Controlled Human Infection for Penicillin Against Streptococcus Pyogenes
- Conditions
- Streptococcus pyogenes pharyngitisStreptococcus pharyngitisStrep throatStreptococcus pyogenes infectionGroup A Streptococcus: B haemolytic pharyngitisGroup A streptococcal infectionAcute rheumatic feverGram positive bacterial infectionBacterial infectionRecurrent rheumatic fever
- Registration Number
- ACTRN12621000751875
- Lead Sponsor
- Telethon Kids Institute
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 60
Healthy adult males and non-pregnant, non-lactating females without risk factors for severe Strep A diseases including congenital or acquired immunological dysfunction, pre-existing cardiac valvular dysfunction or previous invasive Strep A infection or delayed sequelae.
Participants who meet all the inclusion criteria are eligible to be a participant in the trial:
1.Males or females, aged 18 - 40 years (inclusive) on the day of informed consent.
2.Body mass index of 18.0 - 32.0 kg/m2, inclusive, and body weight greater than or equal to 50.0kg at screening
3.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.
4.Systolic blood pressure (SBP) of 90 mmHg to 140 mmHg and diastolic blood pressure (DBP) of 40 mmHg to 90 mmHg. Vital signs can be repeated up to two times.
5.Resting heart rate (HR) of 40-100 bpm (confirmed by one repeat) at screening.
6.Females must be non-pregnant, non-lactating or postmenopausal (defined as at least 1 year of amenorrhoea without alternate cause as confirmed by follicle-stimulating hormone [FSH] greater than or equal to 40mIU/mL), or verbally confirmed to be surgically sterile for at least 6 months prior to dosing.
7.Females of childbearing potential must agree to use a barrier method of contraception (e.g. condoms, diaphragms, or cervical caps) from the time of signing informed consent until 30 days after final dose of azithromycin, even if they are already on another hormonal method of contraception (e.g. oral or implantable contraceptives). The barrier method alone is sufficient contraception for female participants.
8.Must be willing and able to read, understand, and sign the participant information and consent form. Willing to comply with all study requirements, including the inpatient confinement period and outpatient visits for the duration of the study (approx. 1 month).
9.Willing to abstain from the use of mouthwash from the day of screening until the first outpatient visit.
10.Must be willing for insertion and have adequate sites for placement of indwelling intravenous cannulae and midline intravenous catheter.
Patients who meet any of these criteria are not eligible for participation in the trial:
1.Evidence of pre-existing immunity to the challenge strain, defined for this study as a high serum IgG to a peptide comprising the first fifty amino acids of the M75 protein (N-terminal hypervariable region) measured by ELISA.
2.Currently taking penicillins or use of any penicillin-based antibiotics from screening through to the final study visit. The use of probenecid, NSAIDs, or other medications which may significantly alter PenG PK will also not be permitted within 14 days prior to study drug administration until completion of the final follow-up visit. Sporadic NSAID use ( less than 5 occasions) in the 14 days prior to drug administration will be allowed, but the need for ongoing regular NSAIDS will render the person ineligible due to NSAIDS effects on proximal tubular penicillin excretion and the potential to promote severe infections with Strep A.
3.Any corticosteroid, immunomodulator or anticoagulant use 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.
4.Use of prescription or non-prescription drugs (except for oral contraceptive pill in healthy adult females) 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.
5.History of any clinically important cardiac, endocrine, haematological, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, and renal, or other major disease, as determined by the Investigator.
6.History of hospitalisation for illness within the six months prior to enrolment into study, or major surgery within the 12 months prior to enrolment into study.
7.History of tonsillectomy, adenoidectomy or splenectomy.
8.Known or suspected autoimmune disease or impairment/alteration of immune function resulting from:
a.Congenital or acquired immunodeficiency (including IgA deficiency)
b.Receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months.
9.History of a severe drug reaction or severe allergic reaction (eg. anaphylaxis, convulsions) or clinically significant allergic disease diagnosed by a Physician.
10.Personal or family history of severe Strep A infection or sequelae (such as acute rheumatic fever, rheumatic heart disease, post-streptococcal glomerulonephritis) or invasive Strep A disease (toxic shock syndrome, necrotizing fasciitis, bloodstream infection, pleural empyema, meningitis, puerperal sepsis).
11.Clinically significant disease or any condition or disease that might affect drug absorption, distribution, or excretion, e.g. gastrectomy, diarrhoea.
12.Any vaccination within the last 28 days (except for seasonal influenza
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Presence of acute symptomatic Strep A pharyngitis assessed by a clinician according to a case definition based on ICD-10 criteria for Streptococcal pharyngitis.[ Participants will be assessed for primary outcome starting from 12 hours following oropharyngeal application of challenge inoculum, and 12 hourly thereafter until development of acute symptomatic Strep A pharyngitis or day 5, whichever is earlier]
- Secondary Outcome Measures
Name Time Method Strep A colonisation of the pharynx assessed as evidenced by microbiological isolation (through NAT or culture) in absence of clinical pharyngitis[ Participants will have throat swabs taken starting from 12 hours following oropharyngeal application of challenge inoculum, and 12 hourly thereafter until development of acute symptomatic Strep A pharyngitis or day 5, whichever is earlier.];Salivary penicillin concentration assessed using a validated assay[ Saliva samples will be taken prior to challenge, and at diagnosis of acute symptomatic Strep A pharyngitis (if applicable) and prior to discharge from confinement (up to 6 days post-admission).]