COVID-19 Infection
Conditions
Keywords
COVID-19, Coronavirus Infections, Respiratory Tract Infections, Pneumonia, Viral, Virus Diseases, Camostat, Protease Inhibitors, Enzyme Inhibitors, Serine Proteinase Inhibitors
Brief summary
This is a phase II randomised, multicentre, prospective, open label clinical trial. The trial aims to recruit patients who test positive for COVID-19 who have mild symptoms and therefore can treat their symptoms in the community. Patients who test positive for COVID-19 at hospital may also be able to participate.
Detailed description
Coronavirus-induced disease 2019 (COVID-19) caused by SARS-CoV-2 infection is a highly contagious disease with a high and unpredictable morbidity and mortality, for which there is currently no specific treatment. Progression from a mild fatigue, fever and cough, to severe respiratory failure requiring mechanical ventilation may occur 1 to 2 weeks into the disease. This provides a window of opportunity in which patients in the early phase of the disease could be treated with a disease-modifying agent, to halt disease progression, prevent hospital admissions with respiratory failure and prevent death. Camostat is a serine protease inhibitor in clinical use in Japan since 1985 to treat patients with chronic pancreatitis (inflammation of the pancreas) and has an acceptable safety profile. Camostat has been shown to inhibit SARS-CoV-2 entry into epithelial cells in vitro. A trial of this repurposed drug for treatment of COVID-19 in humans is urgently required to assess its impact on disease progression to respiratory failure and whether it can reduce mortality. This trial will recruit up to 100 patients. Patients will be randomised into a treatment arm (camostat tablets) or control arm (best supportive care). Community patients will be called daily at home for 14 days by the clinical trial team to collect symptoms and record the general well-being of the patient. For those patients recruited from hospital, visits will continue in hospital, where feasible, until discharge when home visits will be able to continue. The primary aim of this trial is to further assess the safety and toxicity profile of camostat to support integration into a Phase III trial. Secondary aims are to determine if camostat can reduce the clinical progression of COVID-19 and therefore the need for hospital admission and supplemental oxygen as well as include collection of patient reported health status, severity of symptoms and biological markers of the virus and confirm PK profile for the active metabolite of camostat. As the understanding of COVID-19 develops and improves, the inclusion criteria may be adapted to support the trial outcomes. Patients will be recruited through various settings which may include primary care 'COVID-19 hub' clinics, COVID-19 community-based testing centres, identification through other hospital departments, NHS digital, Test and Trace (or equivalent) or other clinical environments.
Interventions
DRUGCamostat
Patient to receive treatment with camostat tablets, 200mg four times daily (qds) for 14 days.
Sponsors
Latus Therapeutics
Cancer Research UK
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient willing and able to give informed consent 2. Adults, 18 years of age and above 3. Symptomatic COVID-19 infection 4. Evidence of current COVID-19 infection from a validated assay
Exclusion criteria
The patient may not enter the trial if ANY of the following apply: 1. Significant electrolyte disturbance (e.g. hyperkalaemia, potassium \> site specific upper limit of normal) 2. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and/or Alkaline Phosphatase (ALP) ≥ 2.5 x ULN 3. Any condition that, in the Investigator's opinion, would not make the patient a good candidate for the clinical trial or would prevent adequate compliance with trial therapy e.g. mild cognitive impairment (unable to follow instructions for self-assessment readings as assessed by the Investigator). 4. Patients on long term supplementary oxygen requirement (patients for whom hospital admission would not be considered e.g. care plan in the community is in place, are not excluded) 5. Known hypersensitivity to camostat 6. Platelet count \<100 x 10\^9/L 7. Co-enrolment with a Clinical Trial of an Investigational Medicinal Product (CTIMP) will not be permitted. Co-enrolment with a clinical investigation of a Medical Device or a non-interventional clinical study will be considered on a study-by-study basis and in discussion with the relevant Chief Investigators and Sponsors and industrial collaborators. 8. Co-enrolment involving non-interventional research (including questionnaire or tissue only studies) will be allowed provided this is not expected to affect the outcomes of both studies or place undue burden upon participants and their families. 9. Female patients who are able to become pregnant (or are already pregnant or lactating). However, those patients who are of child bearing potential and have a negative serum or urine pregnancy test before enrolment and agree to use two forms of contraception (one effective form plus a barrier method \[oral, injected or implanted hormonal contraception and condom; intra-uterine device and condom; diaphragm with spermicidal gel and condom\]) or agree to sexual abstinence\*, effective from the first administration of camostat, throughout the trial and for 28 days afterwards are considered eligible. (\*Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence \[e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.) 10. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using a barrier method of contraception \[condom plus spermicide\] or to sexual abstinence\* effective from the first administration of camostat, throughout the trial and for 28 days afterwards. Men with partners of child-bearing potential must also be willing to ensure that their partner uses an effective method of contraception for the same duration for example, hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual abstinence). Men with pregnant or lactating partners must be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure of the foetus or neonate. (\*Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence \[e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.) 11. Significant cardiovascular disease (as assessed via the participant's medical record and history) as defined by: 1. History of congestive heart failure requiring therapy (New York Heart Association \[NYHA\] III or IV) 2. History of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry 3. Presence of severe valvular heart disease 4. Presence of a ventricular arrhythmia requiring treatment Known allergic reactions to components of camostat e.g., lactose intolerance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Camostat Related AEs and SAEs. | Days 1 - 28 | Number of AEs and SAEs assessed as related to camostat by the Investigator. |
| Number of AEs by Severity Grade | Days 1 - 28 | Number of AEs by Severity Grade (mild, moderate, severe) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK Parameter Time to Maximum Concentration (Tmax) of GBPA | Days 7 and 14 | Time to maximum concentration (Tmax) of GBPA, as assessed by population estimates from population PK analysis. |
| PK Parameter Area Under the Curve (AUC) of GBPA | Days 7 and 14 | Area under the curve (AUC) of GBPA, as assessed by population estimates from population PK analysis. |
| PK Parameter to Confirm Half-life (T1/2) of GBPA | Days 1 - 28 | Half-life (T1/2) of GBPA as assessed by population estimates from population PK analysis |
| Number of Community Patients Admitted to Hospital Due to COVID-19 | Days 1 - 28 | Number of patients who were recruited in community healthcare settings who were subsequently admitted to hospital due to COVID-19. |
| Number of Ventilator - Free Days | Days 1 - 28 | Number of days from Day 1 that each patient did not require ventilation (median and range). |
| Time to Worst Point on the Scale or Deterioration of Two Points or More (From Randomisation) on 9 Point Category Ordinal Scale Ranging From '0 - Uninfected, no Clinical or Virological Evidence of Infection' to '8 - Death' | Days 1 - 28 | Median time and range to worst point on the scale or deterioration of two points or more (from randomisation) on 9 point category ordinal scale. The scale was described in the protocol as follows: '0 - Uninfected, no clinical or virological evidence of infection, 1 - Ambulatory, no limitation of activities, 2 - Ambulatory, limitation of activities, 3 - Hospitalised - mild disease, no oxygen therapy, 4 - Hospitalised - mild disease, oxygen by mask or nasal prongs, 5 - Hospitalised - severe disease, non-invasive, ventilation or high-flow oxygen, 6 - Hospitalised - severe disease, intubation and mechanical ventilation, 7 - Hospitalised - severe disease, ventilation and additional organ support - vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO), 8 - Death' |
| Number of Oxygen Free Days | Days 1 - 28 | Number of days from Day 1 that each patient did not supplementary oxygen (median and range). |
| PK Parameter Maximum Concentration (Cmax) of 4-(4-Guanidinobenzoyloxy)Phenylacetic Acid (GBPA). | Days 7 and 14 | Maximum concentration (Cmax) of GBPA as assessed by population estimates from population PK analysis. |
Countries
United Kingdom
Participant flow
Recruitment details
Trial participants were enrolled at four trial sites between 23 September 2020 and 23 June 2021.
