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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02754609
Registration number
NCT02754609
Ethics application status
Date submitted
26/04/2016
Date registered
28/04/2016
Titles & IDs
Public title
Hookworm Therapy for Coeliac Disease
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Scientific title
Hookworm Therapy for Coeliac Disease: A Phase 1B Safety and Dose-ranging Clinical Trial Examining Sustained Gluten Consumption in Hookworm-naive and Hookworm-infection People With Coeliac Disease
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Secondary ID [1]
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CT-2016-CTN-01363-1
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Universal Trial Number (UTN)
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Trial acronym
NainCeD-3
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Celiac Disease
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Condition category
Condition code
Infection
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Other infectious diseases
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Inflammatory and Immune System
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0
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Autoimmune diseases
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Oral and Gastrointestinal
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0
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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
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Human Genetics and Inherited Disorders
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0
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Other human genetics and inherited disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - Gluten micro-challenge
Other interventions - Inadvertent gluten challenge
Other interventions - Moderate gluten challenge
Other interventions - Liberal diet
Other interventions - Necator americanus-hookworm larvae L3-10
Other interventions - Tabasco® Sauce
Other interventions - Necator americanus-hookworm larvae L3-20
Other interventions - Gluten free diet
Experimental: Necator americanus-hookworm larvae L3-10 - A total of 40 participants week 0 and week 8 will have low dose hookworms present in 2-3 drops of water applied to their skin and then covered in a light dressing. The hookworms are Necator americanus-hookworm larvae L3; 10 L3 in 200 microliter (uL) of deionized water presented in an Eppendorf tube. All participants will undergo interventions of Gluten free diet, Gluten micro-challenge, Inadvertent gluten challenge and Moderate gluten challenge. At week 42, participants will have the option of going on the liberal diet.
Placebo comparator: Tabasco® Sauce - A total of 10 participants at week 0 and week 8 will have Tabasco® Sauce present in 2-3 drops of water applied to their skin and covered in a light dressing. Tabasco® Sauce is an ideal placebo as the sensation to the skin is similar to a hookworm. All participants will undergo interventions of Gluten free diet, Gluten micro-challenge, Inadvertent gluten challenge and Moderate gluten challenge.
Experimental: Necator americanus-hookworm larvae L3-20 - A total of 10 participants at week 0 and week 8 will have medium dose hookworms present in 2-3 drops of water applied to their skin and then covered in a light dressing. The hookworms are Necator americanus-hookworm larvae L3; 20 L3 in 200 uL of deionized water presented in an Eppendorf tube. All participants will undergo interventions of Gluten free diet, Gluten micro-challenge, Inadvertent gluten challenge and Moderate gluten challenge. At week 42, participants will have the option of going on the liberal diet.
Other interventions: Gluten micro-challenge
From week 12 to week 24, all participants will start a gluten micro-challenge from 10mg/day for the first 2 weeks escalating over the this period to 50mg/day at the end of week 24.
Other interventions: Inadvertent gluten challenge
From week 24 to week 36, all participants will be on gluten 50mg/day and 1g twice weekly.
Other interventions: Moderate gluten challenge
From week 36 to week 42, all participants will be on gluten 2g/day.
Other interventions: Liberal diet
From week 42, all participants will be unblinded and those who have received hookworm therapy have the option to go on a liberal diet of more than 10g of gluten/day from week 42 to week 94.
Other interventions: Necator americanus-hookworm larvae L3-10
A total of 40 participants at week 0 and week 8 will have hookworms L3-10 present in 2-3 drops of water applied to their skin and then covered in a light dressing.
Other interventions: Tabasco® Sauce
Arm: Placebo Comparator: Tabasco® Sauce A total of 10 participants at week 0 and week 8 will have Tabasco® Sauce present in 2-3 drops of water applied to their skin and covered in a light dressing
Other interventions: Necator americanus-hookworm larvae L3-20
A total of 40 participants at week 0 and week 8 will have hookworms L3-20 present in 2-3 drops of water applied to their skin and then covered in a light dressing.
Other interventions: Gluten free diet
From week 0 to week 12, all participants will be on a gluten free diet.
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Intervention code [1]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Safety of 30-week gluten challenge
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Assessment method [1]
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The primary outcome will be the safety of an escalating 30-week gluten challenge in hookworm naïve or hookworm infected people with CeD following a medium-high dose hookworm infection, assessed by the change of duodenal villous height to crypt depth ratio (V:C) between pre-trial (week -2) and post-challenge (week 42). This will be a binary variable defined as safe if gluten challenge is completed and V:C ratio \>2.0 and there is \<20% change in its value from baseline or fail if drop out occurs prior to the completion of the gluten challenge or V:C ratio is \<2.0 or its change from baseline is \>20%.
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Timepoint [1]
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44 weeks
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Secondary outcome [1]
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Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 42
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Assessment method [1]
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This secondary outcome is the mucosal intraepithelial lymphocyte count measured from tissue collected per-endoscopy comparing baseline (week -2) to week 42 to assess the safety of administrating hookworms vs placebo.
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Timepoint [1]
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14 weeks
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Secondary outcome [2]
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Difference in V:C ratio between baseline (week -2) and week 42
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Assessment method [2]
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This secondary outcome assesses the duodenal mucosal villous height to crypt depth ratio (V:C) measured from tissue collected per-endoscopy comparing baseline (week -2) to week 42 to assess the safety of administrating hookworms vs placebo.
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Timepoint [2]
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14 weeks
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Secondary outcome [3]
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Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 42
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Assessment method [3]
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This secondary outcome is the mucosal intraepithelial lymphocyte count measured from tissue collected per-endoscopy comparing baseline (week -2) to week 42 to assess the effect of medium level of gluten exposure in participants who have received placebo or L3-10 hookworms.
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Timepoint [3]
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38 weeks
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Secondary outcome [4]
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Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 36
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Assessment method [4]
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This secondary outcome is the mucosal intraepithelial lymphocyte count measured from tissue collected per-endoscopy comparing baseline (week -2) to week 36 to assess the effect of intermittent gluten in all participants.
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Timepoint [4]
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44 weeks
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Secondary outcome [5]
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Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 94
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Assessment method [5]
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This secondary outcome is the mucosal intraepithelial lymphocyte count measured from tissue collected per-endoscopy comparing baseline (week -2) to week 94 to assess the effect of a liberal diet in participants who have received hookworm L3-10 or L3-20 hookworms.
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Timepoint [5]
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96 weeks
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Secondary outcome [6]
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Difference in Celiac Symptom Index (CSI Questionnaire) between baseline (week 0) and week 36
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Assessment method [6]
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This secondary outcome is the analysis of the weekly CSI questionnaire from baseline (week 0) to week 36 to assess the effect of inadvertent gluten in all participants.
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Timepoint [6]
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36 weeks
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Secondary outcome [7]
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Difference in Celiac Symptom Index (CSI Questionnaire) between baseline (week 0) and week 42
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Assessment method [7]
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This secondary outcome is the analysis of the weekly CSI questionnaire from baseline (week 0) to week 42 to assess the effect of moderate gluten in all participants.
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Timepoint [7]
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42 weeks
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Secondary outcome [8]
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Difference in Celiac Symptom Index (CSI Questionnaire) between baseline (week 0) and week 94
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Assessment method [8]
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This secondary outcome is the analysis of the weekly CSI questionnaire from baseline (week 0) to week 42 to assess the effect of a liberal diet in participants who have received L3-10 or L3-20 hookworms.
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Timepoint [8]
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94 weeks
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Secondary outcome [9]
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Difference in Celiac-Quality of Life Score (QOL questionnaire) between baseline (week 0) and week 36
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Assessment method [9]
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This secondary outcome is the analysis of the QOL questionnaire from baseline (week 0) to week 36 to assess the effect of inadvertent gluten in all participants.
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Timepoint [9]
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36 weeks
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Secondary outcome [10]
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Difference in Celiac-Quality of Life Score (QOL questionnaire) between baseline (week 0) and week 42
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Assessment method [10]
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This secondary outcome is the analysis of the QOL questionnaire from baseline (week 0) to week 42 to assess the effect of moderate gluten in all participants.
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Timepoint [10]
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42 weeks
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Secondary outcome [11]
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Difference in Celiac-Quality of Life Score (QOL questionnaire) between baseline (week 0) and week 94
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Assessment method [11]
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This secondary outcome is the analysis of the QOL questionnaire from baseline (week 0) to week 94 to assess the effect of a liberal diet in participants who have received L3-10 or L3-20 hookworms.
