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A Clinical Study to Develop a Controlled Human Infection Model Using Leishmania Major-infected Sand Flies (LEISHChallenge)

Primary Purpose

Leishmaniasis, Cutaneous Leishmaniases, Insect Bites

Status

Active

Phase

Not Applicable

Locations

United Kingdom

Study Type

Interventional

Intervention

biting by Phlebotomus duboscqi infected with Leishmania major

About this trial

This is an interventional other trial for Leishmaniasis focused on measuring Leishmaniasis, Cutaneous Leishmaniases, Controlled Human Infection Model, Human Challenge, Sand Fly, Phlebotomus

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Healthy adults aged 18 to 50 years on the day of screening
Willing to give consent for exposure to Leishmania-infected sand fly with the intention of causing a cutaneous leishmaniasis lesion
Willing and able to give written informed consent
Willing to undergo Hepatitis B, Hepatitis C & HIV testing
Willing to undergo a pregnancy test during screening and follow-up visits and must not be breastfeeding
Willing to refrain from blood donation during the study
Using a reliable and effective form of contraception (pre-menopausal female participants)
Judged, in the opinion of a medically qualified Clinical Investigator, to be able and likely to comply with all study requirements as set out in the protocol
Without any other significant health problems as determined by medical history, physical examination, results of screening tests and the clinical judgment of a medically qualified Clinical Investigator
Available for the duration of the study
Willing to refrain from travel to regions where Leishmania-transmitting sand flies are present, from recruitment until an appropriate point (judged by study investigators).
Willing to consent to a copy of the past medical history to be provided by the participants GP (General Practitioner) practice.
Agree to registration on a national database of study & trial subjects to prevent over-volunteering (TOPS)
Willing to give consent for study investigators to contact the participants GP in the event of a significant abnormality being observed
Willing to show identification documents to confirm identity
Willing to give consent to biopsy(s) of suspected cutaneous leishmaniasis lesions

Exclusion Criteria:

Receipt of any vaccine within 21 days of screening
Administration of immunoglobulins and/or any blood products within the three months preceding the planned study.
History of significant allergic disease/atopy (e.g. eczema, hay fever, asthma) or reactions; or a history of severe or multiple allergies to drugs or pharmaceutical agents, as judged by the clinical investigators
Any significant chronic skin condition as judged by the clinical investigators
Any history of confirmed Leishmaniasis infection
Any history of travel within the last 30 days to regions where Leishmania major-transmitting sand flies are endemic*.
Any history of more than 30 continuous days stay in regions where Leishmania major-transmitting sand flies are endemic within the last 10 years*.
Any history of severe local or general reaction to insect bites, defined as
Local: extensive, indurated redness and swelling involving most of the antero-lateral thigh or the major circumference of the arm, not resolving within 72 hours
General: fever ≥ 39.5°C, anaphylaxis, bronchospasm, laryngeal oedema, collapse, convulsions or encephalopathy within 48 hours
Any history of anaphylaxis
Females - current pregnancy, less than 12 weeks postpartum, lactating or willingness/intention to become pregnant during the study.
Any clinically significant abnormal finding on screening biochemistry or haematology blood tests as judged by study investigators
Total IgE (immunoglobulin E) levels > 214 IU/ml
Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months
A diagnosis of diabetes type 1 or type 2 or significantly raised HbA1c (>48mmol/mol)
Active Tuberculosis, leprosy, or malnutrition
Any significant chronic illness requiring hospital specialist input as judged by study investigators
Any significant psychiatric conditions as judged by general practitioner and/or study clinical team
Unlikely to comply with the study protocol
Participating in significant current or recent research (involving an investigational medicinal product or other significant intervention) within the past 3 months (as judged by study investigators)
Any other significant disease, disorder, finding or medical history, which, in the opinion of a medically qualified Clinical Investigator, may either put the participant at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study

Sites / Locations

Translational Research Facility, Department of Biology, University of York

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Leishmania infected-Phlebotomus duboscqi human challenge

Arm Description

There is no clear indication in the medical literature to determine which of the major sand fly vectors of Leishmania major - Phlebotomus papatasi or Phlebotomus duboscqi, will be most effective at transmitting infection to a human host. Both species have a similar mode of feeding and can support L. major development. In our previous study, FLYBITE, no significant difference in biting rates on humans was observed. Based on pre-clinical data , Phlebotomus duboscqi was determined to be the lead candidate for use in this study. If all the 6 participants have developed lesions within the 6-month follow up after Leishmania challenge, the challenge phase of the study is completed. If only 5 participants have developed lesions, then a further 6 participants will undergo Leishmania challenge by P. duboscqi. If only 4 or less subjects in the first cohort develop lesions, then the investigators will switch vector to P. papatasi and a further 6 subjects will undergo Leishmania challenge.

