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Trial registered on ANZCTR

Registration number

ACTRN12621000751875

Ethics application status

Approved

Date submitted

16/04/2021

Date registered

15/06/2021

Date last updated

9/10/2023

Date data sharing statement initially provided

15/06/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Controlled Human Infection for Penicillin Against Streptococcus Pyogenes

Scientific title

A double blinded, placebo controlled, randomised trial to determine the minimum plasma penicillin concentration required to prevent Strep A pharyngitis in healthy volunteers

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1264-9535

Trial acronym

CHIPS

Linked study record

NCT03361163 (CHIVAS-M75) is a parent study of CHIPS. It established the safety and efficacy of the human challenge model with Strep A M-75 strain in healthy human volunteers. The same strain and challenge methods will be replicated in CHIPS. In addition, CHIPS will build on the findings of CHIVAS-M75 by randomising participants to different penicillin steady state concentrations prior to the challenge to further evaluate minimum effective dose of penicillin in prevention of Strep A pharyngitis.

Health condition

Health condition(s) or problem(s) studied:

Streptococcus pyogenes pharyngitis

Streptococcus pharyngitis

Strep throat

Streptococcus pyogenes infection

Group A Streptococcus: B haemolytic pharyngitis

Group A streptococcal infection

Gram positive bacterial infection

Bacterial infection

Acute rheumatic fever

Recurrent rheumatic fever

Condition category

Condition code

Infection

Studies of infection and infectious agents

Infection

Other infectious diseases

Inflammatory and Immune System

Other inflammatory or immune system disorders

Respiratory

Other respiratory disorders / diseases

Blood

Other blood disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Double-blind, placebo-controlled, randomised, dose-ranging trial designed to determine the minimum effective steady-state plasma penicillin concentration required to prevent pharyngitis following direct oropharyngeal inoculation of Streptococcus pyogenes – Strain emm75 (Strep A; M75).

Healthy volunteers will be recruited and randomised to receive to one of 5 possible steady state concentrations of penicillin (as benzylpenicillin sodium) commencing with 0 (placebo), 3, 6, 12 and 20ng/mL as a continuous intravenous infusion (with options to add or drop arms after an interim review) for up to 5 days. The dose of benzylpenicillin required to achieve the different steady state plasma concentrations (0, 3, 6, 12 and 20ng/mL) for each participant will be calculated based on individualised pharmacokinetic assessment. This will involve a "dose finding" visit where all participants will be given a bolus dose of IV benzylpenicillin 600mg with monitoring of plasma penicillin concentrations for subsequent 6 hours to inform individual pharmacokinetics.

At least 12 hours after starting continuous penicillin infusion, participants will receive Strep A oropharyngeal challenge (emm75 Streptococcus pyogenes (Strep A M75, strain 611024)) by direct oropharyngeal application using a sterile-tipped Dacron swab after immersion for 10 seconds in a 1mL vial containing 1-3x10^5 colony forming units (CFU) of the challenge strain. Participants will be confined for up to the next 6 days with regular clinical and laboratory assessments to monitor for develop of Strep A pharyngitis. Continuous intravenous penicillin infusion will continue until day 5 or development of clinical pharyngitis.

All participants, regardless of development of pharyngitis, will receive a non-penicillin oral antibiotic (PO azithromycin 500mg daily for 5 days) at Day 5 to treat or eradicate Strep A.

Intervention code [1]

Prevention

Intervention code [2]

Treatment: Drugs

Intervention code [3]

Treatment: Other

Comparator / control treatment

Active: All participants will receive one oropharyngeal challenge application of Strep A M75 inoculum as described above. The control group will receive no penicillin in their continuous infusion (0ng/mL arm) and will only receive 0.9% sodium chloride (normal saline) infusion. All participants will receive continuous infusions (penicillin or placebo according to randomisation) until development of pharyngitis or Day 5, whichever is earlier

Strep A oropharyngeal challenge will occur after participants have commenced the randomised intravenous infusion for at least 12 hours.

Control group

Placebo

Outcomes

Primary outcome [1]

Presence of acute symptomatic Strep A pharyngitis assessed by a clinician according to a case definition based on ICD-10 criteria for Streptococcal pharyngitis.

Timepoint [1]

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 [1]

Strep A colonisation of the pharynx assessed as evidenced by microbiological isolation (through NAT or culture) in absence of clinical pharyngitis

Timepoint [1]

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.

Secondary outcome [2]

Salivary penicillin concentration assessed using a validated assay

Timepoint [2]

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).

Eligibility

Key inclusion criteria

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.

Minimum age

18 Years

Maximum age

40 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

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) or use of any antibiotic therapy during the 14 days before challenge.

13. Presence of an acute infectious disease or febrile illness (e.g., sub-lingual temperature greater than equal to 37.5°C) within the five days prior to challenge with Strep A M75.

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

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

16. Laboratory tests that fail to meet the following thresholds: one repeat will be allowed at discretion of the investigator to confirm eligibility.
a. Haematology: Haemoglobin, haematocrit, red cell count, white cell count with differentials, platelet count, MCH, MCV, MCHC– parameters within gender-specific reference intervals from the local laboratory unless deemed not clinically significant by the investigator.
b. Clinical chemistry within gender-specific reference intervals from the local laboratory unless deemed not clinically significant by the investigator: urea, glucose, creatinine, sodium, potassium, chloride and bicarbonate, lactate dehydrogenase, calcium, total protein, magnesium, phosphate, albumin, cholesterol, and uric acid. For renal function, an eGFR greater than 90ml/min/m2 will be considered normal using the CKD-EPI without albuminuria on dipstick.
c. Liver function tests: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, conjugated bilirubin, gamma-glutamyl transferase [<1.5 x ULN (ALT, GGT, Total Bilirubin; local laboratory gender-specific reference ranges) will be considered not clinically significant].
d. Negative HIV serology, Hepatitis B Surface Ag testing and hepatitis C serology.
e. Females with a negative serum pregnancy test at screening and negative urine pregnancy test at Baseline and Day -1 check-in

17. 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.

18. History or presence of alcohol abuse (defined as regular alcohol consumption of more than 40g or 4 standard drinks per day) or drug habituation, or any prior intravenous usage of an illicit substance.

19. 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 (e.g. the participant has stated in advance that they consumed a prescription or OTC product which contained the detected drug) and the participant has a negative urine drug screen on retest.

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

21. Known hypersensitivity or other contraindication to use of penicillin, azithromycin or any other beta-lactam or macrolide antibiotic(s).

22. Known hypersensitivity to soya protein.

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

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

25. History of severe infections requiring hospitalisation for intravenous antibiotics (within the last 10 years). Exceptions to this would include a short course of intravenous antibiotics for appendicitis, biliary sepsis, diverticulitis and cellulitis.

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

27. Presence of implants (except for contraceptive implants) or prosthesis (e.g. artificial joints, pacemakers).

28. Receipt of another investigational product within the 30 days prior to screening involving an investigational product or other intervention that might affect risk of invasive Strep A infection or compromise the integrity of the study (e.g. significant volumes of blood already taken in previous study).

29. 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.

30. 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.

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Clinical staff, patient and outcome assessors will remain blinded to the treatment allocation for the duration of the study. Allocation information will be stored in a password-protected file on a secure server. This list will be provided securely to the pharmacy and unblinded members of the analytical team. Code-break envelopes containing the details of treatment allocation will be provided to the study site for emergency unblinding. These will only be utilised for unblinding in the case where knowledge of the treatment allocation is required for emergency treatment of the participant.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

block randomisation in groups of 5 will occur using a verified random number generator in the R statistical package by the study statistician.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes

Intervention assignment

Parallel

Other design features

Phase

Phase 1 / Phase 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

Based on simulations, a maximum of 60 participants are required (recruited in 4 cohorts of equal size; starting with 5 treatment arms) to detect the minimum effective dose (MED) between 0-20 ng/mL, with a power of >80% and a Type 1 error of <5%. Trial simulations were based on: (i) an anticipated 25% of placebo participants symptom-free at the end of Study Day 5 (ii) a monotonic normal dynamic linear model (NDLM) with weakly informative prior distributions; (iii) equal allocation to all treatment arms; (iv) interim analyses after each cohort has completed (i.e. every 15 participants); (v) a high target of 90% symptom-free and a low target of 80% symptom-free in determining the MED; (vi) stopping rules for success if the p(MED>low target) is greater than 80% and for futility if the p(MED>upper target) is less than 10%. Trial operating characteristics were calculated for 8 scenarios, ranging from null efficacy to MED detected at the highest dose level.

A statistical analysis plan (SAP) will be written prior to the enrolment of participants for the first cohort. It will contain details of how anticipated intercurrent (post randomisation) events and missing data will be handled within the estimand framework (ICH E9 (R1) guidelines). Further details will also be provided on the Bayesian log-logistic model for modelling the dose-response, including specification of the weakly informative priors and sensitivity analyses for the primary endpoint, and derivation of the posterior distribution for minimum effective dose for evaluation of the decision criteria that trigger trial adaptations.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/08/2022

Actual

24/08/2022

Date of last participant enrolment

Anticipated

1/08/2023

Actual

8/06/2023

Date of last data collection

Anticipated

1/09/2023

Actual

25/07/2023

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Linear Clinical Research - Nedlands

Recruitment postcode(s) [1]

6009 - Nedlands

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

GPO Box 1421, Canberra ACT 2601 Australia

Country [1]

Australia

Primary sponsor type

Other

Name

Telethon Kids Institute

Address

Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009

Country

Australia

Secondary sponsor category [1]

Other

Name [1]

Linear Clinical Research

Address [1]

1 Hospital Avenue, B-Block, 1st Floor, Nedlands WA 6009,

Country [1]

Australia

Other collaborator category [1]

University

Name [1]

University of Western Australia

Address [1]

35 Stirling Hwy, Crawley WA 6009

Country [1]

Australia

Other collaborator category [2]

University

Name [2]

Curtin University

Address [2]

Kent St, Bentley WA 6102

Country [2]

Australia

Other collaborator category [3]

Other

Name [3]

Murdoch Children's Research Institute

Address [3]

Royal Children's Hospital, 50 Flemington Rd, Parkville VIC 3052

Country [3]

Australia

Other collaborator category [4]

University

Name [4]

University of Melbourne

Address [4]

University of Melbourne, Parkville VIC 3010

Country [4]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Limited

Ethics committee address [1]

123 Glen Osmond Road Eastwood Adelaide, South Australia 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

31/03/2021

Approval date [1]

03/05/2021

Ethics approval number [1]

Summary

Brief summary

The CHIPS Trial is a double-blinded, randomised dose-ranging trial designed to determine the minimum effective steady-state penicillin concentrations required to prevent pharyngitis caused by Strep A. This trial will use a world-first fully validated human challenge model for Strep A infection which has been developed in Australia by members of our team as a tool to test different interventions in the fight against acute rheumatic fever (ARF) and rheumatic heart disease (RHD). If the CHIPS Trial determines that the minimum concentration required to prevent Strep A pharyngitis is lower than the currently accepted target of 20 ng/mL, this will transform the penicillin reformulation landscape toward a new long acting penicillin implant and provide opportunities to make data-driven changes to recommendations of currently available penicillin preparations used for secondary prophylaxis of ARF and RHD.

Trial website

https://www.telethonkids.org.au/projects/the-chips-trial/

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Laurens Manning

Address

The University of Western Australia (M582), 35 Stirling Highway, 6009 Perth WA Australia

Country

Australia

Phone

+61 863191254

Fax

[email protected]

Contact person for public queries

Name

Thel Hla

Address

Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009

Country

Australia

Phone

+61 863191254

Fax

[email protected]

Contact person for scientific queries

Name

Thel Hla

Address

Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009

Country

Australia

Phone

+61 863191254

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Individual participant data will not be made publicly available.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
17095	Statistical analysis plan					381803-(Uploaded-09-10-2023-12-45-47)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Stability of benzylpenicillin for continuous intravenous infusions: An isotonic formulation for therapeutic use and a low-dose formulation for clinical trial.	2022	https://dx.doi.org/10.1016/j.jiac.2022.04.016
Dimensions AI	Study protocol for controlled human infection for penicillin G against Streptococcus pyogenes: a double-blinded, placebo-controlled, randomised trial to determine the minimum concentration required to prevent experimental pharyngitis (the CHIPS trial)	2022	https://doi.org/10.1136/bmjopen-2022-064022
Dimensions AI	Searching for Strep A in the clinical environment during a human challenge trial: a sub-study protocol	2023	https://doi.org/10.1099/acmi.0.000650.v3

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically