|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|E.1.1.1||Medical condition in easily understood language ||
|E.1.1.2||Therapeutic area ||Diseases [C] - Respiratory Tract Diseases [C08]
|E.1.2 Medical condition or disease under investigation
|E.1.2||Classification code ||10051905
|E.1.2||Term ||Coronavirus infection
|E.1.2||System Organ Class ||10021881 - Infections and infestations
|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 ||
|•Stage 1: To evaluate the efficacy of candidate agents as add on therapies to Standard of Care (SoC) in patients hospitalised with COVID 19 in a screening stage.
•Stage 2: To confirm the efficacy of identified efficacious candidate agents in patients hospitalised with COVID 19 in an expansion stage.
|E.2.2||Secondary objectives of the trial ||
• To evaluate the ability to prevent deterioration according to the ordinal scale by 1, 2, or 3 points
• To evaluate the number of oxygen free days.
• To evaluate ventilator-free days and incidence and duration of any form of new ventilation use.
• To evaluate SARS CoV 2 viral load.
• To evaluate response rate. (see primary endpoint for definition of responder).
• To evaluate time to discharge.
• To evaluate overall mortality.
• Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2),
• To evaluate the safety of candidate agents as add on therapy to SoC in patients with COVID-19.
• To evaluate intensive care unit (ICU) and hospitalisation length.
• To evaluate National Early Warning Score 2 (NEWS2).
Additional sub protocol(ACCORD-2-002) secondary objectives
To evaluate the pharmacokinetic exposure to bemcentinib in Covid-19
To evaluate pharmacodynamic response to bemcentinib by circulating biomarkers (GAS6, soluble AXL
|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||
Title: ACCORD 2: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID 19 in Hospitalised Patients
Sub Protocol (ACCORD-2-003), Date: 29Apr2020, Version: Protocol Amendment 01 Final) The objectives and endpoints are as for the master protocol.
This form is for a sub-protocol. (Title: None, Sub-protocol Number: ACCORD 2-004, Date: 1 May 2020, Version: Final) The objectives and endpoints are as for the master protocol:
Sub-protocol ACCORD 2-006
Sub-protocol ACCORD 2-005
Sub-protocol ACCORD 2-008
|E.3||Principal inclusion criteria ||
|Patients are eligible to be included in the study only if all of the following criteria apply (as well as all criteria from the appropriate sub-protocol):
1. Adults (≥18 years) with SARS-CoV-2 infection confirmed by laboratory tests and/or point of care tests (which may include results from a test that was performed prior to hospital admission if, in the opinion of the Investigator, it is relevant to ongoing COVID-19).
2. Patients with symptoms and/or signs consistent with COVID-19, requiring treatment.
3. A score of Grade 3 to 5 on the 9-point ordinal scale.
4. a) Male patients:
• A male patient must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period.
b) Female patients:
• A female patient is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least 1 of the following conditions applies:
i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5.
ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 90 days after the last dose of study treatment.
5. Women who are lactating who agree not to breastfeed their child during the study and for a fixed period of time (following guidance that will be given by the investigator as appropriate
CONFIDENTIAL ACCORD-2-001 – Master Protocol (Amendment 02)
Final, 02 June 2020 32
for any candidate agent administered) after termination of study therapy (they may continue to express milk away from the child during this period, but this milk must be discarded).
6. Ability to provide informed consent signed by the study patient or legally authorized representative.
In addition for the sub-protocol ACCORD-2-003:
a) Male subjects
A male subject must agree to use contraception as detailed in Appendix 2 of this protocol during the treatment period and for at least 12 weeks after the last dose of study treatment and refrain from donating sperm during this period.
b) Female subjects
A female subject is eligible to participate if she is not pregnant (see Appendix 2), not breastfeeding, and at least 1 of the following conditions applies:
i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 2 OR
ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during the treatment period and for at least 12 weeks after the last dose of study treatment
In addition for the sub-protocol ACCORD-2-004:
A male subject must agree to use contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 12 weeks after the last dose of study treatment and refrain from donating sperm during this period.
