ANZCTR - Registration

Registration number

ACTRN12621000339853

Ethics application status

Approved

Date submitted

27/01/2021

Date registered

25/03/2021

Date last updated

21/01/2024

Date data sharing statement initially provided

25/03/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Understanding drug concentrations in the body on the optimisation of sexually transmitted infections (STIs) treatments.

Scientific title

Use of pharmacokinetics to evaluate the dosing of antibiotics in adults with non-genital sexually transmitted infections (STIs)

Secondary ID [1]

NIL

Universal Trial Number (UTN)

NIL

Trial acronym

STI-PK

Linked study record

NIL

Health condition

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

Anorectal Chlamydia trachomatis (CT)

Oropharyngeal Chlamydia trachomatis (CT)

Anorectal Neisseria gonorrhoeae (NG)

Oropharyngeal Neisseria gonorrhoeae (NG)

Condition category

Condition code

Infection

Sexually transmitted infections

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

INFECTED participants: Participants diagnosed with chlamydia will be treated with oral doxycycline 100mg twice a day for 7 days. Survey and pill count will be undertaken at the last follow up to determine adherence.
Those diagnosed with gonorrhoea will be given one of the treatments below as per recommended guidelines

- ceftriaxone 500mg (in 2mL 1% lignocaine) intramuscularly PLUS oral azithromycin 2g as single doses. Azithromycin can also be given as 1g dose followed by 1g 6-12 hours later (Australian STI Management Guidelines for use in primary care 2018). Ceftriaxone injection and the first 1g dose of azithromycin will administered/directly observed by the nurse. The second 1g dose of azithromycin will be assured by sending a reminder sms to take the dose. The timing of the second dose will also be recorded. If the 2g dose is taken all at once, this will be directly observed.

- ceftriaxone 1g (in 3.5mL 1% lignocaine) intramuscularly as single dose (2020 European Guidelines for the diagnosis and treatment of gonorrhoea in adults AND 2018 UK national guideline for the management of infection with Neisseria gonorrhoeae). Ceftriaxone injection will be directly administered by the nurse.

- oral cefixime 400mg as a single dose when susceptibility is known (WHO GUIDELINES FOR THE
Treatment of Neisseria gonorrhoeae 2016). The dose will be taken under direct observation by the nurse.

- oral ciprofloxacin 500mg as a single dose when susceptibility is known (2020 European Guidelines for the diagnosis and treatment of gonorrhoea in adults). The dose will be taken under direct observation by the nurse.

NON-INFECTED participants: In addition to participants diagnosed with chlamydia or gonorrhoea, we will also recruit healthy, non-infected participants.
Non-infected participants will be given the same antibiotics as for infected participants but no susceptibility testing will be needed for cefixime or ciprofloxacin i.e. healthy individuals will be given below. The choice of antibiotic prescribed is based on the timing of the participants recruitment - with each of the 5 drugs being studied being equally distributed across the total target sample size i.e. consecutive, block allocation in order of drugs listed below.

- oral doxycycline 100mg twice a day for 7 days (Australian STI Management Guidelines for use in primary care 2018). Survey and pill count will be undertaken at the last follow up to determine adherence.

- ceftriaxone 500mg (in 2mL 1% lignocaine) intramuscularly PLUS oral azithromycin 2g as single doses. Azithromycin can also be given as 1g dose followed by 1g 6-12 hours later (Australian STI Management Guidelines for use in primary care 2018). Ceftriaxone injection and the first 1g dose of azithromycin will administered/directly observed by the nurse. The second 1g dose of azithromycin will be assured by sending a reminder sms to take the dose. The timing of the second dose will also be recorded. If the 2g dose is taken all at once, this will be directly observed.

- ceftriaxone 1g (in 3.5mL 1% lignocaine) intramuscularly as single dose (2020 European Guidelines for the diagnosis and treatment of gonorrhoea in adults AND 2018 UK national guideline for the management of infection with Neisseria gonorrhoeae). Ceftriaxone injection will be directly administered by the nurse.

- oral cefixime 400mg as a single dose (WHO GUIDELINES FOR THE
Treatment of Neisseria gonorrhoeae 2016). The dose will be taken under direct observation by the nurse.