Outcomes

Primary Outcome Measures

The take rate of parasitologically confirmed cutaneous leishmaniasis lesions in study subjects

As the purpose is to develop a Controlled Human Infection Model with a high take rate, and as curative interventions will be carried out very early in the disease course, the P. duboscqi sand fly infected by Leishmania major has been chosen for the first six eligible and consented volunteers. The investigators will assess the 'take rate', that is the number of subjects developing parasitologically confirmed cutaneous leishmaniasis (PCCL) lesions. If 6/6 subjects develop PCCL lesions no further recruitment will take place; if only < 6 subjects develop PCCL lesions, then the investigators will follow an adaptive design.

Determine rate of adverse events, determined by data collection through history, clinical examination & blood tests.

The development of any study-associated serious adverse events or grade 3 adverse events at day 3 post-biting will result in a temporary halt and review of the sand fly biting schedule. Therefore the investigators will review the safety outcomes 3 days after all biting procedures in real time for each pair of subjects. Successful treatment of cutaneous leishmaniasis lesions in participants, and absence of lesions at 1 year follow up.

Secondary Outcome Measures

Determine rate of cutaneous leishmaniasis lesion development following infected sand fly bite

As determined by clinical examination, then biopsy and parasitological confirmation

Determine response to Leishmania major-infected sand fly bite in terms of immunohistology and immunopathology

Analysis of immune and inflammatory response (for example macrophage and T cell phenotype) and histology compatible with CL.

Determine parasite load in cutaneous leishmaniasis lesions in comparison to number of sand fly bites received and rate of lesion development

By polymerase chain reaction (PCR) analysis of biopsy tissue of lesion site

Determine acceptance and psychological impact of Leishmania major-infected sand fly challenge

Using psychometric questionnaires and focus groups

Full Information

NCT ID

NCT04512742

First Posted

August 11, 2020

Last Updated

October 28, 2022

Sponsor

University of York

Collaborators

Medical Research Council, Department for International Development, United Kingdom

1. Study Identification

Unique Protocol Identification Number

NCT04512742

Brief Title

A Clinical Study to Develop a Controlled Human Infection Model Using Leishmania Major-infected Sand Flies

Acronym

LEISHChallenge

Official Title

A Clinical Study to Develop a Controlled Human Infection Model Using Leishmania Major-infected Sand Flies

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

October 16, 2021 (Actual)

Primary Completion Date

November 2022 (Anticipated)

Study Completion Date

November 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of York

Collaborators

Medical Research Council, Department for International Development, United Kingdom

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The disease leishmaniasis mainly occurs in hot and tropical countries, affects millions of people and causes around 20,000 deaths across the world every year. Leishmaniasis is caused by the Leishmania parasite and is transmitted by sand flies. The parasite is tiny and not visible to the naked eye, whereas the sand fly is visible but small and inconspicuous. There are different types of leishmaniasis which can affect the skin (cutaneous leishmaniasis) or the internal organs of the body (visceral leishmaniasis). Some of the milder forms will produce skin problems which will be localised, whilst other forms of leishmaniasis will cause widespread skin changes. The skin lesions of cutaneous leishmaniasis can be disfiguring if left untreated. There are some treatments for leishmaniasis but many of them are not easy to use or don't work well. Therefore, new treatments are needed including vaccines that prevent or work against leishmaniasis. A solution being adopted for other diseases, which the investigators now wish to adopt for leishmaniasis is to develop a 'Controlled human infection model' (CHIM). These models involve deliberate exposure of individuals to an infection, in order to better understand how the disease works and to test potential vaccines and treatments. They have contributed knowledge that has led to advances in the development of treatments. This is study builds on an our initial successful study, FLYBITE, where uninfected (disease-free) sand flies were used to test the safety aspects and ensure that sand flies were able to bite human participants in a controlled environment. The investigators observed no major adverse effects and it was well tolerated by participants. The investigators therefore wish to proceed to a study using sand flies infected with a form of leishmaniasis that causes localised skin disease and is treatable, on the pathway to assessing future vaccines.

