Immune Reconstitution of Immunosuppressed Sepsis Patients

Study Overview
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Brief Summary
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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-7A (Immune Reconstitution of Immunosuppressed Sepsis patients). A parallel study will be performed in United State of America to allow a common statistical analysis of the primary end points and analysis for the enrolled patient population.

Detailed Description
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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.

Official Title
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A Multicenter, Randomized, Double-blinded, Placebo-controlled Study of IL-7 to Restore Absolute Lymphocyte Counts in Sepsis Patients

Conditions
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Severe Sepsis With Septic Shock

Intervention / Treatment
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* Drug: Interleukin-7
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of age ≥ 18 yrs and older but < 80 yrs Patients with persistent suspected sepsis at 48-120 hrs after admission Two or more criteria for the systemic inflammatory response syndrome (SIRS) (see reference #19 for SIRS criteria) and a clinically or microbiologically suspected infection. 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 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 IL-7 study. 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. Predicted length of stay in the ICU of up to two weeks after starting drug therapy treatment in the trial Ability to obtain a signed informed consent from patient or LAR consent. Exclusion Criteria: Cancer with current chemotherapy or radiotherapy and/or .receipt of chemotherapy or radiotherapy within the last 6 weeks 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 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. Patients who have received solid organ transplant or bone marrow transplant Patients with active or a history of acute or chronic lymphocytic leukemia AIDS-defining illness (category C) diagnosed within the last 12 months prior to study entry History of splenectomy Any hematologic disease associated with hypersplenism, such as thalassemia, hereditary spherocytosis, Gaucher's Disease, and autoimmune hemolytic anemia Pregnant or lactating women 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. 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 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 Prisoners

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYT107 high frequency<br>Patients will receive Interleukin-7 (CYT107 liquid solution) at 10µg/kg twice a week for 4 weeks | Drug: Interleukin-7<br>* IM administration of CYT107 recombinant glycosylated human IL-7 (SC administration for patients with INR>2.5 or platelet count < 35,000<br>* Other names: CYT 107;|
| Experimental: CYT107 low frequency<br>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 | Drug: Interleukin-7<br>* IM administration of CYT107 recombinant glycosylated human IL-7 (SC administration for patients with INR>2.5 or platelet count < 35,000<br>* Other names: CYT 107;Drug: Placebo<br>* IM administration of Placebo (SC administration for patients with INR>2.5 or platelet count < 35,000<br>* Other names: NaCl 0.9%;|
| Placebo Comparator: Control<br>Patients will receive Placebo (NaCl 0.9%) twice a week for 4 weeks | Drug: Placebo<br>* IM administration of Placebo (SC administration for patients with INR>2.5 or platelet count < 35,000<br>* Other names: NaCl 0.9%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| White blood count | Number of patients with absolute lymphocyte counts (Multiply the Lymphocytes percentage above by the total number White Blood Count) increased by more than 50% from baseline at Day 42 Kinetic of immune restoration through weekly measures of Absolute Lymphocyte Counts | day 1 to Day 42 | 
| lymphocyte percentage | Number of patients with absolute lymphocyte counts (Multiply the Lymphocytes percentage above by the total number White Blood Count) increased by more than 50% from baseline at Day 42 Kinetic of immune restoration through weekly measures of Absolute Lymphocyte Counts | Day 1 to Day 42 | 
| Incidence of treatment-Emergent Adverse Events | Clinical occurrence of adverse events (AEs) and serious adverse events (SAEs) during the duration of the study period ending day 42, as assessed by DAIDS (2.0) | Day 1 to Day 42 | 
| Mortality |  | Day 60 | 
| Mortality |  | Day 190 | 
| Mortality |  | Day 180 | 
| Mortality |  | Day 360 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CYT107 Pharmacokinetic Cmax | CYT107 PK: Measure of Peak plasma concentration Cmax at Day 1 and Day 22 | Day 1 and Day 22 | 
| CYT107 Pharmacokinetic AUC | CYT107 PK: Measure of Area under plasma concentration versus time curve at day 1 and day 22 | Day 1 and Day 22 | 
| CYT107 Pharmacokinetic half life | CYT107 PK: Measure plasma concentration half life at day 1 and day 22 | Day 1 and Day 22 | 
| Quantification of positive binding antibodies against CYT107 | number of patients with positive binding antibodies against CYT107 at Day 1, Day 11, Day 22, Day 60, Day 180 if Day 60 is positive and Day 360 if Day 180 is positive. | Day 1, Day 11, Day 22, Day 60, Day 180 and Day 360 | 
| Specific CYT107 neutralizing antibodies | Number of patients with CYT107 neutralizing antibodies if positive binding antibodies against CYT107 is detected. | Day 1, Day 11, Day 22, Day 60, Day 180 and Day 360 | 
| Incidence of hospital acquired secondary infections | Incidence of hospital acquired secondary infections at Day 42 | Day 42 | 
| SOFA score | SOFA score at Day 0 Day 4, Day 8, Day 15, Day 22, Day 29. | Day 0 Day 4, Day 8, Day 15, Day 22, Day 29 | 
| APACHE II score | APACHE II score at Day 0, Day 4, Day 8, Day 15, Day 22, Day 29. | Day 0, Day 4, Day 8, Day 15, Day 22, Day 29 | 
| CYT107 Pharmacodynamic | CYT107 effects on cell counts: T-CD4+, T-CD8+, T-CD127+ (IL-7R), monocyte HLA-DR+ | Day 1, Day 8, Day 15, Day 22, Day 29 |