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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
Results First Posted : March 24, 2021
Last Update Posted : March 24, 2021
Sponsor:
Information provided by (Responsible Party):
Adrenomed AG

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.

Condition or disease Intervention/treatment Phase
Septic Shock Biological: Adrecizumab Biological: Placebo Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 301 participants
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
Official Title: 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
Actual Study Start Date : December 12, 2017
Actual Primary Completion Date : December 20, 2019
Actual Study Completion Date : December 20, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Shock

Arm Intervention/treatment
Experimental: Treatment Arm A
Intravenous infusion over approximately 1 hour of single i.v. dose of 2 mg/kg Adrecizumab (treatment arm A)
Biological: Adrecizumab
Single i.v. dose of 2 mg/kg (treatment arm A) or 4 mg/kg (treatment arm B)

Experimental: Treatment Arm B
Intravenous infusion over approximately 1 hour of single i.v. dose of 4 mg/kg Adrecizumab (treatment arm B)
Biological: Adrecizumab
Single i.v. dose of 2 mg/kg (treatment arm A) or 4 mg/kg (treatment arm B)

Placebo Comparator: Control group
Intravenous infusion over approximately 1 hour of single i.v. dose of Placebo of Adrecizumab (control group)
Biological: Placebo
Single i.v. dose of placebo (control group)




Primary Outcome Measures :
  1. Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Mortality) [ Time Frame: 90 days ]
    The endpoints for the primary objective is mortality evaluated over the 90 days study period.

  2. 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

  3. Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Frequency of TEAEs) [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period. Number of participants with treatment-emergent adverse events per treatment group.

  4. Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs) - Mild Severity [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period. Number of participants with treatment-emergent adverse events per treatment group with mild severity treatment emergent events.

  5. Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs) - Moderate Severity [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period. Number of participants with treatment-emergent adverse events per treatment group with moderate severity treatment emergent events.

  6. Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs) - Severe Severity [ Time Frame: 90 days ]
    The endpoints for the primary objective are to determine over the 90 days study period. Number of participants with treatment-emergent adverse events per treatment group with severe severity treatment emergent events.


Secondary Outcome Measures :
  1. 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.

    Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome.


  2. Sepsis Support Index (SSI) [ Time Frame: 28 days ]
    Sepsis Support Index (SSI) at 28 day follow-up Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome.

  3. Penalized Sepsis Support Index (pSSI) at 14 Day Follow-up [ Time Frame: day 14 ]

    Penalized Sepsis Support Index (pSSI) at day 14, 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.

    Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome.


  4. 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. Count of participants with either persistent organ dysfunction or death at Day 14 and Day 28. Persistent Organ Dysfunction is defined as the persistence of organ dysfunction requiring supportive technologies during the convalescent phase of critical illness and it is present when a patient has an ongoing requirement for vasopressors, dialysis, or mechanical ventilation at the outcome assessments time points, as defined by Heyland et al.; Persistent organ dysfunction plus death: a novel,composite outcome measure for critical care trials. Critical Care 2011, 15.

  5. Mortality Rate [ Time Frame: day 28 ]
    Day 28 mortality rate

  6. SSI and pSSI Excluding the Renal Component [ Time Frame: day 14 and day 28 ]
    Sepsis Support Index (SSI) and penalized Sepsis Support Index (pSSI) excluding the renal component. pSSI is a version of the SSI where mortality is given extra weight: Patients being alive during the 14 days' follow up will have an SSI ranging up to 14, while patients who died within that period will be assigned a score of "14 plus the number of days not being alive". Thus the SSI and pSSI score may range between zero and 28. A higher score means a worse outcome. The number of participants analyzed differs per row due to missing data.

  7. SSI Weighted for Mortality [ Time Frame: day 14 ]
    Sepsis Support Index (SSI) Weighted for Mortality. Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome.

  8. Individual Sepsis Support Index Components [ Time Frame: day 14 and day 28 ]

    Individual Sepsis Support Index (SSI) components (hemodynamic, respiratory and renal failure) with and without mortality.

    Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome. The number of participants analyzed differs per row due to missing data.


  9. Sequential Organ Failure Assessment (SOFA) Score : Composite Measure: SOFA Score and Its Changes Over Time [ Time Frame: 28 days ]

    Sequential Organ Failure Assessment (SOFA) Score:

    SOFA score change at Day 3 - baseline, delta = difference between maximum and minimum score during ICU stay, mean/maximum/total daily score during ICU stay, SOFA-3 (score limited to cardiovascular, respiratory and renal function). Measured at baseline and Day 3.

    SOFA score: Minimum possible score is 0, maximum is 24. A higher score meas a worse outcome. Measured at baseline, Day 2 to Day 28.

    SOFA-3 score: Minimum possible score is 0, maximum is 12. A higher score meas a worse outcome. Measured at baseline, Day 2 to Day 28.


