Septic ShockPhase 2AdrenOSS-2NCT03085758
Treatment of Patients With Early Septic Shock and Bio-Adrenomedullin(ADM) Concentration > 70 pg/ml With ADRECIZUMAB
A Phase 2 study testing Adrecizumab in people with Septic Shock, run by Adrenomed AG at 30 sites in 4 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Septic Shock
- What is being tested?
- Adrecizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 301 participants
- Where
- 30 sitesin 4 countries
- Study dates
- 12 Dec 2017to 20 Dec 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 16Show fewer
- 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
Trial locations and contacts
30 sites in 4 countries.
30 sites in 4 countries
France16 sites
Medical Intensive Care Medicine, Centre hospital - universitaire
Angers, Cedex, 49933
CH Victor Dupouy
Argenteuil, Cedex, 95107
University Hospital of Clermont-Ferrand, Dept. of Perioperative Medicine
Clermont-Ferrand, 63003
Hopital Beaujon; Anesthesie Reanimation
Clichy, Cedex, 92118
AP-HP, Hopital Louis Mourier, Réanimation Médicale
Colombes, 92700
CHD-Vendée
La Roche-sur-Yon, 85000
Hôpital de Bicêtre, Service d'anesthésie-réanimation chirurgicale
Le Kremlin-Bicêtre, 94270
CHU de Limoges
Limoges, Cedex, 87042
CHU de Nantes; Medicine Intensive Reanimation
Nantes, Cedex, 44093
Hôpital Lariboisière, Dept. d'Anesthesie
Paris, 75010
Hôpital Lariboisière, Réanimation Médicale et Traumatologique
Paris, 75010
Hôpital Saint-Louis, Service d'Anesthésie-Réanimation
Paris, 75010
Hôpital Européen Georges Pompidou, Service d'Anesthésie-Réanimation Chirurgicale, Université Paris Descartes
Paris, 75015
Nouvel Hopital Civil
Strasbourg, 67091
Hôpital de Hautepierre , Hôpitaux Universitaires de Strasbourg, Unité de Réanimation Chirurgicale, Service d'Anesthésie-Réanimation Chirurgicale
Strasbourg, 67200
CHRU Bretonneau, Medecine Intensive Réanimation
Tours, Cedex, 37044
Germany5 sites
Universitätsklinikum Aachen, Klinik für Operative Intensivmedizin
Aachen, 52074
Universitätsklinikum Hamburg-Eppendorf Klinik für Intensivmedizin
Hamburg, 20246
Universitätsklinikum Jena Klinik für Anästhesiologie und Intensivmedizin
Jena, 07747
Universitätsklinikum Münster Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
Münster, 48149
Universitätsmedizin Rostock Klinik und Poliklinik für Anästhesiologie und Intensivtherapie
Rostock, 18057
Netherlands5 sites
Gelderse Vallei Hospital, Department of Intensive Care
Ede, 6716 RP
Medisch Spectrum Twente, Department of Intensive Care
Enschede, 7512 KZ
Zuyderland Medical Center, Department of Intensive Care
Heerlen, 6401 CX
Radboud UMC Intensive Care
Nijmegen, 6525 GA
Canisius-Wilhelmina-Ziekenhuis (CWZ), Intensive Care
Nijmegen, 6532 SZ
Belgium4 sites
Clinique Universitaire Saint-Luc (UCL Bruxelles)
Brussels, 1200
Antwerp University Hospital (UZA), Critical Care Medicine
Edegem, 2650
Groupe Jolimont, Hospitalier de Jolimont
Haine-Saint-Paul, 7100
Clinique St. Pierre, Intensive Care
Ottignies, 1340
About this study
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
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.
Read the 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).
