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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03361163




Registration number
NCT03361163
Ethics application status
Date submitted
14/11/2017
Date registered
4/12/2017
Date last updated
19/05/2020

Titles & IDs
Public title
Controlled Human Infection for Vaccination Against Streptococcus Pyogenes
Scientific title
Group A Streptococcal Human Challenge Study: Building a Pharyngitis Model to Accelerate Vaccine Development
Secondary ID [1] 0 0
CHIVAS-M75
Universal Trial Number (UTN)
Trial acronym
CHIVAS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Streptococcus Pyogenes Pharyngitis 0 0
Streptococcus Pharyngitis 0 0
Strep Throat 0 0
Streptococcus Pyogenes Infection 0 0
Group A Streptococcus: B Hemolytic Pharyngitis 0 0
Group A Streptococcal Infection 0 0
Gram-Positive Bacterial Infections 0 0
Bacterial Infections 0 0
Condition category
Condition code
Infection 0 0 0 0
Studies of infection and infectious agents
Infection 0 0 0 0
Other infectious diseases
Infection 0 0 0 0
Sexually transmitted infections
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Blood 0 0 0 0
Other blood disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - emm75 Streptococcus pyogenes (GAS M75, strain 611024)

Experimental: GAS oropharyngeal challenge - Biological: emm75 Streptococcus pyogenes (GAS M75, strain 611024)
Direct oropharyngeal application using a sterile-tipped Dacron swab after immersion for 10 seconds in a 1mL vial containing 1-3x10^4 to 1-3x10^8 colony forming units (CFU) of the challenge strain (depending on dose group allocation).


Other interventions: emm75 Streptococcus pyogenes (GAS M75, strain 611024)
Direct oropharyngeal application by swab following immersion in a solution containing a specified concentration (dose) of GAS M75.
Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Proportion of participants at each GAS M75 dose level meeting the study pharyngitis endpoint
Timepoint [1] 0 0
Up to 6 days after challenge dose administered.

Eligibility
Key inclusion criteria
- Males or females, aged 18 - 40 years (inclusive) on the day of informed consent.

- Medically healthy, determined by medical history, physical examination, transthoracic
echocardiogram, non-clinically significant laboratory profiles, vital signs, and
12-lead ECG at screening, as deemed by the investigator.

- No active or chronic diseases/disorders, no history of hospitalisation for illness
within the six months prior to enrolment into study, and no major surgery within the
12 months prior to enrolment into study.

- Body mass index of 18.0 - 32.0 kg/m2 and body weight = 50.0kg

- Systolic blood pressure (SBP) of 90 mmHg - 140 mmHg and diastolic blood pressure (DBP)
of 50 mmHg - 90 mmHg. Vital signs can be repeated up to two times.

- Resting heart rate (HR), as measured by ECG of 40bpm - 100 bpm (confirmed by one
repeat at screening).

- Females must be non-pregnant, non-lactating or postmenopausal for at least 1 year (as
confirmed by follicle-stimulating hormone [FSH]), or surgically sterile for at least 6
months prior to dosing.

- All male and females of childbearing potential must agree to use two forms of
acceptable contraception from the time of signing informed consent until 30 days after
final dose of rifampicin.

- Acceptable forms of contraception include: barrier method (eg. condom, diaphragm);
pharmacological hormonal methods (oral contraceptive pill, long-acting implantable,
intrauterine device).

- Rifampicin may reduce the activity of oral and implantable contraceptives (not
intrauterine devices) so additional use of a barrier method is required for 30 days
after the final dose of rifampicin for participants using these methods.

- Participants who abstain from penile-vaginal intercourse are eligible when this is
their preferred and usual lifestyle. These participants must not be planning in vitro
fertilization within the study and follow-up period.

- Must be willing and able to read, understand, and sign the participant information and
consent form.

- Able and willing (in the Investigator's opinion) to comply with all study
requirements, including the in-patient confinement period and outpatient visits for
the duration of the study (approximately 6 months including follow-up visits).
Minimum age
18 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- History of any clinically important cardiac, endocrinologic, hematologic, hepatic,
immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric,
and renal, or other major disease, as determined by the Investigator.

