Efficacy and Safety of QGE031 (Ligelizumab) in Patients With Peanut Allergy

Phase 3TerminatedNCT04984876

Novartis Pharmaceuticals211 enrolled

Overview

This was a 52-week, Phase 3 multi-center, randomized, double-blind and placebo-controlled study to assess the safety and clinical efficacy of two dosing regimens of ligelizumab (240 mg and 120 mg) SC q4w (subcutaneous injection every 4 weeks) in participants with a medically confirmed diagnosis of Immunoglobulin E (IgE) mediated peanut allergy.

Participants were randomized to ligelizumab 240 mg, ligelizumab 120 mg, or placebo (5 treatment arms, randomization ratio of 2:2:2:2:1) for the double-blind placebo-controlled treatment period (up to Week 12). Participants initially assigned to the 8-week placebo arms received the first dose of blinded ligelizumab treatment at the Week 8 visit. Participants initially assigned to the 16-week placebo arm received the last dose of placebo before the Double Blind Placebo Controlled Food Challenge (DBPCFC) at Week 12 and the first dose of blinded ligelizumab treatment at the Week 16 visit. At the start of the study, recruitment was restricted to 12-55-year-old participants. After approximately 60 adolescent participants (defined as 12-17 yrs of age) had completed all Week 12 assessments, an interim analysis (IA1) on Pharmacokinetics (PK) and selected Pharmacodynamics (PD) data (total IgE and basophil bound High affinity immunoglobulin E receptor 1 (FcƐRI)) was performed (safety was reviewed by a Data Monitoring Committee - DMC). Independent sponsor members who were responsible for PK/ PD data analysis and Modeling \& Simulation were unblinded to the results of this interim analysis. The planned intent of this analysis was to confirm the dosing strategy for the youngest age group, 6-11 yrs and once the dose was to be confirmed, recruitment was supposed to be open for this age group. However, Novartis made a strategic decision to close recruitment in the study CQGE031G12301 and to terminate the study early, once all eligible participants in the study had completed week 12 assessments and the 16-week safety follow-up period. This decision was based on a blinded data review, which showed evidence of efficacy without the detection of any safety signal and that efficacy may be optimized with a different dosing regimen. Due to this decision, the final population size was 211, with only adolescent and adult participants (12 - 17yrs, and 18 - 55yrs) recruited.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

211

Conditions

Allergy, Peanut

Interventions

ligelizumabDRUG

Subcutaneous injection once every 4 weeks

PlaceboDRUG

Subcutaneous injection once every 4 weeks

Eligibility

Sex: ALLMin age: 6 YearsMax age: 55 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. Signed informed consent and/or assent (where applicable) was obtained prior to study participation. Participant (and parent/legal guardian) was able to understand and provide informed consent and assent, as applicable. If a minor participant providing assent reaches the age of legal majority (as defined by local law), he/she was re-consented (ICF) at the next study visit. 2. Male or female participants who were 6 to 55 yrs of age at the time of signing informed consent/assent. 3. Documented medical history of allergy to peanuts or peanut-containing foods. 4. Positive peanut-specific IgE (peanut sIgE), ≥ 0.35 kUA/L at Screening Visit 1. 5. Positive SPT for peanut allergen at Screening Visit 1. This is defined as the average diameter (longest diameter and mid-point orthogonal diameter) ≥ 4 mm wheal compared to the negative control. 6. A positive peanut DBPCFC at baseline (Screening Visit 2, Part 1 and Part 2 DBPCFC) defined as the occurrence of dose-limiting symptoms at a single dose ≤ 100 mg of peanut protein. Eligibility to proceed with the DBPCFC requires presence of all inclusion and absence of all exclusion criteria. 7. Participants must weigh ≥ 20 kg at Screening Visit 1. 8. Participants must be able to receive injections (study treatment), participate in the DBPCFC, and must be willing to continue avoiding exposure to peanuts and any other foods that they are allergic to throughout this study. Key Exclusion Criteria: 1. History of hypersensitivity to ligelizumab or its excipients, or to other biologics (i.e., to murine, chimeric or human antibodies). 2. Hypersensitivity or intolerance to any of the matrix components used within the material for the oral food challenge. 3. History of severe or life-threatening hypersensitivity event needing an ICU (intensive care unit) admission or intubation within 60 days prior to baseline DBPCFC (Screening Visit 2). 4. Total IgE \>2000 IU/mL at Screening Visit 1. 5. Participants with uncontrolled asthma (according to Global Initiative for Asthma (GINA) guidelines, GINA 2020) who meet any of the following criteria: * FEV1 \<80% of participant's predicted normal value at Screening Visit 1 * One hospitalization for asthma within 12 months prior to Screening Visit 1 6. Current or previous history of a mast cell disorder, including mastocytosis. 7. Platelets \< 100'000/μL at Screening Visit 1. 8. Female participants not on oral contraception with a stable dose for a minimum of 3 months prior to taking study treatment. 9. Participants with evidence of helminthic parasitic infection as evidenced by stools being positive for a pathogenic organism according to local guidelines at Screening Visit 1 (before start of Screening Visit 2). If stool testing is positive for pathogenic organisms, the participant should not be randomized and should not be allowed to be rescreened.

Locations (55)

Outcomes

Primary Outcomes

Percentage of Participants Who Tolerated a Single Dose of >= 600 mg (1044 mg Cumulative Tolerated Dose) of Peanut Protein Without Dose-limiting Symptoms at Week 12

Responder rate was defined as the percentage of participants tolerating a single dose of \>= 600 mg (1044 mg cumulative tolerated dose) of peanut protein without dose-limiting symptoms during the double blind placebo controlled food challenge (DBPCFC) conducted at Week 12. The cumulative tolerated dose is the sum of the tolerated doses, not including the reactive dose. Dose-limiting symptoms indicate a true allergic reaction occurring during administration of a single dose of peanut protein at the DBPCFC that should preclude the administration of any further doses in the view of the investigator. Symptoms that require administration of any rescue medication were considered dose-limiting symptoms. Participants with treatment discontinuation or missing more than 1 doses of study drug prior to Week 12 due to reasons other than operational complications caused by public health emergency were considered non-responders.

Time frame: Week 12

Secondary Outcomes

Percentage of Participants Who Tolerated a Single Dose of >= 1000 mg (2044 mg Cumulative Tolerated Dose) of Peanut Protein Without Dose-limiting Symptoms at Week 12

Responder rate was defined as the percentage of participants tolerating a single dose of \>= 1000 mg (2044 mg cumulative tolerated dose) of peanut protein without dose-limiting symptoms during the double blind placebo controlled food challenge (DBPCFC) conducted at Week 12. The cumulative tolerated dose is the sum of the tolerated doses, not including the reactive dose. Dose-limiting symptoms indicate a true allergic reaction occurring during administration of a single dose of peanut protein at the DBPCFC that should preclude the administration of any further doses in the view of the investigator. Symptoms that require administration of any rescue medication were considered dose-limiting symptoms. Participants with treatment discontinuation or missing more than 1 doses of study drug prior to Week 12 due to reasons other than operational complications caused by public health emergency were considered non-responders.

Time frame: Week 12

Percentage of Participants Who Tolerated a Single Dose of 3000 mg (5044 mg Cumulative Tolerated Dose) of Peanut Protein Without Dose-limiting Symptoms at Week 12

Data from ClinicalTrials.gov

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Allervie Clinical Research

Birmingham, Alabama, United States

Allergy and Immunology Associates

Scottsdale, Arizona, United States

Arkansas Children's Hospital

Little Rock, Arkansas, United States

Allergy and Asthma Associates of Santa Clara Vally Center

San Jose, California, United States

Allergy and Asthma Clinical Research Inc

Walnut Creek, California, United States

UCHealth Outpatient Pavilion

Aurora, Colorado, United States

Asthma and Allergy Associates P C

Colorado Springs, Colorado, United States

Colorado Allergy and Asthma Ctr PC

Denver, Colorado, United States

Univ of South Florida Asthma Allergy and Immunology CRU

Tampa, Florida, United States

Childrens Healthcare of Atlanta

Atlanta, Georgia, United States

...and 45 more locations

Responder rate was defined as the percentage of participants tolerating a single dose of 3000 mg (5044 mg cumulative tolerated dose) of peanut protein without dose-limiting symptoms during the double blind placebo controlled food challenge (DBPCFC) conducted at Week 12. The cumulative tolerated dose is the sum of the tolerated doses, not including the reactive dose. Dose-limiting symptoms indicate a true allergic reaction occurring during administration of a single dose of peanut protein at the DBPCFC that should preclude the administration of any further doses in the view of the investigator. Symptoms that require administration of any rescue medication were considered dose-limiting symptoms. Participants with treatment discontinuation or missing more than 1 doses of study drug prior to Week 12 due to reasons other than operational complications caused by public health emergency were considered non-responders.

Percentage of Maximum Severity of Symptoms Occurring at Any Challenge Dose of Peanut Protein up to and Including 1000 mg at Week 12

Symptom severity occurring at any challenge dose of peanut protein up to and including 1000 mg during the DBPCFC conducted at Week 12 was categorized as 4 levels: None, Mild, Moderate, Severe. The CoFAR grading system was used to categorize the symptom severity as mild, moderate and severe. Symptom severity for participants who completed DBPCFC without any symptom were categorized as none.