Participants by arm
| Arm | Count |
|---|---|
| Camostat Patient to receive treatment with camostat tablets, 200mg four times daily (qds) for 14 days.
Camostat: Patient to receive treatment with camostat tablets, 200mg four times daily (qds) for 14 days. | 16 |
| Control Arm Patient to receive best supportive care. | 18 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Randomisation Phase | Adverse Event | 1 | 0 |
| Treatment Phase | Adverse Event | 0 | 1 |
| Treatment Phase | Hospital admission and treatment stopped in hospital | 1 | 0 |
| Treatment Phase | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Camostat | Control Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 3 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 15 Participants | 29 Participants |
| Race/Ethnicity, Customized Any other White background | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian / Asian British- Indian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian / Asian British- Pakistani | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White- English / Welsh / Scottish / Northern Irish / British | 15 Participants | 15 Participants | 30 Participants |
| Region of Enrollment United Kingdom | 16 participants | 18 participants | 34 participants |
| Sex: Female, Male Female | 9 Participants | 10 Participants | 19 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 18 |
| other Total, other adverse events | 14 / 16 | 13 / 18 |
| serious Total, serious adverse events | 4 / 16 | 1 / 18 |
Outcome results
Primary
Number of AEs by Severity Grade
Number of AEs by Severity Grade (mild, moderate, severe)
Time frame: Days 1 - 28
Population: All enrolled patients who received at least one dose of camostat (or complete Day 1 of the control arm).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Camostat | Number of AEs by Severity Grade | Total Mild AEs | 25 Adverse Events |
| Camostat | Number of AEs by Severity Grade | Total Moderate AEs | 10 Adverse Events |
| Camostat | Number of AEs by Severity Grade | Total Severe AEs | 2 Adverse Events |
| Camostat | Number of AEs by Severity Grade | Total Mild AEs related to Camostat | 5 Adverse Events |
| Camostat | Number of AEs by Severity Grade | Total Moderate AEs related to Camostat | 6 Adverse Events |
| Camostat | Number of AEs by Severity Grade | Total Severe AEs related to Camostat | 0 Adverse Events |
| Control Arm | Number of AEs by Severity Grade | Total Moderate AEs related to Camostat | NA Adverse Events |
| Control Arm | Number of AEs by Severity Grade | Total Mild AEs | 25 Adverse Events |
| Control Arm | Number of AEs by Severity Grade | Total Mild AEs related to Camostat | NA Adverse Events |
| Control Arm | Number of AEs by Severity Grade | Total Moderate AEs | 5 Adverse Events |
| Control Arm | Number of AEs by Severity Grade | Total Severe AEs related to Camostat | NA Adverse Events |
| Control Arm | Number of AEs by Severity Grade | Total Severe AEs | 2 Adverse Events |
Primary
Number of Camostat Related AEs and SAEs.
Number of AEs and SAEs assessed as related to camostat by the Investigator.
Time frame: Days 1 - 28
Population: All enrolled patients who received at least one dose of camostat. As only participants in the Camostat Arm received camostat, this outcome measure is reported in the Camostat Arm only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Camostat | Number of Camostat Related AEs and SAEs. | Total AEs related to Camostat | 11 Adverse Events |
| Camostat | Number of Camostat Related AEs and SAEs. | Total SAEs related to Camostat | 0 Adverse Events |
Secondary
Number of Community Patients Admitted to Hospital Due to COVID-19
Number of patients who were recruited in community healthcare settings who were subsequently admitted to hospital due to COVID-19.
Time frame: Days 1 - 28
Population: Treatment arm patients who received camostat for a minimum of five days, and control arm patients who completed up to Day 14 or came off trial at an earlier timepoint due to an endpoint (e.g. hospitalisation).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Camostat | Number of Community Patients Admitted to Hospital Due to COVID-19 | 2 Participants |
| Control Arm | Number of Community Patients Admitted to Hospital Due to COVID-19 | 3 Participants |
Secondary
Number of Oxygen Free Days
Number of days from Day 1 that each patient did not supplementary oxygen (median and range).
