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Controlled Human Infection for Vaccination Against Streptococcus Pyogenes (CHIVAS)

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ClinicalTrials.gov Identifier: NCT03361163
Recruitment Status : Recruiting
First Posted : December 4, 2017
Last Update Posted : March 7, 2019
Sponsor:
Collaborators:
University of Melbourne
Nucleus Network Ltd
National Health and Medical Research Council, Australia
Telethon Kids Institute
The Peter Doherty Institute for Infection and Immunity
Queen Fabiola Children's University Hospital
Griffith University
University of Wollongong
The University of Queensland
University of Auckland, New Zealand
University of Tennessee Health Science Center
Information provided by (Responsible Party):
Andrew Steer, Murdoch Childrens Research Institute

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.


Condition or disease Intervention/treatment Phase
Streptococcus Pyogenes Pharyngitis Streptococcus Pharyngitis Strep Throat Streptococcus Pyogenes Infection Group A Streptococcus: B Hemolytic Pharyngitis Group A Streptococcal Infection Gram-Positive Bacterial Infections Bacterial Infections Biological: emm75 Streptococcus pyogenes (GAS M75, strain 611024) Phase 1

Detailed Description:

Group A Streptococcus (GAS) is a ubiquitous human pathogen. Its impact begins in early childhood and is felt most by those who have the least. Globally, the health services impact of GAS disease in all its forms is immense and strikes at every level from primary to intensive care. Despite recognition of the need for GAS vaccine development, there are major obstacles impeding progress. A human challenge model promises to help to shift inertia in GAS vaccine development.

The objective of this study is to use an observational, dose-escalation, inpatient trial to determine the dose of GAS administered by direct oropharyngeal inoculation required to reliably produce a pharyngitis attack rate of ≥ 60% in carefully screened healthy adult volunteers. A GAS strain has been specially selected and prepared for this study to ensure safety and clinical relevance. Potential participants aged 18 to 40 years, the age range associated with the lowest risk of invasive GAS disease, will be carefully screened to minimise risk and maximise the likelihood of achieving the pharyngitis endpoint.

The results of three human GAS pharyngeal vaccine-challenge studies from the 1970s are encouraging, and reassuring. GAS challenge did cause pharyngitis and was safe, with all participants responding to antibiotics and none experiencing complications, despite these studies using more aggressive GAS strains.

The study design involves direct oropharyngeal inoculation of GAS to sequential cohorts. Up to four doses will be tested, from 1 x 10^5 cfu/mL (lower than previous GAS challenge studies) to a maximum of 1 x 10^8 cfu/mL. A minimum of 20 and maximum of 80 participants will be challenged. The challenge procedure aligns closely that used successfully in the 1970s GAS human challenge studies. An incubation period of 36 to 72 hours is expected before onset of symptoms. Participants will be intensively monitored inpatients for up to six days after challenge. The primary outcome measure is GAS pharyngitis, as defined by a combination of positive clinical and laboratory features. All participants developing pharyngitis will be treated with antibiotics and and those without pharyngitis will also be treated after 5 days. Participants will be followed as outpatients at 1 week, and 1, 3, and 6 months after discharge.

A challenge model also promises an unprecedented opportunity to use modern techniques to describe the immunobiology of GAS infection. Blood and saliva samples will be collected at multiple timepoints before, during, and after the challenge. Testing of serial samples will add a dynamic next level to the clinical foundations of the challenge model, enabling in-depth comparison between participants developing pharyngitis or not and paving the way to identifying immune correlates of protection.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Sequential Assignment
Intervention Model Description: Observational, sequential, dose-escalation
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Group A Streptococcal Human Challenge Study: Building a Pharyngitis Model to Accelerate Vaccine Development
Actual Study Start Date : June 27, 2018
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : November 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sore Throat

Arm Intervention/treatment
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 1-3x10^5 to 1-3x10^8 colony forming units (CFU) of the challenge strain (depending on dose group allocation).

Biological: 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.
Other Names:
  • GAS M75
  • Group A Streptococcus challenge inoculum




Primary Outcome Measures :
  1. Proportion of participants at each GAS M75 dose level meeting the study pharyngitis endpoint [ Time Frame: Up to 6 days after challenge dose administered. ]
    Proportion of participants at each GAS M75 dose level who develop pharyngitis, using a combined clinical-microbiological definition comprising sore throat, physical examination signs of pharyngitis and tonsillitis, and microbiological confirmation of GAS by culture and nucleic acid amplification test of throat swabs.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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).

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03361163


Contacts
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Contact: Janet Wong, MBBS,BSc +61385939804 j.wong2@nucleusnetwork.com.au
Contact: Joshua Osowicki, MBBS +61383416200 josh.osowicki@mcri.edu.au

Locations
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Australia, Victoria
Centre for Clinical Studies (Nucleus Network Limited) Recruiting
Melbourne, Victoria, Australia, 3004
Contact: Janet Wong, MBBS, BSc    +61385939804    j.wong2@nucleusnetwork.com.au   
Principal Investigator: Janet Wong, MBBS, BSc         
Sponsors and Collaborators
Andrew Steer
University of Melbourne
Nucleus Network Ltd
National Health and Medical Research Council, Australia
Telethon Kids Institute
The Peter Doherty Institute for Infection and Immunity
Queen Fabiola Children's University Hospital
Griffith University
University of Wollongong
The University of Queensland
University of Auckland, New Zealand
University of Tennessee Health Science Center
Investigators
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Principal Investigator: Janet Wong, MBBS,BSc Senior Medical Officer, Nucleus Network Limited
Principal Investigator: Andrew C Steer, MBBS,MPH,PhD Group A Streptococcal Research Group, Murdoch Children's Research Institute

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Responsible Party: Andrew Steer, Professor, Group A Streptococcal Research Group Leader, Murdoch Childrens Research Institute
ClinicalTrials.gov Identifier: NCT03361163     History of Changes
Other Study ID Numbers: CHIVAS-M75
First Posted: December 4, 2017    Key Record Dates
Last Update Posted: March 7, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by Andrew Steer, Murdoch Childrens Research Institute:
Streptococcus pyogenes pharyngitis
Streptococcus Pharyngitis
Strep Throat
Streptococcus pyogenes Infection
Group A Streptococcus: B Hemolytic Pharyngitis
Group A Streptococcal Infection
Controlled human infection model
Challenge study

Additional relevant MeSH terms:
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Streptococcal Infections
Infection
Communicable Diseases
Bacterial Infections
Hemolysis
Pharyngitis
Gram-Positive Bacterial Infections
Pathologic Processes
Pharyngeal Diseases
Stomatognathic Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Otorhinolaryngologic Diseases