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Trial record 1 of 1 for:    NCT03085758
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Treatment of Patients With Early Septic Shock and Bio-Adrenomedullin(ADM) Concentration > 70 pg/ml With ADRECIZUMAB (AdrenOSS-2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03085758
Recruitment Status : Completed
First Posted : March 21, 2017
Last Update Posted : June 24, 2020
Sponsor:
Information provided by (Responsible Party):
Adrenomed AG

Tracking Information
First Submitted Date  ICMJE February 22, 2017
First Posted Date  ICMJE March 21, 2017
Last Update Posted Date June 24, 2020
Actual Study Start Date  ICMJE December 12, 2017
Actual Primary Completion Date December 20, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 23, 2020)
  • Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Mortality) [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period: Mortality related to ADRECIZUMAB
  • Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: interruption of infusion) [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period: Interruption of infusion due to intolerability of ADRECIZUMAB
  • Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: severity and frequency of TEAEs) [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period: Changes in severity and frequency of treatment-emergent adverse events
Original Primary Outcome Measures  ICMJE
 (submitted: March 15, 2017)
  • Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Mortality) [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period: Mortality related to ADRECIZUMAB
  • Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: interruption of infusion) [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period: Interruption of infusion due to intolerability of ADRECIZUMAB
  • Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: new treatment emergent AEs) [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period: New treatment-emergent adverse events related to ADRECIZUMAB
  • Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: severity and frequency of AEs) [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period: Changes in severity and frequency of treatment-emergent adverse events
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2020)
  • Efficacy to be determined by Sepsis Support Index (SSI) [ Time Frame: 14 days ]
    The primary efficacy endpoint of this study is the Sepsis Support Index (SSI) defined as: days with organ support or dead within 14 day follow up More precisely: In the time frame of 14 day follow-up, each day on support with vasopressor, and/or mechanical ventilation, and/or renal dysfunction (defined as renal SOFA = 4), or not alive, is counted as 1. The sum over the follow up period is defined as SSI.
  • Sepsis Support Index (SSI) [ Time Frame: 28 days ]
    Sepsis Support Index (SSI) at 28 day follow-up
  • Penalized Sepsis Support Index (pSSI) at 14 and 28 day follow-up [ Time Frame: day 14 and day 28 ]
    Penalized Sepsis Support Index (pSSI) at 14 and 28 day follow-up, defined similar to the SSI with the exception that patients that die get penalized by assigning the maximum value, i.e. the pSSI is set to 14 or 28, respectively
  • Persistent organ dysfunction or death at 14 and 28 day follow-up [ Time Frame: day 14 and day 28 ]
    Persistent organ dysfunction or death at 14 and 28 day follow-up
  • Mortality Rate [ Time Frame: day 28 and day 90 ]
    Day 28 and day 90 mortality rate
  • SSI and pSSI excluding the renal component [ Time Frame: 90 days ]
    SSI and pSSI excluding the renal component
  • SSI weighted for mortality [ Time Frame: 90 days ]
    SSI weighted for mortality
  • Individual Sepsis Support Index components [ Time Frame: 90 days ]
    Individual Sepsis Support Index components (hemodynamic, respiratory and renal failure) with and without mortality
  • Sequential Organ Failure Assessment (SOFA) Score : Composite measure: SOFA score and its changes over time [ Time Frame: 90 days ]
    Sequential Organ Failure Assessment (SOFA) Score:
    • Mean/maximum/total daily SOFA score during stay at ICU
    • Delta SOFA score, defined as maximum versus minimum SOFA during ICU stay
    • Change in SOFA score within 48 hours
    • SOFA-3 (score limited to cardiovascular, respiratory and renal function)
  • Improvement in renal function [ Time Frame: day 1, day 3 and day 7 ]
    Improvement in renal function as change in penKid and creatinine (day 3 - day 1, day 7 - day 1)
  • Duration of stay at ICU/ hospital [ Time Frame: 90 days ]
    Duration of stay at ICU/ hospital
  • Changes of functional parameter Mean Arterial Pressure during stay at ICU [ Time Frame: 90 days ]
    Changes of Mean Arterial Pressure (MAP)
  • Changes of functional parameter creatinine during stay at ICU [ Time Frame: 90 days ]
    Changes of creatinine
  • Changes of functional Parameter Partial Pressure of Oxygen in Arterial Blood(PaO2) / Fraction of inspired oxygen (FiO2) during stay at ICU [ Time Frame: 90 days ]
    Changes of PaO2/FiO2
  • Changes of functional Parameter blood lactate during stay at ICU [ Time Frame: 90 days ]
    Changes of blood lactate
  • Changes of functional Parameter fluid balance during stay at ICU [ Time Frame: 90 days ]
    Changes of fluid balance
  • Changes of functional Parameter Mid-Regional pro-Adrenomedullin (MR-proADM) during stay at ICU [ Time Frame: 90 days ]
    Changes of MR-proADM
  • Changes of functional parameter inflammatory marker Procalcitonine (PCT) during stay at ICU [ Time Frame: 90 days ]
    Changes of inflammatory marker PCT
  • Changes of functional Parameter inflammatory marker Interleukin-6 (IL-6) during stay at ICU [ Time Frame: 90 days ]
    Changes of inflammatory marker IL-6
  • Changes of functional Parameter dipeptidyl peptidase 3 (DPP3) during stay at ICU [ Time Frame: 90 days ]
    Changes of DPP3
  • Vasopressor use [ Time Frame: 90 days ]
    Vasopressor use (drug, highest/lowest dose, duration)
  • Patient reported outcomes : Quality of Life by Euro-QoL-5 [ Time Frame: day 28 and day 90 ]
    Patient reported outcomes : Quality of Life by Euro-QoL-5 (day 28 and day 90)
  • Vital signs [ Time Frame: 90 days ]
    Vital signs (heart rate, blood pressure)
Original Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2017)
