Recombinant Interleukin-7 (CYT107) to Restore Absolute Lymphocyte Counts in Sepsis Patients

Study Overview
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Brief Summary
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This phase II randomized study will assess the effect of receiving IV recombinant human IL-7 (CYT107) versus placebo in lymphopenic sepsis patients The aim is to confirm the immune cell reconstitution observed in other studies and other patient populations among which the IRIS-7 A&B study which was conducted in the same patient population.

Detailed Description
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Lymphopenic sepsis Patients will be randomized 3:1 to receive either: a) Intravenous (IV) administration of CYT107 at 10 μg/kg twice a week for 3 weeks or b) IV placebo (normal saline). The effect of CYT107 on Lymphocyte and various T cell populations will be documented with a focus on the first 29 days. Stopping rules will apply if ALC increases to >2.5 times the upper limit of normal range. The IRIS-7C & D studies will be conducted at multiple sites in France and the United States. All sites will use the same study design and similar study protocol for a common statistical analysis of 40 evaluable participants.

Official Title
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International, Multicenter, Randomized, Double-blinded, Placebo-controlled Study of Recombinant Interleukin-7 (CYT107) to Restore Absolute Lymphocyte Counts (ALC) in Patients With Sepsis

Conditions
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Sepsis, Severe

Intervention / Treatment
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* Biological: CYT107
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A written, signed informed consent, by the patient or the patient's legally authorized representative Participants with an absolute lymphocyte count (ALC) ≤ 900 cells/mm3, at two time points at least twelve hours apart, following diagnosis of vasopressor dependent sepsis and, the second time point should not be performed earlier than 48 hours after sepsis diagnosis, study drug treatment initiation is required no later than 120 hours (up to 5 days) after the last qualifying ALC ≤ 900 cells/mm3 measure, and the average value of the two qualifying ALC counts will serve as a baseline to express the percent increase at day 29, or at hospital discharge. Patients in the ICU with onset of vasopressor dependent sepsis defined as hypotension requiring treatment with any vasopressor(s) for at least 6 hours to maintain a systolic pressure ≥ 90 mmHg or a mean arterial pressure ≥65 mmHg AND at least 1 of the 2 organ dysfunction criteria below: Acute respiratory failure defined as the need for invasive mechanical ventilation for at least 24 hours to support pulmonary function Acute kidney injury defined as creatinine > 2.0 mg/dL (based on new abnormal result following onset of sepsis) OR urine output < 0.5 mL/kg/hr for > 4 hours despite adequate fluid resuscitation. In the presence of pre-existing impairment of renal function (defined as a serum creatinine concentration >2 times the upper limit of the normal reference range prior to the onset of sepsis), the patient must meet the other organ dysfunction criteria. Anticipated hospital duration of up to approx. three weeks after initiating study drug treatment to allow 6 study drug administrations (Days 18 or 19 would be final dose) This study permits the re-enrollment of a participant who may have been discontinued as a pre-treatment screen failure and/or prior to study drug treatment. Age and reproductive status: Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment Women must not be breastfeeding Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with CYT107 plus 5 half-lives of CYT107 (the terminal half-life of CYT107 is up to 2 days) plus 30 days (duration of ovulatory cycle) for a total of 2 months post-treatment completion. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with CYT107 plus 5 half-lives of CYT107 plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment completion. In addition, male participants must be willing to refrain from sperm donation during this time. Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements but still must undergo pregnancy testing. Exclusion Criteria: Cancer with current chemotherapy or radiotherapy (receipt of chemotherapy or radiotherapy for cancer within the last 6 weeks). All patients with current, or history of, hematologic malignancy (including, but not limited to, ALL, AML, CLL, CML, etc.) or lymphoma will be excluded, regardless of receipt of recent chemotherapy Patients with minimal chance of survival and life expectancy less than 3-5 days as defined by an APACHE II score of ≥ 35 at time of consideration for study eligibility Patients with history or current evidence of autoimmune disease including for example: myasthenia gravis, Guillain Barre syndrome, systemic lupus erythematosus, multiple sclerosis, scleroderma, ulcerative colitis, Crohn's disease, autoimmune hepatitis, Wegener's etc. Patients who have received a 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 Known history of chronic HBV infection and not on treatment with HBV nucleoside analogues prior to the current hospitalization or HBV DNA > 100 IU/mL Known history of infection with HCV and currently undergoing treatment for HCV infections or has detectable HCV RNA Known history of tuberculosis and currently undergoing treatment for tuberculosis History of splenectomy Any hematologic disease associated with hypersplenism, such as thalassemia, hereditary spherocytosis, Gaucher's Disease, and autoimmune hemolytic anemia Participation in another investigational interventional study testing a drug or a medical device within the last 3 months prior to study entry Patients receiving immunosuppressive drugs, e.g., TNF-alpha inhibitors, for any 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 : IL-2, Interferons α, β and γ, GM-CSF, G-CSF, HIV vaccines, immunosuppressive drugs, hydroxyurea, immunoglobulins, adoptive cell therapy Prior exposure to IL 7 or other drugs specifically targeting T cells Presence of an advanced directive to withhold or withdraw life-sustaining treatment, DNR order or no CPR order, or comfort measures only order Patients for whom prognosis is poor and source control of septic event is considered unlikely per the clinical and research teams. Patients under guardianship

