| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Coronavirus-induced disease (COVID-19) (SARS coronavirus 2, or SARS-CoV-2) |
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| E.1.1.1 | Medical condition in easily understood language |
| Coronavirus-induced disease (COVID-19) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10051905 |
| E.1.2 | Term | Coronavirus infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 |
Master Protocol:
Phase I - To find the optimal dose of each drug (candidate) (or combination of candidates)
Phase II - To determine the effect each candidate has on improving patients clinical outcome (using the WHO clinical severity score) and safety of each candidate and recommend whether it should be evaluated further in a large phase II/III trial.
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| E.2.2 | Secondary objectives of the trial |
Master Protocol:
Phase I - How safe is the treatment
Phase II: To assess the effects of study treatments on:
- The need for (and duration) of oxygen support (including mechanical ventilation)
- The length of time people remain in hospital (including time in intensive care)
- Clinical improvement at various timepoints
- Side effects seen
In addition in EIDD-2801-Candidate Specific Trial 2
- Patient Reported Outcomes |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Master Protocol:
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 candidate-specific trial protocol):
1. Adults (≥18 years) with laboratory-confirmed* SARS-CoV-2 infection (PCR)
2. Ability to provide informed consent signed by study patient or legally acceptable representative
3. Women of childbearing potential (WOCBP) and male patients who are sexually active with WOCBP must agree to use a highly effective method of contraception from the first administration of trial treatment, throughout trial treatment and for the duration outlined in the candidate-specific trial protocol after the last dose of trial treatment
*If any CSTs are included in the community setting, the CST protocol will clarify whether patients with suspected SARS-CoV-2 infection are also eligible.
Standard additional criteria that may be applied per candidate-specific trial protocol:
Group A (severe disease)
Patients with clinical status of Grades 5 (hospitalised, oxygen by mask or nasal prongs), 6 (hospitalised, non-invasive ventilation or high flow oxygen), 7 (hospitalised, intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥200), 8 (hospitalised mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressors or 9 (hospitalised, mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis or ECMO) (as defined by the WHO Clinical Progression Scale.
Group B (mild-moderate disease)
4b. Ambulant or hospitalised patients with peripheral capillary oxygen saturation (SpO2) >94% RA.
Nomacopan Candidate-Specific Trial:
Additional inclusion criteria specific to this CST are:
1. Adults (≥18 years) with laboratory-confirmed SARS-CoV-2 infection (PCR) who are within 5 days of symptom onset.
4. A score of grade 4, 5, 6 or 7 on the 9-Point Ordinal Scale*
Grade 6 and 7 will only be accepted when second cohort open to recruitment.
CST-2 (EIDD-2801) additional inclusion criteria:
5. Has signs or symptoms of COVID-19 that began within 5 days of the planned first dose of study drug.
6. Is in generally good health (except for current respiratory infection) and is free of uncontrolled chronic conditions.
7. Is willing and able to comply with all study procedures and attending weekly clinic visits through the 4th week.
8. Has someone, aged ≥ 16 living in the same household during the dosing period.
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| E.4 | Principal exclusion criteria |
Master Protocol:
Patients are excluded from the study if any of the following criteria apply (as well as all criteria from the appropriate candidate-specific trial protocol):
1. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >5 times the upper limit of normal (ULN)
2.Stage 4 severe chronic kidney disease or requiring dialysis (i.e., estimated glomerular filtration rate <30 mL/min/1.73 m2)
3.Pregnant or breast feeding
4. Anticipated transfer to another hospital which is not a study site within 72 hours
5. Allergy to any study medication
6. Patients taking other prohibited drugs (as outline in CST protocol) within 30 days or 5 times the half-life (whichever is longer) of enrolment
7. Patients participating in another CTIMP trial
Nomacopan Candidate-Specific Trial:
For the purpose of the nomacopan candidate-specific trial, appendix exclusion criteria 6 has been amended from the Master protocol as follows, to restrict the population of patients that will be included in the trial:
6. Patients taking the following prohibited drugs:
• Other complement inhibiting drug such as eculizumab (Soliris®).
• Any other drug which directly inhibits cytokines, chemokines or proinflammatory mediators such as tocilizumab (Actemra®/RoActremra®), anakinra (Kineret®), etanercept (Enbrel®), infliximab (Remicade®) or adalimumab (Humira®).
N.B. Whilst it is not thought that there is likely to be any adverse interaction between nomacopan and any of these drugs, in the context of a clinical trial, it would be impossible to distinguish the effects of those agents from that of nomacopan. Corticosteroids, antivirals and antibiotics are permitted in conjunction with nomacopan therapy.
