymphoid tissue in HIV patients with a subsequent reduction in markers of 
inflammation.(31)  Thus, we believe that CYT107 will improve host immunity and thereby lead 
to a  decrease in hospital acquired  secondary infections in  septic patients.   
Consequently, we hope to see a decrease in secondary opportunistic type bacterial and fungal 
infections in septic patients treated with CYT107 compared to septic patients who are treated 
with placebo (Control group). We will use the Center for Disease Control criteria for definition 
of ICU-acquired infections.  Because it is often difficult to determine if a secondary hospital 
acquired infection is present, a panel of 3 experienced ICU physicians, “The Secondary 
Infection Evaluation Committee”, will be used to evaluate and grade whether a secondary 
hospital acquired infection is present.  These 3 physicians will be blinded to patient treatment 
with CYT107 versus placebo.  These 3 physicians will not be members of the investigative team 
but rather colleagues of the investigators.  They will meet either in person or by teleconference 
once a month or as deemed necessary by the Investigator to judge secondary infections.  
4.0 
Study Design 
4.1 
Overall Design 
This is a phase II, multi-center, double-blinded, placebo-controlled, randomized study aimed at 
comparing, two dosing frequencies of CYT107 and placebo in patients with sepsis. The study 
will be performed in parallel at multiple sites in the United States and France using identical 
study design and data collection. The results of the French and US investigative teams will be 


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combined for preliminary and final analysis. A REDCap database will be used for data 
management for all sites. A central computerized randomization center will be used to allocate 
treatments in both the US and French studies. The current protocol deals with the United States 
investigative study.  For this preliminary trial of CYT107, there will be 4 investigative sites in 
the US, however, study enrollment is planned to take place at the coordinating site, Vanderbilt 
University Medical Center.  If this current study demonstrates that CYT107 is safe and effective 
in increasing the ALC in septic patients, a larger trial of CYT107 will be conducted and 
additional sites in both countries may be recruited.  The list of investigators and trial sites in the 
US are the following:  
• Edward Sherwood MD, PhD; Professor of Anesthesiology, Vanderbilt 
University School of Medicine  
• Richard Hotchkiss MD; Professor of Anesthesiology, Medicine, and 
Surgery, Washington University School of Medicine 
• Elliott Crouser MD, Professor of Medicine, Ohio State School of Medicine  
• Lyle Moldawer Ph.D., Professor of Surgery, University of Florida, 
Gainesville, School of Medicine. 
4.2 
Study Treatment 
Up to thirty patients may be enrolled at 4 sites in the US, i.e., Vanderbilt, Ohio State, University 
of Florida, and Washington University School of Medicine, however, it is anticipated that the 
initial enrollment of 30 subjects will occur at Vanderbilt, Washington University and Limoges 
in France. (Note:  the French sites may also enroll up to 30 patients such that a total of 30 
evaluable patients will be available from the two countries).  In the event that patient accrual is 
delayed in one country, all patients will be recruited from either the US or France alone.  A 
computerized protocol will implement permuted block randomization in blocks of size three. 
This scheme ensures balance across the treatment groups for every third randomization.  A 
maximum of 20 septic patients will be treated with CYT107 at a dose of 10µg/kg.  There will be 
two dosing regimens as illustrated in Figure 8 (below).  CYT107 will be administered intra-
muscularly at the dose of 10µg/kg (IBW), once or twice a week for a four week cycle. Ten 
septic patients will have CYT107 administered twice a week for 4 weeks.  Ten septic patients 
will have two doses of CYT107 administered during the first week followed by one dose of 
CYT107 in conjunction with 1 dose of placebo for 3 additional weeks. Ten septic patients will 
receive placebo twice a week for four weeks along with routine standard of care per the clinical 
providers. 
 
At approx. 48-120 hrs after admission for sepsis, those septic patients who meet the 
Inclusion/Exclusion criteria (see previous section) and provided written informed consent, will 
be entered into the study. The first dose of CYT107 (as indicated below) is at approx. 48-120 hrs 
after sepsis onset.  The initial dose of study drug will be administered only in the ICU by the PI 
or research nurse. If patients have an INR greater than 2.5 or a platelet count less than 35,000, 
CYT107 will be administered by the subcutaneous route rather than by intra-muscular injection.   


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A staggered approach to CYT107 treatment will be used in which treatment will not be initiated 
in a newly enrolled patient until 24 hours after the previously enrolled patient has received the 
second dose of CYT107 without evidence of serious adverse event (SAE) occurrence.  
In patients with coagulopathy (INR greater than 2.5 or a platelet count less than 35,000), 
CYT107 will be administrated subcutaneously. 
 
 
Figure 8 Schematic study design of CYT107 Protocol  
schematic "preliminary study" design
Week 4
Week 5
Week 6
days
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 … 28 29 … 35 36 … 42
X
X
X
X
X
X
X
X
X
X
X
P
X
P
X
P
PBO P
P
P
P
P
P
P
P
ALC
X
X
X
X
X
X
X
X
X
X
IL-7 admin in 10 patients "high frequency dosing"
IL-7 admin in 10 patients" low frequency dosing"
primary end points : 
10 Placebo Controls
determination of ALC recovery and IL-7 clinical tolerance
Absolute Lympho Counts
TREATMENT
FOLLOW UP
IL-7
Week 1
Week 2
Week 3
 
 
Dosing regimen for CYT107 in septic patients showed administration details of the “high 
frequency dosing” – (shown in red color) or the low frequency dosing (shown in blue color).  
The ALC is quantitated weekly throughout 6 weeks duration.  Given that CYT107 will boost host 
immunity, we predict that patients treated with CYT107 will have decreased incidence of new 
secondary infection, decreased hospital readmissions (which generally are due to new 
secondary infections), and improved 60 day, 90 day, 180 days and one year mortality. Thus, 
these parameters will be recorded in all patients.  The 60 day, 90 day, and one year data will be 
obtained by telephone interview, physician records, or by interrogating appropriate databases 
and newspaper obituary records. The patients will not have to be seen in clinic.  
Additional experimental details:  
• Patients with severe sepsis and organ failure who are admitted to the ICU are candidates. 
Septic patients who are not being treated in the ICU are not candidates for study 
enrollment.   
• Septic patients will continue to receive the CYT107 to complete the full dose schedule 
even if their sepsis has resolved if they remain in the acute care hospital setting. Patients 
will not receive additional doses of CYT107 if they are discharged from the hospital.  
If patients who are enrolled in the study fail to complete two weeks of the protocol for any 
reason such as death, discharge or transfer from the hospital, or study withdrawal decision by 
family or physician, then the patient will not be considered to have had an acceptable course of 
therapy with CYT107 to allow evaluation of its effects.   The next patient to be recruited into the 
CYT107 study will be assigned the next randomization treatment until all groups have enrolled 
at least 10 subjects.  In this manner, the investigators will be able to maintain proper patient 


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randomization to evaluate CYT107’s efficacy.  Note: research data for all subjects that 
underwent randomization and treatment will be completed regardless of length of time on study 
and will be entered into the database and reported to all Committees including the DSMB, FDA, 
IRB, etc.   
4.3 Endpoints 
4.3.1   Primary Biological Activity & Safety Study Endpoints  
1) Weekly measures of absolute lymphocyte counts (ALC) will be performed to determine 
the kinetics of restoration of ALC.  Specifically, we will quantitate the increase of ALC 
at day 42 +/- 3 days, expressed as a percentage of baseline value determined at the time 
point that CYT107 was first administered (day 1). We will determine the number of 
patients who reach a 50% increase over the baseline value and we will also determine the 
percentage of patients reaching an ALC > 1200 at day 42 +/- 3 days in each group. 
2) Assessment of the clinical, biological, and immunological effects of CYT107 as well as its 
safety and tolerability, i.e., incidence and scoring of all adverse events: AEs and SAEs 
all over the study period, ending day 42 +/- 3 days, will be recorded and evaluated by the 
DSMB, Steering Committee, and secondary infections committee.  
 