Detailed Description

This is a clinical study in up to twelve healthy Leishmania-naïve subjects aged between 18 and 50 years old who develop a confirmed sand fly bite. Initially six subjects will be studied and exposed to biting by Phlebotomus duboscqi infected by Leishmania major. An adaptive design will be used, that has been pragmatically designed to minimise unnecessary exposure of volunteers to Leishmania and maximise the likelihood of developing a reproducible Controlled Human Infection Model. The primary objective is the development of a controlled human infection model of Leishmania major using sand fly transmission which is (a) effective and (b) safe. The first six subjects will be exposed to biting by Phlebotomus duboscqi (sand fly species) infected by Leishmania major (species of leishmaniasis causing cutaneous, ie skin disease) and assess the 'take rate', that is the number of subjects developing parasitologically confirmed cutaneous leishmaniasis (PCCL) lesions. If 6/6 subjects develop PCCL lesions no further recruitment will take place; if only < 6 subjects develop PCCL lesions, then an adaptive design will be followed. This study is based on an initial study, entitled FLYBITE (clinicaltrials.gov identifier: NCT03999970). the FLYBITE study was a clinical study to develop a sand fly biting protocol using pathogen-free blood-fed sand flies. Twelve healthy participants were enrolled into the study and all 12 participants experienced at least one successful sand fly bite.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leishmaniasis, Cutaneous Leishmaniases, Insect Bites

Keywords

Leishmaniasis, Cutaneous Leishmaniases, Controlled Human Infection Model, Human Challenge, Sand Fly, Phlebotomus

7. Study Design

Primary Purpose

Other

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Model Description

Controlled human infection study, with an adaptive design. The first six subjects will be exposed to biting by Phlebotomus duboscqi infected by Leishmania major and assess the 'take rate', that is the number of subjects developing parasitologically confirmed cutaneous leishmaniasis (PCCL) lesions. If 6/6 subjects develop PCCL lesions no further recruitment will take place; if only < 6 subjects develop PCCL lesions, then an adaptive design will be followed as described elsewhere.

Masking

None (Open Label)

Allocation

N/A

Enrollment

14 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Leishmania infected-Phlebotomus duboscqi human challenge

Arm Type

Other

Arm Description

Intervention Type

Other

Intervention Name(s)

biting by Phlebotomus duboscqi infected with Leishmania major

Intervention Description

The first six subjects will be exposed to biting by Phlebotomus duboscqi infected by Leishmania major and assess the 'take rate', that is the number of subjects developing parasitologically confirmed cutaneous leishmaniasis (PCCL) lesions. If 6/6 subjects develop PCCL lesions no further recruitment will take place; if only < 6 subjects develop PCCL lesions, then an adaptive design will be followed.

Primary Outcome Measure Information:

Title

The take rate of parasitologically confirmed cutaneous leishmaniasis lesions in study subjects

Description

Time Frame

1 year

Title

Determine rate of adverse events, determined by data collection through history, clinical examination & blood tests.

Description

Time Frame

1 year

Secondary Outcome Measure Information:

Title

Determine rate of cutaneous leishmaniasis lesion development following infected sand fly bite

Description

As determined by clinical examination, then biopsy and parasitological confirmation

Time Frame

1 year

Title

Determine response to Leishmania major-infected sand fly bite in terms of immunohistology and immunopathology

Description

Analysis of immune and inflammatory response (for example macrophage and T cell phenotype) and histology compatible with CL.