Additional exclusion criteria specific to this candidate specific appendix are:
8. Weight less than 50kg or more than 100kg
CST-2 (EIDD-2801) additional exclusion criteria:
8. Has a febrile respiratory illness that includes pneumonia that results in hospitalisation, or requires hospitalisation, oxygenation, mechanical ventilation, or other supportive modalities.
9. Has a platelet count less than 50x10^9/L.
10. Is experiencing adverse events or laboratory abnormalities that are Grade 3 or above based on the CTCAE v5 grading.
11. Has clinically significant liver dysfunction or renal impairment.
12. Has history of Hepatitis C infection or concurrent bacterial pneumonia.
13. Has received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 30 days prior to the first dose of study drug.
14. In the opinion of the investigator, has significant end-organ disease as a result of relevant comorbidities: chronic kidney disease, congestive heart failure, peripheral vascular disease including diabetic ulcers.
15. Has a SaO2<95% by oximetry or has lung disease that requires supplemental oxygen or maintenance steroids.
16. Has any condition that would, in the opinion of the investigator, put the patient at increased risk for participation in a clinical study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Master Protocol Co-primary endpoints:
For dose finding (phase I)
• Dose limiting toxicities (Safety and Tolerability of drug under study – CTCAE v5 Grade ≥3 adverse events)
For efficacy evaluation (phase II) one of the following depending on the population the candidate is being evaluated in:
• Group A (severe disease)
Time to clinical improvement: Improvement will be determined according to the WHO Progression Scale. Improvement, defined by a minimum 2-step change in the scale, will be analysed as time to event, measured up to 29 days from randomisation.
• Group B (mild-moderate disease)
Pharmacodynamics of drug defined as time to negative viral titres in nose and/or throat swab, measured up to 29 days from randomisation.
Nomacopan Candidate-Specific Trial:
Time to clinical improvement: improvement will be determined according to the WHO clinical severity score (WHO Working Group on the Clinical Characteristics of COVID-19 infection 9-point ordinal scale). Improvement, defined by a minimum 2-step change in the scale, will be analysed as time to event, measured up to day 29.
For CST-2 (EIDD-2801):
To determine the safety and tolerability of multiple ascending doses of EIDD-2801.
Efficacy Objective: To determine the ability of EIDD-2801 to improve viral clearance (time to negative PCR). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Master:
PI:
Treatment will be evaluated for safety and tolerability at day 7 post randomisation using a state-of-the-art Bayesian dose-escalation model.
• Group A (severe disease)
Time to clinical improvement measured up to 29 days from randomisation.
• Group B (mild-moderate disease)
Pharmacodynamics of drug defined as time to negative viral titres in nose and/or throat swab, measured up to 29 days from randomisation.
Nomacopan Candidate-Specific Trial:
Safety will be assessed during the treatment period, up to 14 days from first treatment. Assessment of efficacy will be based on the hazard ratio for time to clinical improvement, measured up to day 9.
CST-2 (EIDD-2801):
Phase I: over 7 days (from first dose)
Phase II: Up to day 29 (from randomisation) |
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| E.5.2 | Secondary end point(s) |
Master protocol:
Phase I:
Safety: Adverse event rate according to CTCAE v5
Phase II:
• Proportion of patients with clinical improvement (as defined above) at day 8, 15 and day 29
• Change at day 8 and 15 from randomisation in the WHO Clinical Progression Scale
• Time to a one point change on the WHO Clinical Progression Scale
• The ratio of the oxygen saturation to fractional inspired oxygen concentration (SpO2/FiO2)
• Time to discharge from randomisation
• Proportion of patient discharged by days 8, 15 and 29
• Admission rate and time in ICU
• White cell count, haemoglobin, platelets, creatinine, and ALT on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29
• Mortality at Days 8, 15 and 29
• Time to death from registration
• Duration (days) of oxygen use and oxygen-free days
• Duration (days) of mechanical ventilation and mechanical ventilation-free days
• Incidence of new mechanical ventilation use and duration (days) of new mechanical ventilation use
• Actual versus planned candidate treatment received
• NEWS2 assessed daily while hospitalised
• Change in viral load over time
• SARS-CoV-2 in OP swab at baseline
• Biomarkers for response
Nomacopan candidate-specific protocol - No additional secondary endpoints.
CST-2 (EIDD-2801)
• Concentrations of EIDD-2801 and -1931 in plasma, nasal swab, tears, blood spots (Ph I & II)
• Qualitative (and quantitative when possible) PCR for SARS-CoV-2 by nasal swab. (Ph I)
• Patient Reported Outcome Measures (Ph I & II)
• Actual versus planned treatment (Ph I & II)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints outline within secondary endpoints outlined above. |
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Standard of care or Placebo |
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| 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 | 23 |
| 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
|
| For regulatory purposes the end of trial will be when the last participant in the last candidate-specific trial has completed the last data point. |
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| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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