To determine whether administration of almitrine bismesylate can ameliorate hypoxaemia in Covid-19 and augment effectiveness of supplementary oxygen therapy and respiratory support.
- Conditions
- Covid-19MedDRA version: 21.1Level: PTClassification code 10001053Term: Acute respiratory failureSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disordersTherapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]
- Registration Number
- EUCTR2020-002567-57-GB
- Lead Sponsor
- niversity of Oxford / Clinical Trials and Research Governance
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 112
• 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.
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 92
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20
• 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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To determine whether administration of almitrine bismesylate can ameliorate hypoxaemia in Covid-19 and augment the effectiveness of supplemental oxygen therapy and respiratory support.<br><br>;Secondary Objective: To measure the time to de-escalation of respiratory support (if it occurs)<br>To assess the impact of the oral almitrine on daily circulating almitrine levels.<br>To assess the impact of almitrine on mortality from COVID-19<br><br>Physiological sub-study: <br>To understand the relationship between oral almitrine administration and arterial oxygenation<br>To understand the relationship between oral almitrine administration and plasma almitrine levels.<br>;Primary end point(s): Change in level of respiratory support over 7 days of treatment ;Timepoint(s) of evaluation of this end point: Daily level of respiratory support for 7 days during almitrine/placebo administration
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Time to de-escalation of respiratory support (if it occurs).<br><br>Daily blood almitrine concentrations.<br><br>Mortality at 30 days captured via medical records / phone follow up. <br><br>Sub-Study<br>Time profile for change in PaO2/FiO2 and blood almitrine concentration hourly over 4 hours post almitrine/placebo. <br><br>Time profile of blood almitrine concentration hourly over 4 hours post almitrine/placebo <br>;Timepoint(s) of evaluation of this end point: During 7 days after administration of almitrine/placebo.<br><br>During 7 days after administration of almitrine/placebo.<br><br>Mortality at 30 day<br><br>Sub-study<br>During 4 hours after administration of almitrine/placebo.<br><br>During 4 hours after administration of almitrine/placebo