COVID19
Conditions
Brief summary
The rationale in severe COVID19 infection is to undertake PEX to aid reduction of the hyperinflammation and reduce the morbidity and mortality to the lungs, but also systemically, such as the heart, kidneys and brain. A feasibility study of PEX therapy has been undertaken and confirmed a reduction in the inflammatory markers, no VTE/arterial events and normalisation of the renal function and cardiac function throughout the period of therapy. As plasma exchange is an intensive treatment modality, blocks of 5 daily PEX will be undertaken. Further blocks of PEX treatment can be initiated as dictated by the clinical and laboratory parameters. Unlike many therapeutic schedules, there is no immunosuppression associated with PEX; indeed, the resulting decrease in inflammatory markers were shown to be associated with an increase and sustained lymphocytes count.
Detailed description
COVID19 is a viral pandemic associated with primarily respiratory pathology, in the form of microvascular and macrovascular thrombosis. In patients requiring hospital admission, there is severe disease, requiring respiratory support, from high dose oxygen therapy or ventilatory assistance, which may be invasive or non invasive. The pathology of COVID19 is poorly understood, but it is accepted there is an inflammatory-thrombotic basis. Despite current therapeutic platforms, there is no consensus on a specific therapy within a trial setting that has proven benefit in severe COVID 19. Thrombotic microangiopathies, such as TTP, are a different disease, but have a comparable prothrombotic phenotype, and similar or higher inflammatory parameters, including D Dimers, ferritin, LDH and IL-6 at acute presentation and resolve with plasma exchange (PEX). The rationale in severe COVID19 infection is to undertake PEX to aid reduction of the hyperinflammation and reduce the morbidity and mortality to the lungs, but also systemically, such as the heart, kidneys and brain. A feasibility study of PEX therapy has been undertaken and confirmed a reduction in the inflammatory markers, no VTE/arterial events and normalisation of the renal function and cardiac function throughout the period of therapy. As plasma exchange is an intensive treatment modality, blocks of 5 daily PEX will be undertaken. Further blocks of PEX treatment can be initiated as dictated by the clinical and laboratory parameters. Unlike many therapeutic schedules, there is no immunosuppression associated with PEX; indeed, the resulting decrease in inflammatory markers were shown to be associated with an increase and sustained lymphocytes count. Therefore, as patients with COVID-19 have elevated procoagulant factors including VWF and factor VIII secondary to direct endothelial activation. This is associated with an exaggerated pro-inflammatory immune response and microvascular thrombosis; resulting in multi-organ dysfunction and eventually death. PEX will improve coagulopathy, as measured by VWF:ADAMTS 13 ratio and D Dimers, with an associated reduction in inflammation, organ-related microthrombosis, and ventilatory support.
Interventions
DRUGOCTAPLAS
plasma exchange
Sponsors
University College, London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-70 * Proven COVID-19/high clinical suspicion of COVID-19 * Hypoxia/respiratory compromise defined as requiring respiratory support of \>2L/min of oxygen by nasal cannulae to maintain SpO2\<96%. * Raised inflammatory parameters: at least 2 of the following: 1. Raised LDH (\> 2 x ULN) 2. Raised D Dimers (\> 2X ULN) 3. Raised CRP (\>2X ULN) * Females of childbearing potential have a negative pregnancy test within 7 days prior to being randomised. Participants are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal
Exclusion criteria
* Significant co-morbid illness with treatment escalation limited to CPAP * Active bleeding * PF ratio \< 100 on mechanical ventilation OR noradrenaline requirement \> 0.5mcg/kg/min to maintain MAP \> 65mmHg (suggests futility) * Known allergies to Octaplas or excipients * Females who are pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Inflammatory Marker Reduction of at Least 50% at Any Efficacy Time Point | The inflammatory markers recorded in this study are C reactive protein (CRP), lactate dehydrogenase(LDH) and D-Dimer, and we consider whether there is a reduction during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28). | The primary outcome in this study is a binary outcome indicating whether there was a reduction of at least 50% (compared to baseline) in two or more inflammatory markers \[CRP, LDH, D-Dimer\] during acomparable duration of treatment with either PEX or Standard of Care after study initiation. |
| Change in Inflammatory Marker-CRP | We consider whether there is a reduction in inflammatory marker CRP during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28). | To compare the change in inflammatory marker CRP with Plasma Exchange and control groups in patients with severe COVID-19. Measured as number of participants who experienced a reduction of 50% at any follow-up time point. |
| Change in Inflammatory Marker-D Dimer | We consider whether there is a reduction in inflammatory marker D-dimer during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28). | To compare the change in inflammatory marker D-dimer with Plasma Exchange and control groups in patients with severe COVID-19. Measured as number of participants who experienced a reduction of 50% at any follow-up time point. |
| Change in Inflammatory Marker-LDH | We consider whether there is a reduction in inflammatory marker LDH during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28). | To compare the change in inflammatory marker LDH with Plasma Exchange and control groups in patients with severe COVID-19. Measured as number of participants who experienced a reduction of 50% at any follow-up time point. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| STANDARD OF CARE Standard patient care for severe COVID-19 | 11 |
| Plasma Exchange Standard patient care for severe COVID-19 with. plasma exchange daily for 5 days x 3 courses as required
OCTAPLAS: plasma exchange | 12 |
| Total | 23 |
Baseline characteristics
| Characteristic | Total | Plasma Exchange | STANDARD OF CARE |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 3 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 9 Participants | 7 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 4 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 11 Participants | 4 Participants | 7 Participants |
| Region of Enrollment United Kingdom | 23 participants | 12 participants | 11 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 19 Participants | 10 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 11 | 2 / 11 |
| other Total, other adverse events | 11 / 11 | 10 / 11 |
| serious Total, serious adverse events | 4 / 11 | 6 / 11 |
Outcome results
Primary
Change in Inflammatory Marker-CRP
To compare the change in inflammatory marker CRP with Plasma Exchange and control groups in patients with severe COVID-19. Measured as number of participants who experienced a reduction of 50% at any follow-up time point.
