Hookworm Therapy for Coeliac Disease
Condition: Celiac Disease
MeSH terms: Hookworm Infections; Celiac Disease
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      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.

      Aim 1&2/Clinical study: 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%.

      Secondary outcomes include safety of low and medium intensity hookworm infection at
      intermediate (12 weeks and 24 weeks) endpoints of an escalating gluten challenge, assessed by
      incidence of adverse events, serious adverse events as well as general health. Secondary
      outcome measures include changes in V:C ratio from baseline to intermediate endpoints,
      progression through successful gluten challenge phases of the trial including a liberal diet,
      mucosal intraepithelial lymphocyte count, Celiac Symptom Index (CSI questionnaire),
      Celiac-Quality of Life Score (QOL questionnaire) and the serum immunoglobulin A (IgA) tissue
      transglutaminase (tTG) level of all cohorts.

      Aims 3&4/Associated in vitro cell measures and ex vivo mucosal stimulation investigations:
      The associated studies are designed to more fully explore the immunological processes
      underpinning the clinical outcomes, and to take advantage of mucosal tissue collected in
      excess of the clinical requirements to test individual components of hookworm secretions
      which we believe hold great potential as future therapies. These experiments are complex and
      often depend on the quality of tissue and the cells collected.

      Study Procedure: After written informed consent is obtained at the screening visit and prior
      to enrolment Participants may require some haematological work to confirm eligibility.
      Participants will be randomized to receive hookworm larvae (L3-10 or L3-20) suspended in 2-3
      drops of water applied to the skin and covered with a light dressing, or Tabasco® Sauce in
      solution (Placebo Comparator). Before inoculation, each Participant will complete a QOL
      questionnaire, submit a fresh faecal specimen, and undergo a blood draw and duodenal biopsy.
      Thereafter each week for the duration of participation, a food diary and CSI questionnaire
      will be submitted. At designated times, gluten will be introduced in escalating volumes.
      Blood, faecal and biopsy collections, and a QOL questionnaire will also be collected. To
      better evaluate the independent effect of L3 on host immunity, the L3-20 cohort will undergo
      an endoscopy at week 12 in lieu of the week 36 intervention.

      Safety Parameters/Analysis: General health assessments, physical examination and vital signs
      will be obtained at screening and thereafter at designated clinic visits (or symptom driven
      as required). Incidence and severity of Adverse and Serious Events including evidence of
      gluten intolerance and hookworm related complications of Participants will be evaluated
      formally through structured questionnaires (CSI weekly and QOL at the designated times) to be
      scrutinised by the designated research nurse and informally through Participant initiated
      personal contact with a research nurse or clinician. As well, blood for clinical safety and
      histological results will be scrutinised contemporaneously (by a designated research nurse or
      designated researcher) for incidence and severity of laboratory abnormalities. Blood results
      and symptom scores will be coded in a re-identifiable format before adding to an
      access-restricted and secure database. Screening blood tests to include serum pregnancy test
      at screening (a positive test will exclude the Participant from entering the trial) and urine
      pregnancy test if pregnancy is suspected throughout the trial. The 12-month progression to a
      liberal diet will be monitored by tTG evaluated monthly, with monthly CSI evaluation and
      Participant contact.

      Laboratory Parameters/Analysis: Blood analysis: Complete blood count (CBC), IgA-tTG titre,
      liver and renal function and iron tests and a screening serum pregnancy test will be
      performed at Sullivan Nicolaides Pathology (SNP) in Australia and Canterbury Health
      Laboratories in New Zealand. From the residual blood, peripheral blood mononuclear cells will
      be harvested (when circumstances permit) and serum will be stored.

      Faecal analysis: Samples will be collected in anaerobic collection bags with an aliquot to be
      transferred into a provided screw top plastic jar, both to be frozen at -20°C for short term
      storage and transport, and stored at -80°C long-term for parasite egg quantitative polymerase
      chain reaction (qPCR) analysis to be performed by nominated un-blinded personnel supervised
      by Prof. James McCarthy at QIMR Berghofer Medical Research Institute, with the results to
      remain blinded to all other trial personnel. Faecal samples will also be stored for future
      analysis of bacterial communities (the microbiota).

      Mucosal analysis: Duodenal biopsies (14 pinch biopsies, consistent with previous trials) will
      be taken by a nationally and trial accredited gastroenterologist supported by a sedationist
      in an accredited facility. Four biopsies will be committed for conventional histology. To
      ensure standardisation the Biopsy forceps to be used will be Boston Scientific Radial Jaw® 4
      - 2.8mm. Paraffin embedded tissue sections (3 μm) will be stained with H&E and anti-cluster
      of differentiation 3 (anti-CD3). Clinical histopathology will be supervised by a specialist
      in gastrointestinal pathology (A/Prof. Andrew Clouston) and reported contemporaneously for
      clinical purposes. Best representative field images from each case will be selected by Prof.
      Clouston, then coded in re-identifiable format before adding to an access-restricted and
      secure database, and later scored for intraepithelial lymphocytes (IEL)% and V:C by a single
      pathologist (Dr. Greg Miller). At each time point, two four biopsy tissue samples will be
      stored at -80°C in 10% glycerolRNA stabilisation solution for future gene expression and
      microbiota analyses.

      Total Blood volume: 50 ml per collection x 6 from week minus 4 to week 42. 10 ml per month
      for 12 months. Total 420 ml over 2 years.

      Sample size determination: Gluten consumption is toxic when consumed by people with CeD.
      Unlike a conventional trial testing an intervention to reverse disease, this trial relies on
      gluten toxicity to promote disease activity. The trial primarily evaluates the safety of
      gluten exposure in CeD in hookworm-infected Participants. The escalating gluten challenge
      proposed is unprecedented, and whilst liberal gluten consumption is consumed by many people
      with CeD either though ignorance of diagnosis or a conscious decision not to comply with
      medical advice, it is anticipated this challenge will adversely affect the unprotected
      placebo controls. Consistent with this concern, the control cohort has been kept small. The
      study will consist of 60 participants, with 10 in the control group, 40 in the low-dose
      hookworm group (L3-10) and 10 in the medium-dose hookworm group (L3-20).
    

Intervention name(s): Gluten micro-challenge; Inadvertent gluten challenge; Moderate gluten challenge; Liberal diet; Necator americanus-hookworm larvae L3-10; Tabasco® Sauce; Necator americanus-hookworm larvae L3-20; Gluten free diet
Intervention type(s): Other; Other; Other; Other; Other; Other; Other; Other
Intervention description(s): 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.; From week 24 to week 36, all participants will be on gluten 50mg/day and 1g twice weekly.; From week 36 to week 42, all participants will be on gluten 2g/day.; 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.; 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.; 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; 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.; From week 0 to week 12, all participants will be on a gluten free diet.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Placebo, 20 hookworm L3 or 40 hookworm L3
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Celiac Disease; Necator americanus; Helminths; Autoimmunity; Clinical Trials, Phase I; Randomized Controlled Trial