A Study of IL-7 to Restore Absolute Lymphocyte Counts in Sepsis Patients

Severe Sepsis With Septic Shock Clinical Trial

— IRIS-7-B  

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02640807
• Other study ID #: CLI-107-15
• Status: Completed
• Phase: Phase 2
• Start date: January 2016
• Est. completion date: August 27, 2018

Study information

• Verified date: August 2018
• Source: Revimmune
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: August 27, 2018
• Est. primary completion date: August 27, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

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Related Conditions & MeSH terms

• Sepsis
• Severe Sepsis With Septic Shock
• Toxemia

Intervention

Drug:
• 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

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (3)

Lead Sponsor	Collaborator
Revimmune	Vanderbilt University School of Medicine, Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (11)

Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD 2nd, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011 Dec 21; — View Citation

Hall MW, Knatz NL, Vetterly C, Tomarello S, Wewers MD, Volk HD, Carcillo JA. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011 Mar;37(3):525-32. doi: 10.1007/s00134-010-2088-x. Epub 201 — View Citation

Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis seesaw: tilting toward immunosuppression. Nat Med. 2009 May;15(5):496-7. doi: 10.1038/nm0509-496. — View Citation

Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003 Jan 9;348(2):138-50. Review. — View Citation

Hotchkiss RS, Moldawer LL. Parallels between cancer and infectious disease. N Engl J Med. 2014 Jul 24;371(4):380-3. doi: 10.1056/NEJMcibr1404664. — View Citation

Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013 Mar;13(3):260-8. doi: 10.1016/S1473-3099(13)70001-X. Review. — View Citation

Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013 Dec;13(12):862-74. doi: 10.1038/nri3552. Epub 2013 Nov 15. Review. — View Citation

Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelièvre JD, Boué F, Molina JM, Rouzioux C, Avettand-Fénoêl V, Croughs T, Beq S, Thiébaut R, Chêne G, Morre M, Delfraissy JF. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J C — View Citation

Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol. 2011 May;11(5):330-42. doi: 10.1038/nri2970. Review. — View Citation

Morre M, Beq S. Interleukin-7 and immune reconstitution in cancer patients: a new paradigm for dramatically increasing overall survival. Target Oncol. 2012 Mar;7(1):55-68. doi: 10.1007/s11523-012-0210-4. Epub 2012 Mar 2. Review. — View Citation

Unsinger J, Burnham CA, McDonough J, Morre M, Prakash PS, Caldwell CC, Dunne WM Jr, Hotchkiss RS. Interleukin-7 ameliorates immune dysfunction and improves survival in a 2-hit model of fungal sepsis. J Infect Dis. 2012 Aug 15;206(4):606-16. doi: 10.1093/i — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
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	Day 0 to 42
Secondary	CYT107 Effect on Absolute Lymphocyte Count	Number of Patients with Absolute Lymphocyte Count > 1.2 at Day 42	Day 42
Secondary	CYT107 Immunogenicity	number of patients with binding or neutralizing antibodies against CYT107 at Day 60	Day 60