4.3.2 Secondary Biological Activity Study Endpoints 
1) PK Sessions: Briefly each patient will be sampled on day 1 and day 22 at 0 (pre-
dose), 1, 3, 5, 7, 9 and 24 hrs post CYT107 administration. Main PK parameters will 
be assessed including Model-independent PK analysis will be used to estimate Tmax, 
Cmax, half-life, clearance and area-under-the-curve (AUC).  
2) Pharmacodynamics effects on immune markers: The investigative sites will also 
examine the effect of CYT107 to restore function of immune effector cells in patients 
with sepsis.   
i. 
Effect of CYT107 to increase the percentage of patients reaching an 
ALC>1200 in each dosing group. (An ALC of 1200 represents the lower limit 
of normal for most hospital laboratories.)  
ii. 
Effect of CYT107 on absolute numbers of CD4+T and CD8+T over the study 
period,  
iii. 
Effects on circulating monocyte HLA-DR expression  
iv. 
Effects on whole blood LPS-stimulated TNF-α 
v. 
Assessment of CYT107 immunogenicity by detection and quantification of 
binding antibodies and detection of neutralizing antibodies in positive 
samples. 
3) 
Incidence and type of opportunistic secondary infections: We will compare the 
effect of CYT107 to reduce hospital-acquired secondary infections in CYT107 septic 
patients versus a control group of septic patients who receive placebo.  The rate of 
hospital-acquire secondary infections at day 42 is ~ 40%.(20) We postulate that CYT107 
will reduce the rate of secondary infections by ~ 30-40%.  We will also examine other 
clinical measures in the CYT107-treated septic patients and compare outcomes 
including: SOFA scores, ICU free days, hospital free days, ventilator free days, decrease 


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in readmissions to ICU for recurrent infections.  We will also record at approx. 60, 90, 
180 and 365 day (1 year) general health status and survival.   
 
All end points will be evaluated in a global analysis, pooling the results of the US and French 
sites using REDCap as the common patient database. Results will be visible to all investigative 
centers. 
 
4.4 
Duration of the study 
Patients will be treated with CYT107 or placebo for 4 weeks duration and undergo laboratory 
monitoring of various organ functions as detailed previously for the 28 days following the initial 
treatment. The ALC will be followed for an additional 14 days due to continuing effects of 
CYT107. Primary end points will be measured at approximately Day 42 +/- 3 days. Patient 
outcomes regarding secondary infections, readmission to hospitals, mortality, etc. will be 
followed at approximately 60, 90, 180 and 365 days after CYT107 therapy is initiated. Long 
term survival (1 year survival) will be recorded using a variety of means including physician 
records, patient telephone communication, and searches of mortality databases. 
5. Study Population 
5.1  Inclusion Criteria:  
1) Patients of age ≥ 18 yrs to 80 yrs 
2) Patients with persistent suspected sepsis at 48-120 hrs after admission  
3) Two or more criteria for the systemic inflammatory response syndrome (SIRS) (see 
reference (19) for SIRS criteria) and a clinically or microbiologically suspected infection.  
 
4) At least one organ failure as defined by a SOFA score of ≥2 at any time point during the 
48-120 hrs after admission to the ICU 
  
5) Requirement of vasopressor treatment as follows: i) epinephrine or norepinephrine at ≥ 
0.05 µg/kg/min ideal body weight; ii) vasopressin, or iii) dopamine at ≥ 4-5 μg/kg/min 
ideal body weight, continuously for 4  hrs or more, provided that at least 20 ml/kg of ideal 
body weight of crystalloid or an equivalent volume of colloid was administered during the 
24-hour interval surrounding the start of vasopressor treatment,  to maintain  systolic 
pressure ≥ 90 mmHg or a mean arterial pressure ≥ 60 mmHg at any time point during their 
sepsis course preceding enrollment into the CYT107 study.   
  
6) Lymphopenia with an absolute lymphocyte count ≤ 900 cells/mm3 at either the day of 
consent or the day prior to consent during their ICU stay 
 
7) Predicted length of stay in the ICU of up to two weeks  after starting drug therapy 
treatment in the trial 
8) Ability to obtain a signed informed consent from patient or LAR consent. 
 


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5.2 Exclusion Criteria 
1) Cancer with current chemotherapy or radiotherapy (Receipt of chemotherapy or 
radiotherapy within the last 6 weeks). All patients with current, or a history of, hematologic 
malignancy (including, but not limited to, ALL, AML, CLL, CML, etc.) or lymphoma will 
be excluded, regardless of receipt of recent chemotherapy. 
 
2) Cardiopulmonary resuscitation within the previous 4 weeks without objective evidence of 
full neurologic recovery) or patients who have minimal chance of survival and are not 
expected to live > 3-5 days as defined by an APACHE II score of ≥ 35 at time of 
consideration for study eligibility. 
 
3) Patients with a history of or who currently have evidence of autoimmune disease including 
for example: myasthenia gravis, Guillain Barre syndrome, systemic lupus erythematosis, 
multiple sclerosis, scleroderma, ulcerative colitis, Crohn’s disease, autoimmune hepatitis, 
Wegener’s etc. 
 
4) Patients who have received solid organ transplant or bone marrow transplant  
 
5) Patients with active or a history of acute or chronic lymphocytic leukemia 
 
6) AIDS-defining illness (category C) diagnosed within the last 12 months prior to study entry  
 
7) History of splenectomy 
 
8) Any hematologic disease associated with hypersplenism, such as thalassemia, hereditary 
spherocytosis, Gaucher’s Disease, and autoimmune hemolytic anemia  
 
9)  Pregnant or lactating women 
 
10)  Participation in another investigational interventional study within the last 6 months prior to 
study entry, with the exception of studies aimed at testing sedation products belonging to 
standard of care such as Propofol, Dexmedetomidine, Midazolam 
 
11)  Patients receiving immunosuppressive drugs, e.g., TNF-alpha inhibitors, for rheumatoid 
arthritis, inflammatory bowel disease or any other reason, or systemic corticosteroids other  
than hydrocortisone at a dose of ≤ 300 mg/day 
 
12)  Patients receiving concurrent immunotherapy or biologic agents; including growth factors, 
cytokines and interleukins other than the study medication, for example IL-2, growth factors, 
interferons, HIV vaccines, immunosuppressive drugs, hydroxyurea, immunoglobulins, 
adoptive cell therapy. 
 


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13) Prisoners 
 
5.3 
Study ID Numbers  
Study ID numbers are assigned using an alpha-numeric sequence. The 2 first letters will signify 
the study center followed by sequential assignment of ID number in numerical order (WU-01, 
WU-02, etc. - Center ID numbers are defined in the center list- see Appendix).  Each subject 
consented and enrolled will be assigned the next available number for the individual sites. 
 
6. 
Study Visits and Procedures 
All protocol related procedures are described in Appendix II: Flow charts of the study. 
6.1 
Screening period 
The following procedures will be performed at the screening visit or during the screening 
period: 
• Dated and signed patient informed consent (by the patient or family member)  
• Each site will assign the subject the next available study ID number  
• Inclusion/exclusion criteria checklist review  
• Demographics, relevant medical/surgical history, Sepsis history, APACHE II score, 
SOFA score, GLASGOW coma scale 
• Physical examination and lymphoid system examination 
• 12-lead electrocardiogram (EKG) and interpretation (pretreatment EKG) 
• Spleen ultrasound (Pre-treatment) 
• Pregnancy test if female of childbearing potential without known contraceptive method 
• Cardiac check: presence of vasopressors, EKG, MAP, HR, pHa 
• Respiratory check: PaO2, FiO2 (A-a Grad if FiO2 ≥ 0.5) 
• Kidney functions: Creatinine, Urine analysis, 24hrs diuresis 
• Liver function: ALT, AST, Bilirubin 
• Sampling for: 
o Hematology (ALC, WBC, ANC, Mono, Platelets) and blood chemistry (including 
CRP, PT, PTT) as described in the flow chart,  
o PBMC for phenotyping and functionality test (CD3, CD4, CD8 T cells, HLA-DR 
expression, whole blood TNF-alpha production) as described in flow chart, 
 
Data from laboratory tests and procedures performed as standard of care (SOC) during the 
screening period will be utilized for applying screening criteria. All remaining tests and 
procedures listed in Appendix 2 will be conducted for research purposes only and ordered by the 
PI. 
 
6.2 
Randomization 
The randomization list will comprise three arms “CYT107 High frequency Arm” and “CYT107 
Low frequency Arm”, and placebo Arm. A permuted-block randomization will be used in 
blocks of size of 3 and an allocation ratio of 1:1:1, stratified by study country (US and France).  
Subjects will be allocated randomly within each block. This procedure will be repeated until at 


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least  10 evaluable subjects are randomly assigned to each treatment group, totaling at least 30 
evaluable subjects (between US and France). 
Screening data, including lab results from screening and any relevant medical information, will 
be reviewed by the Research Nurse Coordinator and PI at each academic medical center for 
confirmation of all inclusion/exclusion criteria and randomization authorization. 
After randomization authorization is granted by the PI at the responsible institution, the 
randomization assignment will be generated by computer.  Each subject will be assigned the 
next available number. Subjects, investigators, and all study team members will be blinded to 
drug treatment.  In the case of dropouts (either subject- or investigator-initiated), subjects will be 
replaced, to provide the required number of subjects.  Randomization of replacements will be as 
follows:  
 
1.  Subjects withdrawn prior to randomization (prior to receiving CYT107 or placebo) will 
simply be replaced and the next subject will receive the same randomization assignment. 
2.   CYT107 treated subjects who are withdrawn after randomization while receiving the 
study drug treatments but prior to Day 14 will be replaced using with the next subject 
receiving the next randomization assignment. This will continue until a minimum of 10 
patients have been randomized to each of the 3 cohorts and remained on study treatment 
through Day 13. 
3.  Subjects withdrawn or completing at least two weeks of study drug treatment will be 
considered evaluable and the following subject will receive the next scheduled randomization 
sequence. 
 