Time frame: We consider whether there is a reduction in inflammatory marker CRP during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28).
Population: Note: 23 patients with severe COVID-19 were randomised. One patient withdrew from the study 1 day after randomisation and their data has been excluded from the analysis. There were no follow-up data for a further two participants for this endpoint (1 from each arm) and hence they were omitted from this analysis, so data from a total of 20 participants was analysed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| STANDARD OF CARE | Change in Inflammatory Marker-CRP | 8 Participants |
| Plasma Exchange | Change in Inflammatory Marker-CRP | 7 Participants |
Comparison: The primary analysis will involve a comparison of the binary outcome '50% reduction in inflammation marker CRP' between the PEX and Standard of Care (control) trial arms using a chi-squared test. The risk difference (and ratio) will be estimated with a 95% confidence interval.p-value: 0.606Chi-squared
Primary
Change in Inflammatory Marker-D Dimer
To compare the change in inflammatory marker D-dimer with Plasma Exchange and control groups in patients with severe COVID-19. Measured as number of participants who experienced a reduction of 50% at any follow-up time point.
Time frame: We consider whether there is a reduction in inflammatory marker D-dimer during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28).
Population: Note: 23 patients with severe COVID-19 were randomised. One patient withdrew from the study 1 day after randomisation and their data has been excluded from the analysis. There were no follow-up data for a further three participants for this endpoint (1 from standard of care arm and 2 from plasma exchange arm) and hence they were omitted from this analysis, so data from a total of 19 participants was analysed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| STANDARD OF CARE | Change in Inflammatory Marker-D Dimer | 4 Participants |
| Plasma Exchange | Change in Inflammatory Marker-D Dimer | 6 Participants |
Comparison: The primary analysis will involve a comparison of the binary outcome '50% reduction in inflammation marker D-Dimer' between the PEX and Standard of Care (control) trial arms using a chi-squared test. The risk difference (and ratio) will be estimated with a 95% confidence interval.p-value: 0.245Chi-squared
Primary
Change in Inflammatory Marker-LDH
To compare the change in inflammatory marker LDH with Plasma Exchange and control groups in patients with severe COVID-19. Measured as number of participants who experienced a reduction of 50% at any follow-up time point.
Time frame: We consider whether there is a reduction in inflammatory marker LDH during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28).
Population: Note: 23 patients with severe COVID-19 were randomised. One patient withdrew from the study 1 day after randomisation and their data has been excluded from the analysis. There were no follow-up data for a further two participants for this endpoint (1 from each arm) and hence they were omitted from this analysis, so data from a total of 20 participants was analysed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| STANDARD OF CARE | Change in Inflammatory Marker-LDH | 5 Participants |
| Plasma Exchange | Change in Inflammatory Marker-LDH | 6 Participants |
Comparison: The primary analysis will involve a comparison of the binary outcome '50% reduction in inflammation marker LDH' between the PEX and Standard of Care (control) trial arms using a chi-squared test. The risk difference (and ratio) will be estimated with a 95% confidence interval.p-value: 0.653Chi-squared
Primary
Number of Participants With Inflammatory Marker Reduction of at Least 50% at Any Efficacy Time Point
The primary outcome in this study is a binary outcome indicating whether there was a reduction of at least 50% (compared to baseline) in two or more inflammatory markers \[CRP, LDH, D-Dimer\] during acomparable duration of treatment with either PEX or Standard of Care after study initiation.
Time frame: The inflammatory markers recorded in this study are C reactive protein (CRP), lactate dehydrogenase(LDH) and D-Dimer, and we consider whether there is a reduction during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28).
Population: Note: 23 patients with severe COVID-19 were randomised. One patient withdrew from the study 1 day after randomisation and their data has been excluded from the analysis. There were no follow-up data for a further two participants for this endpoint (1 from each arm) and hence they were omitted from this analysis, so data from a total of 20 participants was analysed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| STANDARD OF CARE | Number of Participants With Inflammatory Marker Reduction of at Least 50% at Any Efficacy Time Point | 5 Participants |
| Plasma Exchange | Number of Participants With Inflammatory Marker Reduction of at Least 50% at Any Efficacy Time Point | 8 Participants |
Comparison: The primary analysis will involve a comparison of the binary outcome '50% reduction in at least two inflammation markers' between the PEX and Standard of Care (control) trial arms using a chi-squared test. The risk difference (and ratio) will be estimated with a 95% confidence interval.p-value: 0.16Chi-squared