Time frame: Week 12

Percentage of Participants Who Tolerated a Single Dose of >= 1000 mg (2044 mg Cumulative Tolerated Dose) of Peanut Protein Without Dose-limiting Symptoms at Week 12 After 4 Weeks of Treatment

Responder rate was defined as the percentage of participants tolerating a single dose of \>= 1000 mg (2044 mg cumulative tolerated dose) of peanut protein without dose-limiting symptoms during the double blind placebo controlled food challenge (DBPCFC) conducted at Week 12 after 4 weeks of treatment (8 weeks of placebo + 4 weeks of ligelizumab treatment versus 12 weeks of placebo). The cumulative tolerated dose is the sum of the tolerated doses, not including the reactive dose. Participants with treatment discontinuation or missing more than 1 doses of study drug prior to Week 12 due to reasons other than operational complications caused by public health emergency were considered non-responders.

Time frame: Week 12

Percentage of Participants Who Tolerated the Specified Peanut Protein Dose Without Dose-limiting Symptoms at Week 52

Responder rate was defined as the percentage of participants tolerating the specified peanut protein doses (\>= 600 mg (1044 mg cumulative tolerated dose), \>= 1000 mg (2044 mg cumulative tolerated dose) or 3000 mg (5044 mg cumulative tolerated dose)) of peanut protein without dose-limiting symptoms during the double blind placebo controlled food challenge (DBPCFC) conducted at Week 52. The cumulative tolerated dose is the sum of the tolerated doses, not including the reactive dose. Dose-limiting symptoms indicate a true allergic reaction occurring during administration of a single dose of peanut protein at the DBPCFC that should preclude the administration of any further doses in the view of the investigator. Symptoms that require administration of any rescue medication were considered dose-limiting symptoms.

Time frame: Week 52

Change From Baseline in Maximum Tolerated Dose (MTD) of Peanut Protein Without Dose-limiting Symptoms During the DBPCFC at Week 12 and Week 52

Change from baseline in maximum tolerated dose (MTD) of peanut protein without dose-limiting symptoms during the DBPCFC at Week 12 and Week 52. Dose-limiting symptoms indicate a true allergic reaction occurring during administration of a single dose of peanut protein at the DBPCFC that should preclude the administration of any further doses in the view of the investigator.

Time frame: Baseline, Week 12, Week 52

Change From Baseline in Peanut-specific Immunoglobulin E (IgE) at Week 12 and Week 52

Change from baseline of serum levels of peanut-specific immunoglobulin E (IgE)

Time frame: Baseline, Week 12, Week 52

Change From Baseline in Peanut-specific Immunoglobulin G4 (IgG4) at Week 12 and Week 52

Change from baseline of serum levels of peanut-specific immunoglobulin G4 (IgG4)

Time frame: Baseline, Week 12, Week 52

Change From Baseline in Skin Prick Test (SPT) Mean Wheal Diameters at Week 16/Week 56

The Skin Prick Test (SPT) is a widely used diagnostic tool for identifying allergen-specific IgE-mediated allergies. During the test, a small amount of allergen, in this case, peanut allergen, is introduced into the skin. The allergen interacts with specific IgE antibodies bound to cutaneous mast cells. This interaction can cause a reaction, resulting in a wheal and flare on the skin. The size of the wheal and flare, specifically the longest diameter and the midpoint orthogonal diameter, were evaluated at each site and the average size of the wheal and flare across all sites was summarized and reported. Considering the study termination, SPT originally scheduled at Week 56 was performed 4 weeks after Week 12 assessment in some patients.

Time frame: Baseline, Week 16/Week 56

Change From Baseline in Total and Domain Scores in the Food Allergy Quality of Life Questionnaire (FAQLQ) Teenager Form (FAQLQ-TF)

The Food Allergy Quality of Life Questionnaire (FAQLQ) Teenager Form (FAQLQ-TF) is a self-reported instrument designed for adolescents aged 13-17 to assess the impact of food allergy on health-related quality of life (HRQoL). The questionnaire includes three domains (Emotional Impact (EI), Allergen Avoidance and Dietary Restrictions (AADR) and Risk of Accidental Exposure (RAE)). Each item is scored on a 7-point scale (coded as 1-7 in analysis), with a higher score indicating greater impairment in HRQoL. The total score and the domain scores are calculated as the arithmetic average of all completed items. If more than one item in any domain is missing, a domain score should not be calculated for that case. However, a total score could still be calculated if 20% or fewer of the items are missing. Therefore, the range for each item, domain, and the total score is from 1 (minimum) to 7 (maximum). The higher the score, the greater the impairment in HRQoL.