  • Efficacy to be determined by Sepsis Support Index (SSI) [ Time Frame: 14 days ]
    The primary efficacy endpoint of this study is the Sepsis Support Index (SSI) defined as: days with organ support or dead within 14 day follow up More precisely: In the time frame of 14 day follow-up, each day on support with vasopressor, and/or mechanical ventilation, and/or renal dysfunction (defined as renal SOFA = 4), or not alive, is counted as 1. The sum over the follow up period is defined as SSI.
  • Sepsis Support Index (SSI) [ Time Frame: 28 days ]
    Sepsis Support Index (SSI) at 28 day follow-up
  • Penalized Sepsis Support Index (pSSI) at 14 and 28 day follow-up [ Time Frame: day 14 and day 28 ]
    Penalized Sepsis Support Index (pSSI) at 14 and 28 day follow-up, defined similar to the SSI with the exception that patients that die get penalized by assigning the maximum value, i.e. the pSSI is set to 14 or 28, respectively
  • Persistent organ dysfunction or death at 14 and 28 day follow-up [ Time Frame: day 14 and day 28 ]
    Persistent organ dysfunction or death at 14 and 28 day follow-up
  • Mortality Rate [ Time Frame: day 28 and day 90 ]
    Day 28 and day 90 mortality rate
  • SSI and pSSI excluding the renal component [ Time Frame: 90 days ]
    SSI and pSSI excluding the renal component
  • Individual Sepsis Support Index components [ Time Frame: 90 days ]
    Individual Sepsis Support Index components (hemodynamic, respiratory and renal failure) with and without mortality
  • Sequential Organ Failure Assessment (SOFA) Score : Composite measure: SOFA score and its changes over time [ Time Frame: 90 days ]
    Sequential Organ Failure Assessment (SOFA) Score:
    • Mean/maximum/total daily SOFA score during stay at ICU
    • Delta SOFA score, defined as maximum versus minimum SOFA during ICU stay
    • Change in SOFA score within 48 hours
    • SOFA-3 (score limited to cardiovascular, respiratory and renal function)
  • Improvement in renal function [ Time Frame: day 1, day 3 and day 7 ]
    Improvement in renal function as change in penKid and creatinine (day 3 - day 1, day 7 - day 1)
  • Length of stay at ICU/ hospital [ Time Frame: 90 days ]
    Length of stay at ICU/ hospital
  • Changes of functional parameter Mean Arterial Pressure during stay at ICU [ Time Frame: 90 days ]
    Changes of Mean Arterial Pressure (MAP)
  • Changes of functional parameter creatinine during stay at ICU [ Time Frame: 90 days ]
    Changes of creatinine
  • Changes of functional Parameter Partial Pressure of Oxygen in Arterial Blood(PaO2) / Fraction of inspired oxygen (FiO2) during stay at ICU [ Time Frame: 90 days ]
    Changes of PaO2/FiO2
  • Changes of functional Parameter blood lactate during stay at ICU [ Time Frame: 90 days ]
    Changes of blood lactate
  • Changes of functional Parameter fluid balance during stay at ICU [ Time Frame: 90 days ]
    Changes of fluid balance
  • Changes of functional Parameter Mid-Regional pro-Adrenomedullin (MR-proADM) during stay at ICU [ Time Frame: 90 days ]
    Changes of MR-proADM
  • Changes of functional parameter inflammatory marker Procalcitonine (PCT) during stay at ICU [ Time Frame: 90 days ]
    Changes of inflammatory marker PCT
  • Changes of functional Parameter inflammatory marker Interleukin-6 (IL-6) during stay at ICU [ Time Frame: 90 days ]
    Changes of inflammatory marker IL-6
  • Vasopressor use [ Time Frame: 90 days ]
    Vasopressor use (drug, highest/lowest dose, duration)
  • APACHE II score measurement [ Time Frame: 90 days ]
    APACHE II score measurement
  • Patient reported outcomes : Quality of Life by Euro-QoL-5 [ Time Frame: day 1, day 28 and day 90 ]
    Patient reported outcomes : Quality of Life by Euro-QoL-5 (day 1, day 28 and day 90)
  • Vital signs [ Time Frame: 90 days ]
    Vital signs (heart rate, blood pressure)
Current Other Pre-specified Outcome Measures
 (submitted: June 23, 2020)
  • In sub-study key Pharmacokinetic Parameters peak plasma concentrations (Cmax) are to be determined in 80 patients [ Time Frame: 28 days ]
    peak plasma concentrations (Cmax) prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
  • In sub-study key Pharmacokinetic Parameters time to Cmax (tmax) are to be determined in 80 patients [ Time Frame: 28 days ]
    Time to Cmax (tmax)
  • In sub-study key Pharmacokinetic Parameter AUC is to be determined in 80 patients [ Time Frame: 28 days ]
    systemic exposure : Area under the plasma concentration versus time curve (AUC) prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
  • In sub-study key Pharmacokinetic Parameter volume of distribution is to be determined in 80 patients [ Time Frame: 28 days ]
    volume of distribution (V) prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
  • In sub-study key Pharmacokinetic Parameter systemic clearance is to be determined in 80 patients [ Time Frame: 28 days ]
    systemic clearance (CL)prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
  • In sub-study key Pharmacokinetic Parameter Elimination half-life is to be determined in 80 patients [ Time Frame: 28 days ]
    elimination half-life (t½) prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
Original Other Pre-specified Outcome Measures
 (submitted: March 15, 2017)
  • In sub-study key Pharmacokinetic Parameters peak plasma concentrations (Cmax) are to be determined in 80 patients [ Time Frame: 28 days ]
    peak plasma concentrations (Cmax) at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
  • In sub-study key Pharmacokinetic Parameter AUC is to be determined in 80 patients [ Time Frame: 28 days ]
    systemic exposure : Area under the plasma concentration versus time curve (AUC) at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
  • In sub-study key Pharmacokinetic Parameter volume of distribution is to be determined in 80 patients [ Time Frame: 28 days ]
    volume of distribution (V) at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
  • In sub-study key Pharmacokinetic Parameter systemic clearance is to be determined in 80 patients [ Time Frame: 28 days ]
    systemic clearance (CL) at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
  • In sub-study key Pharmacokinetic Parameter Elimination half-life is to be determined in 80 patients [ Time Frame: 28 days ]
    elimination half-life (t½) at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
 
