Bordetella Pertussis Colonisation Challenge Study

NCT03751514 | Unknown DMC

• 2 other identifiers: RHM MED139617/SC/0006
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

This is a prospective controlled human challenge study consisting of two phases; Phase A: Development of a B. pertussis human challenge model; pilot to establish the standard inoculum Phase B: Development of a modified B. pertussis human challenge model

Conditions

Whooping Cough

Keywords

Bordetella Pertussis

Outcome Measures

Primary Outcomes (1)

• Phase A - Inoculum Dose Determination

  The inoculum dose required to cause the safe colonisation of 70% of volunteers who are challenged. A starting inoculum of 10\^3 bacteria will be used and incrementally increased until microbiologically proven Bp infection by positive culture of Bp from a nasopharyngeal swab (CFU/mL). Swabs are taken between time points day 0 and day 14 and compare with baseline.

  Up to volunteer visit Day 14

Secondary Outcomes (11)

• Phase A and B - Immune Responses to exposure to Bordetella pertussis

  Up to volunteer visit Week 52

• Phase A - Accuracy of Inoculum Dosing Evaluation

  Up to volunteer visit Day 7

• Phase A and B - Number of participants with Bp exposure-related adverse events as assessed by study specific adverse event grading system based on CTCAE v4.0

  Up to volunteer visit Day 365

• Phase A - Earliest Timepoint for Colonisation of the Nasopharynx

  Up to volunteer visit Day 14

• Phase A and B - Bacterial Dynamics after Challenge

  Up to volunteer visit Day 14

Study Arms (3)

Phase A - SI

EXPERIMENTAL

Phase A aims to determine a 'standard inoculum' dose (SI), which results in safe colonisation of 70% of volunteers. The SI will be identified in a dose escalating or de-escalating experiment commencing at 10-3 colony forming units B. pertussis administered intranasally. Each group of volunteers will be inoculated at half log-fold increasing/decreasing doses until the endpoint is reached. The experiment will be continued until the SI yields 10 subjects who are colonised at day 14. Intervention to be administered: Bordetella Pertussis B1917

Biological: Bordetella Pertussis B1917; Drug: Azithromycin 500 mg

Phase B Inoculum

EXPERIMENTAL

Phase B, using study data from phase A, will be used to design a more practical model - if possible conducted partially in an outpatient setting, which will be conditional on safety and transmission evidence. The final protocol for phase B will be presented as a protocol amendment, it will be based on the SI and colonisation period identified in Phase A. The SI determined in phase A will be used for all volunteers and eradication therapy will be given after the colonisation period based on the data of phase A. Approximately 30 individuals will receive the intranasal SI and will be treated with azithromycin for three days at the end of the colonisation period. Intervention to be administered: Bordetella Pertussis B1917

Biological: Bordetella Pertussis B1917; Drug: Azithromycin 500 mg

Phase B Sham

EXPERIMENTAL

Phase B, using study data from phase A, will be used to design a more practical model - if possible conducted partially in an outpatient setting, which will be conditional on safety and transmission evidence. Approximately 15 individuals will not receive the Bordetella Pertussis B1917, instead they will be given an intranasal sham of sterile saline and will be treated with azithromycin 500mg for three days at the end of the 'colonisation' period.

Drug: Azithromycin 500 mg; Other: Sterile Saline

Interventions

Bordetella Pertussis B1917 BIOLOGICAL

The B. pertussis isolate to be used in this human colonisation model is strain B1917, which is representative of current isolates in Europe. The strain, isolated in 2000 from a Dutch patient with B. pertussis disease, expresses Prn, PT and Filamentous Haemagglutinin (FHA). This strain has been extensively characterised in the mouse model as well as by proteomics and transcriptomics and has a closed genome available. It is fully sensitive to azithromycin in vitro. Providing there are no safety concerns the standard inoculum (SI) will be identified in a dose escalating or de-escalating experiment commencing at 103 colony forming units administered intranasally.

Also known as: Whooping cough bacteria

Phase A - SI; Phase B Inoculum

Azithromycin 500 mg DRUG

To ameliorate risk of transmission of B. pertussis B1917 to the environment and household contacts, Azithromycin 500 mg once a day for 3 days will be given to eradicate colonisation with B. pertussis. The inoculum strain is fully sensitive to this antibiotic. Previous studies show that azithromycin eradicates colonisation in 97% of people in 48 hours.

