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Trial registered on ANZCTR


Registration number
ACTRN12622000349741
Ethics application status
Approved
Date submitted
15/02/2022
Date registered
25/02/2022
Date last updated
31/01/2023
Date data sharing statement initially provided
25/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
'One injection vs. three': Clinical evaluation of a single, high dose subcutaneous infusion of benzathine penicillin G for treatment of syphilis (SCIP Syphilis)
Scientific title
'One injection vs. three': Evaluation of the safety and tolerability of a single, high dose subcutaneous infusion of benzathine penicillin G for treatment of syphilis (SCIP Syphilis)
Secondary ID [1] 306438 0
None
Universal Trial Number (UTN)
U1111-1271-3685
Trial acronym
SCIP Syphilis
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Syphilis 325278 0
Condition category
Condition code
Infection 322677 322677 0 0
Sexually transmitted infections
Infection 322678 322678 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
7.2 MU (13.8mL) benzathine penicillin G (BPG) as Bicillin® L-A given as a single (once-only) subcutaneous infusion (over 10 - 30 minutes) in adults for treatment of non-central nervous system (CNS) syphilis infections.

Intervention code [1] 322871 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330474 0
Safety and tolerability of 7.2MU Bicillin® L-A given by subcutaneous infusion for treatment of non-CNS syphilis infection, assessed as a composite using adverse events, numerical pain scoring and local skin irritation.

Adverse events will be collected by participant self-report (during phone calls and in-person reviews) and clinical examination during the follow up visits. Based on prior results from healthy human volunteers (n=24), common adverse events following subcutaneous infusion included swelling, bruising and changes to pigmentation at site of injection.

Pain scoring will be measured using the numeric rating scale (NRS), which is a valid method for recording pain in this setting. The NRS has been validated in adults for recording pain; the scoring system has 11 (0-10) different values anchored by terms describing pain severity extremes: 0=none, 1-3=mild, 4-6=moderate, and 7-10=severe. A score of 10 indicates the worst pain imaginable.

Local skin irritation will be monitored using a participant questionnaire (modified Skindex-16) regarding symptoms of pain, character, itchiness, pallor or erythema, bleeding, and heat at the injection site.
Timepoint [1] 330474 0
Adverse events will be assessed from time of infusion and each follow up at day 1, 2, 3, 7. 14 and weeks 3, 6, 12, 24 post infusion.

Pain scoring will be taken at: infusion completion, day 1, 2, 3, 7 and 14 post infusion.

Participants will complete a modified Skindex-16 questionnaire on days 1, 2, 3, 7 and 14 post infusion.
Secondary outcome [1] 406378 0
Need for repeat treatment for syphilis infection within 6 months post infusion, due to treatment failure (assessed using treponemal serology and need for repeat treatment determined by the treating practitioner)
Timepoint [1] 406378 0
Treponemal serology (specific and non-specific) at recruitment, and weeks 3, 6, 12 and 24 post infusion.
Secondary outcome [2] 406384 0
Plasma penicillin concentration at 21 days post 7.2 MU Bicillin® L-A administered by a single subcutaneous infusion as a surrogate predictor for treatment efficacy
Timepoint [2] 406384 0
Plasma penicillin concentration at 21 days post-infusion
Secondary outcome [3] 406385 0
Change in titre of non-treponemal specific serology as a surrogate marker for treatment efficacy
Timepoint [3] 406385 0
non-treponemal specific serology (RPR) at 24 weeks post-infusion
Secondary outcome [4] 406386 0
Time above plasma concentration of penicillin of 0.018mg/mL (for T. pallidum) post infusion of 7.2 MU of BPG
Timepoint [4] 406386 0
Plasma penicillin concentration samples will be taken at baseline, weeks 3, 6 and 12 following infusion
Secondary outcome [5] 406477 0
Qualitative exploration of patient's experience and perception of receiving subcutaneous infusion using semi-structured face-to-face interviews using scripted questions.
Timepoint [5] 406477 0
Qualitative interviews will be conducted immediately following infusion, at weeks 3 and 24 post-infusion follow up visits

Eligibility
Key inclusion criteria
(a) Males and non-pregnant females aged older than 18 years
(b) Diagnosis of syphilis infection (made by a medical practitioner) AND requiring treatment with BPG in the form of Bicillin® L-A. This is defined as follows:
i. Positive treponemal serology (Total antibody AND TPPA)
ii. Primary syphilis (diagnosed clinically) with PCR confirmation of T. pallidum
(c) No prior documented allergy to penicillin.
(d) No history of anaphylactic reaction to cephalosporin antibiotics.
(e) Participants who are considered likely to adhere to the trial guidelines for the duration of the trial and are willing and deemed reliable to attend follow up appointments as outlined in the protocol.
(f) Able to provide informed consent in accordance with Good Clinical Practice.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(a) Pregnant or breastfeeding females
(b) Diagnosis of neurosyphilis (CNS, otic or optic syphilis) made by a medical practitioner
(c) Known hypersensitivity or contraindication to use of penicillin.
(d) Existing dermatological conditions or other abnormalities (e.g., extensive scarring) that may affect skin integrity at the site of injection, especially abdomen or lateral hips.
(e) Presence of significant co-morbidities which is likely to impact patient’s participation the study, as assessed by a medical practitioner

