A Study of IL-7 to Restore Absolute Lymphocyte Counts in Sepsis Patients

Phase 2

Completed

Conditions: Severe Sepsis With Septic Shock

Interventions: Drug: Interleukin-7
Drug: Placebo

Registration Number: NCT02640807

Lead Sponsor: Revimmune

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 27

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CYT107 high frequency	Interleukin-7	Patients will receive Interleukin-7 (CYT107 liquid solution) at 10µg/kg twice a week for 4 weeks
CYT107 low frequency	Interleukin-7	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
Control	Placebo	Patients will receive Placebo (NaCl 0.9%) twice a week for 4 weeks
CYT107 low frequency	Placebo	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

Primary Outcome Measures

Name	Time	Method
Immune Reconstitution of Lymphocytopenic Sepsis Patients	Day 0 to 42	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

Secondary Outcome Measures

Name	Time	Method
CYT107 Effect on Absolute Lymphocyte Count	Day 42	Number of Patients with Absolute Lymphocyte Count \> 1.2 at Day 42
CYT107 Immunogenicity	Day 60	number of patients with binding or neutralizing antibodies against CYT107 at Day 60