Also known as: Zithromax

Phase A - SI; Phase B Inoculum; Phase B Sham

Sterile Saline OTHER

To compare against B. pertussis, some volunteers will be enrolled onto the Sham arm. These volunteers will not receive B. pertussis but instead be given sterile saline

Also known as: Sham

Phase B Sham

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy adults aged 18 to 45 years inclusive on the day of screening
• Fully conversant in the English language
• Able to communicate easily by both mobile telephone and text messaging
• Able and willing (in the investigator's opinion) to comply with all study requirements
• Written informed consent to participate in the trial
• Willingness to take a curative antibiotic regimen after inoculation with B. pertussis according to the study protocol
• Agreement to be admitted to the National Institute for Health Research (NIHR)-Clinical research facility (CRF) Southampton for 17 days for phase A (from inoculation until two days after the eradication therapy is given) and for the duration necessary for phase B, depending on phase A results
• Able to answer all questions on the informed consent quiz correctly

You may not qualify if:

• Individuals who have inviolable commitments within 3 months of discharge from the inpatient phase of the study to make contact with:
• unimmunised or partially immunised children and infants aged \< 1 year
• pregnant women \>32 weeks who have not received pertussis vaccination at least a week prior to contact
• Individuals who have household contacts working with
• unimmunised or partially immunised children and infants aged \< 1 year
• pregnant women \>32 weeks who have not received pertussis vaccination at least a week prior to contact
• Phase A only: Volunteers will be excluded from this study if they have evidence of recent exposure to B. pertussis, as determined by anti-PT IgG ELISA (\>20 IU/mL)
• B. pertussis detected on nasopharyngeal swab taken before the challenge
• Individuals who have a signs of a current infection at the time of inoculation with B. pertussis
• Individuals who have participated in other interventional clinical trials in the last 12 weeks
• Individuals who have a history of receiving B. pertussis vaccination in the last 5 years
• Individuals who have a history of never being vaccinated against B. pertussis
• Current smokers defined as having had a cigarette/cigar in the last week.
• Use of systemic antibiotics within 30 days of or during the challenge
• Any confirmed or suspected immunosuppressive or immune-deficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (topical steroids are allowed)

Sponsors & Collaborators

• University of Southampton: lead
• Public Health England: collaborator
• University Hospital Southampton NHS Foundation Trust: collaborator

Study Sites (1)

NIHR Wellcome Trust Clinical Research Facility, Southampton General Hospital

Southampton, Hampshire, SO16 6YD, United Kingdom

RECRUITING

Related Publications (2)

• Diks AM, de Graaf H, Teodosio C, Groenland RJ, de Mooij B, Ibrahim M, Hill AR, Read RC, van Dongen JJ, Berkowska MA; IMI-2 PERISCOPE Consortium. Distinct early cellular kinetics in participants protected against colonization upon Bordetella pertussis challenge. J Clin Invest. 2023 Mar 1;133(5):e163121. doi: 10.1172/JCI163121.

  PMID: 36649086 DERIVED

• de Graaf H, Ibrahim M, Hill AR, Gbesemete D, Vaughan AT, Gorringe A, Preston A, Buisman AM, Faust SN, Kester KE, Berbers GAM, Diavatopoulos DA, Read RC. Controlled Human Infection With Bordetella pertussis Induces Asymptomatic, Immunizing Colonization. Clin Infect Dis. 2020 Jul 11;71(2):403-411. doi: 10.1093/cid/ciz840.

  PMID: 31562530 DERIVED

MeSH Terms

Conditions

Whooping Cough

Interventions

Azithromycin; salicylhydroxamic acid

Condition Hierarchy (Ancestors)

Bordetella Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Officials

• Robert C Read, MB MD FRCP

  University of Southampton

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hans de Graaf, MRCPCH

CONTACT

02381204989; H.De-Graaf@soton.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Human challenge study

Study Record Dates

• First Submitted: August 15, 2017
• First Posted: November 23, 2018
• Study Start: May 22, 2017
• Primary Completion: February 2, 2021
• Study Completion: February 2, 2021
• Last Updated: February 27, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)