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
A pragmatic sample size of 40 is chosen to allow for demonstration of tolerability and safety in a target patient population with non-CNS syphilis infection. Assuming that 95% of dosed participants will have penicillin concentrations >18ng/mL at 21 days (expected based on prior pharmacokinetic study in healthy adults), a sample size of at least 33 will estimate the expected proportion (of participants with penicillin concentrations >18ng/mL at 21 days) with 7.5% absolute precision and 95% confidence.

NONMEM compiler will be used for pharmacokinetic analysis. Given the sparse pharmacokinetic sampling planned, the observed concentrations will be assessed with respect to population pharmacokinetic model derived from a previous study of SC administration in healthy volunteers.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2023
Actual
Date of last participant enrolment
Anticipated
1/03/2024
Actual
Date of last data collection
Anticipated
1/09/2024
Actual
Sample size
Target
40
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 21743 0
Fremantle Hospital and Health Service - Fremantle
Recruitment postcode(s) [1] 36797 0
6160 - Fremantle

Funding & Sponsors
Funding source category [1] 310785 0
Government body
Name [1] 310785 0
Australian Department of Health (Medical Research Future Fund
Country [1] 310785 0
Australia
Primary sponsor type
Hospital
Name
South Metropolitan Health Service
Address
14 Barry Marshall Parade, Murdoch, WA 6150
Country
Australia
Secondary sponsor category [1] 312035 0
None
Name [1] 312035 0
Address [1] 312035 0
Country [1] 312035 0
Other collaborator category [1] 282161 0
University
Name [1] 282161 0
Curtin University
Address [1] 282161 0
Kent St, Bentley, WA 6102
Country [1] 282161 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310359 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [1] 310359 0
Level 2, Education Building, Fiona Stanley Hospital
14 Barry Marshall Parade
Murdoch, Western Australia 6150
Australia
Ethics committee country [1] 310359 0
Australia
Date submitted for ethics approval [1] 310359 0
30/11/2021
Approval date [1] 310359 0
23/12/2021
Ethics approval number [1] 310359 0
RGS5165

Summary
Brief summary
Australia is currently in the midst of a syphilis epidemic which began a decade ago. Benzathine penicillin G (BPG) is the treatment of choice for non-CNS syphilis infections. Primary, secondary or early latent syphilis is treated with 2.4 million units (MU) of BPG, while late latent syphilis requires 2.4 MU weekly for 3 weeks in total. BPG is typically administered by IM injection which is associated with significant pain and distress in the recipient. This has been shown to negatively impact adherence, especially where multiple doses are indicated.

Subcutaneous (SC) administration of BPG is a potentially more efficacious alternative to IM injection. Prior work done by our group in healthy adult volunteers have demonstrated acceptable tolerability and a superior pharmacokinetic profile.

Our study aims to demonstrate the safety and tolerability of a single 7.2MU dose of BPG given as a subcutaneous infusion for treatment of syphilis. Secondary objectives are to demonstrate efficacy of SC BPG and estimate duration that plasma penicillin concentrations remain above the target of 18mg/mL. Primary outcome is the assessment of safety and tolerability including serious adverse events or reactions. Secondary outcomes are the change in nontreponemal specific serology titre at 6 months, plasma penicillin concentrations at 3 weeks and proportion of patients with treatment failure requiring re-treatment at 6 months.

We will recruit 40 adult patients with confirmed syphilis infection from those referred to the sexual health service at Fremantle Hospital. The study will also incorporate a qualitative component exploring patient's experience and perception of receiving subcutaneous infusion. Participants will be followed up for 6 months from day of treatment.

If we are successful in demonstrating safety, tolerability and efficacy of SC high dose penicillin in non-CNS syphilis infections, this has the potential to radically transform the treatment paradigm.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117374 0
A/Prof Laurens Manning
Address 117374 0
The University of Western Australia (M582), 35 Stirling Highway, Crawley, WA 6009, Australia
Country 117374 0
Australia
Phone 117374 0
+61861511156
Fax 117374 0
Email 117374 0
[email protected]
Contact person for public queries
Name 117375 0
Thel Hla
Address 117375 0
Fiona Stanley Hospital, Robin Warren Drive, Murdoch, WA 6150
Country 117375 0
Australia
Phone 117375 0
+61863191254
Fax 117375 0
Email 117375 0
[email protected]
Contact person for scientific queries
Name 117376 0
Thel Hla
Address 117376 0
Fiona Stanley Hospital, Robin Warren Drive, Murdoch, WA 6150
Country 117376 0
Australia
Phone 117376 0
+61863191254
Fax 117376 0
Email 117376 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.