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Low Dose Multi-Nut Oral Immunotherapy in Pre-schoolers With a Multi-Nut Allergy (LMNOP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05049512
Recruitment Status : Recruiting
First Posted : September 20, 2021
Last Update Posted : November 19, 2021
Sponsor:
Information provided by (Responsible Party):
Murdoch Childrens Research Institute

Brief Summary:

The LMNOP trial will be a 2-armed, open-label, randomised controlled trial (RCT), 2:1. Over a period of 18 months, children in the Multi-Nut Oral Immunotherapy Treatment (OIT) Group (experimental arm) will undergo low dose OIT to two nuts they are allergic to. At this time, children in the Standard Care Group (control arm) will be instructed to strictly avoid consuming two nuts they are allergic to. Avoiding consuming nut allergens is the standard care advice for children with peanut/tree nut allergies in Australia. The trial will assess the difference in the proportion of participants undergoing Multi-Nut OIT who can achieve sustained unresponsiveness (SU) compared to the proportion of participants avoiding nuts who develop natural tolerance (NT), i.e. grow out of their allergy. SU is when a participant can pass an oral food challenge (OFC) after having paused OIT treatment for several weeks. Participants will be between the ages of 18 and 36 months at the time of screening. The first 12 participants enrolled will be part of the pilot phase, with a total of n = 45 for the main trial.

It is hypothesised that there will be a higher proportion of participants in the Multi-Nut OIT Group versus the Standard Care Group who pass the OFC following the 18-month treatment phase. That is, a higher proportion of participants in the Multi-Nut OIT Group will achieve SU compared to participants in the Standard Care Group achieving NT.


Condition or disease Intervention/treatment Phase
Allergy, Nut Other: Multi-nut OIT Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Low Dose Multi-Nut Oral Immunotherapy in Pre-schoolers (LMNOP): a Pragmatic Randomised Controlled Trial of Low Dose Multi-Nut Oral Immunotherapy Versus Standard Care for the Treatment of Multi-Nut Allergies in Young Children
Actual Study Start Date : November 16, 2021
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Multi-nut OIT
Participants will have a personalised combination of two nuts they are allergic to for their multi-nut OIT (a. peanut, b. almond, c. cashew, d. hazelnut, e. walnut). In the escalation visit, participants will receive 5 increasing doses of personalised multi-nut OIT in clinic at 20-minute intervals: 1 mg, 3 mg, 6 mg, 12 mg, 24 mg total nut protein, 12 mg/nut. The build-up phase will consist of daily home doses of multi-nut OIT and clinic visits every 2 weeks for up-dosing, up to a maintenance dose of 600 mg total protein, 300 mg/nut, over 3-8 months. In the maintenance phase, participants will continue to take their multi-nut OIT dose of 600 mg total protein each day at home for the remainder of the 18 months, with visits to the clinic every 3 months.
Other: Multi-nut OIT
Finely ground pure peanut, almond, cashew, hazelnut, and walnut.

No Intervention: Standard Care
Strict avoidance of the 2 study nuts the participants are allergic to over 18 months - a. peanut, b. almond, c. cashew, d. hazelnut, e. walnut, as per standard care instructions for children with allergies in Australia.



Primary Outcome Measures :
  1. Main Trial: Comparison of the number of participants who pass their OFC after the 18-month treatment phase for both study nuts between the Multi-Nut OIT Group and Standard Care Group [ Time Frame: At 18 months post commencement of treatment ]
    In both groups, passing requires participants tolerating all OFC doses for both of their study nuts. For the Multi-Nut OIT Group, participants must pass their OFC at the end of the 18-month treatment phase, and then pass another OFC after 4 weeks of no OIT. For the Standard Care Group, participants must pass their OFC after the 18-month period. Participants have a personalised combination of two nuts: a. peanut, b. almond, c. cashew, d. hazelnut, e. walnut, as nominated at study screening.


Secondary Outcome Measures :
  1. Main Trial: Difference between the Multi-nut OIT Group in comparison to the Standard Care Group in the proportion and severity of reported adverse events (AE) related to study nut ingestion during the 18-month treatment phase [ Time Frame: During the 18-month treatment phase ]
    Number and severity of AEs as assessed by standardised predetermined criteria, related to study peanut/tree nut ingestion from randomisation to end of the 18-month treatment phase collected via OFC and clinic visit observations and medical history taken, and parent questionnaire diaries.

  2. Main Trial: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from screening to 18 months in quality of life scores for the children, measured by the Food Allergy Quality of Life-Parent Form (FAQL-PF) [ Time Frame: Screening and at 18 months ]
    The Food Allergy Quality of Life Questionnaires (FAQLQ) are disease-specific health-related quality of life questionnaires for patients with food allergy. The FAQL-PF completed by parents of children aged 0-12 years, consists of 30 items over 3 domains: emotional impact, food anxiety, social and dietary restrictions. Total and domain scores are calculated by dividing the sum of completed items by the number of competed items.

  3. Main Trial: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from screening to 18 months in quality of life scores for the parents using the ICEpop CAPability measure for Adults (ICECAP-A) [ Time Frame: Screening and at 18 months ]
    The ICECAP-A questionnaire is a measure of capability well-being for adults. It has been developed in the United Kingdom (UK) using in-depth and semi-structured qualitative research with adults over the age of 18; values for the UK, obtained using best-worst scaling, are available. The instrument contains five attributes - stability, attachment, autonomy, achievement, and enjoyment, each with four levels. Research on the instrument's validity, reliability, feasibility of use and sensitivity to change are still ongoing.

  4. Main Trial: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from screening to 18 months in State/Trait anxiety using the State/Trait Anxiety Inventory (STAI) [ Time Frame: Screening and at 18 months ]
    The STAI is a psychological inventory based on a 4-point Likert scale and consists of 40 questions on a self-report basis. The STAI measures two types of anxiety - state anxiety, or anxiety about an event, and trait anxiety, or anxiety level as a personal characteristic. Higher scores are positively correlated with higher levels of anxiety.

  5. Main Trial: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in the number of allergy-related healthcare visits from randomisation to 18 months [ Time Frame: Randomisation to 18 months ]
    Captured per number of hospitalisations, Emergency Room (ER) visits, physician office visits, and medications/number of prescriptions using linked data to Medicare healthcare usage (Medical Benefits Scheme (MBS) and Pharmaceutical Benefits Scheme (PBS)) and Victorian Data Linkage for hospital presentations (Victorian Admitted Episodes Dataset (VAED)).

  6. Main Trial: Difference between the two groups in change in SPT wheal size at screening and at 18 months [ Time Frame: Screening and at 18 months ]
    Measured by SPT wheal size for each child's study nuts at screening and at 18 months.

  7. Main Trial: Difference between the two groups in change in levels of specific Immunoglobulin E (sIgE) at screening and at 18 months [ Time Frame: Screening and at 18 months ]
    Measured by levels of sIgE for each child's study nuts at screening and at 18 months.

  8. Main Trial: Difference between the two groups in change in levels of specific Immunoglobulin G4 (sIgG4) at screening and at 18 months [ Time Frame: Screening and at 18 months ]
    Measured by levels of sIgG4 for each child's study nuts at screening and at 18 months.

  9. Main Trial: Difference between the two groups in change in levels of component-resolved diagnostic (CRD) at screening and at 18 months [ Time Frame: Screening and at 18 months ]
    Measured by levels of CRD for each child's study nuts at screening and at 18 months. CRD is an approach utilised to characterize the molecular components of each allergen involved in a sIgE-mediated response.

  10. Main Trial: Difference between the two groups in change in levels of basophil activation test (BAT) at screening and at 18 months [ Time Frame: Screening and at 18 months ]
    Measured by levels of BAT for each child's study nuts at screening and at 18 months.

  11. Main Trial: Total number of missed doses overall (all participants) in the Multi-Nut OIT Group over the 18 month treatment phase [ Time Frame: During the 18-month treatment phase ]
    Compliance will be measured by daily parent diary records of doses consumed. Total number of missed daily doses overall (all participants).

  12. Main Trial: Mean number of missed daily doses per participant in the Multi-Nut OIT Group over the 18 month treatment phase [ Time Frame: During the 18-month treatment phase ]
    Compliance will be measured by daily parent diary records of doses consumed. Total number of missed daily doses averaged per participant.

  13. Main Trial Ad Libitum Phase: Comparison of the number of participants who pass their OFC after the 12 month Ad Libitum phase for both study nuts between the Multi-Nut OIT Group and Standard Care Group [ Time Frame: At 32 months ]
    In both groups, passing requires tolerating all OFC doses for both of their study nuts.

  14. Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in the proportion and severity of reported AEs related to study nut ingestion during the 12-month Ad libitum phase [ Time Frame: During the 12 month Ad libitum phase ]
    Number and severity of AEs as assessed by standardised predetermined criteria, related to study peanut/tree nut ingestion from the start to the end of the 12-month Ad libitum phase collected via end of trial OFC observation and medical history, and parent 1-monthly questionnaires.

  15. Main Trial: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from the start to the end of the Ad libitum phase in quality of life scores for the children, measured by the FAQL-PF [ Time Frame: At the 18-month treatment phase assessment and at the 12 month Ad libitum phase assessment ]
    The Food Allergy Quality of Life Questionnaires (FAQLQ) are disease-specific health-related quality of life questionnaires for patients with food allergy. The FAQL-PF completed by parents of children aged 0-12 years, consists of 30 items over 3 domains: emotional impact, food anxiety, social and dietary restrictions. Total and domain scores are calculated by dividing the sum of completed items by the number of competed items.

  16. Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from the start to the end of the Ad libitum phase in quality of life scores for the parents using the ICECAP-A [ Time Frame: At the 18-month treatment phase assessment and at the 12 month Ad libitum phase assessment ]
    The ICECAP-A questionnaire is a measure of capability well-being for adults. It has been developed in the UK using in-depth and semi-structured qualitative research with adults over the age of 18; values for the UK, obtained using best-worst scaling, are available. The instrument contains five attributes - stability, attachment, autonomy, achievement, and enjoyment, each with four levels. Research on the instrument's validity, reliability, feasibility of use and sensitivity to change are still ongoing.

  17. Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from the start to the end of the Ad libitum phase in State/Trait anxiety using the STAI [ Time Frame: At the 18-month treatment phase assessment and at the 12 month Ad libitum phase assessment ]
    The STAI is a psychological inventory based on a 4-point Likert scale and consists of 40 questions on a self-report basis. The STAI measures two types of anxiety - state anxiety, or anxiety about an event, and trait anxiety, or anxiety level as a personal characteristic. Higher scores are positively correlated with higher levels of anxiety.

  18. Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in the number of allergy-related healthcare visits during the 12-month Ad libitum phase [ Time Frame: During the 12-month Ad libitum phase ]
    Captured per number of hospitalisations, ER visits, physician office visits, and medications/number of prescriptions using linked data to Medicare healthcare usage (MBS/PBS) and Victorian Data Linkage for hospital presentations (VAED)

  19. Main Trial Ad Libitum Phase: Difference between the two groups in change in SPT wheal size from 18-months treatment phase assessment to the 12-month Ad libitum phase assessment [ Time Frame: At the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment ]
    Measured by SPT wheal size for each child's study nuts at the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment.

  20. Main Trial Ad Libitum Phase: Difference between the two groups in change in levels of sIgE from 18-months treatment phase assessment to the 12-month Ad libitum phase assessment [ Time Frame: At the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment ]
    Measured by levels of sIgE each child's study nuts at the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment.

  21. Main Trial Ad Libitum Phase: Difference between the two groups in change in levels of sIgG4 from 18-months treatment phase assessment to the 12-month Ad libitum phase assessment [ Time Frame: At the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment ]
    Measured by levels of sIgG4 for each child's study nuts at the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment.

  22. Main Trial Ad Libitum Phase: Difference between the two groups in change levels of CRD from 18-months treatment phase assessment to the 12-month Ad libitum phase assessment [ Time Frame: At the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment ]
    Measured by levels of CRD for each child's study nuts at the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment. CRD is an approach utilised to characterize the molecular components of each allergen involved in a sIgE-mediated response.

  23. Main Trial Ad Libitum Phase: Difference between the two groups in change levels of BAT from 18-months treatment phase assessment to the 12-month Ad libitum phase assessment [ Time Frame: At the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment ]
    Measured by levels of BAT for each child's study nuts at the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment.

  24. Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in the amount of study nut consumption during the Ad libitum phase [ Time Frame: During the 12-month Ad libitum phase ]
    Amount of study nut consumption during the Ad libitum phase based on parent 1-monthly questionnaires.

  25. Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in the frequency of study nut consumption during the Ad libitum phase [ Time Frame: During the 12-month Ad libitum phase ]
    Frequency of study nut consumption during the Ad libitum phase based on parent 1-monthly questionnaires.

  26. Pilot Phase: Number of children at screening who refuse, are eligible, or are ineligible [ Time Frame: At study screening, up to 4 weeks before starting treatment ]

    Pilot Phase: At screening, number of children who:

    1. refuse to participate
    2. are eligible
    3. are ineligible (and reason)

  27. Pilot Phase: Number of children at recruitment who agree or refuse to participate [ Time Frame: At study recruitment, up to 4 weeks before starting treatment ]

    At recruitment, number of eligible children who:

    1. agree to be in the study
    2. who refuse to be in the study

  28. Pilot Phase: Number of participants in the Multi-Nut OIT Group who complete escalation [ Time Frame: At completion of first day of treatment ]
    Number of children in the Multi-Nut OIT Group who complete all escalation doses

  29. Pilot Phase: Number of participants in the Multi-Nut OIT Group who complete the build-up phase [ Time Frame: At completion of build-up, between 3-8 months after commencing treatment ]
    Number of participants in the Multi-Nut OIT Group who complete build-up

  30. Pilot Phase: Number of participants in the Multi-Nut OIT Group and the Standard Care Group who withdraw, discontinue, and/or experience 1 or more protocol violations [ Time Frame: During the 18 month treatment phase ]

    Number of participants in either arm who:

    1. withdraw
    2. discontinue the treatment prior to 18 months
    3. experience 1 or more protocol violations

  31. Pilot Phase: Number and severity of AEs during the screening OFC for all participants [ Time Frame: At study screening, up to 4 weeks before starting treatment ]
    Number and severity of AEs as assessed by standardised predetermined criteria during the screening OFC.

  32. Pilot Phase: Number and severity of AEs for the Multi-Nut OIT Group during escalation [ Time Frame: At completion of first day of treatment ]
    Number and severity of AEs as assessed by standardised predetermined criteria during escalation.

  33. Pilot Phase: Number and severity of AEs for the Multi-Nut OIT Group during the build-up phase [ Time Frame: During the build-up phase, between 3-8 month period after commencing treatment ]
    Number and severity of AEs as assessed by standardised predetermined criteria during build-up.

  34. Pilot Phase: Total number of missed doses overall (all participants) in the Multi-Nut OIT Group over the build-up phase [ Time Frame: During the build-up phase, between 3-8 month period after commencing treatment ]
    Based on parent diary entries. Number of missed daily doses overall (all participants).

  35. Pilot Phase: Mean number of missed daily doses per participant in the Multi-Nut OIT Group over the build-up phase [ Time Frame: During the build-up phase, between 3-8 month period after commencing treatment ]
    Based on parent diary entries. Number of missed daily doses averaged per participant.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Months to 36 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Is between the ages of 18 and 36 months at the time of Screening visit 1
  • Has a legally acceptable representative capable of understanding the informed consent document and providing consent on the participant's behalf
  • IgE-mediated allergy to 2 of peanut, almond, cashew, hazelnut or walnut, confirmed by:

Nut 1 pre-screening:

For at least one of almond, cashew, hazelnut or walnut (Nut 1)*:

  1. History of ingestion with IgE-mediated reaction (birth to present) AND
  2. History of SPT ≥3mm OR History of sIgE ≥0.35 number of kilounits per liter (KuL) AND

Nut 2 pre-screening:

For a second nut out of peanut, almond, cashew, hazelnut or walnut (Nut 2):

History of SPT ≥3mm OR History sIgE ≥0.35 KuL

In clinic screening: Participants meeting pre-screening criteria for Nuts 1 and 2 above will be invited for in-clinic screening

  1. SPT: wheal size ≥3mm at Visit 1 for 2 of peanut, almond, cashew, hazelnut or walnut AND
  2. OFC: react to ≤3000 mg protein top dose (4449 mg cumulative) in open, single nut OFC for 2 of peanut, almond, cashew, hazelnut or walnut

OFC not needed if:

History of failed OFC within past 3 months (confirmed by investigator review of discharge summary) OR History of anaphylaxis after ingestion within past 3 months based on investigator judgement +/- review of ER/Ambulance/medical notes

*Peanut is not included as Nut 1 to reduce the incidence of screening children with a peanut allergy only - children with peanut allergy may have been advised to avoid all other nuts. We require children to have eaten and reacted to at least one tree nut, and then the 2nd nut, which children may or may not have eaten, can be peanut or a tree nut.

