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    Summary
    EudraCT Number:2018-003977-93
    Sponsor's Protocol Code Number:87RI-0015
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-03-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2018-003977-93
    A.3Full title of the trial
    International, multicenter, randomized, double-blinded, placebo-controlled study of Recombinant Interleukin-7 (CYT107) to restore absolute lymphocyte counts (ALC) in patients with Sepsis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    International, multicenter, randomized, double-blinded, placebo-controlled study of Recombinant Interleukin-7 (CYT107) to restore absolute lymphocyte counts (ALC) in patients with Sepsis
    A.3.2Name or abbreviated title of the trial where available
    IRIS-7 C
    A.4.1Sponsor's protocol code number87RI-0015
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRevImmune
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRevImmune
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHU de Limoges
    B.5.2Functional name of contact pointRenaud Martin
    B.5.3 Address:
    B.5.3.1Street Address2 Avenue Martin Luther King
    B.5.3.2Town/ cityLimoges
    B.5.3.3Post code87042
    B.5.3.4CountryFrance
    B.5.4Telephone number+33555056349
    B.5.5Fax number+33555056696
    B.5.6E-mailrenaud.martin@chu-limoges.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCYT 107
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCYT 107
    D.3.9.2Current sponsor codeCYT 107
    D.3.9.3Other descriptive nameGLYCOSYLATED RECOMBINANT HUMAN INTERLEUKIN-7
    D.3.9.4EV Substance CodeSUB89974
    D.3.10 Strength
    D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Sepsis
    E.1.1.1Medical condition in easily understood language
    Sepsis
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to determine if IL-7 therapy will induce an increase in absolute lymphocyte count (ALC) of ≥ 50% at day 29 timepoint (or hospital discharge) following completion of study drug treatment in participants with vasopressor dependent sepsis.
    E.2.2Secondary objectives of the trial
    a)To compare the incidence of grade 3-4 adverse events for CYT107 vs. placebo
    b)To compare the effect of CYT107 versus placebo on the frequency of secondary infections and on the length of stay inICU, readmissions to ICU and organ support free days (OSFDs) during index hospitalization following study treatment initiation, and on the frequency of re-hospitalization
    c)To assess the impact of CYT107 on all-cause mortality
    d)To determine the effect of CYT107 on absolute CD4+ and CD8+ Tcell counts
    e)To track and evaluate other known biomarkers of sepsis: absolute lymphocyte counts, monocyte HLA-DR expression, soluble IL-7 receptor (CD127) expression, circulating levels of cytokines (IL-6, IL- 10 and TNF- α)
    f)To characterize CYT107 pharmacokinetics (PK) in patients with sepsis on day 1 and day 15 using IV route of administration
    g)To characterize CYT107 immunogenicity by detection and quantification of binding antibodies, and detection of neutralizing antibodies if positive.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. A written, signed informed consent, by the patient or the patient’s legally authorized representative, and the anticipated ability for participant to be re-consented in the future for ongoing study participation
    2. Men and women ages ≥ 18 – 85 years of age
    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,
    a. the second time point should not be performed earlier than 48 hours after sepsis diagnosis,
    b. 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
    c. 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:
    a. Acute respiratory failure defined as the need for invasive mechanical ventilation for at least 24 hours to support pulmonary function
    b. 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:
    a. 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
    b. Women must not be breastfeeding
    c. 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.
    d. 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.
    e. Azospermic males are exempt from contraceptive requirements.
    f. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements but still must undergo pregnancy testing as described in this section.
    E.4Principal 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 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. History of splenectomy
    10. Any hematologic disease associated with hypersplenism, such as thalassemia, hereditary
    spherocytosis, Gaucher’s Disease, and autoimmune hemolytic anemia
    11. Participation in another investigational interventional study testing a drug or a medical device within the last 3 months prior to study entry
    12. 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
    13. 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
    14. Prior exposure to IL 7 or other drugs specifically targeting T cells
    15. Presence of an advanced directive to withhold or withdraw life-sustaining treatment, DNR order or no CPR order, or comfort measures only order
    16. Patients for whom prognosis is poor and source control of septic event is considered unlikely per the clinical and research teams.
    17. Patients under guardianship
    E.5 End points
    E.5.1Primary end point(s)
    Weekly measures of absolute lymphocyte counts (ALC) will be performed to determine the kinetics of restoration of ALC. Specifically, we will quantitate the increase of ALC at day 29, expressed as a percentage of baseline value determined by ALC on two time points prior to study treatment (Day 1) during the screening period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    29 days
    E.5.2Secondary end point(s)
    a)Incidence and scoring of all grade 3-4 adverse events within 90 days after study treatment initiation
    b)Incidence of secondary infections within 90 days after treatment initiation based on pre-specified criteria as adjudicated by the Secondary Infections Committee (SIC), Number of days in ICU, readmissions to ICU, and organ support free days (OSFDs) following study treatment initiation during index hospitalization, Incidence of re-hospitalization within 90 days following study treatment initiation
    c)All-cause mortality at 90 days after study treatment initiation
    d)Absolute numbers of CD4+ and CD8+T-cell counts through day 90
    e)Examine and evaluate immune biomarkers:
    i. Percentage of patients reaching absolute lymphocyte counts (ALC) > 1200 in each dosing group
    ii. Effects on soluble and cellular IL-7 receptor (CD127) expression and their role in interpreting the CYT107 pharmacokinetics
    iii. Effects on circulating monocyte HLA-DR expression
    iv. Effects on whole blood circulating cytokines (IL-6, IL-10, TNF-α)
    f)PK Sessions: Participants will undergo serial blood sampling on days 1
    and day 15 at 0 (pre-dose), 1, 3, 5, 7, 9 and 24 hrs post CYT107
    administration. Model-independent PK analysis will be used to estimate Tmax, Cmax, half-life, clearance and area-under-the-curve (AUC)
    g)Assessment of CYT107 immunogenicity by detection and quantification of binding antibodies and detection of neutralizing antibodies in positive samples (see Section 1.3)
    E.5.2.1Timepoint(s) of evaluation of this end point
    180 days
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    the last visit of the last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patient under mechanically respiration
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-03-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-13
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-10-06
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