  10. Change in Renal Function (Creatinine) [ Time Frame: day 1, day 3 and day 7 ]
    Change in renal function as change in creatinine (day 3 - day 1, day 7 - day 1)

  11. Duration of Stay at ICU/ Hospital [ Time Frame: 90 days ]
    Duration of stay at ICU / hospital. The number of participants analyzed differs per row due to missing data.

  12. Changes of Functional Parameter Mean Arterial Pressure During Stay at ICU [ Time Frame: 28 days ]
    Changes of Mean Arterial Pressure (MAP). Change from baseline to day 28/last day in ICU was calculated (value at day 28 or last collected value minus value at baseline). MAP was collected at screening and daily from day 1 to day 28 or discharge as well as on the follow-up visit day 28. Vital signs were assessed as min/max values within 24 hours except at screening and on the follow-up visit day 28.

  13. Changes of Functional Parameter Creatinine During Stay at ICU [ Time Frame: 28 days ]
    Changes of creatinine. Measurement for baseline and Day 28 given. Creatinine was measured in the daily blood sample during ICU stay until discharge or Day 28 in a local laboratory assessment.

  14. Changes of Functional Parameter Partial Pressure of Oxygen in Arterial Blood(PaO2) / Fraction of Inspired Oxygen (FiO2) During Stay at ICU [ Time Frame: 28 days ]
    Changes of Partial Pressure of Oxygen in Arterial Blood (PaO2) / Fraction of inspired oxygen (FiO2) from baseline to the last observed value are measured. PaO2 and FiO2 was collected if an arterial line was in place. The arterial blood was assessed for PaO2 and FiO2. Both were measured in mmHg.

  15. Changes of Functional Parameter Blood Lactate During Stay at ICU [ Time Frame: 28 days ]
    Changes of blood lactate from baseline to Day 28 or discharge. Blood lactate was measured in the daily blood sample from baseline to ICU discharge or until Day 28.

  16. Changes of Functional Parameter Fluid Balance During Stay at ICU [ Time Frame: 28 days ]

    Changes of fluid balance - Last Observed Value. Percentage of Participants with low (</=1000 mL) and high (>1000 mL) Fluid balance at the last observed value.

    Daily fluid intake will be calculated as the sum of all intravenous and oral fluids. The daily fluid output will be calculated as the sum of the volume of urine output, ultrafiltration fluid, drain fluid, and estimated gastrointestinal losses (including stools only in the presence of profound diarrhea). Insensitive losses will not be taken into account because they are difficult to assess reliably. Daily fluid balance (according to baseline patient weight) will be calculated by subtracting the total fluid output from the total intake.


  17. Changes of Functional Parameter Mid-Regional Pro-Adrenomedullin (MR-proADM) During Stay at ICU [ Time Frame: 28 days ]
    Changes of Mid-Regional pro-Adrenomedullin (MR-proADM) between baseline and last observed value. MR-proADM was measured in the blood samples taken during the ICU stay prior to start of IMP infusion (day 1) and within the time frame of 24 hours (+/- 10 hours) after end of IMP infusion (day 2), at 48 hours, 96 hours and 144 hours after end of infusion (+/- 10 hours) or between scheduled assessments, if discharged earlier from ICU (whatever comes first).

  18. Changes of Functional Parameter Inflammatory Marker Procalcitonine (PCT) During Stay at ICU [ Time Frame: 28 days ]
    Changes of inflammatory marker Procalcitonine (PCT) between baseline and last observed value. PCT was measured in the blood samples taken during the ICU stay prior to start of IMP infusion (day 1) and within the time frame of 24 hours (+/- 10 hours) after end of IMP infusion (day 2), at 48 hours, 96 hours and 144 hours after end of infusion (+/- 10 hours) or between scheduled assessments, if discharged earlier from ICU (whatever comes first).

  19. Changes of Functional Parameter Inflammatory Marker Interleukin-6 (IL-6) During Stay at ICU [ Time Frame: 28 days ]
    Changes of inflammatory marker Interleukin-6 (IL-6) between baseline and last observed value. IL-6 was measured in the blood samples taken during the ICU stay prior to start of IMP infusion (day 1) and within the time frame of 24 hours (+/- 10 hours) after end of IMP infusion (day 2), at 48 hours, 96 hours and 144 hours after end of infusion (+/- 10 hours) or between scheduled assessments, if discharged earlier from ICU (whatever comes first).

  20. Changes of Functional Parameter Dipeptidyl Peptidase 3 (DPP3) During Stay at ICU [ Time Frame: 28 days ]
    Changes of dipeptidyl peptidase 3 (DPP3) between baseline and last observed value. DPP3 was measured in the blood samples taken during the ICU stay prior to start of IMP infusion (day 1) and within the time frame of 24 hours (+/- 10 hours) after end of IMP infusion (day 2), at 48 hours, 96 hours and 144 hours after end of infusion (+/- 10 hours) or between scheduled assessments, if discharged earlier from ICU (whatever comes first).

  21. Vasopressor Use (Drug, Highest Dose) [ Time Frame: 28 days ]
    Vasopressor use (drug, highest dose). Vasopressor use was recorded from admission to ICU at time point of diagnosis of septic shock and daily thereafter from day 1 through day 28 or discharge from ICU (whatever comes first).

  22. Patient Reported Outcomes : Quality of Life by Euro-QoL-5 [ Time Frame: day 28 and day 90 ]
    Patient reported outcomes: Quality of Life Form by EuroQoL Group, version "Euro-QoL-5" (day 28 and day 90). Change 1 = Visual analog scale (VAS) at discharge - VAS at day 90. Change 2 = VAS at day 28 - VAS at day 90. Minimum value on the scale is 0, maximum value on the scale is 100. A lower score indicates a worse outcome. As the change between two scores is calculated, a negative number indicates a worsening.

  23. Vital Signs [ Time Frame: 7 days ]
    Vital signs: heart rate (beat per minute) Change from baseline to Day 7.

  24. Penalized Sepsis Support Index (pSSI) at 28 Day Follow-up [ Time Frame: day 28 ]
    Penalized Sepsis Support Index (pSSI) at 28 day follow-up, is a version of the SSI where mortality is given extra weight: Patients being alive duringthe 14 days' follow up will have an SSI ranging up to 14 (as defined above), while patients who died within that period will be assigned a score of "14 plus the number of days not being alive". Thus the weighted SSI score may range between zero and 28. A higher score means a worse outcome.

  25. Vasopressor Use (Drug, Lowest Dose) [ Time Frame: 28 days ]
    Vasopressor use (drug, lowest dose). Vasopressor use was recorded from admission to ICU at time point of diagnosis of septic shock and daily thereafter from day 1 through day 28 or discharge from ICU (whatever comes first).

  26. Vasopressor Use (Drug, Duration) [ Time Frame: 28 days ]
    Vasopressor use (drug, duration). Vasopressor use was recorded from admission to ICU at time point of diagnosis of septic shock and daily thereafter from day 1 through day 28 or discharge from ICU (whatever comes first).

  27. Change in Renal Function (penKid) [ Time Frame: day 1, day 3 and day 7 ]
    Change in renal function as change in penKid (day 3 - day 1, day 7 - day 1). penKid was measured in the blood samples taken during the ICU stay prior to start of IMP infusion (day 1) and within the time frame of 24 hours (+/- 10 hours) after end of IMP infusion (day 2), at 48 hours, 96 hours and 144 hours after end of infusion (+/- 10 hours) or between scheduled assessments, if discharged earlier from ICU (whatever comes first).

  28. Vital Signs - Blood Pressure [ Time Frame: 7 days ]
    Vital signs: blood pressure - mean arterial pressure (MAP) mmHg Change from baseline to Day 7.


Other Outcome Measures:
  1. 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). Time points at which blood samples were taken prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after IMP administration.

  2. 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 hours (h)

  3. 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). Time points at which blood samples were taken prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after IMP administration.

  4. In Sub-study Key Pharmacokinetic Parameter Volume of Distribution is to be Determined in 80 Patients [ Time Frame: 28 days ]
    volume of distribution (V). Time points at which blood samples were taken prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after IMP administration.

  5. In Sub-study Key Pharmacokinetic Parameter Systemic Clearance is to be Determined in 80 Patients [ Time Frame: 28 days ]
    systemic clearance (CL). Time points at which blood samples were taken prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after IMP administration.

  6. In Sub-study Key Pharmacokinetic Parameter Elimination Half-life is to be Determined in 80 Patients [ Time Frame: 28 days ]
    elimination half-life (t½). Time points at which blood samples were taken prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after IMP administration.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03085758


Locations
Show Show 30 study locations
Sponsors and Collaborators
Adrenomed AG
Investigators
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Study Director: Jens Zimmermann, Dr. Adrenomed AG
  Study Documents (Full-Text)

Documents provided by Adrenomed AG:
Study Protocol  [PDF] August 28, 2019
Statistical Analysis Plan  [PDF] February 5, 2020

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Adrenomed AG
ClinicalTrials.gov Identifier: NCT03085758    
Other Study ID Numbers: ADR-02
First Posted: March 21, 2017    Key Record Dates
Results First Posted: March 24, 2021
Last Update Posted: March 24, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Adrenomed AG:
Early Septic Shock
Additional relevant MeSH terms:
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Shock, Septic
Shock
Pathologic Processes
Sepsis
Infections
Systemic Inflammatory Response Syndrome
Inflammation