Treatment of Patients With Early Septic Shock and Bio-Adrenomedullin(ADM) Concentration > 70 pg/ml With ADRECIZUMAB

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Septic Shock

Intervention / Treatment
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* Biological: Adrecizumab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent by patient or legal representative (according to country - specific regulations) Male and female patient, age ≥ 18 years Body weight 50 kg - 120 kg Bio-ADM concentration > 70 pg/ml Patient with early septic shock (start of vasopressor therapy < 12 hours) Women of childbearing potential must have a negative serum or urine pregnancy test before randomization Highly effective method of contraception must be maintained for 6 months after study start by women of childbearing potential and sexually active men. No care limitation Exclusion Criteria: Moribund 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 Patients that required cardiopulmonary resuscitation in the last 4 weeks prior to evaluation for enrollment Severe Chronic Obstructive Pulmonary Disease (COPD) with chronic oxygen need at home (GOLD IV) Any organ or bone marrow transplant within the past 24 weeks 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 Uncontrolled hematological / oncological malignancies Absolute neutropenia < 500 per µL Severe chronic liver disease (Child-Pugh C) Systemic fungal infection or active tuberculosis Neuromuscular disorders that impact breathing / spontaneous ventilation Burns > 30% of body surface Plasmapheresis Breastfeeding women Participation in a clinical trial involving another investigational drug within 4 weeks prior to inclusion Unwilling or unable to be fully evaluated for all follow-up visits

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double Blind, Placebo-Controlled, Randomized, Multicenter Proof of Concept and Dose-Finding Phase II Clinical Trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm A<br>Intravenous infusion over approximately 1 hour of single i.v. dose of 2 mg/kg Adrecizumab (treatment arm A) | Biological: Adrecizumab<br>* Single i.v. dose of 2 mg/kg (treatment arm A) or 4 mg/kg (treatment arm B)<br>|
| Experimental: Treatment Arm B<br>Intravenous infusion over approximately 1 hour of single i.v. dose of 4 mg/kg Adrecizumab (treatment arm B) | Biological: Adrecizumab<br>* Single i.v. dose of 2 mg/kg (treatment arm A) or 4 mg/kg (treatment arm B)<br>|
| Placebo Comparator: Control group<br>Intravenous infusion over approximately 1 hour of single i.v. dose of Placebo of Adrecizumab (control group) | Biological: Placebo<br>* Single i.v. dose of placebo (control group)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Mortality) | The endpoints for the primary objective is mortality evaluated over the 90 days study period. | 90 days | 
| Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Interruption of Infusion) | The endpoints for the primary objective are to determine over the 90 days study period: Interruption of infusion due to intolerability of ADRECIZUMAB | 90 days | 
| Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Frequency of TEAEs) | 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. | 90 days | 
| Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs) - Mild Severity | 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. | 90 days | 
| Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs) - Moderate Severity | 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. | 90 days | 
| Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs) - Severe Severity | 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. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy to be Determined by Sepsis Support Index (SSI) | 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. | 14 days | 
| Sepsis Support Index (SSI) | 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. | 28 days | 
| Penalized Sepsis Support Index (pSSI) at 14 Day Follow-up | 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. | day 14 | 
| Persistent Organ Dysfunction or Death at 14 and 28 Day Follow-up | 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. | day 14 and day 28 | 
| Mortality Rate | Day 28 mortality rate | day 28 | 
| SSI and pSSI Excluding the Renal Component | 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. | day 14 and day 28 | 
| SSI Weighted for Mortality | Sepsis Support Index (SSI) Weighted for Mortality. Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome. | day 14 | 
| Individual Sepsis Support Index Components | 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. | day 14 and day 28 | 
| Sequential Organ Failure Assessment (SOFA) Score : Composite Measure: SOFA Score and Its Changes Over Time | 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. | 28 days | 
| Change in Renal Function (Creatinine) | Change in renal function as change in creatinine (day 3 - day 1, day 7 - day 1) | day 1, day 3 and day 7 | 
| Duration of Stay at ICU/ Hospital | Duration of stay at ICU / hospital. The number of participants analyzed differs per row due to missing data. | 90 days | 
| Changes of Functional Parameter Mean Arterial Pressure During Stay at ICU | 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. | 28 days | 
| Changes of Functional Parameter Creatinine During Stay at ICU | 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. | 28 days | 
| Changes of Functional Parameter Partial Pressure of Oxygen in Arterial Blood(PaO2) / Fraction of Inspired Oxygen (FiO2) During Stay at ICU | 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. | 28 days | 
| Changes of Functional Parameter Blood Lactate During Stay at ICU | 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. | 28 days | 
| Changes of Functional Parameter Fluid Balance During Stay at ICU | 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. | 28 days | 
| Changes of Functional Parameter Mid-Regional Pro-Adrenomedullin (MR-proADM) During Stay at ICU | 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). | 28 days | 
| Changes of Functional Parameter Inflammatory Marker Procalcitonine (PCT) During Stay at ICU | 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). | 28 days | 
| Changes of Functional Parameter Inflammatory Marker Interleukin-6 (IL-6) During Stay at ICU | 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). | 28 days | 
| Changes of Functional Parameter Dipeptidyl Peptidase 3 (DPP3) During Stay at ICU | 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). | 28 days | 
| Vasopressor Use (Drug, Highest Dose) | 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). | 28 days | 
| Patient Reported Outcomes : Quality of Life by Euro-QoL-5 | 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. | day 28 and day 90 | 
| Vital Signs | Vital signs: heart rate (beat per minute) Change from baseline to Day 7. | 7 days | 
| Penalized Sepsis Support Index (pSSI) at 28 Day Follow-up | 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. | day 28 | 
| Vasopressor Use (Drug, Lowest Dose) | 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). | 28 days | 
| Vasopressor Use (Drug, Duration) | 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). | 28 days | 
| Change in Renal Function (penKid) | 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). | day 1, day 3 and day 7 | 
| Vital Signs - Blood Pressure | Vital signs: blood pressure - mean arterial pressure (MAP) mmHg Change from baseline to Day 7. | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early Septic Shock