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Trial registered on ANZCTR

Registration number

ACTRN12617000818336

Ethics application status

Approved

Date submitted

29/05/2017

Date registered

5/06/2017

Date last updated

10/11/2020

Date data sharing statement initially provided

28/11/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Safety and tolerability of experimental hookworm infection in humans with metabolic disease

Scientific title

Safety and tolerability of experimental hookworm infection in humans with metabolic disease: Proof of Concept (Phase 1b) clinical trial

Secondary ID [1]

nil known

Universal Trial Number (UTN)

U1111-1196-6430

Trial acronym

WAM

Linked study record

Health condition

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

Diabetes

infection

Condition category

Condition code

Metabolic and Endocrine

Diabetes

Infection

Studies of infection and infectious agents

Metabolic and Endocrine

Metabolic disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Randomised, double-blind, placebo controlled Phase 1b safety and tolerability trial in otherwise healthy adults aged 18-50 with central obesity (waist circumference (WC) >90cm for females, >102 cm for males) and features of MetS (either abnormal TG/HDL cholesterol, BP>=135/85, raised fasting BSL) experimentally infected with 20 or 40 larvae of the human hookworm Necator americanus (20 L3, 40 L3) over 24 months. There will be 3 arms (n=15 receiving 20 L3 dose, n=15 receiving 40 L3 dose and n=15 controls receiving Tabasco sauce placebo).
Inoculation occurs twice at week 0 and week 8. Inoculation involves direct skin administration of 200ul of solution containing either treatment or placebo. Confirmation of infection occurs at week 26 via faecal sample.

Intervention code [1]

Prevention

Intervention code [2]

Treatment: Other

Comparator / control treatment

There will be 3 arms (n=15 receiving 20 L3 dose, n=15 receiving 40 L3 dose and n=15 controls receiving Tabasco sauce placebo).

Control group

Placebo

Outcomes

Primary outcome [1]

The primary, composite outcome will be the safety of experimental inoculation of participants with 20 L3, defined by (a) Number of reported adverse events (AEs), relative to placebo cohort, (b) Assessment of general health and (c) Successful completion of 24 month trial. Adverse reaction could include, but are not limited to, abdominal pain, rash, fever, weight loss, fatigue, nausea. These will be assessed by the trial Doctor as being mild, moderate or severe following clinical examination either by interview in person with trial participant or via phone/internet communication. These adverse events will be documented during each participant contact on the data collection database being maintained with all study data.

Timepoint [1]

At completion of the 24 month trial. Participants will have direct contact with researchers at weeks -6, -4, 0 and 8, and at 6 months, 12 months, 18 months and 24 months. These contact points will be face to face, and the participants will undergo medical examination and questionaire completion.

Secondary outcome [1]

Changes in Insulin Sensitivity from Blood Pathology taken at each particpant contact point during the 24 month trial

Timepoint [1]

Measured at 6 months, 12 months, 18 months and 24 months

Secondary outcome [2]

Change in BMI measured by any alteration in Body Mass (kg) as measured by weight scales relative to height.

Timepoint [2]

Measured at 6 months, 12 months, 18 months and 24 months

Secondary outcome [3]

Change in Waist Circumference (cm) measured by tape measure

Timepoint [3]

Measured at 6 months, 12 months, 18 months and 24 months

Secondary outcome [4]

Change in baterial richness of microbiome measure by shotgun assay of faecal sample

Timepoint [4]

Samples taken for analysis at 6 months, 12 months 18 months and 24 months

Eligibility

Key inclusion criteria

Healthy adults 18-50 years, with central obesity (WC>90cm for females and >102 cm for males) and increased insulin resistance as assessed via abnormal homeostatic model assessment of insulin resistance (HOMA-IR), i.e. HOMA-IR > 2.12 or at least two other features of MetS: elevated blood pressure >135/85 mmHg, dyslipidaemia, or abnormal liver function test suggesting fatty liver disease. Have provided written informed consent and are willing to comply with all Protocol scheduled visits. If of childbearing potential, must be willing to use the acceptable methods of contraception.

Minimum age

18 Years

Maximum age

50 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Pregnancy, established chronic disease (CVD, diabetes, cancer, renal, gut disorder), history of substance abuse or current substance abuse, major allergies, known immunodeficiency disorder, asthma, taking prescribed medications or nutritional supplements likely to interfere with study outcomes, inability to provide informed consent

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Double Blinded, sealed envelopes and containers

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Block randomisation

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 1

Type of endpoint/s

Safety

Statistical methods / analysis

The safety of the hookworm infection, the primary outcome, will be assessed by using a chi-squared test of proportions to determine whether there are differences in the proportions satisfying the safety criteria between the placebo, 20 L3 and 40 L3 hookworm groups. Cox regression models will assess safe progression through the study in each cohort. We will perform standard descriptive statistics on all outcome measures at baseline, all interim points of assessment and at 24 months after inoculation (categorical variables: absolute and relative frequencies; numerical variables: mean and SD or median and IQR). Of particular interest will be changes in weight, visceral fat mass (DXA), insulin sensitivity (HOMA-IR) and adiponectin.