6.3 Post Randomization Period 
See Appendix 2 flowchart for designation of all study related procedures (standard of care 
and/or research purposes only) 
6.3.1 Procedures for Day 0 baseline 
6.3.1.1 Pre CYT107 administration 
• History and Physical examination and lymphoid system examination 
• Blood Sampling for : ALC count,  Baseline PK and Immunogenicity assays 
6.3.1.2 Post CYT107 administration Day 1 Week 1 
• At 1, 3, 5, 7 and 9 hrs post treatment : Blood sampling for CYT107 PK assays  
(approximately 7 mL blood/timepoint from IV line) 
• At 3 hrs post treatment : 
o Vital signs (Temperature, RR, Pulse and BP)  
o Review and record adverse events experienced  
o 12-lead electrocardiogram (ECG) and interpretation  
• At 24 hrs post treatment (Day 2) : Blood sample for PK assay (total blood for PK over 24 
hrs approx. 49mL)  
 
 


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6.3.2 Procedure for Days 4, 8, 15, 22, 29, 42 
• APACHE II score, SOFA score, GLASGOW coma scale 
• Physical examination and lymphoid system examination. 
• Cardiac check: presence of vasopressors, EKG, MAP, HR,  
• Respiratory check: PaO2, FiO2 (A-a Grad if FiO2 ≥ 0.5 and patient on mechanical 
ventilation) 
• Kidney functions: Creatinine, Urine analysis 
• Liver function: ALT, AST, Bilirubin 
• Sampling for: 
 Hematology (ALC, WBC, ANC, Mono, Platelets) and blood chemistry (including 
CRP,  PT, PTT) as described in the flow chart,  
 PBMC for phenotyping and functionality test (CD3, CD4, CD8 T cells, HLA-DR 
expression, whole blood TNF-α as described in flow chart, 
 
6.3.2.1  Additional procedure for day 11 
• Blood sample for Immunogenicity assay 
6.3.2.2 Additional procedure for day 22 
• Before administration : Baseline blood sample for PK assay and Immunogenicity assay 
• At 1, 3, 5, 7 and 9 hrs post treatment : Blood sampling for CYT107 PK assays  
• At 3 hrs post treatment : 
o Vital signs (Temperature, RR, Pulse and BP)  
o 12-lead electrocardiogram (EKG) and interpretation  
• At 24 hrs post treatment (Day 23) : Blood sample for PK assay (total blood for PK over 
24 hrs approx. 49 mL) 
 
6.3.2.3 Additional Procedure for Day 42 
(See Appendix 2 Flow Chart for complete lists of clinical and laboratory studies.) 
• ALC 
• Hematology labs 
 
6.4 Procedure for Days 60, 90, 180 and One Year Follow-up Period  
Patients will be followed for 60, 90, 180 and 365 day outcomes regarding disposition, i.e., 
incidence of new secondary infections, long term status, i.e., still hospitalized, discharged to 
long term care facility or nursing home, discharged to home, and mortality.  
Systematic blood sample for Immunogenicity testing at D60, repeated at day 180 and 360 if not 
negative for anti-CYT107 antibodies. 
 
7.0  
Safety and Biological Assessments    
7.1 
Clinical Safety 
The following assessments will be performed on specified days (see flowchart) prior, during, 
and following therapy: 
• Complete medical history obtained from the electronic medical record which should include 
 Past relevant medical and surgical history whether or not related to Sepsis 
 A complete Sepsis diagnosis and treatment history including actual or estimated 
start and stop dates of anti-sepsis treatments, and a complete history of any 


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prescription medications taken for the treatment of secondary opportunistic 
infections including start and stop dates and dose regimens 
 All home prescription and non-prescription medications and dietary supplements 
will be recorded. All new medications within the last 3 weeks will also be 
recorded.    ,  
• Full physical examination including vital signs (temperature, pulse, resting blood pressure 
and respiratory rate), weight, and particular attention to the CYT107 injection sites. 
• Reporting of AEs to the DSMB through-out study participation according to the “Division 
of AIDS table for grading the severity of adult and pediatric Adverse Events, Version 2.0, 
November, 2014”. Note that we are using the NIAID AIDS table for grading adverse effects 
because CYT107 (like IL-2) has been used in several clinical trials of AIDS patients and its 
potential adverse effects are well described and included in this table.   
• ECG and Ultrasound 
The following will be performed during the study according to the schedule described in 
Appendix II. 
• ECG 12-lead with detailed analysis at screening, three hours after the first dose of 
CYT107 at Day 1 and three hours after CYT107 administration at approximately Day 
22. 
• Spleen ultrasound (3 dimensions): will be performed at screening, and at approximately 
D42. Laboratory Investigations per protocol (appendix 2). 
 
7.1.1 Hematology and biochemistry (See Appendix 2 flow chart) 
Hematology includes:  
hemoglobin, hematocrit, red blood cells, mean corpuscular volume, white blood cells with 
differential (including ALC, platelets, Monocytes, Absolute Neutrophil Counts) Coagulation 
and inflammation markers: Prothrombin Time (PT), Partial Thromboplastin Time (PTT). 
 
Chemistry includes: 
Electrolytes (sodium, potassium, chloride, bicarbonate, calcium, magnesium and phosphorus), 
creatinine, glucose, albumin, liver function tests (total bilirubin, AST, ALT, Alkaline 
Phosphatase), and CRP (C-reactive protein). 
 
7.2  
CYT107 Pharmacokinetics  
Pharmacokinetic profile will be determined in all patients. 
Samples will be collected at D1 and D22 at pre-dose (0) and at approx: 
1, 3, 5, 7, 9 and 24 hrs post dose 
Samples will be analyzed for CYT107 content and data analyzed to determine the main PK 
parameters: Cmax, Tmax, AUC, half-life. 
7.3  
CYT107 Immunogenicity 
Specific CYT107 binding and neutralizing antibody studies will be performed.  
Samples will be collected at D1, D11, D22, and at approximately D60.  


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If the D60 binding antibodies test is positive, samples will be tested for the presence of 
neutralizing antibodies. Another sample will be tested for binding antibodies at approximately 
day 180. The same will be done at approximately D360 if D180 is positive. 
 
7.4  
CYT107 Pharmacodynamics/Immunology 
The immune monitoring will include: 
Differential count of T cells CD3, CD4, CD8 
Monocyte HLA-DR expression 
Whole blood TNF-α production 
 
8.0  
Investigational Medicinal Product (see details in Investigator’s Brochure) 
8.1 
CYT107 
8.1.1  Description  
CYT107 (CYT107) is a recombinant protein belonging to the class of growth factors and more 
specifically to the class of cytokines. CYT107 is a heavily glycosylated and sialylated form of 
recombinant human interleukin-7 expressed from a CHO cell line, composed of 152 amino 
acids, with an average molecular mass as determined by mass spectrometry of 22 kDa and a 
mean pI of 7. The molecular formula of the peptidic sequence only (non glycosylated) is 
C762H1241N213O228S11. The protein contains 3 disulfide bridges (Cys2- Cys 92, Cys 34- Cys 129, 
and Cys 47- Cys 141) and 4 glycosylation sites (3N, 1O).  
8.1.2  Source 
CYT107 used in this clinical trial was manufactured under good manufacturing practice (GMP) 
criteria at a 600 L fermentation and purification scale by PATHEON (Princeton, NJ), for 
REVIMMUNE Inc. At clinical site, the product will be made available to the hospital pharmacy 
by CSM , Fargo, ND58103.  
 