- History of tonsillectomy, adenoidectomy or splenectomy.

- Known or suspected autoimmune disease or impairment/alteration of immune function
resulting from:

- Congenital or acquired immunodeficiency (including immunoglobulin A deficiency)

- Receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation
therapy within the preceding 6 months.

- Presence or history of a severe drug hypersensitivity, or allergic disease diagnosed
and treated by a physician or history of a severe allergic reaction, anaphylaxis or
convulsions following any vaccination or infusion.

- Personal or family history of severe GAS infection or sequelae (such as acute
rheumatic fever, rheumatic heart disease, post-streptococcal glomerulonephritis) or
invasive GAS disease (toxic shock syndrome, necrotizing fasciitis, bloodstream
infection, pleural empyema, meningitis).

- Clinically significant disease or any condition or disease that might affect drug
absorption, distribution or excretion, e.g. gastrectomy, diarrhea.

- Any vaccination within the last 28 days or use of any antibiotic therapy during the 14
days before challenge.

- Presence of acute infectious disease or febrile illness (e.g., sub-lingual temperature
= 38.5°C) within the five days prior to inoculation.

- Significant acute or chronic infection within 14 days prior to inoculation that the
Investigator deems may compromise participant safety.

- Any clinically significant abnormal finding on biochemistry or haematology blood
tests, urine analysis, ECG or transthoracic echocardiogram.

- Positive serologic results for human immunodeficiency virus (HIV) antibodies,
hepatitis B surface antigen (HBsAg), and/or hepatitis C virus (HCV) antibodies.

- Ex-smoker with a >10 pack year smoking history or a current smoker who is unable to
stop smoking for the duration of the study

- History or presence of alcohol abuse (defined as regular alcohol consumption of more
than 40g per day) or drug habituation, or any prior intravenous usage of an illicit
substance.

- A positive urine drug test at screening or admission for confinement (e.g.,
amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates)
unless there is an explanation acceptable to the investigator or sub-investigator
(e.g. the participant has stated in advance that they consumed a prescription or
over-the-counter product which contained the detected drug) and the participant has a
negative urine drug screen on retest.

- A positive alcohol breath test at screening or admission for confinement.

- Known hypersensitivity or other contraindication to use of penicillin, rifampicin or
any other beta-lactam or rifamycin antibiotic(s).

- Known hypersensitivity or contraindication to both azithromycin and clindamycin.

- Known hypersensitivity to soya protein.

- Intolerance of throat swab procedure (exaggerated gag reflex).

- Any systemic corticosteroid (or equivalent) treatment in the 14 days prior to
challenge, or for more than seven consecutive days within the past 3 months.

- Any corticosteroids, anti-inflammatory drugs (besides sporadic use of non-steroidal
anti-inflammatory drugs), immunomodulators or anticoagulants in the previous 3 months,
or anticipated use of such drugs during the study period. Any participant currently
receiving or having previously received immunosuppressive therapy, including systemic
steroids including adrenocorticotrophic hormone (ACTH) or inhaled steroids in dosages
which are associated with hypothalamic-pituitary-adrenal axis suppression such as 1
mg/kg/day of prednisone or its equivalent or chronic use of inhaled high potency
corticosteroids (budesonide 800 µg or fluticasone 750 µg per day). Intranasal
corticosteroid use is not allowed from 14 days prior to admission, during the
confinement period, and is discouraged prior to the first outpatient visit. Topical
corticosteroid use is allowed.

- Use of prescription or non-prescription drugs and herbal supplements (such as St
John´s Wort) within 14 days or 5 half-lives (whichever is the longer) prior to the
inoculation administration. Use of vitamin supplements taken at standard doses is
allowed.

- Participation in a research study that involved blood sampling of more than 450
mL/unit of blood, received or donated blood, blood products and/or plasma derivatives
or any parenteral immunoglobulin preparation within 3 months of informed consent.