Exclusion Criteria:

  • History of severe anaphylaxis (as defined by persistent hypotension, collapse, loss of consciousness, persistent hypoxia or ever needing more than 2 doses of intramuscular adrenaline or an intravenous adrenaline infusion for management of an allergic reaction)
  • Severe anaphylaxis at study screening OFC (defined as persistent hypotension, collapse, loss of consciousness, persistent hypoxia, or requiring more than 2 doses of intramuscular adrenaline or an intravenous adrenaline infusion for management of an allergic reaction)
  • Fails either screening OFC on dose 1 (0.5 mg).
  • Underlying medical conditions that increase the risks associated with anaphylaxis (e.g., cardiac disease or poorly controlled asthma (defined below))
  • Confirmed eosinophilic esophagitis (EoE) or history indicating EoE
  • Current use of beta-blockers or angiotensin-converting enzyme (ACE) inhibitors
  • Receiving systemic immunomodulatory treatment
  • Not commenced or unable to eat solid food
  • Weight <7.5kgs (recommended minimum weight for EpiPen Jr (adrenaline autoinjector))
  • Has a sibling in the study

Defining uncontrolled asthma (Global Initiative for Asthma. Asthma management and prevention for adults and children older than 5 years)

In the past 4 weeks, has the patient had:

Daytime symptoms more than twice/week? Any night waking due to asthma? Short Acting Beta Agonist (SABA) reliever needed more than twice/week? Any activity limitation due to asthma? Uncontrolled - answered yes to 3-4 of these


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05049512


Contacts
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Contact: Kirsten Perrett, MBBS FRACP 039936 ext 6278 kirsten.perrett@rch.org.au
Contact: Megan Mathers, BAppSci(Hon) 039936 ext 6029 megan.mathers@mcri.edu.au

Locations
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Australia, Victoria
Murdoch Children's Research Institute Recruiting
Parkville, Victoria, Australia, 3052
Contact: Kirsten Perrett, MBBS FRACP    039936 ext 6278    kirsten.perrett@rch.org.au   
Principal Investigator: Kirsten Perrett, MBBS FRACP         
Sub-Investigator: Catherine Hornung, PhD         
Sub-Investigator: Paxton Loke, MBBS FRACP         
Sub-Investigator: Tim Brettig, MBBS FRACP         
Sub-Investigator: Dean Tey, MBBS FRACP         
Sub-Investigator: Vicki McWilliam, PhD         
Sub-Investigator: Jennifer Koplin, PhD         
Sub-Investigator: Katherine Lee, PhD         
Sub-Investigator: Rachel Peters, PhD         
Sub-Investigator: Marnie Robinson, MBBS FRACP         
Sub-Investigator: Kim Dalziel, PhD         
Sub-Investigator: Thanh Dang, PhD         
Sub-Investigator: Wendy Norton, MBBS FRACP         
Sponsors and Collaborators
Murdoch Childrens Research Institute
Investigators
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Principal Investigator: Kirsten Perrett, MBBS FRACP Murdoch Children's Research Institute
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Responsible Party: Murdoch Childrens Research Institute
ClinicalTrials.gov Identifier: NCT05049512    
Other Study ID Numbers: 74540
First Posted: September 20, 2021    Key Record Dates
Last Update Posted: November 19, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

The de-identified data set that will be collected for this analysis of the LMNOP trial will be available six months after publication of the primary outcome. The study protocol may be obtained from the Murdoch Children's Research Institute. Prior to releasing any data, the following are required: a data access agreement must be signed between relevant parties; the LMNOP trial investigators must see and approve the analysis plan describing how the data will be analysed; there must be an agreement around appropriate acknowledgment; and any additional costs involved must be covered.

Should the study investigators be unavailable, this role is delegated to the Murdoch Children's Research Institute. Data will only be shared with a recognised research institute, which has approved the proposed analysis plan.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Six months after the publication of the primary outcome
Access Criteria: Prior to releasing any data, the following are required: a data access agreement must be signed between relevant parties; the LMNOP trial investigators must see and approve the analysis plan describing how the data will be analysed; there must be an agreement around appropriate acknowledgment; and any additional costs involved must be covered.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Murdoch Childrens Research Institute:
Oral immunotherapy
Randomised controlled trial
Skin prick test
Oral food challenge
Additional relevant MeSH terms:
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Hypersensitivity
Nut Hypersensitivity
Immune System Diseases
Nut and Peanut Hypersensitivity
Food Hypersensitivity
Hypersensitivity, Immediate