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    Summary
    EudraCT Number:2007-004401-10
    Sponsor's Protocol Code Number:HYPRESS
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-02-28
    Trial results View 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 ConcernedGermany - BfArM
    A.2EudraCT number2007-004401-10
    A.3Full title of the trial
    Hydrocortisone for Prevention of Septic Shock
    Placebo-controlled, randomised, double-blind study to investigate the efficacy and safety of low dose hydrocortisone to prevent the development of septic shock in patients with severe sepsis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The trial investiges if the early administration of the glucocorticoid hydrocortisone in low doses prevents the development of cardiovascular c0llaps (shock) in patients with severe sepsis who are not in shock.
    A.3.2Name or abbreviated title of the trial where available
    HYPRESS
    A.4.1Sponsor's protocol code numberHYPRESS
    A.5.4Other Identifiers
    Name:clinical trialsNumber:NCT 00670254
    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 SponsorCharité Universitätsmedizin Berlin
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportFederal Ministry of Education and Research
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCharité Universitaetsmedizin Berlin
    B.5.2Functional name of contact pointDidier Keh
    B.5.3 Address:
    B.5.3.1Street AddressAugustenburger Platz 1
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13353
    B.5.3.4CountryGermany
    B.5.4Telephone number004930450651048
    B.5.5Fax number0049304507551039
    B.5.6E-maildidier.keh@charite.de
    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 namenot applicable
    D.3.2Product code not applicable
    D.3.4Pharmaceutical form Powder and solvent for solution for infusion
    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.3.9.1CAS number 8000042979
    D.3.9.3Other descriptive nameHYDROCORTISONE HYDROGEN SUCCINATE
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 placeboPowder for solution for infusion
    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
    Patients with severe sepsis
    E.1.1.1Medical condition in easily understood language
    Severe sepsis
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10040047
    E.1.2Term Sepsis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Prevention of the development of septic shock in patients with severe sepsis
    E.2.2Secondary objectives of the trial
    Mortality and survival, length of ICU and hospital stay, time until septic shock develops, organ dysfunctions, duration of mechanical ventilation and renal replacement therapy, incidence of side effects and adverse events (safety), adrenal function at baseline
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Evaluation of Posttraumatic Stress Disorder and Health-related Quality of Life
    Objective: Quationnaires at hospital discharge and after 6 months

    Continuation of the SepNet central blood sample storage bank for identification and validation of future biomarkers of sepsis and evaluation of genetic polymorphisms Evaluation of immune responses to low dose hydrocortisone

    Objectives: blood sampling within the first 7 days after randomisation
    E.3Principal inclusion criteria
    Patients must meet ALL inclusion criteria:
    1. Informed consent from patient, legal representative, proxy, or independent medical consultant.
    2. In women with child bearing potential an effective contraception with a failure rate < 1 %.
    3. Clinical evidence of INFECTION (may be present ≥ 48 hours) –
    At least one of a-d is required.
    a. Pathogenic micro-organism in blood, sputum, urine, or normally sterile body fluid
    b. Identified focus of infection (e.g. ruptured bowel, purulent drainage or sputum)
    c. Presence of granulocytes in normally sterile body fluid
    d. Clinically suspected infection without positive culture of pathogenic microorganism (e.g. new infiltrate in chest X-ray, treated pneumonia, necrotizing fasciitis, purpura fulminans)
    4. Evidence of SIRS (may be present ≥ 48 hours) –
    At least two of a-d are required.
    a. Fever (≥38 °C) or Hypothermia (≤ 36 °C)
    b. Tachycardia (≥ 90 bpm)
    c. Tachypnea (≥ 20 bpm) or hyperventilation (PaCO2 ≤ 33 mmHg [≤ 4.3 kPa], or mechanical ventilation
    d. Leukocytosis (≥ 12.000 / µl) or leukopenia (≤ 4.000 / µl) or ≥ 10 % immature forms
    5. Evidence of ORGAN DYSFUNCTION (may NOT be present ≥ 48 hours –
    At least one organ dysfunction of a-e is required
    a. Encephalopathy: Reduced vigilance, disorientation, agitation, delirium etc. in the absence of psychotropic drugs
    b. Acute renal dysfunction: Oliguria: ≤ 0.5 ml/kg/h ≥ 2 h despite adequate volume replacement and/or creatinine increase > 2 x above the normal upper range, and/or need for renal replacement therapy.
    c. Coagulation dysfunction: Platelets ≤ 100.000/µl or more than 30 % decrease from baseline within 24 hours. Thrombocytopenia may not be due to haemorrhage or immunologically induced.
    d. Pulmonary dysfunction/hypoxemia: PaO2 ≤ 75 mmHg [≤ 10 kPa] at room air or PaO2/FiO2 ≤ 250 mmHg [≤ 33 kPa] with oxygen application. Hypoxemia may not be due to primary cardiac or pulmonary dysfunction (e.g. emphysema)
    e. Microcirculatory dysfunction: Lactate > 1.5 x above the normal upper range and/or base deficit ≥ 5 mmol/l and/or metabolic acidosis with pH < 7.3 and/or depressed capillary refill/mottling and/or significant body edema (capillary leakage syndrome)

    A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner. For subjects using a hormonal contraceptive method, information regarding the product under evaluation and its potential effect on the contraceptive should be addressed [ICH-ORG 1995]
    Due to the severity of the disease and hospitalisation, sexual abstinence during application of the study medication is assumed and may be regarded as an effective method of contraception, even if the investigator is not aware of an alternative mode of applied contraceptive method at the time of inclusion into the study.
    E.4Principal exclusion criteria
    Patients will be excluded for ANY ONE of the following reasons:

    I. Sepsis-induced HYPOTENSION despite adequate volume replacement defined as a mean arterial pressure (MAP) < 65 mmHg or a systolic arterial pressure (SAP) < 90 mmHg, or the use of vasopressors to keep MAP ≥ 65 mmHg or SAP ≥ 90 mmHg, IF any of these conditions persist for 4 hours ore more.

    NOTE: Patients who received transiently vasopressors only during initial resuscitation (volume deficit) or had an iatrogenic-induced hypotension (e.g. intubation, bolus sedation), but are free of vasopressors and have no hypotension for at least two hours after initial resuscitation or the hypotensive event, are defined to be not in shock. It is essential that at the time of allocation of study medication, patients MAY NOT be in septic shock.
    Adequate volume status is defined as a central venous pressure ≥ 8 mmHg in non-ventilated and ≥ 12 mmHg in ventilated patients, and a central venous oxygen saturation ≥ 70 %.
    Vasopressor is defined as dopamine ≥ 5 µg/kg/min or any dose of epinephrine, norepinephrine, vasopressin, or other vasopressor.
    II. Patients with known hypersensitivity to hydrocortison-21-hydrogensuccinate, natrium-monohydrogenphosphate , or mannitol (placebo).
    III. Patients who have a glucocorticoid history AND in whom a continued glucocorticoid therapy may be indicated (e.g. > 10 mg prednisolone equivalent per day for at least 5 days within the last 3 months). Topical or inhaled glucocorticoids are NO exclusion criteria, unless there is an indication for continued systemic glucocorticoid administration.
    IV. Other indications for systemic glucocorticoid therapy (e.g. asthma, COPD, anaphylaxis, autoimmune diseases)
    V. DNR-order
    VI. Moribund patients
    VII. Pregnancy (positive pregnancy test in women with child bearing potential)
    VIII. Breast feeding women
    IX. Age < 18 years
    X. Concomitant or previous (within the last 30 days) participation in an other interventional clinical trial
    XI. Relationship to the investigator (e.g. relatives, colleagues, staff)
    E.5 End points
    E.5.1Primary end point(s)
    Septic shock
    E.5.1.1Timepoint(s) of evaluation of this end point
    14 days
    E.5.2Secondary end point(s)
    28-day mortality (proportion of patients who die within 28 days from any cause)
    • 90 and 180-day mortality
    • ICU-mortality
    • Hospital mortality
    • Time to death from any cause and sepsis-related death
    • Length of ICU stay
    • Length of hospital stay
    • Time to septic shock and/or death within 14 days
    • Frequency and duration of mechanical ventilation until ICU discharge
    • Frequency and duration of renal replacement until ICU discharge
    • Mean total SOFA (organ dysfunction) and mean SOFA sub-scores until ICU discharge but day 14 at maximum
    • Frequency of weaning failure until ICU-discharge
    • Frequency and severity of muscle weakness until ICU-discharge
    • Frequency of GI-bleeding within 28 days
    • Frequency of secondary infections within 28 days
    • Frequency of delirium until ICU-discharge
    • Blood sodium level and frequency of hypernatremia (> 155 mmol/l) within 14 days
    • Blood glucose level and frequency of hyperglycemia (> 150 mg/dl) within 14 days
    • Other AEs or SAEs within 28 days
    E.5.2.1Timepoint(s) of evaluation of this end point
    see E.5.2
    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 No
    E.6.7Pharmacodynamic No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 concerned20
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 trial ends after follow-up (visit) of the last patient.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    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: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 230
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2008-02-28. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    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
    In general, patients are sedated and mechanically ventilated due to the severity of the disease
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state380
    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)
    Routine treatment
    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 Decision2007-02-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-01-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-01-29
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