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Interventional Model Description: International, multicenter, randomized, double-blinded placebo- controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYT107<br>Intravenous (IV) administration of CYT107 at 10 μg/kg twice a week for 3 weeks | Biological: CYT107<br>* IV twice a week at 10µg/kg for 3 weeks<br>* Other names: human recombinant glycosylated Interleukin-7;|
| Placebo Comparator: Placebo<br>Intravenous (IV) administration of the same volume of NaCl 0.9% twice a week for 3 weeks | Drug: Placebos<br>* IV twice a week at the same volume for 3 weeks<br>* Other names: saline solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lymphocyte reconstitution | Change in absolute lymphocyte count (ALC) of ≥ 50%. If this 50% increase over baseline is reached in the placebo group due to natural immune reconstitution, then the day 29 percent increase of ALC over baseline will be compared between the two groups. | day 29 versus baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| adverse events | Incidence and scoring of all grade 3-4 adverse events | 90 days after study treatment initiation | 
| Secondary Infections | Incidence of secondary infections based on pre-specified criteria as adjudicated by the Secondary Infections Committee (SIC) | within 90 days after treatment initiation | 
| Days in the ICU | Number of days in ICU following study treatment initiation during the index hospitalization | within 90 days after treatment initiation | 
| readmissions to the ICU | Number of readmissions to ICU following study treatment initiation during index hospitalization | within 90 days after treatment initiation | 
| organ support free days | Number of organ support free days (OSFDs) following study treatment initiation during the index hospitalization | within 90 days after treatment initiation | 
| re-hospitalization | the incidence of re-hospitalization | within 90 days following study treatment initiation | 
| Mortality rate | All-cause mortality | 90 days after study treatment initiation | 
| T cell reconstitution | Absolute numbers of CD4+ and CD8+T-cell counts | through day 90 | 
| Percentage of patients reaching normal ALC | Percentage of patients reaching absolute lymphocyte counts (ALC) > 1200 | through day 90 | 
| Quantification of IL-7 receptor | Effects on soluble and cellular IL-7 receptor (CD127) expression | through day 90 | 
| Quantification of HLA-DR on monocytes | Effects on circulating monocyte HLA-DR expression | through day 90 | 
| Change of IL-6 blood levels | Effects on whole blood circulating cytokines IL-6 | through day 90 | 
| Change of IL-10 blood levels | Effects on whole blood circulating IL-10 | through day 90 | 
| Change of TNF-α blood levels | Effects on whole blood circulating TNF-α | through day 90 | 
| CYT107 Pharmacokinetic Tmax | determination of Tmax | Day 1 and Day 15 | 
| CYT107 Pharmacokinetic Cmax | determination of Cmax | Day 1 and Day 15 | 
| CYT107 Pharmacokinetic half life | determination of half-life | Day 1 and Day 15 | 
| CYT107 Pharmacokinetic clearance | determination of clearance | Day 1 and Day 15 | 
| CYT107 Pharmacokinetic area under curve | determination of area under curve | Day 1 and Day 15 | 
| anti-CYT107 antibodies | Quantification of circulating anti-CYT107 antibodies | day 1, day 29 or hospital discharge, day 90 and day 180 if previous sample positive | 

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