- oral ciprofloxacin 500mg as a single dose (2020 European Guidelines for the diagnosis and treatment of gonorrhoea in adults). The dose will be taken under direct observation by the nurse.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

oropharyngeal drug concentrations (mcg/g or mL) in tissue using liquid chromatography – Mass Spectrometry (LC-MS) methods.

Timepoint [1]

0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose

Primary outcome [2]

oropharyngeal drug concentrations (mcg/g or mL) in saliva using liquid chromatography – Mass Spectrometry (LC-MS) methods.

Timepoint [2]

0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose

Primary outcome [3]

oropharyngeal drug concentrations (mcg/g or mL) in gingival crevicular fluid (GCF) using liquid chromatography – Mass Spectrometry (LC-MS) methods.

Timepoint [3]

0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose

Secondary outcome [1]

Additional primary outcome 4:
oropharyngeal drug concentrations (mcg/g or mL) in plasma using liquid chromatography – Mass Spectrometry (LC-MS) methods.

Timepoint [1]

Additional primary timepoint 4:
0,1-2,4,6 hours post dose for all drugs

Secondary outcome [2]

Additional primary outcome 5:
oropharyngeal drug concentrations (mcg/g or mL) in whole blood using liquid chromatography – Mass Spectrometry (LC-MS) methods.

Timepoint [2]

Additional primary timepoint 5:
0,1-2,4,6 hours post dose for all drugs

Secondary outcome [3]

Additional primary outcome 6:
oropharyngeal drug concentrations (mcg/g or mL) in polymorphonuclear leukocytes (PMNs) using liquid chromatography – Mass Spectrometry (LC-MS) methods.

Timepoint [3]

Additional primary timepoint 6:
0,1-2,4,6 hours post dose for all drugs

Secondary outcome [4]

Additional primary outcome 7:
Anorectal drug concentrations (mcg/g or mL) in tissue using liquid chromatography – Mass Spectrometry (LC-MS) methods.

Timepoint [4]

Additional primary timepoint 7:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Secondary outcome [5]

Additional primary outcome 8: Anorectal microbiological assessments using minimum inhibitory concentrations (MIC), culture and genomic methods

MIC and culture will not be assessed in healthy, non-infected participants.

Timepoint [5]

Additional primary timepoint 8:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Secondary outcome [6]

Secondary outcome:
pH of saliva using portable pH meter

Timepoint [6]

Secondary timepoint:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Secondary outcome [7]

Secondary outcome:
pH of oral tissue using portable pH machine

Timepoint [7]

Secondary timepoint:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Secondary outcome [8]

Secondary outcome: oropharyngeal microbiological assessments using minimum inhibitory concentrations (MIC), culture and genomic methods

MIC and culture will not be assessed in healthy, non-infected participants

Timepoint [8]

Secondary timepoint:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Secondary outcome [9]

Secondary outcome: anorectal microbiological assessments using minimum inhibitory concentrations (MIC), culture and genomic methods

MIC and culture will not be assessed in healthy, non-infected participants

Timepoint [9]

Secondary timepoint:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Secondary outcome [10]

Secondary outcome:
PK parameters of each drug in blood: These PK parameter are concentrations (total and protein unbound), peak concentrations (Cmax), time to reach Cmax (Tmax), clearance, area under the concentration-time curve (first 24 hours: AUC0-24; total: AUC0-inf), volume of distribution (Vd), and half-life (T1/2) where possible. This will be calculated using nonlinear mixed-effects modelling will be performed using the MC-PEM algorithm in the SADAPT software.

Timepoint [10]

Secondary timepoint: 0,1-2,4,6 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6 post dose.

Secondary outcome [11]

Secondary outcome:
PK parameters of each drug in saliva: These PK parameter are unbound concentrations, peak concentrations (Cmax), time to reach Cmax (Tmax), clearance, area under the concentration-time curve (first 24 hours: AUC0-24; total: AUC0-inf), volume of distribution (Vd), and half-life (T1/2) where possible. This will be calculated using nonlinear mixed-effects modelling will be performed using the MC-PEM algorithm in the SADAPT software.

Timepoint [11]

Secondary timepoint:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Secondary outcome [12]

Secondary outcome:
PK parameters of each drug in GCF: These PK parameter are concentrations (total and unbound if possible), peak concentrations (Cmax), time to reach Cmax (Tmax), clearance, area under the concentration-time curve (first 24 hours: AUC0-24; total: AUC0-inf), volume of distribution (Vd), and half-life (T1/2) where possible. This will be calculated using nonlinear mixed-effects modelling will be performed using the MC-PEM algorithm in the SADAPT software.

