| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Coronavirus disease (COVID-19) |
|
| 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 |
|
| 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 |
| A randomized study assessing amiodarone and verapamil compared with conventional therapy in the early, symptomatic stage of infection in symptomatic patients with confirmed COVID-19 |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)Hospitalized patients with confirmed COVID-19 and symptoms. Confirmation of COVID-19 diagnosis should be made with Real-Time PCR.
2)Written informed consent given prior to any trial-related procedure.
3)Male and female age 18 or more at the time of signing the informed consent.
4)An oxygenation index defined as quotient of partial pressure of oxygen in arterial blood (PaO2, in mmHg) and fraction of inspired oxygen (FiO2) > 200. It is recommended to measure partial pressure of oxygen (PaO2) using an arterial blood gas (ABG). Optionally, if arterial blood cannot be collected, the PaO2 level should be determined according to the table below (Table 1). Fraction of inspired oxygen (FiO2) for different oxygen therapy systems are given in Table 2.
Table 1. SpO2 to pO2 conversion.
SpO2 [%] pO2 [mmHg]
80 44
81 45
82 46
83 47
84 49
85 50
86 51
87 52
88 54
89 56
90 58
91 60
92 64
93 68
94 73
95 80
96 90
97 100
98 112
99 145
Table 2. Fraction of Inspired Oxygen (FiO2) for different methods of oxygen administration.
Oxygen tank flow rate in liters/min FiO2. Fraction of inspired oxygen value
Nasal Cannula
0 0.21
1 0.24
2 0.28
3 0.32
4 0.36
5 0.40
6 0.44
Face mask
5 0.4
6-7 0.5
7-8 0.6
Face mask with reservoir
6 0.6
7 0.7
8 0.8
9 0.9
10 0.95
5)Willingness and ability to comply with the protocol.
6)Contraception and fertility:
A.Female patients:
-must be of non-child-bearing potential i.e. surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening/enrolment) or post-menopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or
-if of child-bearing potential, must have a negative pregnancy test before the first IMP intake (blood / urine pregnancy test). They must agree not to attempt to become pregnant, must not donate ova, and must use a highly effective contraceptive method (see below) together with a barrier method during the clinical trial.
B.Male patients must agree not to father a child or to donate sperm starting at Screening, during the clinical trial. Male patients must also
-abstain from sexual intercourse with a female partner (acceptable only if it is the patient’s usual form of birth control/lifestyle choice), or
-use adequate barrier contraception during treatment with the IMP, and
-if they have a female partner of childbearing potential, the partner should use a highly effective contraceptive method.
-if they have a pregnant partner, they must use condoms while taking the IMP to avoid exposure of the fetus to the IMP
Highly effective methods of contraception meaning.
Highly effective forms of birth control are those with a failure rate less than 1% per year and include:
-oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal contraceptives associated with inhibition of ovulation
-oral, injectable, or implantable progestogen-only hormonal contraceptives associated with inhibition of ovulation
-intrauterine device or intrauterine hormone-releasing system
-bilateral tubal occlusion
-vasectomized partner (i.e. the patient’s male partner underwent effective surgical sterilization before the female patient entered the clinical trial and is the sole sexual partner of the female patient during the clinical trial)
-sexual abstinence (acceptable only if it is the patient’s usual form of birth control/lifestyle choice; periodic abstinence [e.g. calendar, ovulation, symptothermal, postovulation methods] and withdrawal are no acceptable methods of contraception)
Barrier methods of contraception include:
-Condom (without spermicidal foam/gel/film/cream/suppository or fat- or oil-containing lubricants)
-Occlusive cap (diaphragm or cervical/vault caps) with spermicidal gel/film/cream/suppository.
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|
| E.4 | Principal exclusion criteria |
1)Acute respiratory distress syndrome (ARDS).
2)Contraindications for or known hypersensitivity to amiodarone or calcium channel blockers.
3)Long QT syndrome.
4)Prolonged baseline QTc interval (≥450 ms).
5)Cardiogenic shock or severe hypotension (< 90 mmHg).
6)Severe left ventricle dysfunction (left ventricular ejection fraction ≤35%).
7)Severe sinus - node dysfunction with marked sinus bradycardia.
