COV-CHIM01: SARS-CoV-2 (COVID-19) Dose Finding Infection Study
Study Details
Study Description
Brief Summary
A phase I, experimental dose finding, open label, clinical infection, safety and viral detection optimisation in previously SARS-CoV-2 infected (unvaccinated or vaccinated) or uninfected vaccinated volunteers.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This is a phase I dose escalation challenge study in which increasing titres of wild-type SARS-CoV-2 (1x101 TCID_50, 1x102TCID_50, 1x103TCID_50, 1x104TCID_50 and 1x10^5TCID_50) will be administered intranasally to different groups of volunteers in order to achieve a 50% (+/-10%) attack rate as determined by quantitative live viral detection and/or qPCR detection in naso-pharyngeal secretions at two consecutive 12 hourly time points (at least 24 hours after inoculation). A Data Safety Monitoring Board (DSMB) will review safety and quantitative virology at each dose level and will recommend continuation, dose escalation or de-escalation based on emergent data.
Rescue treatment with a single course of oral Paxlovid will commence immediately after any warning symptoms or signs of COVID-19 disease beyond mild disease.
Once the optimal dose of wildtype SARS-CoV-2 has been identified for previously infected volunteers and uninfected vaccinated volunteers (dose escalation groups 1 and 3), further challenge infections in groups 2 and 4 may proceed.
Volunteers will remain in isolation rooms within the clinical trials unit for a minimum of 14 days post inoculation and until demonstration of the absence of live virus in two sequential samples. All 4 groups will together enrol up to 132 volunteers.
This study will be funded by the Wellcome Trust and Department of Health and Social Care (DHSC).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group 1A: Low dose challenge Intranasal viral challenge with 1 x 10^1 TCID_50 in previously infected volunteers N= 6-8 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
| Experimental: Group 1B: Medium dose #1 challenge Intranasal viral challenge with 1 x 10^2 TCID_50 in previously infected volunteers N= 6-8 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
| Experimental: Group 1C: Medium dose #2 challenge Intranasal viral challenge with 1 x 10^3 TCID_50 in previously infected volunteers N= 6-8 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
| Experimental: Group 1D: Medium dose #3 challenge Intranasal viral challenge with 1 x 10^4 TCID_50 in previously infected volunteers N= 4-8 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
| Experimental: Group 1E: High dose challenge Intranasal viral challenge with 1 x 10^5 TCID_50 in previously infected volunteers N= 4-8 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
| Experimental: Group 2: Safety & Dose confirmation Group Intranasal viral challenge with the dose identified from Group 1a-e (1x10^1, 1x10^2, 1x10^3, 1x10^4, or 1x10^5 TCID_50) N=10-30 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
| Experimental: Group 3a: Medium dose #1 challenge Intranasal viral challenge with 1 x 10^2 TCID_50 in previously uninfected, vaccinated volunteers N=6-8 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
| Experimental: Group 3b: Medium dose #2 challenge Intranasal viral challenge with 1 x 10^3 TCID_50 in previously uninfected, vaccinated volunteers N=4-8 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
| Experimental: Group 3c: Medium dose #3 challenge Intranasal viral challenge with 1 x 10^4 TCID_50 in previously uninfected, vaccinated volunteers N=4-8 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
| Experimental: Group 3d: High dose challenge Intranasal viral challenge with 1 x 10^5 TCID_50 in previously uninfected, vaccinated volunteers N=4-8 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
| Experimental: Group 4: Safety & Dose confirmation Group Intranasal viral challenge with the dose identified from Group 3a-d (1x10^2, 1x10^3, 1x10^4 or 1x10^5 TCID_50) N=10-30 participants |
Biological: SARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
|
Outcome Measures
Primary Outcome Measures
- Occurrence of solicited and unsolicited adverse events [Day 84]
To assess safety and human clinical response to wild type SARS-CoV-2 intranasal challenge in both previously SARS- CoV-2 infected (unvaccinated or vaccinated) and uninfected vaccinated participants via occurrence of adverse events (solicited and unsolicited) collected in e-diaries
- Occurrence of adverse events as determined by medical assessment [Day 365]
Collection of AE data at each visit time point after SARS-CoV-2 inoculation (Graded 0-3)
- Selection of optimal dose(s) [Day 14 or until discharge criteria is met]
The SARS-CoV-2 dose required to induce upper respiratory tract infection in 50% (+/-10%) of previously SARS-CoV-2 infected healthy volunteers following intranasal challenge. Defined by laboratory identification of SARS-CoV-2 from nasal and pharyngeal swab, using qPCR and/or quantitative live viral detection at two consecutive 12- hourly time points starting 24 hours post-inoculation and up to discharge from quarantine. Optimal dose to be defined in previously SARS-CoV-2 infected (vaccinated or unvaccinated) and uninfected vaccinated healthy volunteers
Secondary Outcome Measures
- Determination of SARS-CoV-2 viral dynamics [Day 365]
Assess the SARS-CoV-2 viral dynamics in upper respiratory samples from previously infected (vaccinated or unvaccinated) or uninfected vaccinated individuals including: determination of the incubation period, peak viral load and the mean duration of infectious viral shedding from quantitative virology measured using qPCR and/or live viral detection on naso-oropharyngeal samples.