A female subject is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least 1 of the following conditions applies:
i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3.
ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 12 weeks after the last dose of study treatment.
In addition for the sub-protocol ACCORD-2-006:
Antibiotic prophylaxis: PLEASE NOTE that, according to Section 22.214.171.124, all patients must take antibiotic prophylaxis concomitantly, starting with the first dose of zilucoplan.
For Sub study ACCORD 2-005, please refer to the Master protocol.
For Sub study ACCORD 2-008, please refer to the Master protocol.
|E.4||Principal exclusion criteria||
|Patients are excluded from the study if any of the following criteria apply (or any of the criteria from the appropriate sub-protocol):
1. Patients who have previously had a score of 6 or 7 on the 9-point ordinal scale.
2. Any patient whose interests are not best served by study participation, as determined by a senior attending clinician.
3. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >5 × the upper limit of normal (ULN).
4. Known active infection with HIV or hepatitis B or C.
5. Stage 4 severe chronic kidney disease.
6. Anticipated transfer to another hospital that is not a study centre within 72 hours.
7. Allergy to any study medication.
8. Experimental off-label usage of medicinal products as treatments for COVID-19 (except where the product has either been given a positive opinion under the Early Access to Medicines Scheme [EAMS] or is a SARS-CoV-2 vaccine) at the time of enrolment.
9. Patients participating in another clinical study of an investigational medicinal product, unless co-enrolment in the other study has been pre-approved by the Steering Committee.
10. Active tuberculosis defined as requiring current treatment for tuberculosis.
Additional exclusion criteria that are specific to the sub-protocol ACCORD-2-002:
11. Inability to swallow capsules (administration via nasogastric tube is permitted in patients who become unable to swallow after starting the study drug)
12. Patients with a permanent cardiac pacemaker implanted.
13. History of the following cardiac conditions:
a) Myocardial infarction within 3 months prior to the first dose
b) Unstable angina
c) History of clinically significant dysrhythmias (long QT features on ECG, sustained bradycardia [≤55 bpm]), left bundle branch block, or ventricular arrhythmia) or history of familial long QT.
Patients with an implantable cardioverter defibrillator device in place, will be allowed to enrol. Atrial fibrillation will not be a reason for exclusion.
14. Screening 12-lead ECG with a measurable QTc interval according to Fridericia correction (QTcF) >470 msec
In the presence of a temporary cardiac pacemaker, QTcF will need to be calculated from an ECG which has been recorded during a period where ventricular (QRS) complexes without pacing are present. If no unpaced ventricular complexes are present to allow calculation of QTcF, the patient should not be enrolled in this sub-protocol.
15. Clinically significant hypokalaemia. Individuals who do not meet this criterion may be rescreened once, after correction of electrolyte abnormality
16. Therapeutic anticoagulation with vitamin K antagonists. Note: Patients receiving low doses prescribed to maintain
the patency of venous access devices may be included.
17. Previous bowel resection that would interfere with drug absorption
Additional exclusion criteria that are specific to the sub-protocol ACCORD-2-003:
18. Active tuberculosis defined as requiring current treatment for tuberculosis
Active tuberculosis defined as requiring current treatment for tuberculosis
19. A known family history of heart failure defined as either of the following:
a) ≥2 first degree relatives with clinically significant heart failure, or
b) ≥1 first degree relative with heart failure known to be heritable (eg, hypertrophic cardiomyopathy), unless inheritance was previously excluded by genetic testing
Additional exclusion criteria that are specific to the sub-protocol ACCORD-2-004:
• Unable to take acalabrutinib by mouth
• Profound neutropenia and/or profound thrombocytopenia as defined as an absolute neutrophil count < 500/µL and platelet count < 50,000/µL respectively at screening per local laboratory
Additional exclusion criteria that are specific to the sub-protocol ACCORD-2-006:
20.Participants with unresolved or suspected infection with Neisseria meningitidis, or a past history of Neisseria meningitidis (eg, in a complement deficient patient), should not receive treatment with zilucoplan.
