STRESS-L Trial: STudy into the - PowerPoint Presentation

1. STRESS-L Trial: STudy into the REversal of Septic Shock with Landiolol (Beta Blockade)Training for non-GCP trial delegated clinical staffVersion 2.0 05 August 2019

2. Training tool for non-GCP trained medically qualified clinicians listed on the STRESS-L Trial Delegation Log with the following responsibilities:E: review eligibility and sign formF: medical care and supervision of trial participantsK: prescribe medication and treatment. No GCP training is required specifically for this trial for members of staff carrying out these activities as they are part of a person’s normal clinical role and all other protocol activities will be undertaken by a member of the research team (as per HRA/MHRA guidance).A member of staff carrying responsibilities E, F & K who have full GCP training will not be required to read these slides. PURPOSE OF SLIDESSlide 2

3. However, these members of staff must read these training slides consisting of key GCP principles relevant to their role and document this on the Investigator Training Log (and counter-signed by PI).These members of staff must not obtain or assist with the informed consent process meaning they cannot act as Professional Legal Representatives.PURPOSE OF SLIDESSlide 3

4. AgendaIntroduction and study overviewEligibility criteriaTrial drug and prescribingContraindications and expected side effectsGood Clinical PracticeSlide 4

5. Chief Investigator: Dr Tony WhitehouseFunder: NIHR Efficacy and Mechanism Evaluation (EME) programmeSponsor: University Hospitals Birmingham NHS Foundation TrustCoordination: Warwick Clinical Trials Unit Contact: stress-l@warwick.ac.uk General Study InformationSlide 5 Warwick Lead SPM Trial Manager Trial Coordinator Trial Coordinator Trial Administrator Data Entry Clerk Statistician Dr Ranjit Lall Scott Regan Emma Skilton Maddy Flawn Johnny Guck Craig Turner Belinda Ghuman Dr Dipesh Mistry

6. Morelli A et alJAMA. 2013 Oct 23;310(16):1683-91. doi:10.1001/jama.2013.278477.PMID: 24108526BackgroundSlide 6

7. Randomised, controlled open label phase IIb trial comparing usual treatment with usual treatment plus landiolol infusion Multi-centre, approx. 41 UK sitesIdentifying participants admitted to ICU, with septic shock, fluid resuscitated and receiving continuous vasopressor infusion for 24 hoursOverall recruitment target: 340 patientsRecruitment target per site: minimum of 4 participants per year Current planned end of recruitment: Nov 2020Study DesignSlide 7

8. Study Schedule / Data CollectionSlide 8

9. Mean SOFA score over the first 14 days from entry to the trial and whilst in ICUMeasurement of the SOFA score will cease if the patient dies or is discharged from the ICUPrimary OutcomeSlide 9

10. ICU & Hospital Mortality Mortality at day 28 & 90Length of ICU and hospital stayReduction in dose and duration of vasopressor treatment Exploratory Mechanistic Outcomes Safety: The episodes of bradycardia (HR <50 bpm), bradycardia with haemodynamic compromise requiring intervention, significant hypotension requiring intervention (not including temporarily stopping the infusion), heart block, arrhythmia, arrhythmia with haemodynamic compromise requiring intervention will be reportedSecondary OutcomesSlide 10

11. Adults aged 18 years or aboveBeing treated on a Level 2 or 3 facility Septic shock according to internationally accepted definitions*Heart rate ≥95 bpm (24 hours after start of vasopressor therapy)Receiving vasopressor support to maintain a target blood pressure for ≥24 hoursAre being treated with noradrenaline at a rate ≥ 0.1mcg/kg/minInclusion CriteriaSlide 11

12. *Sepsis -3 definitions:confirmed or suspected infection requiring antibiotic therapynew organ dysfunction, as evidenced by an increase in SOFA score ≥2a blood lactate >2 mmol/l at any point during shock resuscitationvasopressor therapy to maintain mean arterial pressure (MAP) ≥65 mmHg In particular the presence of a blood lactate > 2 mmol/l is only necessary for the diagnosis of septic shock and is NOT necessary for randomisation 24 hours laterInclusion CriteriaSlide 12

13. Any form of compensatory tachycardiaAny form of vasodilatory shock that is not caused by sepsisNoradrenaline infusion <0.1mcg/kg/min>72 hours in the current cause of septic shock after start of vasopressor therapyHaving pre-existing severe cardiac dysfunction (NYHA grade 4 or more)Having pre-existing severe pulmonary hypertension (mean PA pressures > 55mmHg)Acute severe bronchospasm (due to asthma or COPD)Untreated second or third degree heart blockUntreated phaeochromocytomaPrinzmetal's anginaExclusion Criteria -1Slide 13

