Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001007325
Ethics application status
Approved
Date submitted
18/04/2017
Date registered
12/07/2017
Date last updated
13/10/2021
Date data sharing statement initially provided
13/10/2021
Date results information initially provided
13/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and Tolerability of Vaccination with Attenuated Hookworm Larvae in Healthy Volunteers
Scientific title
Safety and Tolerability of Vaccination with Attenuated Hookworm Larvae in Healthy Volunteers
Secondary ID [1] 291481 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hookworm infection 302696 0
Condition category
Condition code
Infection 302208 302208 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stage 1
A dose escalation study to define the dose of attenuated larvae for use in stage 2. Optimal dose defined as the number of larvae required to produce a grade 2-3 dermal reaction. Cohorts of 2 participants will be enrolled and receive a single inoculation with attenuated larvae and placebo (Tobasco sauce), via dermal application to the volar aspect of each forearm. Inoculation of participants will be sequential, with safety review (at day 3 post inoculation) before inoculation of the second participant. Cohorts will be enrolled until the desired dermal reaction is produced with safety review before dose escalation.

Cohort 1 and 2 will use 50 and 100 attenuated larvae respectively. Doses for use in future cohorts will be defined by the safety review team. 28 days following inoculation all participants will receive Albendazole (2 x 200mg tablets, PO on empty stomach). If a participant has no dermal reaction (implying no penetrating larvae) the participant may be enrolled in future cohorts. Once a participant has experienced a dermal reaction they are excluded from further participation.

Stage 2
This is a randomised controlled trial comparing vaccination to placebo in protecting against a challenge infection with normal hookworm larvae. Participants will be randomised 1:2 to receive either 2 doses of placebo (Tobasco sauce) or attenuated hookworm vaccine (dose defined in stage 1) via dermal application to the volar aspect of the forearm, 6 weeks apart. All participants will receive Albendazole 400mg (2 x 200mg tablets, PO on empty stomach) 4 weeks following both inoculations.

6 weeks following the second inoculation all participants will receive a challenge dose of 30 normal hookworm larvae by dermal application (15 larvae to each forearm). All participants will be administered Albendazole (2 x 200mg tablets, PO on empty stomach) at the termination of the study (week 11 of stage 2).
Intervention code [1] 297648 0
Prevention
Comparator / control treatment
In both stage 1 and stage 2 Tabasco sauce is used as the comparator. This simulates the itch associated with dermal penetration of hookworm larvae and has been used in previous studies.

Stage 1. Dose escalation study. Participants receive placebo to one arm and attenuated larvae to the other. Tabasco sauce is dermal application to the volar aspect of the forearm.

Stage 2. Placebo controlled trial. Participants receive either placebo or attenuated hookworm larvae. Both are dermally applied to the volar aspect of the forearm
Control group
Placebo

Outcomes
Primary outcome [1] 301621 0
Stage 1. Dermal Reaction.
Dermal reaction will be classified as grades 0-4 according to the size of erythema and induration present at the application site. (0 = <25mm, 1 = 25-50mm, 2 = 51 -100mm, 3 = > 100mm and 4 = Necrosis)
Timepoint [1] 301621 0
Stage 1: Participants will be reviewed at day 1, 3 and 28
Laboratory measurements will be collected at screening and day 28
Primary outcome [2] 302649 0
Stage 2: Safety and tolerability
Adverse effects of inoculation will be assessed by several means:
1. Clinical laboratory measurements
2. Vital signs recording
3. Self reported symptoms collected in a symptom diary
4. The use of a “Solicited Adverse Event Tool” which collects details of dermal, systemic and gastrointestinal symptoms
5. Physical examination by the PI
6. Clinical laboratory measurements
7. All adverse events will be graded using a protocol described grading system.
Timepoint [2] 302649 0
Stage 2:
Participants will be reviewed at day 1, 3, 28, 42, 45, 70, 84, 87, 112, 126 and 161
Laboratory measurements will be collected at screening, day 1, 28, 70, 84, 112 and 161
Safety reviews will occur within 24 hours of any SAE or at the discretion of the PI or IRB.
Secondary outcome [1] 333326 0
Stage 2 only. Faecal hookworm DNA
Timepoint [1] 333326 0
Faecal hookworm DNA will be assessed by qPCR from days 126-161 (10 weeks following challenge dose)