8.1.3  Formulation  
CYT107 is supplied in a 2 mL vial as 0.5 mL of CYT107 (1 mg) in 10 mM Sodium Acetate, 
100 mM NaCl, 50 mM glutamic acid. The pH of the solution is 5 and the osmolality is 320 ± 40 
mOsm. The concentration of CYT107 in solution is 2 mg/ml.  
8.1.4 Stability  
Stability studies will continue throughout the clinical study. Updated stability information will 
be periodically communicated to the hospital pharmacy. 
8.1.5  Special Handling 
There are no specific guidelines for safe handling of CYT107. Institutional guidelines for safe 
handling of proteins in general should be followed. 
8.1.6 CYT107 Preparation 
Syringes containing the CYT107 dose (placebo dose same volume of NaCl 0.9%) will be 
prepared by the hospital pharmacy and delivered to the clinic in a blinded fashion.  The product 


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should be defrosted at least 1 hour before administration. Defrosted product (and possibly put in 
syringe) should be kept refrigerated at +4°C/+8°C until use and for no more than 12 hours. 
 
CYT107 ampoule will only be used if the solution is clear (following visual inspection), the vial 
is undamaged and the use by (expiration) date (if marked on the vial) has not been passed. 
Based on patient’s ideal body weight on day of study entry, the appropriate number of vials of 
CYT107 drug product will be prepared and administered. CYT107 will be kept refrigerated until 
time of immediate administration to the patient. To minimize the chance for contamination, 
sterile or septic technique should be carefully observed during CYT107 solution preparation 
(filling of the syringe) and administration.   
A vial is restricted for use by a single patient. Take no more than 0.5 mL into the syringe. The 
dose to be injected will be divided as necessary into multiple intramuscular injections so that 
each injection will not exceed 0.5 ml in volume.  (Dosing guidelines for ideal body weight make 
the requirement for multiple injections highly unlikely). 
 
8.1.7 Drugs interactions  
Not known; are being presently investigated.  
 
8.2 
CYT107 Presentation and Packaging 
CYT107 is supplied as a sterile colorless liquid in 2 cc glass vials that are packed individually in 
cardboard box. Labels are stuck on vial and box. 
The labeling is following local and GMP rules. The detailed description of labeling is provided 
in the Pharmacy Manual. 
 
8.3 
CYT107 Storage Accountability and Return of Unused Product  
Study product will be stored frozen at -20°C until used.  
The investigator, his/her designee, or hospital pharmacist must maintain complete records of all 
study products received, stored and subsequently dispensed.  
Study product is Revimmune property; at the conclusion of the study, all unused study drug 
must be returned to Revimmune or designee. All unused product should be kept in suitable 
storage conditions until shipped. Unused product should not be used on non-study patients. 
The detailed procedures to be followed by Clinic and Pharmacy are provided in the Pharmacy 
Manual. 
 
8.4 
Study Drug Administration 
Each dose of CYT107 or Placebo will be administered in the hospital by a trained research nurse 
or PI. CYT107 or Placebo will be administered by intramuscular route at the dose of 10 µg/kg 
based on the patient’s ideal body weight unless the patient meets criteria for subcutaneous 
injection (see Sect 4.2 Study Treatment).   


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The volume to be administered will be identical in all groups: 0.005mL/kg:  ex: 0.375mL for 
patients of 75kg. The control group will receive the same volume of saline, dosing to IBW. 
The detailed procedures to be followed by Pharmacy and hospital are provided in the Pharmacy 
Manual including a table of volumes to be administered per patient total body weight. 
 
8.5 
Duration of treatment 
• Patient randomized in the “CYT107 High Frequency Arm” will receive CYT107 
treatment at 10µg/kg at days 1, 4, 8, 11, 15, 18, 22, 25 
• Patient randomized in the “CYT107 Low Frequency Arm” will receive CYT107 
treatment at 10µg/kg at days 1, 4, 8, 15, 22 and placebo (NS: NaCl 0.9%)) at days 11, 18 
and 25. 
• Patient randomized in the “CONTROL Arm” will receive Placebo (NS: NaCl 0.9%) at 
days 1, 4, 8, 11, 15, 19, 22 and 25. 
 
8.5.1 Dose Adjustment According to Patient’s Weight 
8.5.1.1 Obese Persons 
For a patient with a Body Mass Index (BMI) over 30, a corrected weight will be used to 
calculate the final dose the patient will receive.  
The corrected weight will be calculated as follows: 
Corrected weight (kg) = 30 x height2 (in m)  
 
8.6 
CYT107 Administration Permanently Discontinued 
8.6.1 Reasons for CYT107 administration permanently discontinued 
The investigator may interrupt study treatment at any time if a definite contraindication to 
treatment appears such as: 
• Appearance of a critical event as defined in section 12.1 
• Development of an exclusionary condition 
• Requirement for prohibited concomitant medications 
• If the patient or patient’s family decides to switch to comfort measure only and forgo life 
sustaining therapy. 
• Patient request to terminate the study treatment 
• Patient Informed Consent Withdrawal  
• Patient withdrawn per other events at PI discretion 
 
8.6.2 Procedure in case of CYT107 administration permanently discontinued 
If a patient has a premature study treatment discontinuation for any reason, the subject may be 
retained in the study for data collection and testing procedures for remainder of the study period. 
If it is not possible, the last visit may include all tests and procedures scheduled for day29 visit 
plus a blood sample for detection of CYT107 immunogenicity (see appendix 2 Study flowchart). 
These data should be recorded in the research CRF.  
The primary reason for withdrawal will be clearly documented in the patient’s medical record 
and recorded in the CRF.  


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In the specific case of patient consent withdrawal, the investigator must make every effort to 
perform the safety assessments. 
Patients who are withdrawn from the study will be assigned appropriate alternative treatment as 
recommended by the PI in collaboration with the clinical team. 
 
8.7 BLINDING 
 
8.7.1 Organization of Blinding 
The study will be performed in a double-blind manner. The patient, the investigator and 
study center staff will be blinded to study drug allocation. The pharmacist will be 
unblinded to study drug and will prepare study treatment or placebo for a patient as 
specified by the randomization scheme.  
 
8.7.2 Unblinding 
Emergency unblinding of the patient should only be undertaken by the investigator when it is 
essential to treat the subject safely and efficaciously. Most often, study drug discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study subject who 
presents with an emergency condition. The investigator will make be responsible for making a 
decision to unblind in case of a suspected unexpected serious adverse reaction (SUSAR). The 
investigator will obtain the randomization assignment  and a blinded alert will be sent to 
RevImmune, the coordinating center and the study team that a patient has been unblinded. The 
patient will be followed until resolution of the adverse event. All “end of study” assessments 
must be performed. 
8.7.3 Final Unblinding 
For every patient, the main study end points will be reached at day 60. Accordingly when the 
last patient of both IRIS-7A and IRIS-7B studies (i.e. the 30th patients of the two cumulated 
studies) will reach day 60, the database will be locked and the study unblinded for analysis. 
 
8.8 
Concomitant treatments 
8.8.1  Steroids 
Patients enrolled in this clinical trial may be receiving steroids; this will be limited to 
hydrocortisone at a dose no higher than 300 mgs of hydrocortisone daily.  
 
8.8.2 Prohibited Medications 
Are as follows: 
• Concurrent immunotherapy; including growth factors, cytokines and interleukins other 
than 
the study medication, for example IL-2, Interferons, HIV vaccines, 
immunosuppressive drugs, hydroxyurea, immunoglobulins, adoptive cell therapy;  
• Any investigational agent; 
• Systemic corticosteroids other than hydrocortisone at a dose of 300 mgs/day.  
• Biological agent (other cytokines such as IL-2, growth factor, monoclonal antibody); 
• Cytotoxic chemotherapy 
 


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If it becomes obvious, during the course of the study, that administering any of these therapies 
are not in the patient’s best interest, due to the patient’s imminent demise or the patient or the 
patient’s family desire to switch to comfort measures only, (i.e., not to continue aggressive 
care), then study drug treatment will be discontinued. (See section 7.8.2 for details on 
procedures to follow in case of study drug discontinuation).  
 