- Exploratory Immunology: Identification of laboratory markers [Day 365]
Ex-vivo ELISpot to SARS-CoV-2 peptide (sfc/1x10^6 PBMC)
- Exploratory Immunology: Identification of laboratory markers [Day 365]
Innate, B cell and T cell flow cytometry panel to characterise surface cell markers and antigen specific responses to SARS-CoV-2 peptide before and after SARS-CoV-2 inoculation (% population)
- Exploratory Immunology: Identification of laboratory markers [Day 365]
Neutralising peripheral blood antibody analysis to SARS-CoV-2
- Exploratory Immunology: Identification of laboratory markers [Day 365]
Single cell RNA-seq on peripheral blood
- Exploratory Immunology: Identification of laboratory markers [Day 365]
Cytokine analysis on serum and nasal mucosal lining fluid
- Exploratory Immunology: Identification of laboratory markers [Day 365]
ELISA to SARS-CoV-2 peptide from serum and nasal mucosal lining fluid
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Aged 18-30 years on proposed date of enrolment.
-
Body Mass Index (BMI) ≥18.5 kg/m2and ≤28 kg/m2.
-
In good health with no history of clinically significant medical conditions (as described in Exclusion criteria) that would interfere with subject safety, as defined by medical history, physical examination, routine laboratory tests, cardiovascular magnetic resonance imaging or echocardiogram, ECG, pulmonary function tests and Chest X-Ray as determined by the Investigator at a screening evaluation.
-
Volunteer is willing and able to give written informed consent for participation in the study
-
Willing to allow the investigators to discuss the volunteer's medical history with their General Practitioner or any relevant health authority
-
Allow the investigator to register volunteer details with a confidential database (The Over-volunteering Prevention Service) to prevent concurrent entry into clinical studies/trials
-
Agreement to refrain from blood donation during the course of the study
-
- For women of child bearing potential (WOCBP), a willingness to practice continuous effective contraception during the study and, a negative pregnancy test on the day(s) of screening and challenge b. b. For women of child bearing potential (WOCBP) taking the combined oral contraceptive pill, a willingness to use barrier contraception with spermicide during treatment with Paxlovid and for 30 days after completing Paxlovid treatment (should they receive it).
-
Able and willing (in the investigator's opinion) to comply with all study requirements
-
No clinically relevant findings in medical history or on physical examination in the opinion of a clinically qualified investigator, in discussion with the CI if needed
-
For Groups 1 & 2: Previous microbiological confirmation of SARS-CoV-2 infection >3 months prior to enrolment (proof of positive PCR or lateral flow antigen test confirmed via medical notes/or PHE)
-
For Groups 3 & 4: Written or electronic evidence of at least one vaccination against SARS- CoV-2 >21 days prior to enrolment (proof required would include written or electronic evidence from GP/ medical records or electronic NHS COVID pass).
Exclusion Criteria:
- History or evidence of any clinically significant or currently active cardiovascular, (including thromboembolic events), respiratory (excluding SARS CoV-2 infection), dermatological, gastrointestinal, endocrine, haematological, hepatic, immunological, rheumatological, metabolic, urological, renal, neurological or psychiatric illness.
Specifically:
- Volunteers with any history of physician diagnosed and/or objective test confirmed asthma, chronic obstructive pulmonary disease, pulmonary hypertension, reactive airway disease, or chronic lung condition of any aetiology or who have experienced:
- Significant/severe wheeze in the past ii) Respiratory symptoms including wheeze which has ever resulted in hospitalisation iii) Known bronchial hyper reactivity to viruses
-
History of thromboembolic, cardiovascular or cerebrovascular disease
-
History or evidence of diabetes mellitus (Type I or Type II)
-
Any concurrent serious illness including history of malignancy that could interfere with the aims of the study or a subject completing the study. Basal cell carcinoma within 5 years of treatment or with evidence of recurrence is also an exclusion.
-
Migraine with associated neurological symptoms such as hemiplegia or vision loss. Cluster headache/migraine or prophylactic treatment for migraine
-
History or evidence of autoimmune disease or known immunodeficiency of any cause (including HIV).
-
History of severe psychiatric illness at any time (e.g. inpatient stay, psychosis) or current significant active symptoms of anxiety and/or depression or significant claustrophobia. Consider exclusion in the following cases:
- Volunteers with history of anxiety-related symptoms of any severity within the last 2 years if the Generalized Anxiety Disorder-7 score is ≥5 ii) Volunteers with a history of depression of any severity within the last 2 years if the Patient Health Questionnaire-9 score is ≥4 iii) Significant claustrophobia
-
Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following injections or venepuncture.
-
Other major disease that, in the opinion of the Investigator, could interfere with a subject completing the study and necessary investigations.
-
Clinically significant smoking history. Defined as: Current smoker (any smoking including e-cigarettes in the last 3 months) or > 2 pack year smoking history at any time (2 pack years is equivalent to 20 cigarettes daily for 2 years), or use of any nicotine containing products within the last 3 months.
-
History or presence of alcohol addiction, or excessive use of alcohol (average weekly intake in excess of 28 units alcohol; one unit being a half glass of beer, a small glass of wine or a measure of spirits)
-
Clinically significant history of use of drugs of misuse, with evidence of a negative drugs of misuse urine test required at screening and quarantine admission
-
History of anaphylaxis or any allergy likely to be worsened by any component of the study agent or proposed treatment regime.
-
Clinically active rhinitis (including hay fever) or history of moderate to severe rhinitis, or history of seasonal allergic rhinitis likely to be active at time of inclusion into the study and/or requiring regular nasal corticosteroids on at least weekly basis, within 30 days of admission to quarantine.
-
Any significant abnormality altering the anatomy of the nose or nasopharynx, clinically significant history of epistaxis (nose bleeds) or any nasal or sinus surgery within six months of inoculation
-
Clinical, radiological, or laboratory evidence of current active TB disease or latent TB infection
-
Previous VZV pneumonia
-
Positive HBsAg, HCV or HIV antibodies
-
Concurrent use of oral, inhaled or systemic steroid medication or use within the last 6 months (steroids used as a cream or ointment are permissible), or the use of other immunosuppressive agents concurrently or within the last 6 months.
-
Concurrent use of medication contraindicated for use with Paxlovid rescue therapy
-
Administration of immunoglobulins and/or any blood products within the three months preceding the planned study challenge date
-
Current use of any medication or other drug taken through the nasal or inhaled route including cocaine or other recreational drugs
-
Plans to receive a live vaccination 30 days prior to enrolment, or any vaccination (i.e. non-live, including a SARS-CoV-2 vaccine) 21 days prior to enrolment and/or plans to take any vaccination 30 days following enrolment
-
Current pregnancy or pregnancy within the last 6 months, lactation or intention to become pregnant during study period
-
Shares a household with someone with clinically significant immunodeficiency (due to underlying medical condition, medication or pregnancy); or who is extremely clinically vulnerable (previously shielding under Public Health England guidelines)
-
Concurrent participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the study period
-
Laboratory confirmed (PCR or lateral flow antigen test) SARS-Cov-2 infection, evidence of viral pneumonitis on chest radiograph or a high clinical suspicion of COVID-19 disease in the 3 months preceding enrolment.
-
Post COVID-19 symptoms that have not resolved by 1 month prior to enrolment
-
Previous hospitalisation with COVID-19 disease or related complications e.g. pulmonary fibrosis on chest x ray
-
Family history of 1st degree relative aged 50 years or less with sudden cardiac or unexplained death
-
Family history of severe COVID-19 disease or response to any other viral disease e.g. Guillain-Barré
-
Family history unavailable or in opinion of investigators not sufficient to assess criteria 22 and 23.
-
Clinically significant abnormality on screening chest radiograph
-
Clinically significant abnormality of lung function testing
-
Clinically significant structural heart disease detected on CMR or echocardiogram, such as abnormal ventricular systolic function, evidence of previous myocardial infarction, previous myocarditis (on CMR) or significant valvular heart disease (more than mild)
-
Any clinically significant abnormality of screening blood or urine tests
-
Any other significant disease, disorder, or finding, which, in the opinion of the investigator, may either put the volunteer at risk, affect the volunteer's ability to participate in the study or impair interpretation of the study data
-
Venous access deemed inadequate for the phlebotomy and cannulation demands of the study.
For Groups 3 & 4:
-
Previous positive test for SARS CoV-2 infection (PCR or lateral flow antigen test) or a high clinical suspicion of COVID-19 disease at any time.
-
Positive Anti-nucleocapsid IgG at screening, unless explainable by vaccination
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Oxford Clinical Research Facility (OxCRF) | Oxford | Oxon | United Kingdom | OX3 7LE |
| 2 | Centre for Clinical Vaccinology and Tropical Medicine | Oxford | Oxon | United Kingdom | OX3 7LJ |
| 3 | Oxford University Hospital NHS Trust | Oxford | Oxon | United Kingdom | OX3 9DU |
Sponsors and Collaborators
- University of Oxford
Investigators
- Principal Investigator: Helen McShane, MD and PhD, University of Oxford
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- COV-CHIM01