Descriptive Information
Brief Title  ICMJE Treatment of Patients With Early Septic Shock and Bio-Adrenomedullin(ADM) Concentration > 70 pg/ml With ADRECIZUMAB
Official Title  ICMJE A Double-Blind, Placebo-Controlled, Randomized, Multicenter, Proof of Concept and Dose-Finding Phase II Clinical Trial to Investigate the Safety, Tolerability and Efficacy of ADRECIZUMAB in Patients With Septic Shock and Elevated Adrenomedullin
Brief Summary This is a double-blind, placebo-controlled, randomized, multicenter proof of concept and dose-finding phase II study using two doses of ADRECIZUMAB in patients with early septic shock and a bio-ADM plasma concentration at admission of > 70 pg/ml.
Detailed Description

This is a double-blind, placebo-controlled, randomized, multicenter proof of concept and dose-finding phase II study using two doses of ADRECIZUMAB in patients with early septic shock and a bio-ADM plasma concentration at admission of > 70 pg/ml.

"Early" septic shock is defined as a life-threatening organ dysfunction due to dysregulated host response to a proven or suspected infection which leads to a decline of Mean Arterial Pressure (MAP) < 65 mmHg, which is refractory to fluid resuscitation and requires vasopressors. Early is defined as a maximum of less than 12 hours between onset of the cardiovascular organ-dysfunction and administration of ADRECIZUMAB. Refractoriness to fluid resuscitation is defined as a lack of response to the administration of 30 mL of fluid per kilogram of body weight or is determined according to a clinician's assessment of inadequate hemodynamic results.

It is intended to enroll 300 patients from surgical, medical and mixed ICU at multiple centers in Europe.

All patients will be treated according to "International Guidelines for Management of Severe Sepsis and Septic Shock".