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Timepoint [11]
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94 weeks
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Secondary outcome [12]
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Difference in Immunoglobulin A tissue transaminase (tTG) between baseline (week -4) and week 36
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Assessment method [12]
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This secondary outcome is the analysis of the Immunoglobulin A tissue transaminase (tTG) level measured in serum from baseline (week -4) to week 36 to assess the effect of inadvertent gluten in all participants.
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Timepoint [12]
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40 weeks
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Secondary outcome [13]
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Difference in Immunoglobulin A tissue transaminase (tTG) between baseline (week -4) and week 42
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Assessment method [13]
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This secondary outcome is the analysis of the Immunoglobulin A tissue transaminase (tTG) level measured in serum from baseline (week -4) to week 42 to assess the effect of moderate gluten in all participants.
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Timepoint [13]
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46 weeks
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Secondary outcome [14]
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Difference in Immunoglobulin A tissue transaminase (tTG) between baseline (week -4) and week 94
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Assessment method [14]
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The secondary outcome is the analysis of the Immunoglobulin A tissue transaminase (tTG) level measured in serum from baseline (week -4) to week 94 to assess the effect of a liberal diet in participants who have received L3-10 or L3-20 hookworms.
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Timepoint [14]
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98 weeks
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Secondary outcome [15]
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Difference in V:C ratio between baseline (week -2) and week 24
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Assessment method [15]
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This secondary outcome assesses the duodenal mucosal villous height to crypt depth ratio (V:C) measured from tissue collected per-endoscopy comparing baseline (week -2) to week 24 to assess the effect of trace gluten in participants who have received placebo or L3-10 hookworms.
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Timepoint [15]
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38 weeks
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Secondary outcome [16]
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Difference in V:C ratio between baseline (week -2) and week 94
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Assessment method [16]
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This secondary outcome assesses the duodenal mucosal villous height to crypt depth ratio (V:C) measured from tissue collected per-endoscopy comparing baseline (week -2) to week 94 to assess the effect of a liberal diet in participants who have received L3-10 or L3-20 hookworms.
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Timepoint [16]
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96 weeks
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Secondary outcome [17]
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Difference in V:C ratio between baseline (week -2) and week 12
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Assessment method [17]
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This secondary outcome assesses the duodenal mucosal villous height to crypt depth ratio (V:C) measured from tissue collected per-endoscopy comparing baseline (week -2) to week 12 to assess the safety of administrating L3-20 hookworms.
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Timepoint [17]
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14 weeks
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Eligibility
Key inclusion criteria
1. Has provided written informed consent and is willing to comply with all Protocol scheduled visits, treatment plan, laboratory tests, and other trial procedures and in the opinion of the Investigator has a good understanding of the Protocol, the length of the study and the demands of the study.
2. Aged between 18-80 (at time of consent);
3. Have a pre-treatment histological diagnosis of Marsh grade 3 CeD;
4. Have a pre-trial V:C >2.0;
5. Have elevated tTG or endomysial Ab +ve pre-trial;
6. Have been adherent to a gluten-free diet for >6 months pre-enrolment;
7. Have a tTG <20 IU/mL (normal <15) at screening;
8. Have a CSI <35 at screening;
9. If female, has met either of criterion "a or b" below:
1. If of non-childbearing potential, has met 1 of the following - Amenorrheic for at least 2 years, or has had a hysterectomy and/or bilateral oophorectomy at least 8 weeks prior to screening, or has had a tubal ligation at least 8 weeks prior to screening.
2. If of childbearing potential, must be willing to use the acceptable methods of contraception and abide by the timelines as indicated
10. In the opinion of the Investigator is in good general health
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Minimum age
18
Years
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Maximum age
80
Years
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Sex
Both males and females
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Can healthy volunteers participate?
Yes
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Key exclusion criteria
1. Have any finding at screening that in the opinion of the Investigator or medical monitor would compromise the safety of the Participant or affect their ability to adhere to protocol scheduled visits, treatment plan, laboratory tests, and other trial procedures.
2. Have participated in any other clinical trial and/or have received an investigational drug or device within 30 days of screening.
3. Have history or current evidence of any of the following: compromised respiratory function (chronic obstructive pulmonary disease, respiratory depression, signs or symptoms of hypoxia at screening); thyroid pathology (unless stabilized and euthyroid for >3 months at the time of screening); hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection; evidence of clinically significant chronic cardiac, hepatic or renal disease; psychiatric illness (poorly controlled); seizure disorder or any other chronic health issues that in the opinion of the Investigator would exclude the Participant from the trial.
