Clinical trial NCT03821038: Recombinant Interleukin-7 (CYT107) to Restore Absolute Lymphocyte Counts in Sepsis Patients
Official title: International, Multicenter, Randomized, Double-blinded, Placebo-controlled Study of Recombinant Interleukin-7 (CYT107) to Restore Absolute Lymphocyte Counts (ALC) in Patients With Sepsis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Sepsis, Severe
Keywords: Sepsis
IL-7
lymphocytopenia
Lead sponsor: Revimmune
Sponsor class: INDUSTRY
Collaborators: name: Washington University School of Medicine
name: University Hospital, Limoges
name: George Clinical Pty Ltd
First posted: 2019-01-29
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: International, multicenter, randomized, double-blinded placebo- controlled
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. A written, signed informed consent, by the patient or the patient's legally authorized representative
2. 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,

   1. the second time point should not be performed earlier than 48 hours after sepsis diagnosis,
   2. 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
   3. 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.
3. 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:

   1. Acute respiratory failure defined as the need for invasive mechanical ventilation for at least 24 hours to support pulmonary function
   2. 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.
4. 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)
5. 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.
6. Age and reproductive status:

   1. 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
   2. Women must not be breastfeeding
   3. 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.
   4. 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.
   5. Azoospermic males are exempt from contraceptive requirements.
   6. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements but still must undergo pregnancy testing.

Exclusion Criteria:

1. 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
2. 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
3. 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.
4. Patients who have received a 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. 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
8. Known history of infection with HCV and currently undergoing treatment for HCV infections or has detectable HCV RNA
9. Known history of tuberculosis and currently undergoing treatment for tuberculosis
10. History of splenectomy
11. Any hematologic disease associated with hypersplenism, such as thalassemia, hereditary spherocytosis, Gaucher's Disease, and autoimmune hemolytic anemia
12. Participation in another investigational interventional study testing a drug or a medical device within the last 3 months prior to study entry
13. 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
14. 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
15. Prior exposure to IL 7 or other drugs specifically targeting T cells
16. Presence of an advanced directive to withhold or withdraw life-sustaining treatment, DNR order or no CPR order, or comfort measures only order
17. Patients for whom prognosis is poor and source control of septic event is considered unlikely per the clinical and research teams.
18. Patients under guardianship

Primary outcomes:
measure: Lymphocyte reconstitution
timeFrame: day 29 versus baseline
Secondary outcomes:
measure: adverse events
timeFrame: 90 days after study treatment initiation
measure: Secondary Infections
timeFrame: within 90 days after treatment initiation
measure: Days in the ICU
timeFrame: within 90 days after treatment initiation
measure: readmissions to the ICU
timeFrame: within 90 days after treatment initiation
measure: organ support free days
timeFrame: within 90 days after treatment initiation
measure: re-hospitalization
timeFrame: within 90 days following study treatment initiation
measure: Mortality rate
timeFrame: 90 days after study treatment initiation
measure: T cell reconstitution
timeFrame: through day 90
measure: Percentage of patients reaching normal ALC
timeFrame: through day 90
measure: Quantification of IL-7 receptor
timeFrame: through day 90
measure: Quantification of HLA-DR on monocytes
timeFrame: through day 90
measure: Change of IL-6 blood levels
timeFrame: through day 90
measure: Change of IL-10 blood levels
timeFrame: through day 90
measure: Change of TNF-α blood levels
timeFrame: through day 90
measure: CYT107 Pharmacokinetic Tmax
timeFrame: Day 1 and Day 15
measure: CYT107 Pharmacokinetic Cmax
timeFrame: Day 1 and Day 15
measure: CYT107 Pharmacokinetic half life
timeFrame: Day 1 and Day 15
measure: CYT107 Pharmacokinetic clearance
timeFrame: Day 1 and Day 15
measure: CYT107 Pharmacokinetic area under curve
timeFrame: Day 1 and Day 15
measure: anti-CYT107 antibodies
timeFrame: day 1, day 29 or hospital discharge, day 90 and day 180 if previous sample positive
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Angers
country: France
facility: CHU Angers
city: Créteil
country: France
facility: Hopital HENRI MONDOR
city: Dijon
country: France
facility: CHU Dijon Bourgogne
city: Limoges
country: France
facility: University Hospital of Limoges
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Orleans
country: France
facility: Chr Orleans
city: Paris
country: France
facility: Hopital COCHIN
city: Tours
country: France
facility: Chru Bretonneau
Study officials:
affiliation: Washington University School of Medicine
name: Richard Hotchkiss, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Limoges Hospital
name: Bruno François, MD
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.