Eligible patients (confirmed by central verification) will be randomized (1:1:2) to ADRECIZUMAB treatment arm A (2 mg/kg) or to ADRECIZUMAB treatment arm B (4 mg/kg) or to placebo as control group. Patients assigned to the treatment arm A or B will be administered a single dose of ADRECIZUMAB as intravenous infusion over approximately 1 hour; patients assigned to the control group will be administered placebo as intravenous infusion over approximately 1 hour.

As long as the patients are on the ICU, daily measurements of clinical signs and laboratory data will be collected for safety reasons and for determination of Sequential Organ Failure Assessment Score (SOFA score). Additional blood samples for central laboratory analyses will be taken at inclusion on day 1, day 3, day 5, day 7 or day of discharge (whatever comes first) for measurement of biomarkers.

The SOFA score and its components will be determined daily for all patients over the entire stay on the ICU (28 days or until discharge whatever comes first). Safety monitoring for each patient will begin at the time of signing the Informed Consent Form and continue for 90 days after end of short-term infusion of study medication.

At selected study centers a pharmacokinetic (PK) substudy will be performed to determine the profile of ADRECIZUMAB in 80 randomized patients.

An interim analysis for efficacy is planned after 50% of patients have completed the study (n=150).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Double Blind, Placebo-Controlled, Randomized, Multicenter Proof of Concept and Dose-Finding Phase II Clinical Trial
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Septic Shock
Intervention  ICMJE
  • Biological: Adrecizumab
    Single i.v. dose of 2 mg/kg (treatment arm A) or 4 mg/kg (treatment arm B)
  • Biological: Placebo
    Single i.v. dose of placebo (control group)
Study Arms  ICMJE
  • Experimental: Treatment Arm A
    Intravenous infusion over approximately 1 hour of single i.v. dose of 2 mg/kg Adrecizumab (treatment arm A)
    Intervention: Biological: Adrecizumab
  • Experimental: Treatment Arm B
    Intravenous infusion over approximately 1 hour of single i.v. dose of 4 mg/kg Adrecizumab (treatment arm B)
    Intervention: Biological: Adrecizumab
  • Placebo Comparator: Control group
    Intravenous infusion over approximately 1 hour of single i.v. dose of Placebo of Adrecizumab (control group)
    Intervention: Biological: Placebo
Publications * Geven C, Blet A, Kox M, Hartmann O, Scigalla P, Zimmermann J, Marx G, Laterre PF, Mebazaa A, Pickkers P. A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2). BMJ Open. 2019 Feb 19;9(2):e024475. doi: 10.1136/bmjopen-2018-024475.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 23, 2020)
301
Original Estimated Enrollment  ICMJE
 (submitted: March 15, 2017)
300
Actual Study Completion Date  ICMJE December 20, 2019
Actual Primary Completion Date December 20, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Written informed consent by patient or legal representative (according to country - specific regulations)
  2. Male and female patient, age ≥ 18 years
  3. Body weight 50 kg - 120 kg
  4. Bio-ADM concentration > 70 pg/ml
  5. Patient with early septic shock (start of vasopressor therapy < 12 hours)
  6. Women of childbearing potential must have a negative serum or urine pregnancy test before randomization
  7. Highly effective method of contraception must be maintained for 6 months after study start by women of childbearing potential and sexually active men.
  8. No care limitation

Exclusion Criteria:

  1. Moribund
  2. Pre-existing unstable condition (e.g. a recent cerebral hemorrhage or infarct, a recent acute unstable myocardial infarction (all < 3 months), congestive heart failure - New York Heart Association (NYHA) Class IV
  3. Patients that required cardiopulmonary resuscitation in the last 4 weeks prior to evaluation for enrollment
  4. Severe Chronic Obstructive Pulmonary Disease (COPD) with chronic oxygen need at home (GOLD IV)
  5. Any organ or bone marrow transplant within the past 24 weeks
  6. Uncontrolled serious hemorrhage (≥ 2 units of blood / platelets in the previous 24 hrs.). Patients may be considered for enrollment if bleeding has stopped and patient is otherwise qualified
  7. Uncontrolled hematological / oncological malignancies
  8. Absolute neutropenia < 500 per µL
  9. Severe chronic liver disease (Child-Pugh C)
  10. Systemic fungal infection or active tuberculosis
  11. Neuromuscular disorders that impact breathing / spontaneous ventilation
  12. Burns > 30% of body surface
  13. Plasmapheresis
  14. Breastfeeding women
  15. Participation in a clinical trial involving another investigational drug within 4 weeks prior to inclusion
  16. Unwilling or unable to be fully evaluated for all follow-up visits
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   France,   Germany,   Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03085758
Other Study ID Numbers  ICMJE ADR-02
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Adrenomed AG
Study Sponsor  ICMJE Adrenomed AG
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Jens Zimmermann, Dr. Adrenomed AG
PRS Account Adrenomed AG
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP