Severe Sepsis With Septic Shock
Conditions
Keywords
sepsis lymphocytopenia IL-7, immune reconstitution
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.
Interventions
DRUGInterleukin-7
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
DRUGPlacebo
IM administration of Placebo (SC administration for patients with INR\>2.5 or platelet count \< 35,000
Sponsors
Vanderbilt University School of Medicine
Washington University School of Medicine
Revimmune
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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 (Sepsis-related organ failure assessment) 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 (ICU may also include a close medical ward on the same study site where the patient will remain under medical control of the Investigator). 8. Ability to obtain a signed informed consent from patient or LAR (Legally Authorized Representative) 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 \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CYT107 High Frequency Patients will receive Interleukin-7 (CYT107 liquid solution) at 10µg/kg twice a week for 4 weeks
Interleukin-7: 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 | 9 |
| 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
Interleukin-7: 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
Placebo: IM administration of Placebo (SC administration for patients with INR\>2.5 or platelet count \< 35,000 | 8 |
| Control Patients will receive Placebo (NaCl 0.9%) twice a week for 4 weeks
Placebo: IM administration of Placebo (SC administration for patients with INR\>2.5 or platelet count \< 35,000 | 10 |
| Total | 27 |
Baseline characteristics
| Characteristic | CYT107 High Frequency | CYT107 Low Frequency | Control | Total |
|---|---|---|---|---|
| Age, Continuous | 62 years | 68 years | 56 years | 62 years |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Region of Enrollment France | 5 participants | 5 participants | 6 participants | 16 participants |
| Region of Enrollment United States | 4 participants | 3 participants | 4 participants | 11 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 8 Participants | 21 Participants |
| SOFA Score | 6 units on a scale | 5 units on a scale | 8 units on a scale | 6 units on a scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 9 | 1 / 8 | 2 / 10 |
| other Total, other adverse events | 9 / 9 | 8 / 8 | 7 / 10 |
| serious Total, serious adverse events | 7 / 9 | 4 / 8 | 5 / 10 |
Outcome results
Primary
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
Time frame: Day 0 to 42
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CYT107 High Frequency | Immune Reconstitution of Lymphocytopenic Sepsis Patients | 8 Participants |
| CYT107 Low Frequency | Immune Reconstitution of Lymphocytopenic Sepsis Patients | 7 Participants |
| Control | Immune Reconstitution of Lymphocytopenic Sepsis Patients | 8 Participants |
Secondary
CYT107 Effect on Absolute Lymphocyte Count
Number of Patients with Absolute Lymphocyte Count \> 1.2 at Day 42
Time frame: Day 42
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CYT107 High Frequency | CYT107 Effect on Absolute Lymphocyte Count | 6 Participants |
| CYT107 Low Frequency | CYT107 Effect on Absolute Lymphocyte Count | 6 Participants |
| Control | CYT107 Effect on Absolute Lymphocyte Count | 4 Participants |
Secondary
CYT107 Immunogenicity
number of patients with binding or neutralizing antibodies against CYT107 at Day 60
Time frame: Day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CYT107 High Frequency | CYT107 Immunogenicity | 0 Participants |
| CYT107 Low Frequency | CYT107 Immunogenicity | 0 Participants |
| Control | CYT107 Immunogenicity | 0 Participants |