None listed
Conditions
Brief summary
This will be a prospective, dose-escalation, CHIM study that aims to evaluate the capacity of N. gonorrhoeae isolate AUSMDU00053933 to induce a safe and tolerable oropharyngeal gonorrhoea infection in healthy participants, and determine the dose required to produce an infection rate of 60-80%. Only healthy participants who are assigned male at birth and do not have sex with individuals assigned female at birth, aged 18-50, who meet the eligibility criteria described in the protocol will be enrolled in the study. The trial population will include 20-35 participants, enrolled in consecutively inoculated cohorts of 5, until either 20 participants have been challenged with the target dose, or until reaching a maximum of 35 participants. Study participants will be allowed to develop an oropharyngeal gonococcal infection, and upon confirmation of symptomatic gonorrhoea infection, participant request or at the end of the 5 day experimental infection period, participants will receive an intramuscular dose of ceftriaxone. Participants will return for follow up visits 1-, 3-, 7- and 14-days post-treatment for exploratory sample collection and confirmation of cure, with additional safety follow-up visits will occur 30- and 90-days post-inoculation.
Interventions
Experimental oropharyngeal challenge model with Neisseria gonorrhoeae strain AUSMDU00053933.
The intervention product is a strain that is in current circulation, that has been manufactured into dose vials for this trial in Melbourne, Australia. Inoculation will take place at the clinical trial site, Doherty Clinical Trials, in Melbourne.
Participants will be infected with gonorrhoea strain AUSMDU00053933 via direct swab application to the throat. As this intervention is only administered once, a
Experimental oropharyngeal challenge model with Neisseria gonorrhoeae strain AUSMDU00053933. The intervention product is a strain that is in current circulation, that has been manufactured into dose vials for this trial in Melbourne, Australia. Inoculation will take place at the clinical trial site, Doherty Clinical Trials, in Melbourne. Participants will be infected with gonorrhoea strain AUSMDU00053933 via direct swab application to the throat. As this intervention is only administered once, at the clinical trial site, adherence to intervention does not need assessment. The participants will then be monitored daily, in-person by clinical staff during the experimental infection period (until confirmed positive gonorrhoea infection or 5 days maximum post-inoculation) for their safety and to assess for symptoms of gonorrhoea. At the end of the experimental infection period participants will be treated with antibiotics to clear any gonorrhoea infection. Antimicrobial therapy will comprise of single-dose intramuscular ceftriaxone 1000mg in 3.5mL of 1% lignocaine, and does not change based on the infection dose. Following treatment, participants will continue to be monitored over several months via on-site follow-up visits (1, 3, 7 and 14 days following treatment, and 30 and 90 days post-inoculation) to confirm treatment success and ensure that there are no long-term effects from the infection or treatment. A continual reassessment method (CRM) will be used to identify the AUSMDU00053933 dose that can establish oropharyngeal N. gonorrhoeae infection in 60-80% of participants. The CRM dictates that the model is updated after each cohort of five participants completes challenge, and subsequent dose allocation is informed by the model estimate. Up to five dose levels are manufactured for possible use in the trial (10^4 ± 0.5log10 CFU/ml to 10^8 ± 0.5log10 CFU/ml).
Sponsors
The University of Melbourne
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
Male
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male (assigned at birth) aged 18 to 50 years old on the day of informed consent 2. Identifies as a person who has sex with people assigned male at birth and has not had sex with individuals assigned female at birth within the previous 12 months 3. Proficient in English language 4. Total body weight >/=50kg, and a body mass index (BMI) within the range of 18 to 30 kg/m2 5. Able and willing to comply with all study requirements 6. Able to read and understand the participant information, and provide written informed consent to participate in the trial and demonstrate understanding of the study requirements by passing a quiz. 7. Provide written agreement (in the PICF) to comply with infection control guidelines during the experimental gonococcal infection phase until the study team advise that N. gonorrhoeae challenge strain eradication has been confirmed 8. Able and willing to abstain from the use of mouthwash from the day of screening until the end of study
Exclusion criteria
