E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Respiratory failure resulting from Covid-19 disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001053 |
E.1.2 | Term | Acute respiratory failure |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
To determine whether administration of almitrine bismesylate can ameliorate hypoxaemia in Covid-19 and augment the effectiveness of supplemental oxygen therapy and respiratory support.
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E.2.2 | Secondary objectives of the trial |
To measure the time to de-escalation of respiratory support (if it occurs) To assess the impact of the oral almitrine on daily circulating almitrine levels. To assess the impact of almitrine on mortality from COVID-19
Physiological sub-study: To understand the relationship between oral almitrine administration and arterial oxygenation To understand the relationship between oral almitrine administration and plasma almitrine levels.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Hospitalised patients • Male or female, aged 18 and above • Clinically confident or proven Covid-19 disease* who require respiratory support** and who have not undergone significant de-escalation of respiratory support*** (i.e. are not in a recovery phase). • Female participants of childbearing potential must be willing to use effective contraception for two weeks after final dose of IMP. Women will be advised to use a hormonal method, an intrauterine device (IUD) or intrauterine system (IUS), a barrier method or abstinence.
*A clinically confident diagnosis is made where there is either swab positivity for Covid-19, or where the clinical presentation (including any of symptoms, clinical chemistry (e.g. raised D-dimer, raised CRP) and radiology (CXR, CT or ultrasound findings)) is consistent with likely Covid-19 infection. A pre-planned subgroup analysis will compare the primary outcome for those with swab positive and “clinically likely” disease.
**At the time of recruitment, patients will be at least moderate oxygen therapy (>4 l/min O2 flow to mask or nasal cannulae; FiO2 > 0.3 for Venturi mask) to maintain pulse oximeter saturation, SpO2, in the target range set by the treating clinician. Other higher levels of oxygen support (including higher doses of oxygen, non-invasive respiratory support (continuous positive airway pressure (CPAP), high-flow nasal oxygen, or bi-level non-invasive positive pressure ventilation (NIPPV)) and invasive mechanical ventilation via an endotracheal tube can all be included, but patients are excluded if they have received >72 hours of invasive mechanical ventilation during their current illness.
***De-escalation of respiratory support is defined as a significant reduction in respiratory support that maintains saturation within the treating physicians’ target range within 24 hours of inclusion to this study. A significant reduction is any change in mode of oxygen delivery (i.e. intubated to non-invasive ventilation, non-invasive ventilation to standard oxygen therapy, or reduction of standard “wall” oxygen of more than 3 litres / min). Changes less than this will not be considered to be significant.
Additional Inclusion Criteria for the Physiological Sub-Study • Arterial line in place for clinical care • Receiving either non-invasive respiratory support or invasive mechanical ventilation for which the inspired oxygen fraction can be measured.
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E.4 | Principal exclusion criteria |
• Female participant who is pregnant, lactating or planning pregnancy during the course of the trial(women of childbearing potential as determined by the clinician must have a negative urine pregnancy test) • Pre-existing significant liver disease or a baseline AST or ALT which is >3x the upper limit of normal. • A previously established diagnosis of significant pulmonary hypertension defined as a resting pulmonary artery pressure of >50 mmHg on right heart catheter or echocardiography. • Received invasive mechanical ventilation for >72h during current illness, at the time of recruitment into the study • In the clinicians’ view, expected to survive <24 hours • Patients who, in the absence of Covid-19, would be unable to give informed consent. • Hypersensitivity to almitrine |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in level of respiratory support over 7 days of treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Daily level of respiratory support for 7 days during almitrine/placebo administration |
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E.5.2 | Secondary end point(s) |
Time to de-escalation of respiratory support (if it occurs).
Daily blood almitrine concentrations.
Mortality at 30 days captured via medical records / phone follow up.
Sub-Study Time profile for change in PaO2/FiO2 and blood almitrine concentration hourly over 4 hours post almitrine/placebo.
Time profile of blood almitrine concentration hourly over 4 hours post almitrine/placebo
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During 7 days after administration of almitrine/placebo.
During 7 days after administration of almitrine/placebo.
Mortality at 30 day
Sub-study During 4 hours after administration of almitrine/placebo.
During 4 hours after administration of almitrine/placebo |
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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 | No |
E.6.4 | Safety | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 3 |
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 | No |
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
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One month after final data has been collected. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 2 |
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 |