14. A past history of ischaemic stroke or transient ischaemic attack (TIA) or untreated severe carotid stenosisAdvanced Liver Disease with Child-Pugh Score of ≥BKnown sensitivity to beta-blockersPatient / legal representative unwilling to provide written informed consentKnown to be pregnantTerminal illness other than septic shock with a life expectancy < 28 daysParticipants who have been administered an investigational medicinal product for another research trial in the past 30 daysPatients in whom the clinical team feel are about to finish their noradrenaline therapyDecision of withdrawal of care is in place or imminently anticipatedExclusion Criteria -2Slide 14

15. Eligibility FormMedically qualified physician listed on the trial delegation log will confirm eligibility by completing and signing this form provided by the research team Slide 15

16. Name of product: Landiolol hydrochloride 300 mg lyophilised powder Formulation: 300 mg powder for solution for injection and infusionMaximum dosage: 40mcg/kg/min Licensing status: Approved for use in Europe, not currently licensed in the UKIndication: Landiolol is a beta blocker used for supraventricular tachycardia and for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other circumstances where short-term control of the ventricular rate with a short acting agent is desirable. Landiolol is also indicated in non-compensatory sinus tachycardia where, in the physician’s judgment the rapid heart rate requires specific intervention. What is the trial drug (IMP)?Slide 16

17. Refer to IMP Management Manual and Trial Protocol for full details.IMP is refrigerated (must be stored between 2°C and 8°C)Reconstituted drug must not be frozen.A calibrated thermometer must be used on ICU and in pharmacy to monitor IMP stock as per MHRA guidanceEnsure calibration certificates are sent to WCTU and filed in investigator site file. How is the IMP being used?Slide 17

18. Supplied as lyophilisate in vials with a nominal filling volume of 50 ml containing 300mg landiolol hydrochloride. The IMP is a white to almost white powder for solution for infusionInactive ingredients Mannitol E421 and Sodium hydroxide (for pH adjustment)After reconstitution, each ml contains 6 mg landiolol hydrochlorideReconstitute 1 vial with 50 ml of one of the following solutions: NaCl 9 mg/ml (0.9%) solution Glucose 50 mg/ml (5%) solution Ringer’s solution Ringer-lactate solutionHow is the IMP being used?Slide 18

19. Reporting temperature excursionsPlease note, AOP do not respond on weekendsState if you require an urgent response in email.Always ensure STRESS-L are ccd in to all communicationsFollowing excursions do not need to be reported as can be rounded to either 2 or 8 degrees:- 1.6, 1.7, 1.8, 1.9- 8.1, 8.2, 8.3, 8.4Slide 19

20. IMP stock affected by a temperature excursion on ICU can continue to be used over the weekend and bank holidays (up to 96 hours) if no pharmacist is available to dispense unaffected IMP stock from pharmacy.As soon as trial pharmacist is next available, IMP affected stock must be quarantined with excursion reported to AOP and replaced with unaffected IMP stock from pharmacyThis is justified on a risk-based approach as stability data is available to support excursions up to 25 degrees.Out-of-hours temperature excursionsSlide 20

21. What does the IMP look like?Slide 21

22. Conversion table for continuous intravenous infusion: micrograms/kg/min to ml/h (Landiolol hydrocholoride 300 mg/50 ml = 6 mg/ml strength):How is the IMP being used?Body weight (kg)1 mcg/kg/min2mcg/kg/min3mcg/kg/min4mcg/kg/min5mcg/kg/min6mcg/kg/min7mcg/kg/min8mcg/kg/min9mcg/kg/min10mcg/kg/min11mcg/kg/min12mcg/kg/min13mcg/kg/min14mcg/kg/min15mcg/kg/min16mcg/kg/min17mcg/kg/min18mcg/kg/min19mcg/kg/min20mcg/kg/min30mcg/kg/min40mcg/kg/min 400.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.012.016.0ml/h450.50.91.41.82.32.73.23.64.14.55.05.45.96.36.87.27.78.18.69.013.518.0ml/h500.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.015.020.0ml/h550.61.11.72.22.83.33.94.45.05.56.16.67.27.78.38.89.49.910.511.016.522.0ml/h600.61.21.82.43.03.64.24.85.46.06.67.27.88.49.09.610.210.811.412.018.024.0ml/h650.71.32.02.63.33.94.65.25.96.57.27.88.59.19.810.411.111.712.413.019.526.0ml/h700.71.42.12.83.54.24.95.66.37.07.78.49.19.810.511.211.912.613.314.021.028.0ml/h750.81.52.33.03.84.55.36.06.87.58.39.010.810.511.312.012.813.514.315.022.530.0ml/h800.81.62.43.24.04.85.66.47.28.08.89.610.411.212.012.813.614.415.216.024.032.0ml/h850.91.72.63.44.35.16.06.87.78.59.410.211.111.912.813.614.515.316.217.025.534.0ml/h900.91.82.73.64.55.46.37.28.19.09.910.811.712.613.514.415.316.217.118.027.036.0ml/h951.01.92.93.84.85.76.77.68.69.510.511.412.413.314.315.216.217.118.119.028.538.0ml/h1001.02.03.04.05.06.07.08.09.010.011.012.013.014.015.016.017.018.019.020.030.040.0ml/hSlide 22

