Immune Reconstitution of Immunosuppressed Sepsis Patients (IRIS-7a)

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

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.

Study Overview

• Status: Terminated
• Conditions: Severe Sepsis With Septic Shock
• Intervention / Treatment: Drug: Interleukin-7; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Limoges, France
    • CHU LIMOGES Service de Réanimation
  • Lyon, France, 69003
    • Hospice Civil de Lyon - Hôpital Edouard Herriot - Service de Réanimation Médicale
  • Paris, France, 75010
    • Hopital Lariboisière - Service d'anesthésie-réanimation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients of age ≥ 18 yrs and older but < 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 IL-7 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.

Exclusion Criteria:

1. Cancer with current chemotherapy or radiotherapy and/or .receipt of chemotherapy or radiotherapy within the last 6 weeks
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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality		Day 60
Mortality		Day 180
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 190
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

Collaborators and Investigators

• Sponsor: University Hospital, Limoges
• Collaborators: Vanderbilt University Medical Center; Revimmune
• Investigators: Principal Investigator: Bruno FRANCOIS, DM, University Hospital, Limoges

Publications and helpful links

General Publications

• Francois B, Jeannet R, Daix T, Walton AH, Shotwell MS, Unsinger J, Monneret G, Rimmele T, Blood T, Morre M, Gregoire A, Mayo GA, Blood J, Durum SK, Sherwood ER, Hotchkiss RS. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight. 2018 Mar 8;3(5):e98960. doi: 10.1172/jci.insight.98960.

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2016
• Primary Completion (Actual): March 21, 2017
• Study Completion (Actual): November 13, 2017

Study Registration Dates

• First Submitted: February 24, 2016
• First Submitted That Met QC Criteria: June 7, 2016
• First Posted (Estimate): June 13, 2016

Study Record Updates

• Last Update Posted (Actual): November 29, 2017
• Last Update Submitted That Met QC Criteria: November 27, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia
• Other Study ID Numbers: I14037 IRIS-7a

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No