Protocol for a double-blind, randomized controlled trial on the dose-related efficacy of omalizumab in multi-food oral immunotherapy

Study design

The study is a multi-center phase 2b clinical trial and will be conducted in a randomized controlled fashion comparing two dosages of omalizumab to placebo during a symptom-driven multi-food oral immunotherapy (OIT) protocol (Fig. 3). The study will be conducted in five research centers in Canada. This list will be updated on the clinical trial registration site throughout the trial (NCT04045301). Ninety participants will be recruited and randomized 2:2:1 to receive 20 weeks of omalizumab at monthly dosages of 16 mg/kg, 8 mg/kg or placebo. The study drug will be given at full dosage for a total of 12 weeks with a progressive taper during the last 8 weeks. Multi-food OIT will be started after a pre-treatment period of 8 weeks (Table 1). It will be performed with biweekly up-dosing according to a symptom-driven schedule until the target dose of 1500 mg of food protein is reached (500 mg per food). All participants will be consented by site investigators in accordance with the Declaration of Helsinki. A separate consent will be presented for biobanking purposes as per site policies. The study has been approved by the coordinating centers’ Research Ethics Committees and is registered in Clinicaltrials.gov (NCT04045301). Ethics approval will be obtained at each study site prior to initiation. The study will be conducted according to Good Clinical Practices (GCP) and all participating sites will need to provide certifications of GCP/Division 5 training for all those involved in the conduct of the study.

Fig. 3
figure3

Overall study design. DBPCFC: double-blind placebo-controlled food challenge; IFE: initial food escalation; OMA: omalizumab

Table 1 Schedule of procedures

Primary endpoint

Time from initial food escalation (IFE) to target multi-food protein maintenance dose of 1500 mg of total protein (500 mg per food) with study drug.

Secondary endpoints

  1. 1.Change in reactivity threshold to food treatment mix after pre-treatment with study drug.
  2. 2.Average up-dosing speed (i.e. percent amount escalated at each visit) while on study drug.
  3. 3.Allergic adverse events attributable to food dosing throughout the trial.

Participant selection

The study will enroll children, adolescent and adults 6 to 25 years old with at least 3 IgE-mediated food allergies who meet all of the inclusion criteria (Table 2) and none of the exclusion criteria (Table 3).

Table 2 Inclusion criteria
Table 3 Exclusion criteria

Screening

First, participants will be screened to determine their eligibility. During screening, a Double-Blind Placebo-Controlled Food Challenge (DBPCFC) will be performed over two separate days. They will ingest increasing amounts of a smoothie containing either placebo or a mix of three of their allergens in an equivalent stoichiometric ratio for their protein content (1:1:1). Participants will be given increasing doses of food protein until a final dose of 300 mg of total food protein (100 mg per food) is administered. Only participants with an objective reaction to the food treatment mix and an eliciting dose of 300 mg or less of total food protein will be admissible.

Study drug

Once eligibility is confirmed, participant who consent will be randomized using stratified, permuted blocked randomization, using a 2:2:1 allocation. The randomization will be stratified by center and by baseline eliciting dose during DBPCFC (two eliciting dose strata: low eliciting dose (≤ 30 mg of total protein (10 mg per food)) and high eliciting dose [> 30 mg of total protein (10 mg per food)]. They will be randomized to one of the three arm of the study: A: Omalizumab 16 mg/kg per month, B: Omalizumab 8 mg/kg per month or C: Placebo. The online group allocation system will be managed independently by the CHU Ste-Justine Applied Clinical Research Unit.

Participants will be treated with omalizumab at their randomized dosage or placebo for a pre-treatment period of 8 weeks prior to the initial food escalation (IFE). Study drug will be continued for 12 weeks after IFE, for a total of 20 weeks (W-8 to W12). Study drug will be given at full dosage for the first 12 weeks (W-8 to W3) and gradually tapered by reducing the dose by half (50% of initial dosage) from W4 to W7, and again (25% of initial dosage) from W8 to W11 (Fig. 3).

Blinding strategy

Because the investigational product (IP) and the placebo are not exactly similar (greater viscosity with active ingredient) and the volume of IP administered may differ depending on treatment assignment, a specific blinding plan was designed.

Briefly, the site pharmacist responsible for the receipt, accountability as well as the reconstitution of IP will remain unblinded. The unblinded pharmacist will have access to the randomization list for his site and will validate all doses automatically calculated by the online randomization system in RedCAP. An unblinded nurse independent from the rest of the team and without any other role in the study will be responsible for administrating the study drug. The dose will be divided in the same number of distinct injections regardless of study arm, but the volume dispensed will be adjusted accordingly (Table 4). The unblinded pharmacist will pre-draw all syringes following a double-verification of the appropriate dose. The unblinded nurse will thus inject the full volume, which will not be documented in the source documents or the subject’s medical chart. Only the number of injections will be documented. This is to avoid participants inadvertently discussing the number of injections in front of blinded personnel who could then deduce their treatment arm.