9.0 
Statistical Analysis 
9.1 
 Sample Size 
Sample size justification  
The primary endpoint of this trial is to compare two different dosing regimens of CYT107 to 
increase the absolute lymphocyte count (ALC), a marker of immunosuppression in sepsis which 
correlates with mortality. Although CYT107 has not been previously been used to treat patients 
with sepsis, there are data on the effect of CYT107 to increase the absolute numbers of CD4 and 
CD8 T cells in patients with cancer and in patients with HIV (see Figs 2&6 and reference #14).  
As demonstrated in Figs 2 & 6, CYT107 at a dose of 10 micrograms/kg (the dose that will be 
used in the present study) has a very predictable effect to cause a doubling of the number of 
CD4 T cells which are a major component of the absolute lymphocyte count (ALC) in patients 
with HIV.  This effect to increase the absolute numbers of CD4 T cells was consistent in almost 
all patients who were treated with CYT107.  CYT107 has a similar effect (although not quite as 
pronounced) on CD8 T cells.  Therefore, we anticipate that greater than 80% of septic patients 
who are treated with CYT107 at a dose of 10 micrograms/kg (either high frequency dosing 
regimen or the low frequency CYT107 dosing regimen) will increase their ALC by over 50% by 
day 42, whereas less than 20% of patients who receive placebo will exhibit such a change. 
Under these assumptions, a simulation-based power calculation as implemented using the 
primary analytical plan listed in section 9.3.2. In particular, the proposed study design (10 
subjects per treatment arm) was found to have greater than 85% power to detect an equal or 
more extreme treatment effect. Thus, we believe that 10 patients per group is sufficient to show 
a statistically significant effect of CYT107 to increase the ALC by over 50%.   
Two other major goals of the study are to establish the safety of CYT107 in patients with sepsis 
and to determine that the pharmacokinetics and pharmacodynamics are not significantly altered 
in septic patients.  CYT107 has been administered to over 300 patients and has been well 
tolerated with a low incidence of side effects.  (see Investigator’s brochure.) 
 
9.2 
Statistical Analysis 
9.2.1  Analysis Datasets 
9.2.1.1  Definition of protocol deviations 
Major protocol deviations are defined as deviations liable to bias the evaluation of the main 
study endpoint. The following deviations will be considered major: 
• Noncompliance with the inclusion or exclusion criteria 
• Noncompliance with study treatment 
• Intake/administration of prohibited medication(s) 


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All other deviations will, a priori, be considered as minor deviations. However, all deviations 
will be reviewed during a data review meeting before data base lock and statistical analysis. 
This data review will also serve to constitute the analysis datasets. 
 
9.2.1.2 Analysis datasets 
The following subsets of study participants will be defined and analyzed: 
 
1) The Safety dataset (SAF) is defined as those subjects enrolled in the study, who have 
received at least one dose of study treatment.  
 
2) The Full Analysis Activity dataset (FAS) is defined as all enrolled subjects who have 
received all the study treatment (5-low frequency, or 8-high frequency) administrations 
and have an evaluation of the primary Biological Activity Study End Point.  
 
3) The Per Protocol Activity dataset (PP) is defined as all enrolled subjects who have 
been treated consistently with the protocol and have the evaluation of the primary 
Biological Activity Study End Point available. To be considered evaluable, patients in all 
study arms must complete at least 2 weeks of study drug treatment. 
 
9.2.2 Statistical Methods 
Descriptive statistics for baseline characteristics and study outcomes will be presented in 
aggregate and stratified by treatment arm, and separately for the SAF, FAS, PP datasets. 
Descriptive statistics will be implemented as follows: 
1) Continuous variables will be summarized using the sample mean, standard deviation, and 
95% confidence interval for the mean, median, range, and quartiles 
2) Categorical variables will be summarized using sample proportions and the associated 
95% confidence intervals 
Simple inferential analysis will be implemented for certain study outcomes: 
1) Categorical outcomes will be evaluated using simple, ordinal, or multinomial logistic 
regression.  
2) Continuous outcomes will be evaluated using linear regression techniques. Quantitative 
and graphical regression diagnostics will be considered. Data transformations and 
nonparametric methods will be utilized when necessary.  
 
9.2.3  Analysis of the Primary Objective  
A significant improvement in absolute lymphocyte count (ALC) is defined as an increase of 
more than 50% from baseline at any subsequent measurement, up to day 42. All patients will be 
classified as having demonstrated significant improvement in ALC by this definition. The 
frequencies of the resulting dichotomous outcome will be compared across treatment arms using 
simple logistic regression. The odds ratios associated with either treatment, relative to placebo, 
will be estimated and presented with 95% confidence intervals. The overall effect of treatment 
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ALC improvement are identical across treatment arms. These analyses will be implemented 
separately for the PP and FAS datasets defined above (9.2.1.2). 
As a secondary analysis, the full sequence of ALC measurements for all patients will be 
evaluated using mixed effect regression methods, adjusting for baseline ALC and study day, and 
accounting for correlation among sequential repeated measurements. This analysis will permit 
an examination of secular trends in ALC, the interaction of treatment frequency and duration, 
and the variability in treatment effect among study participants. These effects will be 
summarized using estimates and 95% confidence intervals. 
 
 
 
9.2.4 Analysis of Other Biological Activity Endpoints 
Descriptive statistics and simple inferential analyses (as described in 9.2.2) will be provided for 
all other biological activity endpoints.  
 
9.2.5 Analysis of Safety Endpoints 
The safety of r-hCYT107 will be evaluated on all SAF datasets.  
 
 
9.2.5.1  Adverse Events 
Adverse events reported during the study will be coded using the MedDRA terminology. 
Treatment emergent adverse events (TEAE) will be defined as any adverse event which occurs 
or worsens on study treatment during the treatment period. 
 
Numbers and percentages of patients with at least one reported treatment emergent adverse 
event will be tabulated by system organ class and preferred term for: 
• all TEAE 
o all TEAE leading to study drug discontinuation 
o all TEAE of grade 3 or 4 
o all TEAE for which relationship with the study drug is recorded as possible or 
probable 
• by grade 
o all related TEAE leading to drug discontinuation 
o all related TEAE of grade 3 or 4 
 
Recurring adverse events (i.e., adverse events classified with the same preferred term) for a 
given patient will only be counted once and only their most severe intensity or most severe 
relationship to the study treatment will be tabulated. 
 
9.2.5.2 Safety laboratory tests 
Descriptive statistics for laboratory safety tests will be computed at each time points on the raw 
values. If relevant for some parameters, changes from baseline will also be tabulated. 


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Shift tables from baseline will be presented. 
 
9.2.5.3  Vital signs 
Descriptive statistics will be computed at each time point on the raw values. 
 
 
9.2.5.4  Other safety variables  
For Physical and lymphoid examination and ECG; descriptive statistics will be provided at each 
time point. 
 
 
9.2.6  Concomitant Treatments 
Concomitant treatments will be coded with the WHO-DRUG dictionary and the ATC 
classification. They will tabulated by the anatomic, therapeutic and clinical level. 
 
9.3 
Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be written, validated and signed before the first interim 
analysis. This document will describe the detailed methodology for statistical analyses of the 
data collected in both US and French studies.  
An interim analysis will be performed when the last patient of both IRIS-7A and IRIS-7B 
studies (i.e. the 30th patients of the two cumulated studies) will reach day 60, then the database 
will be locked and the study unblinded for analysis. 
Final analysis including follow up controls will be performed when the last patient of both IRIS-
7A and IRIS-7B studies (i.e. the 30th patients of the two cumulated studies) will reach day 360, 
then the database will be definitively locked for final data analysis. 
 
10. 
Trial Organization   
10.1 
Steering Committee 
A steering committee will be set up with the following members: 
- 
Study Chairman 
- 
Investigator from each center  
- 
Medical representative from Revimmune  
- 
Other external participants, as needed 
This committee will meet under various circumstances: 
On an ongoing basis, the Steering Committee will review all Grade ≥ 3 Adverse Events, and 
Critical Event.  
Upon request of the Sponsor and of the DSMB recommendation to evaluate: 
- 
Potential amendment 
- 
Statistical analysis plan  
- 
Results of interim analyses 
- 
Study continuation 
At the end of the study to review the activity and safety data  


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The steering committee meetings can be organized as a conference call. 
 
10.2 
Data Safety Monitoring Board (DSMB) 
The DSMB will be composed of 4 experts who are not involved in the conduct of this trial as 
investigators but are experienced in the management of Sepsis disease and immunotherapy: 
 
• Opal S, MD, Brown University School of Medicine, USA 
• Pandharipande P, MD, Vanderbilt University School of Medicine, USA 
• Harrell F, PhD, Vanderbilt University School of Medicine, USA 
• Moore F, MD, University of Florida School of Medicine, USA 
If need be, the DSMB is free to ask for the advice of one or several other experienced physicians 
whose name and advice, however, must be communicated to the steering committee.  
The mission and rules of DSMB is described in the DSMB charter which will be signed by 
DSMB member before study initiation. 
 