Time Frame

1 year

Title

Determine parasite load in cutaneous leishmaniasis lesions in comparison to number of sand fly bites received and rate of lesion development

Description

By polymerase chain reaction (PCR) analysis of biopsy tissue of lesion site

Time Frame

1 year

Title

Determine acceptance and psychological impact of Leishmania major-infected sand fly challenge

Description

Using psychometric questionnaires and focus groups

Time Frame

1 year

Other Pre-specified Outcome Measures:

Title

Exploratory objectives

Description

In the case of a ≤66% take rate of Leishmania major with Phlebotomus duboscqi, to evaluate the take rate using Phlebotomus papatasi. To deep phenotype and compare CL and normal skin biopsies, in those who agree to donate such, using digital spatial profiling of host and parasite mRNA and protein expression, and mass spectroscopy imaging. To determine human reactogenicity to Leishmania major-infected sand fly bite in macroscopic, dermoscopic, immunological and biochemical terms

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Healthy adults aged 18 to 50 years on the day of screening Willing to give consent for exposure to Leishmania-infected sand fly with the intention of causing a cutaneous leishmaniasis lesion Willing and able to give written informed consent Willing to undergo Hepatitis B, Hepatitis C & HIV testing Willing to undergo a pregnancy test during screening and follow-up visits and must not be breastfeeding Willing to refrain from blood donation during the study Using a reliable and effective form of contraception (pre-menopausal female participants) Judged, in the opinion of a medically qualified Clinical Investigator, to be able and likely to comply with all study requirements as set out in the protocol Without any other significant health problems as determined by medical history, physical examination, results of screening tests and the clinical judgment of a medically qualified Clinical Investigator Available for the duration of the study Willing to refrain from travel to regions where Leishmania-transmitting sand flies are present, from recruitment until an appropriate point (judged by study investigators). Willing to consent to a copy of the past medical history to be provided by the participants GP (General Practitioner) practice. Agree to registration on a national database of study & trial subjects to prevent over-volunteering (TOPS) Willing to give consent for study investigators to contact the participants GP in the event of a significant abnormality being observed Willing to show identification documents to confirm identity Willing to give consent to biopsy(s) of suspected cutaneous leishmaniasis lesions Exclusion Criteria: Receipt of any vaccine within 21 days of screening Administration of immunoglobulins and/or any blood products within the three months preceding the planned study. History of significant allergic disease/atopy (e.g. eczema, hay fever, asthma) or reactions; or a history of severe or multiple allergies to drugs or pharmaceutical agents, as judged by the clinical investigators Any significant chronic skin condition as judged by the clinical investigators Any history of confirmed Leishmaniasis infection Any history of travel within the last 30 days to regions where Leishmania major-transmitting sand flies are endemic*. Any history of more than 30 continuous days stay in regions where Leishmania major-transmitting sand flies are endemic within the last 10 years*. Any history of severe local or general reaction to insect bites, defined as Local: extensive, indurated redness and swelling involving most of the antero-lateral thigh or the major circumference of the arm, not resolving within 72 hours General: fever ≥ 39.5°C, anaphylaxis, bronchospasm, laryngeal oedema, collapse, convulsions or encephalopathy within 48 hours Any history of anaphylaxis Females - current pregnancy, less than 12 weeks postpartum, lactating or willingness/intention to become pregnant during the study. Any clinically significant abnormal finding on screening biochemistry or haematology blood tests as judged by study investigators Total IgE (immunoglobulin E) levels > 214 IU/ml Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months A diagnosis of diabetes type 1 or type 2 or significantly raised HbA1c (>48mmol/mol) Active Tuberculosis, leprosy, or malnutrition Any significant chronic illness requiring hospital specialist input as judged by study investigators Any significant psychiatric conditions as judged by general practitioner and/or study clinical team Unlikely to comply with the study protocol Participating in significant current or recent research (involving an investigational medicinal product or other significant intervention) within the past 3 months (as judged by study investigators) Any other significant disease, disorder, finding or medical history, which, in the opinion of a medically qualified Clinical Investigator, may either put the participant at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Charles Lacey, BMBS, MD

Organizational Affiliation

University of York

Official's Role

Principal Investigator

Facility Information:

Facility Name

Translational Research Facility, Department of Biology, University of York

City

York

State/Province

North Yorkshire

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

34053461

Citation

Parkash V, Jones G, Martin N, Steigmann M, Greensted E, Kaye P, Layton AM, Lacey CJ. Assessing public perception of a sand fly biting study on the pathway to a controlled human infection model for cutaneous leishmaniasis. Res Involv Engagem. 2021 May 30;7(1):33. doi: 10.1186/s40900-021-00277-y.

Results Reference

derived

Links:

URL

https://leishchallenge.org/

Description

Project Website

Learn more about this trial

A Clinical Study to Develop a Controlled Human Infection Model Using Leishmania Major-infected Sand Flies

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