- Conditions
- Septic Shock
- Being tested
- Adrecizumab, Placebo
- Keywords
- Early Septic Shock
- Medical subject headings
- Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AdrecizumabBiological
Single i.v. dose of 2 mg/kg (treatment arm A) or 4 mg/kg (treatment arm B)
PlaceboBiological
Single i.v. dose of placebo (control group)
| Study group | Role | What they receive |
|---|---|---|
| Treatment Arm A | Experimental | Intravenous infusion over approximately 1 hour of single i.v. dose of 2 mg/kg Adrecizumab (treatment arm A) Receives: Biological: Adrecizumab |
| Treatment Arm B | Experimental | Intravenous infusion over approximately 1 hour of single i.v. dose of 4 mg/kg Adrecizumab (treatment arm B) Receives: Biological: Adrecizumab |
| Control group | Placebo comparator | Intravenous infusion over approximately 1 hour of single i.v. dose of Placebo of Adrecizumab (control group) Receives: Biological: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 90 days
Secondary outcomes (27)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: day 14 and day 28
Mortality Rate
Day 28 mortality rate
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 28 days
Change in Renal Function (Creatinine)
Change in renal function as change in creatinine (day 3 - day 1, day 7 - day 1)
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: day 28 and day 90
Vital Signs
Vital signs: heart rate (beat per minute) Change from baseline to Day 7.
Measured: 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.
Measured: day 28
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).
Measured: 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).
Measured: 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.
Measured: 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Mar 2017
- Study start12 Dec 2017
- Primary completion20 Dec 2019
- Study completion20 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Septic ShockStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Double Blind, Placebo-Controlled, Randomized, Multicenter Proof of Concept and Dose-Finding Phase II Clinical Trial
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 301 participants (actual)
Sponsor and investigators
- Lead sponsor
- Adrenomed AG
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Jens Zimmermann, Dr., Study director, Adrenomed AG
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03085758
- Sponsor's protocol ID
- ADR-02
- Acronym
- AdrenOSS-2
- Status last verified
- Jan 2024
- First submitted
- 22 Feb 2017
- Last updated
- 21 Feb 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Laterre PF, Pickkers P, Marx G, Wittebole X, Meziani F, Dugernier T, Huberlant V, Schuerholz T, Francois B, Lascarrou JB, Beishuizen A, Oueslati H, Contou D, Hoiting O, Lacherade JC, Chousterman B, Pottecher J, Bauer M, Godet T, Karakas M, Helms J, Bergmann A, Zimmermann J, Richter K, Hartmann O, Pars M, Mebazaa A; AdrenOSS-2 study participants. Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial. Intensive Care Med. 2021 Nov;47(11):1284-1294. doi: 10.1007/s00134-021-06537-5. Epub 2021 Oct 4.
PubMed 34605947Geven 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.
PubMed 30782906
Study at a glance
From the registry record, last updated by the sponsor on 21 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03085758
- Acronym / sponsor ID
- AdrenOSS-2 / ADR-02
- Conditions
- Septic Shock
- Keywords
- Early Septic Shock
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 301 participants (actual)
- Lead sponsor
- Adrenomed AGIndustry (pharma, biotech, devices)
- Study start
- 12 Dec 2017 (actual)
- Primary completion
- 20 Dec 2019 (actual)
- Study completion
- 20 Dec 2019 (actual)
- First posted
- 21 Mar 2017 (actual)
- Results
- Posted 24 Mar 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
- Model description
- Double Blind, Placebo-Controlled, Randomized, Multicenter Proof of Concept and Dose-Finding Phase II Clinical Trial
| Arm | Type | Receives |
|---|---|---|
| Treatment Arm A | Experimental | Biological: AdrecizumabIntravenous infusion over approximately 1 hour of single i.v. dose of 2 mg/kg Adrecizumab (treatment arm A) |
| Treatment Arm B | Experimental | Biological: AdrecizumabIntravenous infusion over approximately 1 hour of single i.v. dose of 4 mg/kg Adrecizumab (treatment arm B) |
| Control group | Placebo comparator | Biological: PlaceboIntravenous infusion over approximately 1 hour of single i.v. dose of Placebo of Adrecizumab (control group) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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)
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AdrecizumabSingle i.v. dose of 2 mg/kg (treatment arm A) or 4 mg/kg (treatment arm B) | Biological | Treatment Arm A, Treatment Arm B |
| PlaceboSingle i.v. dose of placebo (control group) | Biological | Control group |
Primary outcome
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.