Eligibility
Key inclusion criteria
Participants will be males and non-pregnant, non-lactating females aged between 18 and 65 years.
Participants must have BMI within the range of 18-35 kg/m2 and weigh more than 50 kg.
Participants must understand the procedures involved and agree to participate in the study by giving fully informed, written consent prior to any study assessment.
Participants must be contactable and available for the duration of the clinical trial and be available for up to 2 months following completion of the trial.
Female volunteers of childbearing potential, should be irreversibly surgically sterile (tubal ligation) with or without hysterectomy at least 6 months ago or be using injectable, insertable, transdermal or combination oral contraceptive approved by the Therapeutic Goods Administration (TGA) combined with barrier contraception (female condom or male partners to use condom) through completion of the study and have negative urinary pregnancy tests prior to albendazole use. Menopausal participants (confirmed by follicle-stimulating hormone [FSH]) do not require contraception.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
History of Helminth infection (other than E. vermicularis) or travel to and residence (greater than 2 weeks) in areas of endemic transmission of these parasites.
History of atopy or severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion.
History of allergic reaction, anaphylaxis or otherwise to iodine, amphotericin, albendazole, chilli or other peppers, or Tabasco sauce.
Treatment with immune-modulating medications in the last 6 months.
Current iron deficiency anaemia.
Any vaccination in the last 30 days.
Heavily tattooed forearms

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
17/07/2017
Actual
25/09/2017
Date of last participant enrolment
Anticipated
1/08/2017
Actual
27/03/2018
Date of last data collection
Anticipated
4/09/2018
Actual
24/10/2018
Sample size
Target
21
Accrual to date
Final
22
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 295961 0
Charities/Societies/Foundations
Name [1] 295961 0
QIMR Berghofer
Country [1] 295961 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Rd
Herston QLD 4006
Country
Australia
Secondary sponsor category [1] 294848 0
None
Name [1] 294848 0
Address [1] 294848 0
Country [1] 294848 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297232 0
QIMR Berghofer Human Research Ethics Committee
Ethics committee address [1] 297232 0
300 Herston Rd, Herston Qld 4006
Ethics committee country [1] 297232 0
Australia
Date submitted for ethics approval [1] 297232 0
15/02/2017
Approval date [1] 297232 0
21/04/2017
Ethics approval number [1] 297232 0

Summary
Brief summary
This is a stage 1b placebo controlled clinical trial investigating the safety and tolerability of an attenuated live hookworm vaccine. The study will be performed in two parts.

Stage 1.
The degree to which attenuation will impede the larvae’s ability to penetrate the skin in vivo is unknown.
This is a dose escalation stage performed to de ne the optimal dose to be used in stage 2.
The dose in cohort 1 will be 50 attenuated larvae dermaly applied to the volar aspect of the forearm, approximately 4 inches proximal to the thumb. Dose escalation will occur after safety review following completion of cohort 1.
Cohort 2 will consist of 100 attenuated hookworm larvae applied in the same way. The optimal dose is defined as the number of larvae required to produce a grade 2 -3 dermal reaction.

Cohorts of two participants will be enrolled and inoculated sequentially with attenuated hookworm. Safety and tolerability data will be collected and used to guide the escalation of dose for use in the next cohort.

STAGE 2 Pilot randomised control trial 15 participants will be randomly assigned 1:2 to receive either 2 doses of placebo or attenuated larvae via dermal application 6 weeks apart. Albendazole will be administered 4 weeks following each inoculation. 6 weeks following the second dose all participants will receive a challenge dose of 30 normal hookworm larvae (15 larvae dermaly applied to each forearm).

Albendazole 400mg (200mg tablets, Zentel – Glaxo-Smith-Kline) will be administered at the termination of the studyat week 11.
Outcomes measured will include adverse events, faecal hookworm egg content and immune response
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 73402 0
Dr Paul Chapman
Address 73402 0
QIMR Berghofer Medical Research Institute
300 Herston rd, Herston QLD 4006
Country 73402 0
Australia
Phone 73402 0
+61 423 087 285
Fax 73402 0
Email 73402 0
p.chapmail@gmail.com
Contact person for public queries
Name 73403 0
Dr Paul Chapman
Address 73403 0
QIMR Berghofer Medical Research Institute
300 Herston rd, Herston QLD 4006
Country 73403 0
Australia
Phone 73403 0
+61 423 087 285
Fax 73403 0
Email 73403 0
p.chapmail@gmail.com
Contact person for scientific queries
Name 73404 0
Dr Paul Chapman
Address 73404 0
QIMR Berghofer Medical Research Institute
300 Herston rd, Herston QLD 4006
Country 73404 0
Australia
Phone 73404 0
+61 423 087 285
Fax 73404 0
Email 73404 0
p.chapmail@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
SourceTitleYear of PublicationDOI
EmbaseVaccination of human participants with attenuated Necator americanus hookworm larvae and human challenge in Australia: a dose-finding study and randomised, placebo-controlled, phase 1 trial.2021https://dx.doi.org/10.1016/S1473-3099%2821%2900153-5
EmbaseControlled human infection models to evaluate schistosomiasis and hookworm vaccines: where are we now?.2021https://dx.doi.org/10.1080/14760584.2021.1951244
N.B. These documents automatically identified may not have been verified by the study sponsor.