On an ongoing basis, the DSMB will review:  
• All Critical Events.  
• All treatment emergent adverse events (TEAEs) 
• All SAE assessed by the investigator, by the DSMB, UVEC or by the 3 panel expert 
committee which adjudicates whether the abnormal finding is secondary to CYT107 or 
part of the septic process.   
• Individual data on the size of lymphoid organs.  
The DSMB will review, confirm or discuss the severity grade suggested by the investigator 
assess the causality relationship to CYT107 and the experimental protocol.  
The DSMB will advise the Sponsor regarding study continuation. On an ongoing basis and at 
the end of the study the DSMB, will review the safety data. 
The experts of the DSMB should follow and complete the Causality Assessment Guidelines. 
10.3 
Secondary Infections Evaluation Committee 
Because it is often difficult to determine if a secondary hospital acquired infection is present, a 
panel of 3 experienced ICU physicians will be used to evaluate and grade whether a secondary 
hospital acquired infection is present. These members include:  Dr. John Mazuski, Professor of 
Surgery, Washington University School of Medicine; Dr. Anne Drewry, Assistant Professor of 
Anesthesiology and Critical Care Medicine; Washington University School of Medicine.  Dr. 
Brian Fuller, Assistant Professor of Anesthesiolgy and Emergency Medicine. Washington 
University School of Medicine.  
These 3 physicians will be blinded to patient treatment with CYT107 versus placebo. They will 
not be members of the investigative team but rather colleagues of the investigators.  They will 
meet either in person or by teleconference once a month to judge secondary infections.  
 
11. 
Procedures for Special Events 


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11.1 
Patient Replacement Policy 
For subjects that fail to reach the primary endpoint and for whom the dataset is considered as not 
evaluable (i.e. patients who have failed to complete at least two weeks of study drug treatment), 
the next randomization assignment will be assigned to the next patient to be enrolled on the 
study in order to reach a minimum of 10 evaluable subjects in all cohorts and the targeted 
sample size of 30 evaluable subjects overall.. 
 
11.2 
Patients Lost to Follow-up 
Participation is completely voluntary. At any time a patient and/or the PI may decide to 
discontinue study participation.   
Every effort should be made to obtain information about patients who cannot be contacted for 
follow up. The research team should make reasonable attempts to collect at least minimum 
safety data on all randomized patients, to the extent of their abilities, in accordance with HIPAA 
regulations and IRB approval. 
 
12. 
Adverse Events / Serious Adverse Events / Critical Events 
12.1 
Definitions 
The following standard definitions for adverse events will be used: 
Adverse event: An adverse event is any undesirable or untoward medical event (clinical or non-
clinical e.g. abnormal laboratory/EKG/imaging results) which occurs in a patient or in a patient 
in a clinical trial, who is receiving a pharmacological product, and which is not necessarily 
causally related to the treatment. 
Serious adverse event: A serious adverse event or reaction is any untoward medical occurrence 
that at any dose: 
• results in death 
• is life-threatening (the term “life-threatening” in the definition of “serious” refers to an 
event in which the patient was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe.). 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital abnormality 
• is medically significant (event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition) 


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Unexpected Serious Adverse event: An unexpected adverse event is an event, the nature or 
severity of which is not consistent with CYT107 Investigator’s Brochure (updated at least 
annually). 
Critical event: The following events, occurring after the start of CYT107 and considered to be 
possibly or probably related to the study drug: 
• Any grade ≥ 3 Adverse Event (clinical or biological) 
• Rash ≥ grade 2 
• Any diagnosis of lymphoma confirmed by a pathologist 
• Any adenopathy compromising or threatening organ function (e.g. mediastinal 
adenopathy inducing a respiratory distress; inguinal adenopathy inducing an edema of 
the lower limb; or any adenopathy threatening skin breakdown). 
• Splenomegaly that is accompanied by:  
1) Clinical hypersplenism  
2) Suspicion of a diagnosis of splenic infarct (left upper quadrant pain and imaging 
study compatible with the diagnosis)  
3) Splenic rupture 
 
 
12.2 
Reporting of Adverse Events 
12.2.1 Clinical and Biological Adverse Events 
Any Adverse Events occurring for the time period between the signature of informed consent 
and the End of Study Visit, spontaneously reported by the patient or observed by others, will be 
recorded in the CRF and reported to the DSMB, RevImmune and IRB.  
12.2.1.1 
Nature and severity 
The records will describe the nature, and the severity, using term and severity categories of the 
DAIDs “division of aids table for grading the severity of adult and pediatric adverse Events, 
Version 2.0. 
According to previous clinical studies, Injection site reaction is frequently less than 5X5 cm. In 
consequence, with the objective of precisely determine the occurrence of any Injection Site 
Reaction the DAIDS (Division of Acquired Immunodeficiency Syndrome) has been adapted for 
this adverse event as follows:  


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Table 2  Division of AIDS Table (DAIDS 2.0) Toxicity Scale 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Injection Site Pain or 
Tenderness 
Report only one 
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb 
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization indicated 
Injection Site Erythema 
or Redness13 
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 to 
< 100 cm2 surface 
area OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
 
 
≥ 10 cm in diameter  
OR ≥ 100 cm2 surface 
area OR Ulceration 
OR Secondary 
infection OR Phlebitis 
OR Sterile abscess 
OR Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life- 
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
≤ 15 years of age 
≤ 2.5 cm in diameter 
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area of 
the extremity segment 
involved (e.g., upper 
arm or thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage 
Potentially life- 
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site Pruritus 
Itching localized to 
the injection site that 
is relieved 
spontaneously or in 
< 48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 hours 
treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional activities 
NA 
13 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface 
area. 


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12.2.1.2 
Causality 
Causality defined as the relationship between a study drug and an adverse event assessed 
according to chronological criteria, pharmacological properties of the drug and a search for 
other explanations or contributing factors. The causality is to be evaluated initially by the 
investigator, using the following likelihood scale: 
 
None 
Timing incompatible; appearance before study drug introduction, delay 
before appearance of adverse event too long, or symptoms appeared before 
event; or due to causes other than study drug administration (e.g. disease, 
environment etc.). 
Unlikely 
A clinical event with a temporal relationship to drug administration which 
makes a causal relationship improbable, and in which other drugs, chemicals 
or underlying disease provide plausible explanations. 
Possible 
A clinical event with a reasonable temporal relationship to drug 
administration, and which could also be explained by concurrent disease or 
other drugs or chemicals. Information on drug withdrawal may be lacking or 
unclear. 
Probable/Likely 
A clinical event occurring in a reasonable temporal relationship to drug 
administration, unlikely to be due to concurrent disease or other drugs or 
chemicals. The response to withdrawal (dechallenge) should be clinically 
reasonable. 
 
It will be specified whether the event is Serious or not and if the event is Critical or not 
according to the relevant definition and information regarding Date of Onset, Date of 
Resolution, Actions Taken and Outcome.  
 
Ongoing adverse events should be reviewed at each subsequent assessment. If resolved, the 
details should be recorded in the CRF. If any AE changes for the worse, in frequency of 
attacks/symptoms or in severity, a new record of the event must be started (i.e. distinct reports 
are required for differing frequencies and/or severity of the same event to enable comprehensive 
safety reports and later analysis). 
 
All adverse events, serious or causally related to the treatment or to the research protocol and 
still evolving at the end of the study are to be followed up until their resolution by the 
investigator.  
 
12.2.2 Case of Routine Laboratory Measurements 
A list of the laboratory normal ranges should be supplied at the start of the study by the implied 
laboratories or by the investigator to Revimmune. 
The results of these will be in the CRF, and if they are abnormal a comment or explanation 
should be given, where possible using the following categories: 
• abnormality not clinically significant (NCS) 


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• abnormality clinically significant, but normal for the study population (CS/N) 
• abnormality clinically significant and is an adverse event (CS/AE) 
 
It should be noted that all clinically significant abnormalities, not normal for the study 
population, count as Adverse Events even if they are not related to the use of study medication. 
An Adverse Event Form needs to be completed for all abnormalities falling into this category 
with all its items and the event must be followed in accordance to the same rules 
 
12.3 
Reporting Serious Adverse Events 
All Serious Adverse Events will be reported to the institutional IRB and sent by e-CRF system, 
e-mail, or fax to the DSMB and Sponsor within 24 hours of being notified of the event using the 
SAE Report Form (Initial) in the Study Manual, whatever the relationship to the study drug.  All 
information about the adverse event obtained later by the investigator (outcome, more precise 
medical details, results of investigations, copy of discharge summary etc.) is to be sent as soon 
as possible to the monitor completing an SAE Report Form (follow-up). When this information 
is passed on, care must be taken to continue to respect patient anonymity.  
 
The medical monitor from the coordinating site may contact, or visit the investigator, in order to 
obtain details of the event. 
Following collection of information the case should be reviewed separately by the investigator, 
by Sponsor, by the DSMB. All Serious Adverse Events must be followed by the investigator 
until resolution or stabilization, and a final assessment sent to Sponsor as a SAE Report Form 
(follow-up).  
 
In addition, if the investigator becomes aware of the occurrence of an unexpected Serious 
Adverse Event/ reaction which appears after the end of the study, he or she should inform 
Sponsor and the institutional IRB following the same procedures described above.   
 
SAEs should be reported to IRB/DSMB and FDA according to institutional and federal 
regulations. 
 
12.4 
Assessment of SAE Expectedness and reference document 
The sponsor is responsible of assessing the expectedness of an AE according to the CYT107 
Investigator’s Brochure (latest version v7) used as the reference document.  
 
12.5 
Reporting of Critical Events  
All Critical events have to be sent by e-CRF system, e-mail or fax to Sponsor within 24 hours of 
being notified of the event using the appropriate form (Critical Event report Form).  
The medical Monitor may contact, or visit the investigator, in order to obtain details of the 
event. Following collection of information the case should be reviewed separately by the 
investigator, by Sponsor and by DSMB. 
13.0 
Collection and validation of data, and trial monitoring 


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13.1 
Data Collection 
Electronic Data Capture (EDC) will be used to collect individual data. An electronic Case 
Report Form (eCRF) is designed to contain information necessary for the evaluation of the 
patient and investigational agent. The eCRF must be completed in a timely manner following 
the visit and no more than a week after. The eCRF must be accurate and complete. All 
information required by the protocol is to be recorded in the eCRF based on source data. All 
REDCap data will be made available to the Sponsor  in read-only format to review safety data 
and verify the validity and completeness of the forms.   
 
13.2 
 Source Data 
The investigator and the study nurse coordinator will identify any data that will be recorded 
directly on the CRF and considered as source data (i.e., no prior written or electronic record of 
the data). The study coordinator will document this on the study initiation report and revisit and 
document the use of the CRF as source documents as necessary during the course of the study. 
 
13.3 
 Trial Monitoring 
For the duration of the trial, the respective PI’s at the 4 academic medical centers: 
• Edward Sherwood MD, PhD; Professor of Anesthesiology, Vanderbilt University School 
of Medicine  
• Richard Hotchkiss MD; Professor of Anesthesiology, Medicine, and Surgery, 
Washington University School of Medicine 
• Lyle Moldawer PhD, Professor of Surgery, University of Florida, Gainesville, School of 
Medicine 
• Elliott Crouser MD, Professor of Medicine, Ohio State School of Medicine  
 
These investigators will ensure that all clinical monitoring, data management and data quality 
assurance follow local regulation and International Conference on Harmonization (ICH) Good 
Clinical Practices (GCP).  
At the end of the study, the monitoring team will check that the investigators have all documents 
necessary for archiving. 
 
13.4 
 Data Management/Statistics 
Vanderbilt will be functioning as the CRO for the study and it will be responsible for all data 
management and statistical analysis. The data will be managed through the common database, 
i.e., Red Cap that is available to all academic centers in the United States.   
 
The clinical data are sent from the clinical sites to the database via a web-based e-CRF and are 
stored on a server located at the CRO under ORACLE format. Once the clinical data is cleaned 
and the database is locked, the data will be transferred to SAS for statistical analysis at the CRO 
in charge of the analysis.  
  
13.5 
 Quality Assurance 


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In accordance with local regulations and ICH Good Clinical Practice guidelines, the 
coordinating center may decide that the clinical trial should be audited in order to examine 
whether the quality control procedures are sufficiently and correctly adhered to. The audit can 
take place either at the clinical site or at any other trial drug evaluation site (e.g. laboratory). The 
investigator will be informed beforehand if an auditor (internal or external) is going to visit. 
 
The local regulations and the ICH Good Clinical Practice guidelines also allow for an inspection 
by the health authorities. This inspection is similar to an audit but can take place either at the 
sponsor’s or at the investigator’s premises. 
 
14.0 
Ethical considerations 
14.1 
Informed Consent 
Prior to entering the study, the investigator or designated co-investigator or study nurse, will 
explain to each patient or, in the case that the patient is not able to sign for himself/herself, their 
family member or legal authorized representative (LAR) the nature of the study, its purpose, 
procedures, expected duration, alternative therapy available, and the benefits and risks involved 
in study participation.   
 
Patients/LAR will be provided a consent document and the opportunity to ask questions; 
information will be provided regarding voluntary participation and the ability to withdraw at any 
time from the study without prejudice. After this explanation and before any study-specific 
procedures have been performed, the patient or LAR will voluntarily sign and date an informed 
consent document.   
The patient/LAR will be provided with a copy of the signed informed consent document. The 
original document will be maintained in the patient’s research file, in accordance with all 
HIPAA and IRB regulations. 
  
14.2 
Potential Benefits of CYT107 to Patients with Sepsis  
Sepsis is a disease with a high mortality for which there is no specific treatment other than 
traditional therapy of antibiotics and source control.  The expected mortality in the septic patient 
population in the current study is approximately 40-45% at 60-90 days.  Many of these deaths 
are due to failure to control the primary infection or development of new secondary infections.  
CYT107 reverses many of the sepsis-induced defects in host immunity and this improvement in 
host immunity will likely translate into decreased secondary infections, reduced ICU stay, and 
ultimately, improved survival.  Although the present study is not powered to detect an 
improvement in survival, it is powered to demonstrate an effect of CYT107 to decrease new 
secondary infections which are a major cause of morbidity and mortality in sepsis.   
 
Based upon data from both animal studies and clinical trials, we are extremely hopeful that 
CYT107 will improve morbidity and mortality in sepsis (12, 13, 14, 16, 18, 34).  Studies from 
multiple independent laboratories using clinically relevant animal models of sepsis have shown 
that CYT107 improves survival (16, 18, 34).  Finally, clinical trials of CYT107 in patients with 
cancer, bone marrow reconstitution, HIV, and JC virus induced progressive multi-focal 


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leukoencephalopathy have shown that CYT107 is well tolerated and efficacious.  Clinical trials 
of CYT107 in oncology and in bone marrow reconstitution are being planned.  Therefore, we 
believe that the risk benefit ratio is greatly in favor of use of CYT107 in patients with sepsis.  As 
our group has argued passionately, we believe that CYT107 represents one of the most exciting 
immunotherapeutic agents in infectious disease in the last decade (6, 27, 39).  If this proposed 
study is successful, it could radically change the way that physicians treat many infectious 
disorders including sepsis.    
 
15.0 
Regulatory considerations 
15.1 
Conditions for Conducting the Trial 
15.1.1  Study Initiation Requirements 
The protocol will have to be approved and signed by the representatives of the sponsor and by 
the investigators, as well as having been approved by each appropriate Ethics Committee or 
Institutional Review Board (IRB) in writing, before it can be initiated.  
Prior to shipment of study drug, the investigator must provide Sponsor with at least the 
following documents: 
• Signed final version of the protocol 
• Curriculum vitae or other statement of qualification of the Principal Investigator (PI), 
any sub-investigator, and study coordinator. 
• Ethics Committee/IRB approval letter, list of Ethics Committee (EC)IRB members if the 
PI is the contact of the EC 
• Signed and dated Clinical Trial Agreement between Sponsor and the institution and the 
investigator 
• Completed local forms as required (Pre-study Financial Disclosure, etc…) 
15.1.2  Study Personnel 
The investigator should maintain a list of appropriately qualified persons who are delegated to 
perform significant study-related duties. In addition, the investigator should maintain a study 
delegation sheet to document signatures and initials of all persons authorized to perform any 
research related duties.  
All medically-related decisions should be performed by a person medically qualified.  
Information to the patient and/or LAR prior to consent should be given by a qualified physician 
or nurse member of the research team.  
The PI is responsible for informing the patient’s attending physician(s) when a patient has 
provided informed consent for study participation.  
 
15.2 
Protocol Amendments 
Neither the investigators nor Revimmune can modify the study protocol without mutual 
agreement.  Any change must be made following GCP and must be approved by the appropriate 


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Research Ethics Committee and Regulatory Authorities before implementation, with 2 
exceptions: 
• when necessary to eliminate apparent immediate hazard to the patient 
• when the change involves logistical or administrative aspects of the study 
 
15.3 
Study Funding  
The costs necessary to perform the study will be agreed with the investigator and/or the 
management of the study facility, and will be documented in a separate financial agreement that 
will be signed by the investigator and/or the management of the study facility Sponsor and any 
other Financial Co-Sponsor of the trial. 
 
16. 
Reporting and publication 
16.1 
Confidentiality Agreement 
Investigators agree to hold confidential all information regarding the product being tested, 
including the study methodology, and information developed during the course of this study, 
unless the information has previously been published.  Investigators will ensure that all 
employees respect the same rules. 
 