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: 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.
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.
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.
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.
27 secondary outcomes
Efficacy to be Determined by Sepsis Support Index (SSI)
Time frame: 14 days
Sepsis Support Index (SSI)
Time frame: 28 days
Penalized Sepsis Support Index (pSSI) at 14 Day Follow-up
Time frame: day 14
Persistent Organ Dysfunction or Death at 14 and 28 Day Follow-up
Time frame: day 14 and day 28
Mortality Rate
Time frame: day 28
SSI and pSSI Excluding the Renal Component
Time frame: day 14 and day 28
SSI Weighted for Mortality
Time frame: day 14
Individual Sepsis Support Index Components
Time frame: day 14 and day 28
Sequential Organ Failure Assessment (SOFA) Score : Composite Measure: SOFA Score and Its Changes Over Time
Time frame: 28 days
Change in Renal Function (Creatinine)
Time frame: day 1, day 3 and day 7
Duration of Stay at ICU/ Hospital
Time frame: 90 days
Changes of Functional Parameter Mean Arterial Pressure During Stay at ICU
Time frame: 28 days
Changes of Functional Parameter Creatinine During Stay at ICU
Time frame: 28 days
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 Functional Parameter Blood Lactate During Stay at ICU
Time frame: 28 days
Changes of Functional Parameter Fluid Balance During Stay at ICU
Time frame: 28 days
Changes of Functional Parameter Mid-Regional Pro-Adrenomedullin (MR-proADM) During Stay at ICU
Time frame: 28 days
Changes of Functional Parameter Inflammatory Marker Procalcitonine (PCT) During Stay at ICU
Time frame: 28 days
Changes of Functional Parameter Inflammatory Marker Interleukin-6 (IL-6) During Stay at ICU
Time frame: 28 days
Changes of Functional Parameter Dipeptidyl Peptidase 3 (DPP3) During Stay at ICU
Time frame: 28 days
Vasopressor Use (Drug, Highest Dose)
Time frame: 28 days
Patient Reported Outcomes : Quality of Life by Euro-QoL-5
Time frame: day 28 and day 90
Vital Signs
Time frame: 7 days
Penalized Sepsis Support Index (pSSI) at 28 Day Follow-up
Time frame: day 28
Vasopressor Use (Drug, Duration)
Time frame: 28 days
Change in Renal Function (penKid)
Time frame: day 1, day 3 and day 7
Vital Signs - Blood Pressure
Time frame: 7 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Feb 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34605947Laterre PF, Pickkers P, Marx G, Wittebole X, Meziani F, Dugernier T, Huberlant V, Schuerholz T, Francois B, Lascarrou JB, Beishuizen A, Oueslati H, Contou D, Hoiting O, Lacherade JC, Chousterman B, Pottecher J, Bauer M, Godet T, Karakas M, Helms J, Bergmann A, Zimmermann J, Richter K, Hartmann O, Pars M, Mebazaa A; AdrenOSS-2 study participants. Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial. Intensive Care Med. 2021 Nov;47(11):1284-1294. doi: 10.1007/s00134-021-06537-5. Epub 2021 Oct 4.
- Derived from this study: PubMed 30782906Geven 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.
- Individual participant dataSharing planned: No
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Sepsis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jens Zimmermann, Dr. study director
Adrenomed AG
30 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Adrecizumab in people with Septic Shock, run by Adrenomed AG at 30 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 30 sites in France, Germany, Netherlands, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Mar 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Mortality) (time frame: 90 days). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03085758, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Feb 2024.