Table 4 BOOM trial study drug dosage table

Sealed envelopes indicating participant allocation will be kept at the site pharmacy and at the coordinating center, to be used in case of emergency blinding for reasons of safety only.

Symptom-driven OIT

Multi-food oral immunotherapy will be initiated after the 8-week pre-treatment phase. OIT will be conducted to a mix of three foods from the following list: peanut, milk, egg, wheat, oat, soy, barley, rye, buckwheat, hazelnut, pecan, cashew, pistachio, almond, walnut and sesame.

Initial food escalation

At week 8 (day 1), they will undergo the initial food escalation (IFE), which consists in the ingestion of incremental amounts of their food mix every 30 min following the same schedule as the DBPCFC but continuing up to a total of 1500 mg of protein (Table 5) or up to the occurrence of clinically significant symptoms (Table 6).

Table 5 Double-blind placebo-controlled food challenge (DBPCFC) and initial food escalation (IFE) schedule
Table 6 DBPCFC and IFE stopping rules

Daily home dosing

Subjects will begin daily home dosing with the highest tolerated dose from IFE. Pre-weighted food dose mix will be dispensed in individual cups and subjects will be instructed to ingest their dose every day around the same time. Participants will be trained on the recognition and appropriate management of dosing reactions and co-factors that increase the likelihood of dosing reactions (infection, peak seasonal allergies, asthma exacerbation, acute stress or fatigue, non-steroidal anti-inflammatory drugs, etc.). In the event of co-factor, the OIT dose will be temporarily decreased by half and the next up-dosing will be postponed until after the co-factor has resolved. The OIT dose will be decreased to the last tolerated dose in the event of systemic or moderate-to-severe local reaction.

Up-dosing visits

Participants will return to clinic every other week for a supervised escalation of the food mix amount. To be eligible for up-dosing, the participant must have taken his/her full dose at least 10 times in the last 14 days without any severe local or systemic reaction. On the first up-dosing visit, participants will attempt to double their food amount (+100%). The percent amount escalated on following up-dosing visits will be adjusted based on clinical tolerance to home dosing according to Tables 7 and 8 and until a maintenance dose of 1500 mg of protein (500 mg per food) is reached.

Table 7 Symptom-driven up-dosing rules
Table 8 Allergic reaction assessment tool based on the CoFAR grading system

Participants that react on their escalation will remain on the same dose for another 2 weeks and reattempt up-dosing at half the percent increase of the failed up-dose. If up-dosing fails again, the percent increase will again be decreased by half at each subsequent visit until the up-dose is tolerated.

In the event where the up-dosing rules dictate increasing by a percent amount that was previously failed, then the participant must repeat one additional uneventful visit increasing with the current percentage before proceeding to this new percent increase.

Maintenance

Up-dosing visits will take place following the above-mentioned rules until a maintenance dose of 1500 mg is reached. The subject will remain on that daily dosage for at least 2 weeks after which they will transition to food equivalents. Participants will remain on that maintenance dose until at least 12 months after the IFE.

Concomitant medication

In clinic and at home, acute reactions to DBPCFC or OIT food doses will be treated according to WAO Anaphylaxis Guidelines [38], as deemed appropriate by the investigator. Medication can be prescribed to participants to prevent symptoms related to OIT as in real-life. The indication and choice of prophylactic medication is determined by the investigator. Type 1 and 2 anti-histamines, leukotriene receptor antagonists, proton-pump inhibitors, prostaglandin E1 analogs, mast cell stabilizers or swallowed corticosteroids can be used depending on the situation. Their use will be documented in the patient diary and concomitant medication log. The decision to perform endoscopy/biopsy remains at the investigator’s discretion and should be balanced with the risk of delaying proper treatment. As a reference, the Canadian clinical practice guidelines on OIT recommend that endoscopy and biopsy be used to confirm the diagnosis in suspected cases not responding to dose adjustments or medication [39].

Follow-up of participants

Participants will be followed for a minimum of 12 months after the initial food escalation. Follow-up of participants will end when the last randomized participant has reached 12-month follow-up. Participants discontinuing treatment for any reason will be offered follow-up care and invited to complete an early termination visit to collect all data that would have otherwise been collected at the end of study (Table 1).

Assessment of efficacy

The primary endpoint is defined as the first visit at which an attempt to escalate to 1500 mg of protein of treatment food mix is successful (e.g. the lack of any systemic or of local reaction requiring treatment). This will be reaffirmed on the following visit by confirmation that the dose was successfully maintained at home in the following 2 weeks. The main secondary outcomes will be measured as follows. Extent of pharmacologic desensitization from omalizumab pre-treatment will be measured by comparing the amount of food required to elicit clinically significant symptoms in the IFE compared to baseline DBPCFC (Table 5). Both procedures use the same objective stopping criteria to ensure comparability. Up-dosing speed will be measured as the average of log percent food increase on up-dosing visits between D1 and W12, adjusted for the number of days between visits. Mean cumulative function of allergic adverse events attributable to food dosing will be captured using a daily dosing diary throughout the trial, including during maintenance. The 3-month wash-out period following discontinuation of omalizumab will be of special interest with regards to continued dose tolerance. Allergic events occurring during escalation visits will be documented directly on case report forms. All moderate to severe reactions (CoFAR grade 2 or higher) occurring at home or during up-dosing visits will also be reviewed and documented in the AE log and on the OIT-reaction report form.

Safety variables

All adverse events (AEs) and severe adverse events (SAEs) occurring during the study, including intercurrent illnesses, will be documented in the e-CRF. Reactions attributed to food dosing during OIT will be treated as AEs of special interest (AESI) since they are also measures of treatment efficacy as described above. The following AEs will also be considered AESI given prior reports in relation to omalizumab: arterial thromboembolic events, malignant neoplasms, anaphylaxis/anaphylactoid reactions not attributable to ingestion of food allergen.

The proper reporting of anaphylaxis in this trial poses a specific challenge considering it is an expected side effect of both OIT and omalizumab. A specific anaphylaxis reporting procedure was developed to ensure proper reporting of anaphylaxis causality for drugs studied in the context of food OIT (Fig. 4).

Fig. 4
figure4

Anaphylaxis reporting plan. SUSAR: suspected unexpected serious adverse reaction; ICF: informed consent form; IP: investigational product; AESI: adverse event of special interest, DSMB: Data Safety Monitoring Board; AE: adverse event; HC: Health Canada; REB: Research Ethics Board

Statistical methods

The primary outcome for the trial will be time-to-maintenance dose which will be compared between groups using the stratified log-rank-analysis (stratified by center and baseline eliciting dose during DBPCFC). Each of the three pairwise comparison (omalizumab 16 mg/kg vs omalizumab 8 mg/kg, omalizumab 8 mg/kg vs placebo, omalizumab 16 mg/kg vs placebo) will be evaluated using the Bonferroni correction for multiple tests.

Data will be analyzed using the intent-to-treat approach. In the log-rank analysis, this means that patients who drop-out or are lost to follow-up for any reason will be considered as having never reached the outcome.

To control for the risk of multiple outcome measures, secondary analyses will only be performed if at least one of the active arm is found better than the placebo arm in the primary analysis. Comparison of treatment efficacy based on sex is also planned as an exploratory objective.

Sample size calculation

The sample size will be primarily driven by the 16 vs 8 mg/kg comparison. Assuming a median time-to-maintenance of 2 weeks in the 16 mg/kg arm based our clinical cohort, a sample of 72 participants (36 in each arm) would confer a power of 0.80 to detect a HR = 2.2 of time-to-maintenance with an alpha of 0.017 (considering 3-way testing between the study arms), assuming administrative censoring at 52 weeks. A HR of 2.15 would mean 2.3 additional OIT weeks, which was considered the minimal clinically relevant difference (i.e. one up-dosing visit).

Assuming a median time-to-maintenance of 6 weeks in the 8 mg/kg arm, a sample of 54 participants (18 in placebo arm) would confer a power of 0.80 to detect a HR = 2.54 if a time-to-maintenance with an alpha of 0.017, assuming administrative censoring at 52 weeks. A HR of 2.54 would mean 9.2 additional OIT weeks, which was considered the minimal clinically relevant difference to consider adding adjunct drug therapy.

Quality assurance

The Sponsor will conduct a site visit to verify the qualification of each Investigator, inspect the site facilities, and inform the Investigator of her/his responsibilities and the required procedures for ensuring adequate site selection and correct documentation.

All data generated by the site personnel will be immediately captured electronically at each study center using e-CRFs, with a maximum delay of 3 days. Data from external sources (such as laboratory data) will be imported into the database. Computerized edit-checks will be developed in addition to manual review to detect any discrepancies and to ensure consistency of the data. An electronic audit trail system will be used to track all data changes in the database subsequent to the first data entry.

During the study, a site monitor will conduct site visits to review protocol compliance, compare e-CRF entries and individual subject’s medical records, assess drug accountability, and ensure that the study is being conducted according to ethical and pertinent regulatory requirements. The e-CRF entries will be verified with source documentation. The review of medical records will be performed in a manner to ensure that subject confidentiality is maintained. Site monitoring visits will begin within 2 weeks of the first randomized subject and are planned every 12 weeks thereafter, based on site activity. In addition, the Sponsor may conduct audits at the investigative sites including, but not limited to, drug supply, presence of required documents, the informed consent process, respect of GCP standards and comparison of e-CRFs with source documents.

A Data Safety Monitoring Board (DSMB) composed of 3 independent members and chaired by a clinical trialist with experience in running multi-center food allergy trials will have access to safety reports every 6 months and will make appropriate recommendations to the trial steering committee (composed of the principal investigators from each site, the study coordinator and the study methodologist). There are no interim analysis planned for efficacy outcomes.

Internal audits of the coordinating center (CHU Sainte-Justine) are also planned by the institution pharmaceutical research quality assurance committee to ensure compliance. In addition, external audits by Health Canada could be conducted at any moment during or after the study.

Dissemination

Results of the study will be communicated at scientific conferences and journals. These will be written by the investigators without any restriction or recourse to professional writers.

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