ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12615001275550

Ethics application status

Approved

Date submitted

28/10/2015

Date registered

23/11/2015

Date last updated

10/06/2021

Date data sharing statement initially provided

16/11/2018

Date results information initially provided

16/11/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Open study of Probiotic and Peanut Oral Immunotherapy (PPOIT) for the treatment of peanut allergy in children.

Scientific title

Safety and efficacy of Probiotic and Peanut Oral Immunotherapy (PPOIT) for the induction of sustained unresponsiveness in children with peanut allergy.

Secondary ID [1]

NIL

Universal Trial Number (UTN)

Trial acronym

PPOIT-II

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Peanut allergy

Food Allergy

Condition category

Condition code

Inflammatory and Immune System

Allergies

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

PEANUT FLOUR
Peanut Flour (50% peanut protein) is purchased from a US company (Golden Peanut Company, LTD.

PROBIOTIC (Lactobacillus rhamnosus GG; ATCC 53103)
The probiotic to be used is Lactobacillus rhamnosus GG.
Probiotic will be prepared under strict Food Manufacturing Regulations. Supply will be as dry powder. The daily dose of 2x10^10 cfu will be measured using a 4g scoop. Participants will be instructed to mix the probiotic in water, soy milk or cow’s milk, at a temperature NOT exceeding 38 degrees Celsius.

TREATMENTS AND DOSAGE
DAY 1 RUSH INDUCTION
* In the rush phase, subjects will receive increasing doses of peanut oral immunotherapy every 20 minutes to reach a final dose of 12mg of peanut protein (cumulative dose 24mg peanut protein).
* There will be a maximum of 8 doses administered at a starting dose of 0.1mg.
* Peanut protein will be sprinkled onto food (yoghurt not containing LGG).
* Subjects will receive a single dose of 2x10^10 cfu LGG ( one level scoop mixed into 100 ml of water, at a temperature NOT exceeding 38 degrees Celsius) prior to initiation of the rush phase.
* Probiotic will be administered just prior to the first dose of peanut protein on the rush day and once daily just prior to peanut protein doses throughout the build up and maintenance phases.
* Subjects will be monitored (including at least half hourly vital signs and general nursing assessment of the skin and chest) for 2 hours after the last dose during modified rush.
* The study doctor and study nurse will be present at all times during the rush phase
* The rush phase will be performed in hospital
* Spirometry will be performed on all participants aged 8 or older, and younger participants who are capable of doing spirometry reproducibly, before the participant receives their first dose of peanut oral immunotherapy and 2 hours after receiving the final dose of Day 1 rush induction.
* Subjects who complete the rush protocol without reaction will commence the Buildup Phase at a daily dose of 25mg peanut protein (Dose 9) on the day after the rush induction day.
* If a subject reacts to one of the doses during rush induction, the rush schedule will be ceased and they will commence the Buildup Phase at the dose immediately below the reaction-eliciting dose starting on the day after the rush induction day. The remaining RUSH doses that were not completed on day 1 will be incorporated into the buildup phase (modified buildup schedule for that subject) and subsequent incremental dose increases will proceed through all remaining doses of the RUSH schedule followed by the doses in the buildup schedule. For example, if a reaction occurs following dose 6, the subject will commence the buildup phase at the dose 5 amount and will be instructed to start this reduced dose on the following day).

BUILD UP PHASE
In the buildup phase, the daily dose of peanut OIT will be increased every 2 weeks until a maintenance dose of 2000mg is reached.
* Each dose increase will be administered in hospital under medical supervision.
* Hospital visits for dose increases (updose visits) will be scheduled every 2 weeks. Where indicated, dose adjustments will result in deferment of a dose increase to the next scheduled visit.
* Spirometry will be performed on all participants aged 8 or older, and younger participants who are capable of doing spirometry reproducibly, before the participant receives their first increased dose of peanut oral immunotherapy and 2 hours after receiving the dose.
* Peanut protein will be sprinkled onto food (e.g. yoghurt not containing LGG).
* Subjects will also take a fixed dose of 2x10^10 cfu LGG (one level scoop mixed into 100 ml of water, at a temperature NOT exceeding 38 degrees Celsius) once daily prior to the OIT treatment.
* Subjects will be monitored for 2 hours after the treatment has been administered.

MAINTENANCE PHASE
A maintenance phase, during which participants take a daily dose of 2g peanut protein and a daily dose of 2x10^10 cfu LGG at home, is continued until a total of 18 months PPOIT treatment is completed. If the subject has not completed a minimum of 6 months on maintenance dosing at 18 months, the total duration of treatment will be extended to ensure a minimum of 6 months maintenance dosing.

STRATEGIES TO MONITOR ADHERENCE
We will monitor adherence by daily dosing diary and weighing / counting contents of returned treatment packages.

Intervention code [1]

Treatment: Other

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

The proportion of children who can complete the buildup phase according to protocol. This is assessed by review of study records.