Timepoint [12]

Secondary timepoint:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Secondary outcome [13]

Secondary outcome:
PK parameters of each drug in oropharyngeal tissue: These PK parameter are total concentrations, peak concentrations (Cmax), time to reach Cmax (Tmax), clearance, area under the concentration-time curve (first 24 hours: AUC0-24; total: AUC0-inf), volume of distribution (Vd), and half-life (T1/2) where possible. This will be calculated using nonlinear mixed-effects modelling will be performed using the MC-PEM algorithm in the SADAPT software.

Timepoint [13]

Secondary timepoint:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Secondary outcome [14]

Secondary outcome:
PK parameters of each drug in whole blood from VAMS: These PK parameter are total concentrations, peak concentrations (Cmax), time to reach Cmax (Tmax), clearance, area under the concentration-time curve (first 24 hours: AUC0-24; total: AUC0-inf), volume of distribution (Vd), and half-life (T1/2) where possible. This will be calculated using nonlinear mixed-effects modelling will be performed using the MC-PEM algorithm in the SADAPT software.

Timepoint [14]

Secondary timepoint:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Secondary outcome [15]

Secondary outcome:
PK parameters of each drug in anorectal tissue: These PK parameter are total concentrations, peak concentrations (Cmax), time to reach Cmax (Tmax), clearance, area under the concentration-time curve (first 24 hours: AUC0-24; total: AUC0-inf), volume of distribution (Vd), and half-life (T1/2) where possible. This will be calculated using nonlinear mixed-effects modelling will be performed using the MC-PEM algorithm in the SADAPT software.

Timepoint [15]

Secondary timepoint:
0,1-2,4,6,24 and 48 hours post dose for ciprofloxacin and ceftriaxone monotherapy. For cefixime it’s 0,4,6,24 and 48 hours post dose. For ceftriaxone+Azithro or doxycycline sample times are 0,1-2,4,6,24,48,168 (7 days) and 336 (14 days) post dose.

Eligibility

Key inclusion criteria

(1) Men or women aged 18 years or older who test positive for rectal and/or oropharyngeal infections with CT or NG (they cannot have both infections) using NAAT or culture methods OR (2) healthy (non-infected) men and women.

Both healthy and infected participants must have
(a) Adequate English and comprehension to give informed consent (b) Able to attend all follow up visits (c) Those with gingival or periodontal disease/caries are eligible since >30% of population have these conditions (d) Medicare card (e) fully vaccinated for COVID-19

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

No

Key exclusion criteria

(1) Oral antibiotic use in the last 4 weeks (2) widespread mucosal ulcerations by clinical examination. (3) Infection with both CT and NG) i.e. only single infections at one site are eligible (4) Infection at the same site with Mycoplama genitalium (5) Known contraindications or interactions with any of the treatments (6) Pregnant or breastfeeding women (7) Past participants in this trial (8) transgender people (9) HIV positive participants with CD4 counts less than 250 cells/mm3

Healthy, non-infected participants will not have other infections (CT and NG) including Mycoplama genitalium.

Study design

Statistical methods / analysis

Nonlinear mixed-effects modelling will be performed using the MC-PEM algorithm in the SADAPT software. For each drug the plasma concentration-time profiles will be modelled first. One-, two- and three-compartment models will be evaluated, with linear, saturable or mixed-order elimination. To describe absorption, first- and zero-order, simultaneous or sequential first- and zero-order processes will be tested. Profiles in saliva and tissues will be included subsequently. A minimal physiologically-based PK modelling approach will be used by incorporating cardiac output, blood flow to tissues, physiological tissue volumes and density, and estimating tissue partition coefficients for the different sites of infection, as recently done for antibiotics in bone by AI Landersdorfer et al (data not shown). A three-stage hierarchical Bayesian method will be used as needed. Inter-individual variability for the population PK parameters will be estimated by graphing individual (posthoc) PK estimates against subject characteristics that may explain inter-individual differences in PK (e.g. weight, creatinine clearance) and potential relationships tested by forward inclusion followed by backwards elimination. Model selection will be based on goodness-of-fit plots, visual predictive checks, the normalised prediction distribution error and the objective function. The measured protein binding in plasma and saliva for each drug will be used to simulate the ‘free’ drug PK profiles. Penetration into saliva and infection sites will evaluated by calculating the ratios of the area under the curve (AUC) in saliva or tissue divided by the AUC in plasma. The Cmax, Tmax and elimination half-lives at the different sites will be calculated from the individual fitted estimated PK parameters. For each drug, the relevant PD measure of efficacy, i.e. fT>MIC, fAUC/MIC or Cmax/MIC, will be calculated using the model-predicted PK profiles and the bacteria MIC for each site-specific regimens.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

