A Trial Looking at the Use of Camostat in People Who Have Tested Positive for Coronavirus (COVID-19) (SPIKE-1)

Study Overview
=================
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.

Official Title
-----------------
A Randomised Phase II Trial in Early COVID-19, Assessing Use of Camostat by Blocking SARS-CoV-2 Spike Protein-initiated Membrane Fusion.

Conditions
-----------------
COVID-19 Infection

Intervention / Treatment
-----------------
* Drug: Camostat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient willing and able to give informed consent Adults, 18 years of age and above Symptomatic COVID-19 infection 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: Significant electrolyte disturbance (e.g. hyperkalaemia, potassium > site specific upper limit of normal) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and/or Alkaline Phosphatase (ALP) ≥ 2.5 x ULN 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). 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) Known hypersensitivity to camostat Platelet count <100 x 10^9/L 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. 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. 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.) 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.) Significant cardiovascular disease (as assessed via the participant's medical record and history) as defined by: History of congestive heart failure requiring therapy (New York Heart Association [NYHA] III or IV) History of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry Presence of severe valvular heart disease Presence of a ventricular arrhythmia requiring treatment Known allergic reactions to components of camostat e.g., lactose intolerance

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Camostat<br>Patient to receive treatment with camostat tablets, 200mg four times daily (qds) for 14 days. | Drug: Camostat<br>* Patient to receive treatment with camostat tablets, 200mg four times daily (qds) for 14 days.<br>* Other names: Camostat mesilate;|
| No Intervention: Control arm<br>Patient to receive best supportive care. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Camostat Related AEs and SAEs. | Number of AEs and SAEs assessed as related to camostat by the Investigator. | Days 1 - 28 | 
| Number of AEs by Severity Grade | Number of AEs by Severity Grade (mild, moderate, severe) | Days 1 - 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Days 7 and 14 | 
| 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. | Days 7 and 14 | 
| 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. | Days 7 and 14 | 
| 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 | Days 1 - 28 | 
| 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. | Days 1 - 28 | 
| Number of Oxygen Free Days | Number of days from Day 1 that each patient did not supplementary oxygen (median and range). | Days 1 - 28 | 
| Number of Ventilator - Free Days | Number of days from Day 1 that each patient did not require ventilation (median and range). | Days 1 - 28 | 
| 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' | Days 1 - 28 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, Coronavirus Infections, Respiratory Tract Infections, Pneumonia, Viral, Virus Diseases, Camostat, Protease Inhibitors, Enzyme Inhibitors, Serine Proteinase Inhibitors