23. Starting Landiolol TreatmentIdeally, study drug should be started within 1 hour of randomisationLandiolol should start once:Treating physician is confident adequate fluid resuscitation has been achievedPatient has reached the target MAP pre-defined by the treating clinician overseeing care (suggested target 65-70 mmHg but may vary) using vasopressorsLandiolol can be prescribed up to a maximum of 14 days for the STRESS-L trialSlide 23

24. Administering Landiolol TreatmentParticipants randomised to receive Landiolol will be started on a dose of 1.0 mcg/kg/minLandiolol should be increased every 15 minutes at increments of 1.0 mcg/kg/min, to reach the target heart rate of 80-94 bpm, usually occurring over a period of 6 hoursElimination half-life of 2.3 to 4 minutes so a loading dose is unnecessaryLandiolol may be administered peripherally or centrally but MUST be on a dedicated lineSlide 24

25. Landiolol infusion should be continued to keep pulse rate between 80 and 94. Once the patient is consistently within the target heart rate, the Landiolol Infusion should continue and not be adjusted. If all vasopressor agents have been discontinued for less than 12 hours, the landiolol infusion will continue as per Appendix E.The landiolol should be weaned and, if necessary, stopped whilst the HR is below 80 bpm. It may be restarted according to protocol at any point before the End of Noradrenaline Treatment Visit (EONT)Administering Landiolol TreatmentSlide 25

26. Stopping Landiolol TreatmentReduce Landiolol infusion once all vasopressors have been stopped for 12 hours and the patient is consistently within target heart rate range.However, continue Landiolol infusion if the patient remains tachycardic, even when all vasopressors have stopped for 12 hours.Attempts to wean Landiolol should continue to maintain HR between the target rates of 80-94 bpm. Slide 26

27. Landiolol infusion should not be stopped during procedures including trips to theatre, percutaneous tracheostomy, central line insertions etc.Recommend stopping infusion for at least 12 hours before the patient is discharged from the ICU; however ICU stay should not be prolonged for this. Oral beta blocker use after ICU discharge should be at discretion of the clinicians.Stopping Landiolol TreatmentSlide 27

28. APPENDIX B: Study Drug Infusion ProtocolSlide 28

29. APPENDIX C: STRESS-L Vasopressor Infusion ProtocolSlide 29

30. APPENDIX E: STRESS-L Timing and Weaning of Study DrugSlide 30

31. Protocol Compliance (section 4.3)Slide 31

32. The prescription must be signed by an authorised prescriber named on the trial delegation log. Known allergies should be completed with details of any allergies or ‘none’. When prescribing the following details will be added to the patient’s inpatient chart:For clinical trial use onlySTRESS-L TrialLandiolol hydrochloride 300mgPrescribing and dispensingThe ICU research team will add the Patient Trial ID to the label on the vial (primary packaging) when issued and prior to reconstitution of IMP. Please see below example:For Clinical Trial Use OnlyTrial Name: STRESS-L Participant ID:PI Name: Sponsor: University Hospitals Birmingham NHS Foundation TrustFollowing reconstitution the syringes will have a label added to identify the drug and patient details as per standard local medicines policies. For the purposes of the trial the following information should also be included on the label prior to administration.Pharmacy, syringe and drug line labels can be provided upon request to the coordinating centre. Slide 32

33. See sections 4.3 and 4.4 of SPC and protocol section 3.9.6SPCs for beta blockers currently reflect the contraindications, precautions and warnings for their common indications of hypertension and tachyarrythmias and not for their use in ICU.Contraindications, special warnings, and precautions in the context of Septic ShockSlide 33

34. Contraindications in the SPC are diametrically opposed to the effects under study in STRESS-LSevere Metabolic AcidosisDiabetesPeripheral Vascular DiseaseContraindications, special warnings, and precautions in the context of Septic ShockSlide 34

35. No additional beta blockers should be prescribed for the duration of the ICU stay.If the treating clinician deems beta blockade necessary, a protocol deviation form must be completed on the e-CRF.If a beta blocker has been administered for a pre-exisiting condition regardless of which arm they are randomised to, it can be continued. However, if a patient is receiving a beta blocker for Atrial Fibrillation in the current episode of septic shock, it should be discontinued. AF must be treated with Magnesium, Potassium and Amiodarone.Decision to continue or stop pre-existing blockade remains at the discretion of the treating clinician.Concomitant illnessesSlide 35

36. Antihypertensive agents used in caution with LandiololVerapamil or diltiazem not recommended with atrioventricular conduction abnormalitiesCatecholamine-depleting agents or antisympathomimetic agents may have an additive effect when concomitantly administered with landiolol with marked hypotension and bradycardia.Anaesthetists should be made aware that landiolol enhances the hypotensive effects of anaesthetic agents.Landiolol is metabolised by plasma esterases; drugs such as suxamethonium may decrease the metabolism of landiolol leading to an enhanced bradycardic effect.Concomitant medicationsSlide 36

37. Tabulated summary of adverse reactions for landiolol hydrochloride(Reference Safety Information from Summary of Product Characteristics)Infections and infestationsuncommon: Pneumoniarare: MediastinitisBlood and lymphatic system disordersrare: Thrombocytopenia, platelet disorderMetabolism and nutrition disordersuncommon: Hyponatraemiarare: HyperglycaemiaNervous system disordersuncommon: Cerebral ischemia, headacherare: Cerebral infarction, cerebrovascular accident, seizureCardiac disorderscommon: Bradycardiauncommon: Cardiac arrest, sinus arrest, tachycardiarare: Myocardial infarction, ventricular tachycardia, atrial fibrillation, low cardiac output syndrome, atrioventricular block, bundle branch block right, supraventricular extrasystole, ventricular extrasystoleVascular disorderscommon: Hypotensionuncommon: Hypertensionrare: Shock, hot flushRespiratory, thoracic and mediastinal disordersuncommon: Pulmonary oedemarare: Asthma, respiratory distress, respiratory disorder, bronchospasm, dyspnoea, hypoxiaGastrointestinal disordersuncommon: Vomiting, nausearare: Abdominal discomfort, oral discharge, breath odourHepatobiliary disordersuncommon: Liver disorderrare: HyperbilirubinemiaSkin and subcutaneous tissue disordersrare: Erythema, cold sweatMusculoskeletal and connective tissue disordersrare: Muscle spasmsRenal and urinary disordersrare: Renal failure, acute kidney injury, oliguriaGeneral disorders and administration siteconditionsrare: Pyrexia, chills, chest discomfort, administration site painnot known: Application site pain, injection site reaction, sensation ofPressureInvestigationscommon: Blood pressure decreaseduncommon: Electrocardiogram ST segment depression, cardiac index abnormal, alanine aminotransferase (ALT /GPT) abnormal, aspartate aminotransferase (AST /GOT) abnormal, blood bilirubin abnormal, white blood cell count abnormal, red blood cell count abnormal, haemoglobin abnormal, haematocrit abnormal, platelet count abnormal, blood lactate dehydrogenase abnormal, blood urea abnormal, blood creatinine increased, blood creatine phosphokinaseabnormal, protein total abnormal, blood albumin abnormal, blood sodium abnormal, blood potassium abnormal, blood cholesterol abnormal, blood triglycerides abnormal, protein urine presentrare: Blood pressure increased, electrocardiogram T wave inversion, electrocardiogram: prolonged QRS complex, heart rate decreased, pulmonary arterial pressure increased, PO2 decreased, neutrophil count abnormal, blood alkaline phosphatase abnormal, leukocyte alkaline phosphatase, free fatty acids abnormal, blood chloride abnormal, glucose urineSlide 37

38. Principals of ICH-Good Clinical Practice (GCP)2.1 Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s). 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. 2.3 The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. 2.4 The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. 2.5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol. 2.6 A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion. 2.7 The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. 2.8 Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). 2.9 Freely given informed consent should be obtained from every subject prior to clinical trial participation.2.10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification. 2.11 The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 2.12 Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. 2.13 Systems with procedures that assure the quality of every aspect of the trial should be implemented.Slide 38

39. Principal 3The rights, safety and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.- A participant may withdraw from the trial at any time without giving a reasonPrincipal 6 A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB) / independent ethics committee (IEC) approval / favourable opinion.- Consent needs to be in place before prescribing IMP- The trial needs to be conducted as per ethical approval and so there is no flexibility with the eligibility criteriaPrincipal 7 The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.Principals of ICH-GCPSlide 39

40. Principal 3What is a Serious Adverse Event (SAE)?Disability/incapacityCongenital abnormality/birth defectDeathLife-threateningHospitalisationImportant medical event/medical interventionPlease inform your research team of any possible SAEs as these need to be reported to the trial coordinating centre within 24 hours of becoming aware of the eventSlide 40

41. Principal 8 (the reason for doing this training today!)Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective task(s).Principal 10All clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification.- Eligibility must be documented in the medical records and the paper CRF Principal 12 Investigational products should be manufactured, handled and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.- IMP should be used in accordance with the approved protocolPrincipals of ICH-GCPSlide 41

42. Questions?