For Sub study ACCORD 2-005, please refer to the Master protocol.
For Sub study ACCORD 2-008, please refer to the Master protocol.
|E.5 End points
|E.5.1||Primary end point(s)||
|•Time to sustained clinical improvement of at least 2 points (from randomisation) on a 9 point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses).
9-point category ordinal scale:
0. Uninfected, no clinical or virological evidence of infection
1. Ambulatory, no limitation of activities
2. Ambulatory, limitation of activities
3. Hospitalised – mild disease, no oxygen therapy
4. Hospitalised – mild disease, oxygen by mask or nasal prongs
5. Hospitalised – severe disease, noninvasive ventilation or high flow oxygen
6. Hospitalised – severe disease, intubation and mechanical ventilation
7. Hospitalised – severe disease, ventilation and additional organ support – vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO)
Sub-protocol-ACCORD-2-002: As defined in Master Protocol.
|E.5.1.1||Timepoint(s) of evaluation of this end point||
|As defined in Main protocol
|E.5.2||Secondary end point(s)||
• The proportion of patients not deteriorating according to the ordinal scale by 1, 2, or 3 points on Days 2, 8, 15, and 29.
• Duration (days) of oxygen use and oxygen free days.
• Duration (days) of ventilation and ventilation-free days.
• Incidence of any form of new ventilation use and duration (days) of new ventilation use.
• Duration (days) of organ support.
• Qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) in oropharyngeal/nasal swab while hospitalised on Days 1, 3, 5, 8, 11, 15, and 29
•Response rate (number and %) by treatment arm at Days 2, 8, 15, 22, and 29.
• Time to live discharge from the hospital.
• Mortality at Days 15, 29, and 60.
• Time from treatment start date to death.
•SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death
• Physical examination.
• Clinical laboratory examinations.
• Vital signs (blood pressure/heart rate/temperature/respiratory rate).
• Adverse events.
•Duration (days) of ICU and hospitalisation.
•NEWS2 assessed daily while hospitalised and on Days 15 and 29.
•Time to a NEWS2 of ≤2, maintained for at least 24 hours.
• Ranked trajectory over 29 days, with trajectory ranked as defined in the protocol.
Secondary endpoints in the Master Protocol, will be considered as key secondary endpoints for the purposes of this sub-protocol.
|E.5.2.1||Timepoint(s) of evaluation of this end point||
|Master protocol ACCORD-2-001:
As defined in Main Protocol
PK/PD: blood samples will be analysed for plasma bemcentinib and metabolites and soluble AXL, GAS6 and other blood proteins at pre-dose (Day 1); pre-dose and 6 hours postdose (Day 4), and predose on Days 8 and 15.
As described in E.5.2
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| 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.126.96.36.199||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.8.1.3||Single blind|| No
|E.8.1.4||Double blind || No
|E.8.1.5||Parallel group|| Yes
|E.8.1.6||Cross over || No
|E.188.8.131.52||Other trial design description||
|E.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || No
|E.8.2.4||Number of treatment arms in the trial||2
The trial involves single site in the Member State concerned
|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||10
|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
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
For each sub protocol, the end of the study for that candidate agent will be defined as the date on which the last patient completes the last visit for that sub protocol.
For the overall study, the end of the study will be defined as the date on which the last patient completes the last visit for the final sub protocol to be concluded.
|E.8.9 Initial estimate of the duration of the trial
|E.8.9.1||In the Member State concerned years||1
|E.8.9.1||In the Member State concerned months||0
|E.8.9.1||In the Member State concerned days||0
|E.8.9.2||In all countries concerned by the trial years||0
|E.8.9.2||In all countries concerned by the trial months||0
|E.8.9.2||In all countries concerned by the trial days||0