8)2nd/3rd degree heart block.
9)Bradycardia without pacemaker that has caused syncope.
10)History of severe dysthyroidism. Clinical signs and symtomps of thyroid disease if there are abnormal TSH and thyroxine (fT4)or triiodothyronine (fT3) levels in serum.
11)A-Fib/flutter conducted via accessory pathway (ie,Wolff -Parkinson-White).
12)Women who are pregnant or breastfeeding at study screening.
13)Patient with concurrent disease considered by the Investigator to be clinically significant in the context of the study.
14)Severe mental illness and/or a history or evidence of organic brain disease or dementia considered by the Investigator to be clinically significant in the context of the study, that would compromise the subject’s ability to comply with the study protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary end point of the study is the clinical improvement defined according to WHO classification, that was used in recent COVID-19 trials. The end point is defined as time to first occurrence of clinical improvement assessed on a seven category scale ranging from 1 to 7. Improvement is considered as the increase of one category of the scale or discharge. Lower scores indicate worse outcomes and higher scores outcome improved.
The ordinal scale has the following items, ranging from 1 to 7:
8.Death.
9.Hospitalized patients who require mechanical ventilation, ECMO, or both;
10.Hospitalized patients who require nasal oxygen therapy in high flow, non-invasive mechanical ventilation, or both;
11.Hospitalized patients who require oxygen therapy;
12.Hospitalized patients who do not require oxygen therapy;
13.Not hospitalized, but unable to resume normal activities;
14.Not hospitalized with resumption of normal activities. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be evaluated during the period from the inclusion of the patient until the end of the study. |
|
| E.5.2 | Secondary end point(s) |
•Clinical improvement. Time to first occurrence of clinical improvement assessed on a seven category scale ranging from 1 to 7. [Time Frame: Randomization to day 7, 15 and 28 or discharge].
•Mean change in the 7-point ordinal scale. [Time Frame: Randomization to day 7, 15 and 28 or discharge].
•Mortality. [Time Frame: Randomization to day 28 or discharge].
•Time to resolution of fever [Time Frame: Baseline to Day 28 ] Defined as body temperature (≤36.6°C [axilla], or ≤37.2 °C [oral], or ≤37.8°C [rectal]) for at least 48 hours without antipyretics or until discharge, whichever is sooner. [Time Frame: Randomization to day 28 or discharge].
•Clinical improvement or fever resolution. Composite endpoint. [Time Frame: Randomization to day 7, 15 and 28 or discharge].
•Tachyarrhythmias defined as atrial fibrillation, supraventricular or ventricular tachycardia requiring treatment. [Time Frame: Randomization to day 28 or discharge].
•Mortality or tachyarrhythmias. Composite endpoint. [Time Frame: Randomization to day 28 or discharge].
•Time to clinical improvement from admission using the 7-point ordinal scale. [Time Frame: Randomization to day 28 or discharge].
•Change in NEWS2 score. The National Early Warning Score (NEWS2) score. A higher score is worse. [Time Frame: Randomization to day 7,10 and 15]. Score ranges from 0-20.
•Clinical decline on a 7-point ordinal scale.
•Duration of hospitalization. [Time Frame: Randomization to day 28 or discharge].
•PO2/FIO2 oxygenation index defined as quotient of partial pressure of oxygen in arterial blood (PaO2, in mmHg) and fraction of inspired oxygen (FiO2) [Time Frame: Randomization to day 7,10 and 15 and discharge].
•Clinical improvement. Assessed on a modified seven category scale ranging from 1 to 7. [Time Frame: Randomization to day 15]. Modified scale implies to divide into two categories A and B patients under oxygen therapy (Category A: 94% or more while breathing supplemental oxygen up to an inspired fraction of oxygen (FiO2) of 0.4, and showing no clinical signs of impending fatigue of respiratory muscles); Category B) SpO2 of 93 % or less on supplemental oxygen up to a FiO2 of 0.4, or patient is further deteriorated and thus receiving a FiO2 higher than 0.4, or showing clinical signs of impending fatigue of respiratory muscles. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| conventional therapy for COVID-19 |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Poland |
| Spain |
| Italy |
|
| 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
|
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 17 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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