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

7/06/2017

Actual

1/03/2018

Date of last participant enrolment

Anticipated

Actual

9/12/2019

Date of last data collection

Anticipated

31/03/2022

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Cairns Base Hospital - Cairns

Recruitment postcode(s) [1]

4870 - Cairns

Recruitment postcode(s) [2]

4878 - Smithfield

Recruitment postcode(s) [3]

4811 - James Cook University

Funding & Sponsors

Funding source category [1]

University

Name [1]

James Cook University

Address [1]

PO Box 6811
Building D3
Smithfield University Campus
Smithfield
Cairns
Queensland
4878

Country [1]

Australia

Primary sponsor type

University

Name

James Cook University

Address

PO Box 6811
Building D3
Smithfield University Campus
Cairns
Queensland
4878

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

James Cook University Research Ethics Commitee

Ethics committee address [1]

PO Box 6811
Building D3
James Cook University
Smithfield Campus
Cairns
4878
Queensland

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/03/2017

Approval date [1]

01/05/2017

Ethics approval number [1]

APP1143102

Summary

Brief summary

Safety and tolerability of experimental hookworm infection in humans with metabolic disease: Proof of Concept (Phase 1b) clinical trial Aims:
1.	To establish the acceptability, safety and tolerability of experimental infection with the hookworm Necator americanus (Na) in young obese adults with features of the metabolic syndrome (MetS).
2.	Conduct exploratory studies into the impact of hookworms on stabilizing or improving immune/inflammatory, metabolic and microbiological parameters associated with metabolic disease
Background: Central obesity and subsequent type 2 diabetes (T2DM) are causing a global epidemic of disability and premature death which threatens to bankrupt health systems even in wealthy countries. The vast majority (80%) of all diabetes cases and 88% of deaths occur in low to middle income countries, many of which still have a significant infectious disease burden. T2DM and several associated chronic conditions are increasingly recognized as having common pro-inflammatory pathways and it is these effects which account for much end-organ damage, especially in the liver, muscle, kidneys, vascular endothelium and brain (Calle et al, 2012). Animal studies and more recently, human observational reports from those transitional populations with high prevalence of helminth exposure and metabolic illness, suggest that helminth infection protects against T2DM and MetS (Hayes, 2015; Tracey, 2016). A plausible biological pathway for this effect has been demonstrated in animal models, where helminth infection stimulates a T helper Type 2 (Th2)-type immune response that, in concert with worm-induced regulatory T cell responses may improve insulin sensitivity, either directly or via suppression of pro-inflammatory Th1/Th17 immune responses. There is evidence that this effect is mediated, at least in part, by changes induced by the worm to the host gut microbiota.
Members of the team (AL, PG) have established that experimental inoculation with the human hookworm Necator americanus is safe and efficacious in the treatment of humans with celiac disease (CeD), and which is currently in use in a NHMRC-funded multi-centre clinical trial (ref protocol, Croese 2016). Previous studies have demonstrated that these controlled hookworm infections are associated with a biased Type 2 cytokine response (Gaze at al 2012), with concomitant regulatory T cell responses (Croese et al 2015) that fit the profile of an agent that may be effective at treating the dysregulated inflammation associated with MetS or T2DM.
Thus, we propose to use this experimental human infection model in a proof-of-concept phase 1 trial of safety in healthy young adults with central obesity and features of the Metabolic Syndrome (MetS). 
Hypotheses: That experimental hookworm infection
1.	will be tolerated and safe in otherwise healthy obese young adults;
2.	will induce a biased Type 2 and regulatory immune response and suppression of systemic pro-inflammatory Type 1 immune responses

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Robyn McDermott

Address

PO Box 6811
Building D3
Smithfield University Campus
James Cook University
Cairns
Queensland
Smithfield 4878

Country

Australia

Phone

+ 61 (7) 4232 1575

Fax

robyn.mcdermott@jcu.edu.au

Contact person for public queries

Name

Robyn McDermott

Address

PO Box 6811
Building D3
Smithfield University Campus
James Cook University
Cairns
Smithfield 4878
Queensland

Country

Australia

Phone

+ 61 (7) 4232 1575

Fax

robyn.mcdermott@jcu.edu.au

Contact person for scientific queries

Name

Robyn McDermott

Address

PO Box 6811
Building D3
Smithfield University Campus
James Cook University
Cairns
Smithfield 4878
Queensland

Country

Australia

Phone

+ 61 (7) 4232 1575

Fax

robyn.mcdermott@jcu.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Individual data will be held in a secure database. Published data will be accessible but not accessible as individual data.

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

Source	Title	Year of Publication	DOI
Embase	Safety and tolerability of experimental hookworm infection in humans with metabolic disease: Study protocol for a phase 1b randomised controlled clinical trial.	2019	https://dx.doi.org/10.1186/s12902-019-0461-5
Embase	Immune System Investigation Using Parasitic Helminths.	2021	https://dx.doi.org/10.1146/annurev-immunol-093019-122827
Embase	Effect of experimental hookworm infection on insulin resistance in people at risk of type 2 diabetes.	2023	https://dx.doi.org/10.1038/s41467-023-40263-4

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

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