- History of severe infectious disease requiring hospitalisation for intravenous
antibiotics.

- History of cancer (except adequately treated squamous cell or basal cell carcinoma of
the skin and cervical intraepithelial neoplasia).

- Presence of implants or prosthesis (e.g. artificial joints, pacemakers).

- Participation in another research study within the 30 days prior to enrolment
involving an investigational product or other intervention that might affect risk of
invasive GAS infection or compromise the integrity of the study (e.g. significant
volumes of blood already taken in previous study).

- Any significant disease or disorder which, in the opinion of the Investigator, may
either put the participants at risk because of participation in the study, or may
influence the results of the study, or the participant's ability to participate in the
study.

- Any employee of the sponsor or research site personnel directly affiliated with this
study or their immediate family members defined as a spouse, parent, sibling, or child
whether biological or legally adopted.

- Evidence of pre-existing immunity to the challenge strain as determined by
quantitative +/- functional antibody testing of serum collected at the screening visit

Study design
Purpose of the study
Basic Science
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
10/07/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/04/2020
Sample size
Target
Accrual to date
Final
25
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Centre for Clinical Studies (Nucleus Network Limited) - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne

Funding & Sponsors
Primary sponsor type
Other
Name
Andrew Steer
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
University of Melbourne
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Nucleus Network Ltd
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
National Health and Medical Research Council, Australia
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Telethon Kids Institute
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
The Peter Doherty Institute for Infection and Immunity
Address [5] 0 0
Country [5] 0 0
Other collaborator category [6] 0 0
Other
Name [6] 0 0
Queen Fabiola Children's University Hospital
Address [6] 0 0
Country [6] 0 0
Other collaborator category [7] 0 0
Other
Name [7] 0 0
Griffith University
Address [7] 0 0
Country [7] 0 0
Other collaborator category [8] 0 0
Other
Name [8] 0 0
University of Wollongong
Address [8] 0 0
Country [8] 0 0
Other collaborator category [9] 0 0
Other
Name [9] 0 0
The University of Queensland
Address [9] 0 0
Country [9] 0 0
Other collaborator category [10] 0 0
Other
Name [10] 0 0
University of Auckland, New Zealand
Address [10] 0 0
Country [10] 0 0
Other collaborator category [11] 0 0
Other
Name [11] 0 0
University of Tennessee
Address [11] 0 0
Country [11] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Group A Streptococcus (GAS) infection is a major cause of death and disability globally with
a disproportionately high burden in settings of disadvantage worldwide. Acute infections due
to GAS range from very common superficial skin infections (>150 million prevalent cases) and
pharyngitis (over 600 million incident cases) to life-threatening invasive disease (>600,000
incident cases) such as necrotising fasciitis. Post-infectious GAS sequelae of GAS include
acute rheumatic fever (ARF, ~500,000 incident cases) leading to rheumatic heart disease (RHD,
~34 million prevalent cases), and acute glomerulonephritis. The health services impact of GAS
disease in all its forms is immense and strikes at every level from primary to intensive
care.

Controlled human infection models (CHIMs) have a long history of critical contributions to
vaccine development. Data from CHIMs meeting modern scientific, regulatory, and ethical
standards, are aiding efforts to control over 25 major human pathogens, including bacteria
(e.g. pneumococcus, cholera), viruses (e.g. respiratory syncytial virus, influenza), and
parasites (e.g. malaria, schistosomiasis).

A reliable and safe controlled human infection model of GAS pharyngitis will be an important
part of the global vaccine development effort. To build the model, the investigators are
undertaking a dose-ranging study using an observational, dose-escalation, inpatient trial to
determine the dose of GAS administered by direct oropharyngeal inoculation (bacteria
'painted' onto throat) required to reliably produce a pharyngitis attack rate of = 60% in
carefully screened healthy adult volunteers.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03361163
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Janet Wong, MBBS,BSc
Address 0 0
Senior Medical Officer, Nucleus Network Limited
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03361163