E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
We investigate the efficacy of commercially available glucocorticoid "methylprednisolone" (Solu-Medrol) for reducing the systemic inflammatory response and neurological injury in patients resuscitated after out-of-hospital cardiac arrest. |
Vi undersøger den antiinflammatoriske og neuroprotektive effekt af det kommercielt tilgængelige glukokortikoid "methylprednisolon" (Solu-Medrol) i patienter genoplivet efter hjertestop uden for hospital. |
|
E.1.1.1 | Medical condition in easily understood language |
Patients resuscitated from out-of-hospital cardiac arrest have a high mortality due to a systemic inflammatory response and severe brain injury. We hope that Solu-Medrol can prevent this response. |
Patienter genoplivet efter hjertestop uden for hospital har en høj dødelighed grundet et inflammatorisk respons og svær hjerneskade. Vi håber at Solu-Medrol kan modvirke dette respons. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003109 |
E.1.2 | Term | Arrest cardiac |
E.1.2 | System Organ Class | 100000004849 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to determine the efficacy of the glucocorticoid "methylprednisolone" (Solu-Medrol) compared with placebo. The co-primary endpoints being serial measurements of interleukin-6 (IL-6) and neuron-specific-enolase (NSE) at admission and 24, 48 and 72 hours after admission in patients admitted after resuscitated OHCA. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to determine the effects of the glucocorticoid "methylprednisolone" (Solu-Medrol) on inhibition of inflammation, cardiac protection, neuroprotection, renal protection, endothelial protection, clinical endpoints including survival and neurological outcome, as well as safety. |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A subset of the trial participants will be enrolled in a sub-study focusing on cardiac-, respiratory and neuroprotection. This sub-study will include an echocardiography, a lung ultrasound, a brain MR-imaging and a cardiac MR-imaging; echocardiography and lung ultrasound will be performed the day following admission, on day 3, 4 or 5 and after three months, MR-imaging will be performed at regained consciousness and after three months. The intervention will be administered exactly as dictated by the main trial. Therefore, participation in a sub-study will have no impact on the IMP use. |
|
E.3 | Principal inclusion criteria |
1. Age ≥18 years 2. OHCA of presumed cardiac cause 3. Unconsciousness (GCS ≤8) upon pre-hospital randomization 4. Sustained ROSC for at least 5 minutes 5. Randomization within 30 minutes of sustained ROSC |
|
E.4 | Principal exclusion criteria |
1. Advanced life support TOR exclusion criteria 2. Asystole as primary ECG rhythm 3. Female of child bearing potential (female aged 15-40, decided by the treating physician) 4. Known therapy limitation (known decision made of no resuscitation or intensive therapy) 5. Known allergy to glucocorticoid 6. Known disease making 180-day survival unlikely 7. Known pre-arrest modified Rankin Scale (mRS) score of 4-5 8. Temperature upon admission <30° C 9. >30 minutes to sustained ROSC |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The anti-inflammatory and neuroprotective effect of methylprednisolone decided by measurements of IL-6 and NSE at admission and 24, 48 and 72 hours after admission. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
At admission and 24, 48 and 72 hours after admission. |
|
E.5.2 | Secondary end point(s) |
1. Markers of inflammation: High sensitivity C-reactive protein (hsCRP), leucocyte- and differential count, plasma cytokine levels (IL-1b, IL-2, IL-4, IL-5, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17A, G-CSF, GM-CSF, MCP-1, MIP-1beta, INF-g and tumor-necrosis factor α (TNF-α)) and procalcitonin measured daily the first three days following admission. 2. Markers of kidney and hepatic injury: Daily creatinine levels the first three days from admission. Daily measurements of ALAT, ASAT, BF, bilirubin and INR the first three days from admission. 3. Markers of the coagulation system: Plasma fibrinogen the first three days from admission, and thromboelastography at admission and at 48 hours. 4. Protein and enzymatic protection: Daily proteomics and metabolomics samples the first three days from admission. 5. Hemodynamics: Daily evaluation by Swan-Ganz catheter, bihourly analyses of arterial blood gases the first 36 hours and transthoracic echocardiogram (TTE) measured the day following admission and on either day 3, 4 or 5. 6. Neuroprotection: Daily measurements of TAU, NFL, NFM, NFH and GFAP levels the first three days from admission. Formation of cerebral edema decided by MR-imaging of the brain after regained consciousness and consent. 7. Cardiac protection: Daily measurements of TnT, TnI and CKMB levels the first three days from admission. Infarct size decided by MR-imaging after regained consciousness and consent before discharge from the primary hospital. 8. Respiratory protection: Lung UltraSound (LUS) performed the day following admission and on either day 3, 4 or 5. 9. Clinical endpoints: Survival and neurological outcome, decided by mRS score after five days, at discharge from the intensive ward and the hospital and further at 30- and 180- days following discharge through telephone interview. 10. Follow-up at 90 days following discharge in an ambulatory setting: MoCA-score for assessment of cognitive function and patients will be screened for quality of life, anxiety, depression and the return to daily living with their closest relatives. 11. Safety: Cumulated daily incidence of adverse events the first seven days, including “severe adverse events” and “adverse events with believed relation to the study medicine”. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation of paraclinical endpoints (markers of organ dysfunction) up to three days after admission. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Last contact to the subject will be 6 months (+/- 2 weeks) after last randomization. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |