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

• ClinicalTrials.gov Identifier: NCT04455815
• Recruitment Status: Terminated
• First Posted: July 2, 2020
• Last Update Posted: June 14, 2022
• Sponsor: Cancer Research UK
• Collaborator: Latus Therapeutics
• Information provided by (Responsible Party): Cancer Research UK

Study Description

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.

Condition or disease	Intervention/treatment	Phase
COVID-19 Infection	Drug: Camostat	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: September 25, 2020
• Actual Primary Completion Date: March 3, 2022
• Actual Study Completion Date: March 3, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Camostat; Patient to receive treatment with camostat tablets, 200mg four times daily (qds) for 14 days.	Drug: Camostat; Patient to receive treatment with camostat tablets, 200mg four times daily (qds) for 14 days.; Other Names: Camostat mesylate; Camostat mesilate
No Intervention: Control arm; Patient to receive best supportive care.

Outcome Measures

Primary Outcome Measures :

1. Number of camostat related AEs and SAEs. [ Time Frame: Days 1 - 28 ]
   Number of camostat related AEs and SAEs
2. Number of AEs by severity grade [ Time Frame: Days 1 - 28 ]
   Number of AEs by severity grade (mild, moderate, severe)

Secondary Outcome Measures :

1. PK parameter Maximum concentration (Cmax) of 4-(4-Guanidinobenzoyloxy)phenylacetic acid (GBPA). [ Time Frame: Days 7 and 14 ]
   Maximum concentration (Cmax) of GBPA as assessed by population estimates from population PK analysis
2. PK parameter time to maximum concentration (Tmax) of GBPA, as assessed by population estimates from population PK analysis. [ Time Frame: Days 7 and 14 ]
   Time to maximum concentration (Tmax) of GBPA, as assessed by population estimates from population PK analysis
3. PK parameter area under the curve (AUC) of GBPA [ Time Frame: Days 7 and 14 ]
   Area under the curve (AUC) of GBPA, as assessed by population estimates from population PK analysis
4. PK parameter to confirm half-life (T1/2) of GBPA [ Time Frame: Days 1 - 28 ]
   Half-life (T1/2) of GBPA as assessed by population estimates from population PK analysis
5. Number of community patients admitted to hospital due to COVID-19 [ Time Frame: Days 1 - 28 ]
   Number of community patients admitted to hospital due to COVID-19
6. Number of oxygen free days [ Time Frame: Days 1 - 28 ]
   Number of oxygen free days
7. Number of ventilator - free days [ Time Frame: Days 1 - 28 ]
   Number of ventilator - free days
8. 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' [ Time Frame: 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'

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United Kingdom

Chawton Park Surgery

Alton, United Kingdom

The University of Edinburgh

Edinburgh, United Kingdom

Church Avenue Medical Group

Harrogate, United Kingdom

Oxford University Hospitals NHS Foundation Trust

Oxford, United Kingdom

Trafalgar Medical Practice

Portsmouth, United Kingdom

Preston Lantern Centre

Preston, United Kingdom

Clarence Medical Centre

Rhyl, United Kingdom

Velindre Cancer Centre

Wales, United Kingdom

Eynsham Medical Centre

Witney, United Kingdom

Sponsors and Collaborators

Cancer Research UK

Latus Therapeutics

Investigators

• Principal Investigator: Kevin Dhaliwal, Professor; University of Edinburgh

More Information

Additional Information:

A lay summary of the trial on the Health Research Authority website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Halford S, Wan S, Dragoni I, Silvester J, Nazarov B, Anthony D, Anthony S, Ladds E, Norrie J, Dhaliwal K; CDD SPIKE-1 Project Team. SPIKE-1: A Randomised Phase II/III trial in a community setting, assessing use of camostat in reducing the clinical progression of COVID-19 by blocking SARS-CoV-2 Spike protein-initiated membrane fusion. Trials. 2021 Aug 19;22(1):550. doi: 10.1186/s13063-021-05461-9. Erratum in: Trials. 2022 Apr 21;23(1):336.

• Responsible Party: Cancer Research UK
• ClinicalTrials.gov Identifier: NCT04455815
• Other Study ID Numbers: CRUKD/20/002; 2020-002110-41 ( EudraCT Number )
• First Posted: July 2, 2020
• Last Update Posted: June 14, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cancer Research UK:

COVID-19; Coronavirus Infections; Respiratory Tract Infections; Pneumonia, Viral; Virus Diseases; Camostat; Protease Inhibitors; Enzyme Inhibitors; Serine Proteinase Inhibitors

Additional relevant MeSH terms:

Camostat; Infections; COVID-19; Respiratory Tract Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Gabexate; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Trypsin Inhibitors; Serine Proteinase Inhibitors; Anticoagulants