A Study of IL-7 to Restore Absolute Lymphocyte Counts in 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-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
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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 Two Dosing Frequencies of Recombinant Interleukin-7 (CYT107) Treatment 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 (Sepsis-related organ failure assessment) 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 (ICU may also include a close medical ward on the same study site where the patient will remain under medical control of the Investigator). Ability to obtain a signed informed consent from patient or LAR (Legally Authorized Representative) 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 (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<br>* Other names: CYT107;|
| 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 (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<br>* Other names: CYT107;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 |
| --- | --- | --- |
| Immune Reconstitution of Lymphocytopenic Sepsis Patients | Number of patients showing an increase of Absolute Lymphocyte Count >50% from baseline at Day 42. Kinetic of immune restoration through weekly measures of Absolute Lymphocyte Counts | Day 0 to 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CYT107 Effect on Absolute Lymphocyte Count | Number of Patients with Absolute Lymphocyte Count > 1.2 at Day 42 | Day 42 | 
| CYT107 Immunogenicity | number of patients with binding or neutralizing antibodies against CYT107 at Day 60 | Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis lymphocytopenia IL-7, immune reconstitution