17. 
Archiving 
The investigator is to keep the identification lists of patients for at least 15 years after the 
completion or premature termination of the study.  The medical records of the patients in 
the trial together with other data are to be kept for as long as the hospital, or institution 
allows, but for a minimum of 15 years or according the local regulatory requirement. 
 
The sponsor or subsequent owner is required to keep all other documentation for the life 
of the product studied.  The archived data can be kept in electronic form, provided that a 
back-up copy is kept and that a paper copy can be provided if necessary. 
 
The protocol, ethical and government approvals, together with all other documents 
concerning the study, including any audit and inspection certificates are all to be kept as 
part of the trial master reference file.  All data about adverse events also needs to be kept 
in this trial master file. 
 
All data should be available for inspection by the appropriate authorities on demand. 


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Appendices: 
 
Appendix 1:  Good Clinical Practice 
 
ICH Topic E6 
 
Guideline for Good Clinical Practice 
 
The document is available on the following web site: 
http://www.emea.eu.int/pdfs/human/ich/013595en.pdf 
 
A copy of ‘ICH Topic E6 Guideline for Good Clinical Practice’, step 5 consolidated guideline 
will be provided in the study manual.


 
 
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Appendix 2: Flow Chart 
 
 


 
 
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Appendix Table 3: Correlates of Immune Response to CYT107  
New  
secondary 
infections 
Yes/No 
# Days after 
sepsis onset 
Infection site 
Microbiology 
 
Recurrence of 
primary 
infection 
Yes/No 
Site 
of 
infection 
 
 
 
Readmission 
to ICU 
Yes/No 
Reason 
for 
readmission 
# Days following 
ICU discharge 
 
 
Days in ICU  
 
 
 
 
 
 
Days 
on 
Ventilator 
 
 
 
 
 
 
ICU 
disposition 
Survive/Die 
Discharge 
Home 
Discharge 
LTAC 
Discharge 
Nursing home 
Discharge 
Rehab facility 
Mortality  
(28 days):     (60 days): 
(90 days): 
(365 days): 
 
 
 
 


 
 
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15.  
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cell populations in sepsis and trauma. J Leukoc Biol. mars 2008;83(3):523‑535.  
23.  
Inoue S, Suzuki-Utsunomiya K, Okada Y, Iida Y, Taira T, Miura N, et al. Reduction of 
Immunocompetent T Cells Followed by Prolonged Lymphopenia in Severe Sepsis in the 
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ICU - from diagnosis of infection to monitoring of injury-induced immune dysfunctions. Crit 
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2012;12(7):503‑505.  
26.  
Christaki E, Anyfanti P, Opal SM. Immunomodulatory therapy for sepsis: an update. 
Expert Rev Anti Infect Ther. nov 2011;9(11):1013‑1033.  
27.  
Hotchkiss RS, Opal S. Immunotherapy for sepsis--a new approach against an ancient foe. 
N Engl J Med. 1 juill 2010; 363(1):87‑89.  
28.  
Mazzucchelli R, Durum SK. Interleukin-7 receptor expression: intelligent design. Nat 
Rev Immunol. févr 2007;7(2):144‑154.  
29.  
Vassena L, Miao H, Cimbro R, Malnati MS, Cassina G, Proschan MA, et al. Treatment 
with CYT107 prevents the decline of circulating CD4+ T cells during the acute phase of SIV 
infection in rhesus macaques. PLoS Pathog. 2012; 8(4):e1002636.  


 
 
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30.  
Levy Y, Lacabaratz C, Weiss L, Viard J-P, Goujard C, Lelièvre J-D, et al. Enhanced T 
cell recovery in HIV-1-infected adults through CYT107 treatment. J Clin Invest. avr 
2009;119(4):997‑1007.  
31.  
Sereti I, Estes JD, Thompson WL, Morcock DR, Fischl MA, Croughs T, et al. Decreases 
in colonic and systemic inflammation in chronic HIV infection after CYT107 administration. 
PLoS Pathog. janv 2014;10(1):e1003890.  
32.  
Sereti I, Dunham RM, Spritzler J, Aga E, Proschan MA, Medvik K, et al. CYT107 
administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood. 18 juin 
2009;113(25):6304‑6314.  
33.  
Habersetzer F. Four weeks of CYT107 (CYT107) added to peginterferon (pegIFN) and 
ribavirin (RBV) is safe, induces a broad immune response and HCV viral clearance in genotype 
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34.  
Kasten KR, Prakash PS, Unsinger J, Goetzman HS, England LG, Cave CM, et al. 
Interleukin-7 (CYT107) treatment accelerates neutrophil recruitment through gamma delta T-
cell IL-17 production in a murine model of sepsis. Infect Immun. nov 2010; 78(11):4714‑4722.  
35.  
Munafo, Trinchard-Lugan, Nguyen, Buraglio. Comparative pharmacokinetics and 
pharmacodynamics of recombinant human interferon beta-1a after intramuscular and 
subcutaneous administration. Eur J Neurol Off J Eur Fed Neurol Soc. mars 1998; 5(2):187‑193.  
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recombinant follicle-stimulating hormone absorption: subcutaneous versus intramuscular 
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Sweetser MT, Woodworth J, Swan S, Ticho B. Results of a randomized open-label 
crossover study of the bioequivalence of subcutaneous versus intramuscular administration of 
alefacept. Dermatol Online J. 2006;12(3):1.  
38.  
Trinchard-Lugan I, Ho-Nguyen Q, Bilham WM, Buraglio M, Ythier A, Munafo A. 
Safety, pharmacokinetics and pharmacodynamics of recombinant human tumour necrosis factor-
binding protein-1 (Onercept) injected by intravenous, intramuscular and subcutaneous routes 
into healthy volunteers. Eur Cytokine Netw. sept 2001;12(3):391‑398.  
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Hotchkiss RS, Moldawer L. Parallels between cancer and infectious disease.  New Eng. 
J. Med. 2014; 371:380-2. 
 
 
 

SAP_001.pdf: 
A multicenter, randomized, double-blinded, placebo-controlled study of 
CYT107 to restore absolute lymphocyte counts in sepsis patients 
 
14th December 2015 
 
NCT02640807 
 
Final Statistical Analysis Plan  
 
All statistical analyses will be evaluated on an intent-to-treat basis. That is, data all patients who 
were enrolled in the study and received at least one dose of study drug were analysed. This 
corresponds to the safety dataset (SAF). 
 
Comparisons across treatment groups at baseline will be performed using the Kruskal-Wallis 
test and Fisher exact test. To determine the effect of CYT107 on the incidence of ALC 
improvement by greater than 50% (primary outcome), and mortality, the Fisher exact test will be 
used. For secondary analyses, each outcome variable (e.g., absolute lymphocyte count) will be 
baseline adjusted by subtracting the corresponding baseline value. Baseline adjusted outcomes 
will then be analyzed using linear mixed-effects regression, adjusting for study day (as a 
categorical variable), treatment group, and the interaction between study day and treatment 
group. A study day-by-treatment group interaction will be used to quantify the differential effect 
of intervention over the course of the study, adjusting for baseline response. Study day will be 
treated as a quantitative factor and modeled using a four-knot natural spline. A random intercept 
indexed by study subject will be used to account for within-subject correlation among 
longitudinal measurements. The error variance will be allowed to vary by study day to account 
for heteroscedasticity. The combined treatment effect across all study days will be tested 
against the null hypothesis that the mean outcome is identical among groups at each study day. 
If the combined treatment effect across all study days meets the statistical significance 
threshold (0.05), a series of similar null hypotheses will be used to assess the combined 
treatment effect at each specific study day. These null hypotheses will be tested using a Wald-
type multiple degree-of-freedom test. All tests will be evaluated at the 0.05 level, thus ensuring a 
type-I error rate of 5%. This method ensures that the family of comparisons across study days 
are adjusted such that the type-I error rate for the overall assessment of effectiveness of 
CYT107 on each outcome is preserved at 5%. No additional adjustments will be made to control 
the type-I error rate across different outcomes. Differences in means between treatment groups 
at each time point will be summarized using point estimates and the associated Wald-type 95% 
confidence intervals. In order to estimate the average difference in mean absolute lymphocyte 
count across the two CYT107 groups, relative to placebo, a secondary regression analysis will 
be implemented by combining low and high frequency CYT107 groups. Normal quantile-quantile 
plots of Pearson residuals and fitted-versus-residual plots will be examined to assess for 
deviations from residual normality or homoscedasticity, respectively. Transformations of 
baseline adjusted outcomes will be considered as necessary. All statistical analyses will be 
performed using the latest version of R (http://www.r-project.org).