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

NCT ID: NCT02640807

Last Updated: 2020-07-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-01-31
• Study Completion Date: 2018-08-27

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.

Conditions

Severe Sepsis With Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

CYT107 high frequency

Patients will receive Interleukin-7 (CYT107 liquid solution) at 10µg/kg twice a week for 4 weeks

Group Type: EXPERIMENTAL

Interleukin-7

Intervention Type: DRUG

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

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

Group Type: EXPERIMENTAL

Interleukin-7

Intervention Type: DRUG

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

Intervention Type: DRUG

IM administration of Placebo (SC administration for patients with INR\>2.5 or platelet count \< 35,000

Control

Patients will receive Placebo (NaCl 0.9%) twice a week for 4 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

IM administration of Placebo (SC administration for patients with INR\>2.5 or platelet count \< 35,000

Interventions

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

Intervention Type: DRUG

Placebo

IM administration of Placebo (SC administration for patients with INR\>2.5 or platelet count \< 35,000

Intervention Type: DRUG

Other Intervention Names

CYT107; NaCl 0.9%

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 (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

-

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University School of Medicine

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

Revimmune

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Edward SHERWOOD, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Richard HOTCHKISS, MD, PhD

Role: STUDY_DIRECTOR

Washington University School of Medicine

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 29515037 (View on PubMed)

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. No abstract available.

Reference Type: BACKGROUND

PMID: 25054723 (View on PubMed)

Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003 Jan 9;348(2):138-50. doi: 10.1056/NEJMra021333. No abstract available.

Reference Type: RESULT

PMID: 12519925 (View on PubMed)

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;306(23):2594-605. doi: 10.1001/jama.2011.1829.

Reference Type: RESULT

PMID: 22187279 (View on PubMed)

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 2010 Dec 10.

Reference Type: RESULT

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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.

Reference Type: RESULT

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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.

Reference Type: RESULT

PMID: 23427891 (View on PubMed)

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.

Reference Type: RESULT

PMID: 24232462 (View on PubMed)

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.

Reference Type: RESULT

PMID: 21508983 (View on PubMed)

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.

Reference Type: RESULT

PMID: 22383042 (View on PubMed)

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/infdis/jis383. Epub 2012 Jun 12.

Reference Type: RESULT

PMID: 22693226 (View on PubMed)

Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelievre JD, Boue F, Molina JM, Rouzioux C, Avettand-Fenoel V, Croughs T, Beq S, Thiebaut R, Chene G, Morre M, Delfraissy JF. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest. 2009 Apr;119(4):997-1007. doi: 10.1172/JCI38052. Epub 2009 Mar 16.

Reference Type: RESULT

PMID: 19287090 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

CLI-107-15

Identifier Type: -

Identifier Source: org_study_id