Clinical trial NCT02797431: Immune Reconstitution of Immunosuppressed Sepsis Patients
Official title: A Multicenter, Randomized, Double-blinded, Placebo-controlled Study of IL-7 to Restore Absolute Lymphocyte Counts in Sepsis Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Severe Sepsis With Septic Shock
Lead sponsor: University Hospital, Limoges
Sponsor class: OTHER
Collaborators: name: Revimmune
name: Vanderbilt University Medical Center
First posted: 2016-06-13
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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-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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: White blood count
timeFrame: day 1 to Day 42
measure: lymphocyte percentage
timeFrame: Day 1 to Day 42
measure: Incidence of treatment-Emergent Adverse Events
timeFrame: Day 1 to Day 42
measure: Mortality
timeFrame: Day 60
measure: Mortality
timeFrame: Day 190
measure: Mortality
timeFrame: Day 180
measure: Mortality
timeFrame: Day 360
Secondary outcomes:
measure: CYT107 Pharmacokinetic Cmax
timeFrame: Day 1 and Day 22
measure: CYT107 Pharmacokinetic AUC
timeFrame: Day 1 and Day 22
measure: CYT107 Pharmacokinetic half life
timeFrame: Day 1 and Day 22
measure: Quantification of positive binding antibodies against CYT107
timeFrame: Day 1, Day 11, Day 22, Day 60, Day 180 and Day 360
measure: Specific CYT107 neutralizing antibodies
timeFrame: Day 1, Day 11, Day 22, Day 60, Day 180 and Day 360
measure: Incidence of hospital acquired secondary infections
timeFrame: Day 42
measure: SOFA score
timeFrame: Day 0 Day 4, Day 8, Day 15, Day 22, Day 29
measure: APACHE II score
timeFrame: Day 0, Day 4, Day 8, Day 15, Day 22, Day 29
measure: CYT107 Pharmacodynamic
timeFrame: Day 1, Day 8, Day 15, Day 22, Day 29
Other outcomes:
Locations:
city: Limoges
country: France
facility: CHU LIMOGES Service de Réanimation
city: Lyon
country: France
facility: Hospice Civil de Lyon - Hôpital Edouard Herriot - Service de Réanimation Médicale
city: Paris
country: France
facility: Hopital Lariboisière - Service d'anesthésie-réanimation
Study officials:
affiliation: University Hospital, Limoges
name: Bruno FRANCOIS, DM
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.