Trial registered on ANZCTR


Trial ID
ACTRN12615001275550
Ethics application status
Approved
Date submitted
28/10/2015
Date registered
23/11/2015
Date last updated
17/11/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Open study of Probiotic and Peanut Oral Immunotherapy (PPOIT) with shortened buildup phase for the treatment of peanut allergy in children.
Scientific title
Safety and efficacy of Probiotic and Peanut Oral Immunotherapy (PPOIT) with shortened buildup phase for the induction of sustained unresponsiveness in children with peanut allergy.
Secondary ID [1] 287746 0
NIL
Universal Trial Number (UTN)
Trial acronym
PPOIT-II
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peanut allergy 296611 0
Food Allergy 296612 0
Condition category
Condition code
Inflammatory and Immune System 296852 296852 0 0
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 (16 WEEKS DURATION)
In the buildup phase, the daily dose of peanut OIT will be increased every 2 weeks until a maintenance dose of 2000mg is reached (expected to take 16 weeks).
* 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] 293142 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 296460 0
a. The proportion of children who can complete the buildup phase within 17 weeks - this is assesed by review of study records and allows an additional 1 week to suit family schedules.
Timepoint [1] 296460 0
17 weeks from the first day of OIT.
Primary outcome [2] 296461 0
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] 296461 0
The number of AE and SAE reported during buildup phase.
Secondary outcome [1] 318493 0
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] 318493 0
T2: 18 months after the first day of OIT (the last day of treatment)
Secondary outcome [2] 318494 0
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] 318494 0
T3: 8 weeks after treatment has ceased
Secondary outcome [3] 318495 0
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] 318495 0
T5: 3 years after treatment has ceased
Secondary outcome [4] 318496 0
d. Change in peanut skin prick test wheel size from T0, T1, T2, T3, T4 & T5
Timepoint [4] 318496 0
T0: First day of OIT
T1: 16 weeks after the 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
Secondary outcome [5] 318497 0
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] 318497 0
T0: First day of OIT
T1: 16 weeks after the 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
Secondary outcome [6] 318498 0
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] 318498 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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 a shortened updosing phase of PPOIT.

Specific primary aims will be to determine:
- The proportion of children who can complete the build up phase and reach maintenance dose at 16 weeks,
- 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
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Current
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 4518 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 12119 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 292288 0
Charities/Societies/Foundations
Name [1] 292288 0
Murdoch Childrens Research Institute
Address [1] 292288 0
The Royal Children's Hospital
Flemington Road, Parkville VIC 3052
Country [1] 292288 0
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] 290973 0
None
Name [1] 290973 0
Address [1] 290973 0
Country [1] 290973 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293763 0
The Royal Children's Hospital Human Research Ethics Committee
Ethics committee address [1] 293763 0
Flemington Road
Parkville VIC 3052
Ethics committee country [1] 293763 0
Australia
Date submitted for ethics approval [1] 293763 0
09/09/2015
Approval date [1] 293763 0
19/11/2015
Ethics approval number [1] 293763 0
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. PPOIT-II is an open study to investigate whether we can increase the dose of peanut protein over 4 months (instead of 8 months), similar to other forms of immunotherapy (e.g. for bee venom or pollen immunotherapy). Specifically we want to assess whether this approach is safe and tolerated by participants. 20 children with peanut allergy will take part in the study. Children will take increasing doses of peanut protein and a set amount of probiotic for 16 weeks. Children will then continue on a set maintenance dose until a total of 18 months treatment is completed. Children will be tested for peanut allergy at the start of the study, at the end of PPOIT treatment (18 months) and 2 months and 3 years after treatment.

The discovery of a safe and tolerable treatment for food allergy will have great public health benefit. If this immunotherapy protocol incorporating a shorter buildup phase is well tolerated, this will provide a more acceptable and feasible immunotherapy schedule for patients and families.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61214 0
Prof Mimi Tang
Address 61214 0
Dept of Allergy and Immunology
The Royal Children's Hospital
Flemington Road
Parkville VIC 3052
Country 61214 0
Australia
Phone 61214 0
+61 3 9345 6180
Fax 61214 0
Email 61214 0
mimi.tang@rch.org.au
Contact person for public queries
Name 61215 0
Prof Mimi Tang
Address 61215 0
Dept of Allergy and Immunology
The Royal Children's Hospital
Flemington Road
Parkville VIC 3052
Country 61215 0
Australia
Phone 61215 0
+61 3 9345 6180
Fax 61215 0
Email 61215 0
mimi.tang@rch.org.au
Contact person for scientific queries
Name 61216 0
Prof Mimi Tang
Address 61216 0
Dept of Allergy and Immunology
The Royal Children's Hospital
Flemington Road
Parkville VIC 3052
Country 61216 0
Australia
Phone 61216 0
+61 3 9345 6180
Fax 61216 0
Email 61216 0
mimi.tang@rch.org.au