Time frame: Days 1 - 28
Population: Treatment arm patients who received camostat for a minimum of five days, and control arm patients who completed up to Day 14 or came off trial at an earlier timepoint due to an endpoint (e.g. hospitalisation).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Camostat | Number of Oxygen Free Days | 28 Days |
| Control Arm | Number of Oxygen Free Days | 28 Days |
Secondary
Number of Ventilator - Free Days
Number of days from Day 1 that each patient did not require ventilation (median and range).
Time frame: Days 1 - 28
Population: Treatment arm patients who received camostat for a minimum of five days, and control arm patients who completed up to Day 14 or came off trial at an earlier timepoint due to an endpoint (e.g. hospitalisation).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Camostat | Number of Ventilator - Free Days | 28 Days |
| Control Arm | Number of Ventilator - Free Days | 28 Days |
Secondary
PK Parameter Area Under the Curve (AUC) of GBPA
Area under the curve (AUC) of GBPA, as assessed by population estimates from population PK analysis.
Time frame: Days 7 and 14
Population: Analysis was not completed because no samples were collected for this analysis
Secondary
PK Parameter Maximum Concentration (Cmax) of 4-(4-Guanidinobenzoyloxy)Phenylacetic Acid (GBPA).
Maximum concentration (Cmax) of GBPA as assessed by population estimates from population PK analysis.
Time frame: Days 7 and 14
Population: Analysis was not completed because no samples were collected for this analysis.
Secondary
PK Parameter Time to Maximum Concentration (Tmax) of GBPA
Time to maximum concentration (Tmax) of GBPA, as assessed by population estimates from population PK analysis.
Time frame: Days 7 and 14
Population: Analysis was not completed because no samples were collected for this analysis
Secondary
PK Parameter to Confirm Half-life (T1/2) of GBPA
Half-life (T1/2) of GBPA as assessed by population estimates from population PK analysis
Time frame: Days 1 - 28
Population: Analysis was not completed because no samples were collected for this analysis
Secondary
Time to Worst Point on the Scale or Deterioration of Two Points or More (From Randomisation) on 9 Point Category Ordinal Scale Ranging From '0 - Uninfected, no Clinical or Virological Evidence of Infection' to '8 - Death'
Median time and range to worst point on the scale or deterioration of two points or more (from randomisation) on 9 point category ordinal scale. The scale was described in the protocol as follows: '0 - Uninfected, no clinical or virological evidence of infection, 1 - Ambulatory, no limitation of activities, 2 - Ambulatory, limitation of activities, 3 - Hospitalised - mild disease, no oxygen therapy, 4 - Hospitalised - mild disease, oxygen by mask or nasal prongs, 5 - Hospitalised - severe disease, non-invasive, ventilation or high-flow oxygen, 6 - Hospitalised - severe disease, intubation and mechanical ventilation, 7 - Hospitalised - severe disease, ventilation and additional organ support - vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO), 8 - Death'
Time frame: Days 1 - 28
Population: Treatment arm patients who received camostat for a minimum of five days, and control arm patients who completed up to Day 14 or came off trial at an earlier timepoint due to an endpoint (e.g. hospitalisation).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Camostat | Time to Worst Point on the Scale or Deterioration of Two Points or More (From Randomisation) on 9 Point Category Ordinal Scale Ranging From '0 - Uninfected, no Clinical or Virological Evidence of Infection' to '8 - Death' | 0 Days |
| Control Arm | Time to Worst Point on the Scale or Deterioration of Two Points or More (From Randomisation) on 9 Point Category Ordinal Scale Ranging From '0 - Uninfected, no Clinical or Virological Evidence of Infection' to '8 - Death' | 0 Days |