1. History of any clinically important cardiac, endocrinologic, haematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal or other major disease, as determined by the Investigator 2. History of cancer (except adequately treated squamous cell or basal cell carcinoma of the skin more than 5 years prior) 3. History of hospitalization for illness within the six months prior to enrolment into study or major surgery within the 12 months prior to enrolment into study 4. Presence of implants or prosthesis (e.g. artificial joints, pacemakers) 5. Any clinically significant disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy 6. History of tonsillectomy or adenoidectomy 7. Any known or suspected immunodeficiencies or impairment/alteration of immune function including: • Congenital or acquired immunodeficiency including complement deficiency, antibody deficiency, chronic granulomatous disease, HIV infection or asplenism • Receipt of any immunosuppressive therapy such as anti-cancer chemotherapy or radiotherapy within the preceding 12 months • Any known or suspected autoimmune disorders (mild autoimmune disorders, such as eczema, are not exclusionary and will be determined by the Investigator) 8. Use of any systemic immunomodulatory treatment including eculizumab, corticosteroids (topical corticosteroids acceptable), anti-inflammatories (beside sporadic use of non-steroidal anti-inflammatory drugs), anticoagulants (aspirin acceptable), investigational products, interleukins, interferons or growth factors within the previous three months, or anticipated use of such drugs during the study period. 9. Use of inhaled or intranasal corticosteroid from 14 days prior to challenge until 28 days after inoculation, or confirmation of N. gonorrhoeae challenge strain eradication, whichever is later 10. Use of 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 inoculation. Use of vitamin supplements taken at standard doses is allowed. 11. Known hypersensitivity or other contraindications to the use of cephalosporins, carbapenems or macrolides (including treatment with other medications that are contraindicated with ceftriaxone, azithromycin, and ertapenem and these antimicrobials and cannot be safely withheld), or anaphylaxis to penicillins. 12. Known hypersensitivity to soya protein 13. History of severe infectious disease including i) requirement for hospitalization for intravenous antibiotics; ii) prior N. meningitidis infection such as meningococcal meningitis or meningococcal bacteraemia; iii) ocular or disseminated gonococcal infection (DGI) 14. Significant acute or chronic infection within 14 days prior to inoculation that the Investigator deems may compromise participant safety 15. A history of confirmed N. gonorrhoeae infection at any other site (urogenital, anorectal or oropharyngeal) in the three months prior to challenge, including at screening or pre-enrolment testing 16. Any use of gonococcal-active antimicrobial therapy in the three months prior to challenge (including cephalosporins, carbapenems or macrolides) 17. Prior history of Neisseria meningitidis serogroup B (e.g. 4CMenB) vaccination at any time 18. Any vaccination within the 28 days prior to challenge 19. History or presence of current alcohol abuse (defined as regular alcohol consumption of more than 40g per day), illicit drug use, or any prior intravenous usage of an illicit substance 20. A current active smoker defined as having smoked a cigarette or cigar in the four weeks prior to challenge, or an ex-smoker with a more than 10 pack year smoking history 21. Occupational, household or intimate contact with immunocompromised individuals (including HIV infection, asplenia, malignancy, recurrent, severe infections and chronic immunosuppressant medication within the past 6 months) 22. Occupational or household contact with individuals below 18 years of age 23. Residence in unstable or emergency housing 24. Any employee of the sponsor or research site personnel directly affiliated with this study or their immediate family members defined as spouse, parent, sibling or child whether biologic or legally adopted 25. Participation in another research study involving an investigational product or other intervention within 12 weeks prior to enrolment, at any time during the study and up to 12 weeks after completion of the study 26. Participation in a research study that involves blood sampling of more than 450ml/unit of blood, received or donated blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation within three months before study, plans for donation at any time during the study and up to three months after the last blood test 27. Intolerance of throat swab procedure (exaggerated gag reflex) 28. Any clinically significant abnormal finding on laboratory screening investigations, with specific exclusion criteria including: • Serum creatinine level above 1.1x upper limit of normal (ULN) and deemed clinically significant by the Investigator or delegated study clinician • Serum ALT level above 1.25x ULN and deemed clinically significant by the Investigator or delegated study clinician • White blood count (WBC) below 2.5 or above 15.0 x 109/L and deemed clinically significant by the study Investigator or delegated study clinician • Haemoglobin level below 11.0 g/dl or above ULN and deemed clinically significant by the study Investigator or delegated study clinician • C3 or C4 level below LLN or complement function test outside normal limits • Positive serologic results for human immunodeficiency (HIV) antibodies, hepatitis B surface antigen (HBsAg), and/or hepatitis C virus (HCV) antibodies and positive PCR if Hepatitis C virus antibodies detected, syphilis serology (with evidence of active untreated infection as determined by the Investigator or delegated study clinician) • A positive urine drug test at screening or pre-enrolment (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 over the counter product which contained the detected drug) and the participant has a negative urine drug screen on repeat testing • A positive alcohol breath test at screening or pre-inoculation visits 29. Detection of N. meningitidis on oropharyngeal swab at screening or pre-enrolment testing 30. Any other 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
Outcome results
None listed