Time frame: Baseline, Week 12 Part 1 (10 Days Before Day 1 Oral Food Challenge (OFC)), Week 12 Part 2 (3 Days After Day 2 Oral Food Challenge (OFC))

Change From Baseline in Total and Domain Scores in the Food Allergy Quality of Life Questionnaire (FAQLQ) Adult Form (FAQLQ-AF)

The Food Allergy Quality of Life Questionnaire (FAQLQ) Adult Form (FAQLQ-AF) is a self-reported instrument designed for adults aged 18-55 to assess the impact of food allergy on health-related quality of life (HRQoL). The questionnaire includes four domains (Emotional Impact (EI), Allergen Avoidance and Dietary Restrictions (AADR), Risk of Accidental Exposure (RAE) and Food Allergy Related Health (FAH)). Each item is scored on a 7-point scale (coded as 1-7 in analysis), with a higher score indicating greater impairment in HRQoL. The total score and the domain scores are calculated as the arithmetic average of all completed items. If more than one item in any domain is missing, a domain score should not be calculated for that case. However, a total score could still be calculated if 20% or fewer of the items are missing. Therefore, the range for each item, domain, and the total score is from 1 (minimum) to 7 (maximum). The higher the score, the greater the impairment in HRQoL.

Time frame: Baseline, Week 12 Part 1 (10 Days Before Day 1 Oral Food Challenge (OFC)), Week 12 Part 2 (3 Days After Day 2 Oral Food Challenge (OFC))

Change From Baseline in Total Scores in the Food Allergy Independent Measure (FAIM) - Teenager Form (FAIM-TF)

The Food Allergy Independent Measure (FAIM) - Teenager Form (FAIM-TF) is a self-reported instrument designed for adolescents aged 13-17. It aims to reflect the participant's perceived food allergy severity and food allergy-related risk. The questionnaire consists of six questions; The first four questions assess the participant's food allergy expectation outcomes and the remaining two questions reflect aspects of the perceived severity of food allergy. Each question is scored on a 7-point scale (coded as 1-7 in analysis), with a greater score indicating a higher level of perceived risk or chance of adverse events occurring. The total score is calculated as the arithmetic average of all completed items. If less than 80% of the items within the score are complete, the total score is not calculated. Therefore, the range for each item and the total score is from 1 (minimum) to 7 (maximum). The higher the score, the greater the perceived risk or chance of adverse events occurring.

Time frame: Baseline, Week 12 Part 1 (10 Days Before Day 1 Oral Food Challenge (OFC)), Week 12 Part 2 (3 Days After Day 2 Oral Food Challenge (OFC))

Change From Baseline in Total Scores in the Food Allergy Independent Measure (FAIM) - Adult Form (FAIM-AF)

The Food Allergy Independent Measure (FAIM) - Adult Form (FAIM-AF) is a self-reported instrument designed for adults aged 18-55. It aims to reflect the participant's perceived food allergy severity and food allergy-related risk. The questionnaire consists of six questions; The first four questions assess the participant's food allergy expectation outcomes and the remaining two questions reflect aspects of the perceived severity of food allergy. Each question is scored on a 7-point scale (coded as 1-7 in analysis), with a greater score indicating a higher level of perceived risk or chance of adverse events occurring. The total score is calculated as the arithmetic average of all completed items. If less than 80% of the items within the score are complete, the total score is calculated. Therefore, the range for each item and the total score is from 1 (minimum) to 7 (maximum). The higher the score, the greater the perceived risk or chance of adverse events occurring.

Time frame: Baseline, Week 12 Part 1 (10 Days Before Day 1 Oral Food Challenge (OFC)), Week 12 Part 2 (3 Days After Day 2 Oral Food Challenge (OFC))

Change From Baseline in the SF-36v2 Physical Component Score (PCS) and Mental Component Score (MCS)

The SF-36v2 Health Survey is a 36-item instrument that measures generic health-related quality of life. It is designed for use in surveys of general and specific populations, health policy evaluations and clinical practice and research. It contains 8 scales and 2 component summary indices evaluating physical, social and emotional functioning in addition to general health perceptions and mental health. Responses to items allow for direct calculation of scale scores, while the physical component summary (PCS) and mental component summary (MCS) scores are computed from weighted scale scores. For all scales and summary measures, higher scores indicate better health outcomes (PCS and MCS scores range 0 to 100).

Time frame: Baseline, Week 12 Part 2 (3 Days After Day 2 Oral Food Challenge (OFC))