Timepoint [1]

End of buildup phase

Primary outcome [2]

b. The number of adverse events (AE) and serious adverse events (SAE) per participant during the buildup phase.

Definitions and examples of known/possible adverse reactions and how they will be assessed is detailed below.

Adverse Event (AE): Any untoward medical occurrence in a patient enrolled into this study regardless of its causal relationship to study treatment. Adverse events are classified as serious or non-serious (see below for definition of a serious adverse event).

Serious Adverse Event (SAE): An SAE is defined as any AE that:
* Results in death; or
* Is immediately life threatening; or
* Requires inpatient hospitalisation; or
* Requires prolongation of existing hospitalisation; or
* Results in persistent or significant disability/incapacity; or
* Is a congenital anomaly/birth defect.

AE and SAE will be assessed either observed by the investigator or one of the clinical staff at the study visit/assessment, or reported by the patient spontaneously or in response to a direct question will be evaluated by the investigator, or from the daily dosing diary that captures doses taken and any reactions experienced. The parent will be asked a non-leading question such as: “In general, how has your child been feeling since starting the new treatment/ the last assessment?”

Examples of AE are:
*Mild: Transient or mild discomforts (<48 hours), no or minimal medical intervention/therapy required. These symptoms may include pruritus, swelling or rash, abdominal discomfort or other transient.
* Moderate: Symptoms that produce mild to moderate limitation in activity some assistance may be needed; no or minimal medical intervention/therapy is required. Hospitalisation is possible. These symptoms may include persistent hives, wheezing without dyspnea, abdominal discomfort/ increased vomiting or other symptoms.
* Severe: Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalization is possible. Symptoms may include Bronchospasm with dyspnea, severe abdominal pain, throat tightness with hoarseness, transient hypotension among others. Parenteral medication(s) are usually indicated.

Examples of SAE are:
Extreme limitation in activity, significant assistance required; significant medical therapy / intervention is required; hospitalisation is probable. Symptoms may include persistent hypotension and/or hypoxia with resultant decreased level of consciousness associated with collapse and/or incontinence or other life threatening symptoms.

Timepoint [2]

The number of AE and SAE reported during buildup phase.

Secondary outcome [1]

a. The proportion of children who are desensitized – this will be determined by performing double blind placebo controlled food challenge (DBPCFC) at end of treatment (T2)

Timepoint [1]

T2: 18 months after the first day of OIT (the last day of treatment)

Secondary outcome [2]

b. The proportion of children who attain sustained unresponsiveness – this will be determined by performing DBPCFC 8 weeks after treatment is completed (T3) with strict avoidance of peanut intake between T2 and T3

Timepoint [2]

T3: 8 weeks after treatment has ceased

Secondary outcome [3]

c. The proportion of children who attain sustained unresponsiveness at T3 and maintain long-term sustained unresponsiveness – this will be determined by performing DBPCFC three years after treatment is ceased (T5) after a period of peanut elimination for at least 8 weeks

Timepoint [3]

T5: 3 years after treatment has ceased

Secondary outcome [4]

d. Change in peanut skin prick test wheel size from T0, T1, T2, T3, T4 & T5

Timepoint [4]

T0: First day of OIT T1: end of buildup phase T2: 18 months after the first day of OIT (the last day of treatment) T3: 8 weeks after treatment has ceased T4: 12 months after treatment has ceased T5: 3 years after treatment has ceased

Secondary outcome [5]

e. Change in immunological measures (sIgE and sIgG4) from T0, T1, T2, T3, T4 & T5 - this will be determined by measurement of these parameters in blood samples.

Timepoint [5]

Secondary outcome [6]

f. Quality of life at T0, T2, T3, T4 & T5 – this will be measured using validated Food Allergy Quality of Life Questionnaires. The Parent Form (FAQLQ-PF) will be used for children 0-12 years and the Child Form (FAQLQ-TF) for children > 12 years during the follow up period (ref: Dunn-Galvin et al CEA 2008; 38:977).

Timepoint [6]

T0: First day of OIT
T2: 18 months after the first day of OIT (the last day of treatment)
T3: 8 weeks after treatment has ceased
T4: 12 months after treatment has ceased
T5: 3 years after treatment has ceased

Eligibility

Key inclusion criteria

Children are eligible for the study if they:
* Are aged between 1 year and 12 years of age,
* If they are >10kg (weight considered safe for the prescription and administration of an Epipen)
* There is a confirmed diagnosis of peanut allergy as defined by a failed DBPCFC to peanut and a positive SPT or sIgE to peanut at screening.

Minimum age

1 Years

Maximum age

12 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Children will not be eligible for the study if they have a history of:
* Severe anaphylaxis (as defined by hypotension , collapse, loss of consciousness or hypoxia OR ever needing three (3) or more doses of intramuscular adrenaline or needing intravenous adrenaline infusion for management of anaphylactic reaction)
* FEV1 <85% at rest or FEV1/FVC < 85% at rest or ongoing chronic persistent asthma (as per Australian Asthma Foundation guidelines)
* Underlying medical conditions (eg cardiac disease) that increase the risks associated with anaphylaxis
* Use of beta-blockers
* Inflammatory intestinal conditions, indwelling catheters, gastrostomies, immune-compromised states, post-cardiac and/or gastrointestinal tract surgery, critically-ill and those requiring prolonged hospitalisation or other conditions that may increase the risks of probiotic associated sepsis
* Already taking Probiotics

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation is not concealed

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Not applicable

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Open study

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

The primary aim of the pilot study is to evaluate the safety and tolerability of PPOIT.

Specific primary aims will be to determine:
- The proportion of children who can complete the build up phase according to protocol,
- The number of adverse events (AE) and serious AE per participant during the buildup phase.

The secondary aims are:
- To determine the rate of sustained unresponsiveness (SU) after completion of 18 months of PPOIT using a shortened immunotherapy buildup schedule;
- To determine the rate of desensitisation after completion of 18 months of PPOIT using a shortened immunotherapy buildup schedule;
- To determine the rate of long-term sustained unresponsiveness (SU) at 3 years after completion of 18 months of PPOIT using a shortened immunotherapy updosing schedule;
- To determine the change in skin prick test (SPT) size after completion of 18 months of PPOIT using a shortened immunotherapy buildup schedule;
- To determine the change in blood sIgE and sIgG4 after completion of 18 months of PPOIT using a shortened immunotherapy buildup schedule.

No formal statistical analyses will be performed.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

15/12/2015

Actual

15/12/2015

Date of last participant enrolment

Anticipated

10/02/2016

Actual

25/02/2016

Date of last data collection

Anticipated

22/12/2020

Actual

12/11/2020

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

The Royal Childrens Hospital - Parkville

Recruitment postcode(s) [1]

3052 - Parkville

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Murdoch Childrens Research Institute

Address [1]

The Royal Children's Hospital
Flemington Road, Parkville VIC 3052

Country [1]

Australia

Primary sponsor type

Charities/Societies/Foundations

Name

Murdoch Childrens Research Institute

Address

The Royal Children's Hospital
Flemington Road, Parkville VIC 3052

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Royal Children's Hospital Human Research Ethics Committee

Ethics committee address [1]

Flemington Road
Parkville VIC 3052

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

09/09/2015

Approval date [1]

19/11/2015

Ethics approval number [1]

HREC 35207A

Summary

Brief summary

At present there is no cure for food allergy. People with a food allergy need to avoid the food they are allergic to in order to stay safe. However we know that accidental exposure is common. Research shows that 50% of children with a peanut allergy are accidentally exposed to peanut within 2 years.

Researchers have begun to look at the effectiveness of 'oral immunotherapy' as a treatment for food allergy. In oral immunotherapy, patients with food allergy are given small amounts of the food they are allergic to and tested for food allergy after a set amount of time. Results have been mixed. Studies suggest that oral immunotherapy can induce desensitization (short term ability to tolerate the food allergen while the patient continues on therapy) but has a limited ability to induce sustained unresponsiveness ( longer term ability to tolerate the food allergen after treatment is stopped for at least 2-4 weeks or longer). We conducted a RCT to evaluate a novel combination treatment approach involving administration of probiotic together with oral immunotherapy - Probiotic and Peanut Oral Immunotherapy (PPOIT). In our study we found that just over 80% of children who received PPOIT tolerated peanut after stopping treatment for more than 2 weeks compared with only 4% in the placebo group. PPOIT was highly effective at inducing sustained unresponsiveness - if 9 children were treated with PPOIT, 7 would benefit.

PPOIT participants received a daily dose of probiotic together with peanut protein (peanut flour) for 18 months. The probiotic was taken as a fixed daily dose. The dose of peanut protein was commenced at very low levels then increased every 2 weeks over a period of 8 months to reach a maintenance dose of 2g peanut protein.

This study (PPOIT-II) will build on our previous PPOIT study.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Mimi Tang

Address

Dept of Allergy and Immunology
The Royal Children's Hospital
Flemington Road
Parkville VIC 3052

Country

Australia

Phone

+61 3 9345 6180

Fax

[email protected]

Contact person for public queries

Name

Prof Mimi Tang

Address

Dept of Allergy and Immunology
The Royal Children's Hospital
Flemington Road
Parkville VIC 3052

Country

Australia

Phone

+61 3 9345 6180

Fax

[email protected]

Contact person for scientific queries

Name

Prof Mimi Tang

Address

Dept of Allergy and Immunology
The Royal Children's Hospital
Flemington Road
Parkville VIC 3052

Country

Australia

Phone

+61 3 9345 6180

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

undecided at present

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

Source	Title	Year of Publication	DOI
Embase	Probiotic peanut oral immunotherapy is associated with long-term persistence of 8-week sustained unresponsiveness and long-lasting quality-of-life improvement.	2022	https://dx.doi.org/10.1111/cea.14137

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically