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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
28/11/2018
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] 292080 0
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
303331 0
infection 303503 0
Condition category
Condition code
Metabolic and Endocrine 302765 302765 0 0
Diabetes
Infection 302919 302919 0 0
Studies of infection and infectious agents
Metabolic and Endocrine 302920 302920 0 0
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] 298100 0
Prevention
Intervention code [2] 298222 0
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] 302150 0
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] 302150 0
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] 334970 0
Changes in Insulin Sensitivity from Blood Pathology taken at each particpant contact point during the 24 month trial
Timepoint [1] 334970 0
Measured at 6 months, 12 months, 18 months and 24 months
Secondary outcome [2] 335606 0
Change in BMI measured by any alteration in Body Mass (kg) as measured by weight scales relative to height.
Timepoint [2] 335606 0
Measured at 6 months, 12 months, 18 months and 24 months
Secondary outcome [3] 335607 0
Change in Waist Circumference (cm) measured by tape measure
Timepoint [3] 335607 0
Measured at 6 months, 12 months, 18 months and 24 months
Secondary outcome [4] 335608 0
Change in baterial richness of microbiome measure by shotgun assay of faecal sample
Timepoint [4] 335608 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Pregnancy, tobacco smoking, 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
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 8028 0
Cairns Base Hospital - Cairns
Recruitment postcode(s) [1] 16014 0
4870 - Cairns
Recruitment postcode(s) [2] 16015 0
4878 - Smithfield

Funding & Sponsors
Funding source category [1] 296481 0
University
Name [1] 296481 0
James Cook University
Address [1] 296481 0
PO Box 6811
Building D3
Smithfield University Campus
Smithfield
Cairns
Queensland
4878
Country [1] 296481 0
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] 295559 0
None
Name [1] 295559 0
Address [1] 295559 0
Country [1] 295559 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297703 0
James Cook University Research Ethics Commitee
Ethics committee address [1] 297703 0
PO Box 6811
Building D3
James Cook University
Smithfield Campus
Cairns
4878
Queensland
Ethics committee country [1] 297703 0
Australia
Date submitted for ethics approval [1] 297703 0
01/03/2017
Approval date [1] 297703 0
01/05/2017
Ethics approval number [1] 297703 0
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 74886 0
Prof Robyn McDermott
Address 74886 0
PO Box 6811
Building D3
Smithfield University Campus
James Cook University
Cairns
Queensland
Smithfield 4878
Country 74886 0
Australia
Phone 74886 0
+ 61 (7) 4232 1575
Fax 74886 0
Email 74886 0
robyn.mcdermott@jcu.edu.au
Contact person for public queries
Name 74887 0
Prof Robyn McDermott
Address 74887 0
PO Box 6811
Building D3
Smithfield University Campus
James Cook University
Cairns
Smithfield 4878
Queensland
Country 74887 0
Australia
Phone 74887 0
+ 61 (7) 4232 1575
Fax 74887 0
Email 74887 0
robyn.mcdermott@jcu.edu.au
Contact person for scientific queries
Name 74888 0
Prof Robyn McDermott
Address 74888 0
PO Box 6811
Building D3
Smithfield University Campus
James Cook University
Cairns
Smithfield 4878
Queensland
Country 74888 0
Australia
Phone 74888 0
+ 61 (7) 4232 1575
Fax 74888 0
Email 74888 0
robyn.mcdermott@jcu.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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?
Study protocol
Clinical study report
Summary results
Not applicable