4. History of substance abuse or current substance abuse that in the opinion of the Investigator would exclude the Participant from the trial.
5. Have a history of intolerance, allergy or hypersensitivity to the proposed placebo - Tabasco® Sauce or any of its known ingredients.
6. Have a history of intolerance, allergy or hypersensitivity to the proposed anthelmintic - mebendazole.
7. Have a history of intolerance, allergy or hypersensitivity to the proposed chemicals used in preparation of N.americanus - amphotericin B and Betadine that in the opinion of the Investigator would exclude the Participant from the trial.
8. Current requirement for consistent use of anti-inflammatory drugs (includes prescription and over the counter medication >2 doses per week, that in the opinion of the Investigator would significantly alter the Participant's immunity), aspirin exceeding 125 mg/day or the use of immunotherapeutics;
9. Diagnosis of cancer which has been in remission for < 5 years, excluding Participants with adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
10. Poor venous access making the Participant unable to comply with the safety laboratory testing and/or endoscopy sedation requirements.
11. Are an employee of the Sponsor, Investigator or study centre or immediate family of such employees or the Investigator.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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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
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/09/2016
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/10/2019
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Sample size
Target
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Accrual to date
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Final
54
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Recruitment in Australia
Recruitment state(s)
QLD
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Recruitment hospital [1]
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Prince Charles Hospital - Brisbane
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Recruitment hospital [2]
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Logan Hospital - Logan
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Recruitment hospital [3]
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Townsville Hospital - Townsville
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Recruitment postcode(s) [1]
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4032 - Brisbane
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Recruitment postcode(s) [2]
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4131 - Logan
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Recruitment postcode(s) [3]
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4812 - Townsville
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Recruitment outside Australia
Country [1]
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New Zealand
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State/province [1]
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Christchurch
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Funding & Sponsors
Primary sponsor type
Other
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Name
James Cook University, Queensland, Australia
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Address
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Country
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Other collaborator category [1]
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Government body
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Name [1]
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Townsville Hospital
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Address [1]
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Country [1]
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Other collaborator category [2]
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Government body
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Name [2]
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The Prince Charles Hospital
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Address [2]
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Other collaborator category [3]
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Other
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Name [3]
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Christchurch Hospital
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Address [3]
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Country [3]
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Other collaborator category [4]
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Government body
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Name [4]
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Logan Hospital, Queensland
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Address [4]
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Country [4]
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Other collaborator category [5]
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Other
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Name [5]
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Australian Institute of Tropical Health and Medicine
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Address [5]
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Country [5]
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Other collaborator category [6]
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Other
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Name [6]
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QIMR Berghofer Medical Research Institute
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Address [6]
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Country [6]
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Other collaborator category [7]
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Other
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Name [7]
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National Health and Medical Research Council, Australia
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Address [7]
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Country [7]
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Ethics approval
Ethics application status
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Summary
Brief summary
This trial is a Phase 1b multicentre, multinational, randomized, double-blind with single-blind arm and open label extension phase, placebo controlled, clinical trial evaluating the safety and predictability of an escalating gluten consumption to activate Coeliac Disease (CeD) in (a) a small cohort of people with diet-managed CeD treated with a placebo (n=10), and in (b) cohorts following low (L3-10; n=40) and medium (L3-20; n=10) dose hookworm inocula. The investigators 4 aims for the study are: Aim 1: Undertake a multiple-phase and escalating gluten challenge assessing safety to gluten exposure in hookworm-naïve and hookworm-infected people with CeD. Aim 2: This phase Ib study recognizes that the evidence supporting this novel intervention is rudimentary and addresses amongst others the following questions: (a) The importance of L3 dose on Participant health, and (b) the importance of L3 dose on the safety of escalating gluten challenge and (c) the need for a comparator group should a phase II trial be warranted. Aim 3: Examine the changes in intestinal T cell responses induced by hookworm infection and gluten exposure. Aim 4: Assess the impact of hookworm infection and purified hookworm-derived proteins on gluten peptide-specific immune responses ex vivo.
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Trial website
https://clinicaltrials.gov/study/NCT02754609
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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John Croese, MBBS, MD
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Address
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Prince Charles Hospital
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Phone
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Fax
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Email
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/study/NCT02754609