21/03/2022

Actual

29/03/2022

Date of last participant enrolment

Anticipated

21/02/2023

Actual

21/02/2023

Date of last data collection

Anticipated

28/02/2023

Actual

8/03/2023

Sample size

Target

60

Accrual to date

Final

60

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [2]

Melbourne Sexual Health Centre (MSHC) - Carlton

Recruitment hospital [3]

The Crane General Practice - Clifton Hill

Recruitment postcode(s) [1]

3050 - Parkville

Recruitment postcode(s) [2]

3053 - Carlton

Recruitment postcode(s) [3]

3068 - Clifton Hill

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council (NHMRC)

Country [1]

Australia

Primary sponsor type

University

Name

University of Melbourne

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health Human Research Ethics Committee

Ethics committee address [1]

Level 2
South West
300 Grattan Street
Parkville 3053 Victoria

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

26/02/2021

Approval date [1]

23/03/2021

Ethics approval number [1]

Summary

Brief summary

Every day, more than one million people globally are diagnosed with the four most common non-viral sexually transmitted infections (STIs) and gonorrhoea and chlamydia are the two most common bacterial STIs. In Australia, rates are at increasing rapidly with their highest levels in recent years. Infections in women can cause infertility, and in both sexes, increase HIV acquisition and transmission. Treatment failure is an increasing issue and may be due to factors related to the bacteria (e.g. antibiotic resistance), the individual (e.g. immune response, vomiting/diarrhoea) or how the body processes the drug (its ‘pharmacokinetics’, or PK). Antibiotic resistance for STIs has developed so rapidly that in 2017, the World Health Organization (WHO) declared resistant gonorrhoea as an urgent global threat with the real danger that it may soon be untreatable. We now know that treatment failures occur more often at non-genital (‘extra-genital’) sites such as the mouth or rectum, with current treatment cure for chlamydia or gonorrhoea being up to 20% lower than at the genital site. We also know the mouth/oropharynx drives STI transmission through oral sex, kissing and use of saliva during sex so effective treatments for non-genital infections are critical to stop ongoing transmission. Rectal infections in women can result in persisting vaginal infection from cross contamination between the two sites. There are only a few new drugs in development to treat STIs, but they are many years away and may not be sufficiently effective, especially not for the mouth/oropharynx. Therefore, clinicians must optimise what drugs we have now, but without clinical trial evidence, they must rely on pharmacokinetic (PK) data to guide this decision making. However, there are few PK data available for the mouth or rectum. This project will develop innovative techniques to generate the first comprehensive data in the mouth and rectum for four commonly used antibiotics used to treat STIs – cefixime, ceftriaxone, ciprofloxacin, azithromycin and doxycycline. After this we will apply these methods to emerging drugs currently being tested in trials that have not been marketed yet. This is to ensure new drugs in the pipeline will be effective against STIs. These data will address the urgent global call for data to inform STI treatment guidelines.

Trial website

https://mspgh.unimelb.edu.au/research-groups/centre-for-epidemiology-and-biostatistics-research/sexual-health/optimisation-of-treatments-for-stis-pharmacokinetics-study-sti-pk-project

Public notes

Contacts

Principal investigator

Name

Dr Fabian Kong

Address

University of Melbourne
Level 3, 207 Bouverie st
Carlton , Victoria, 3053

Country

Australia

Phone

+61390353039

Email

[email protected]

Contact person for public queries

Name

Fabian Kong

Address

University of Melbourne
Level 3, 207 Bouverie st
Carlton, Victoria, 3053

Country

Australia

Phone

+61390353039

Email

[email protected]

Contact person for scientific queries

Name

Fabian Kong

Address

University of Melbourne
Level 3, 207 Bouverie st
Carlton , Victoria, 3053

Country

Australia

Phone

+61390353039

Email

[email protected]

Trial Review

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