Efficacy and Safety of Barzolvolimab in Chronic Inducible Urticaria: A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study

Trial ID: 2024-516988-87-00
Protocol: CDX0159-07
Sponsor: Celldex Therapeutics Inc.

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Diseases & Conditions

Cold urticaria

Objectives

The primary objective of this study is to evaluate the **efficacy** of different dose regimens of CDX-0159 compared to placebo in achieving a negative provocation test in patients with H1-antihistamine refractory Chronic Inducible Urticaria (CIndU) in each subtype, specifically Cold Urticaria (ColdU) and Symptomatic Dermographism (SD). This is clinically relevant as it aims to address the unmet need for effective treatment options in patients who do not respond to standard H1-antihistamine therapy, potentially improving their quality of life by reducing symptoms and disease burden.

Secondary objectives include: - Evaluating the efficacy of different dose regimens of CDX-0159 compared to placebo in improving provocation thresholds and itch triggered by provocation tests in each CIndU subtype. - Assessing the efficacy of different dose regimens of CDX-0159 compared to placebo in achieving a negative provocation test and improving itch in combined CIndU patients. - Evaluating the safety profile of different dose regimens of CDX-0159 compared to placebo in each CIndU subtype and in combined CIndU patients.

Participants

The clinical trial involves a total of **83 participants** diagnosed with **Chronic Inducible Urticaria** (CIndU), specifically focusing on subtypes ColdU and SD. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their diagnosis of ColdU or SD for at least three months prior to the screening visit, with their condition remaining uncontrolled despite a stable regimen of a second-generation non-sedating H1-antihistamine. The trial includes individuals whose urticaria symptoms persist despite treatment, as evidenced by recurrent pruritic wheals with or without angioedema. Participants are required to have a stable health status, with specific laboratory parameters such as hemoglobin, white blood count, and liver enzymes within defined limits. The trial population is not restricted by gender, and both male and female subjects are included, with considerations for effective contraception methods for participants of childbearing potential. The study does not provide specific information on lifestyle factors such as diet or physical activity. The trial includes a vulnerable population, ensuring that all participants have provided informed consent and are willing to comply with study requirements, including the completion of a daily diary.

Plans and Procedures

The clinical trial is a **Phase 2 randomized, double-blind, placebo-controlled, dose-ranging study** designed to assess the efficacy and safety of **CDX-0159** in patients with **Chronic Inducible Urticaria** (CIndU). The trial aims to evaluate different dose regimens of CDX-0159 compared to placebo in achieving a negative provocation test in patients with H1-antihistamine refractory CIndU, specifically in the subtypes of Cold Urticaria (ColdU) and Symptomatic Dermographism (SD). The study is expected to last until September 2025, with participant recruitment having commenced in August 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis duration, and treatment history. The screening process includes provocation tests to establish baseline urticaria activity. Following successful screening, participants will be randomized and begin the treatment phase, which involves regular follow-up visits to monitor efficacy and safety outcomes. The primary endpoint is the proportion of patients achieving a negative provocation test at Week 12. Secondary endpoints include changes in urticaria activity scores and the incidence of treatment-emergent adverse events over a 20-week treatment period.

The expected length of participant involvement is approximately 23 weeks, with conditions for early termination including significant adverse events or non-compliance with study protocols. Participants are required to maintain a stable regimen of second-generation non-sedating H1-antihistamines throughout the study. The trial is conducted under strict adherence to ethical guidelines, ensuring informed consent and compliance with all study requirements.

Treatment

The clinical trial involves the administration of **Barzolvolimab**, a **concentrate for solution for infusion**. This investigational medication is a humanized IgG1k monoclonal antibody targeting the KIT receptor, also known by its sponsor product code, CDX-0159. The pharmaceutical form of Barzolvolimab is a concentrate intended for subcutaneous administration. The maximum daily dose is 300 mg, with a total maximum dose of 300 mg over the treatment period. The treatment duration is set for a maximum of 23 weeks. The active substance, Barzolvolimab, is derived from a protein of other origin, specifically designed to target chronic inducible urticaria (CIndU) in patients who are refractory to H1 antihistamines.

In this study, Barzolvolimab is compared against a placebo to evaluate its efficacy and safety in achieving a negative provocation test in patients with chronic inducible urticaria, including subtypes such as cold urticaria (ColdU) and symptomatic dermographism (SD). The trial is conducted in a randomized, double-blind, placebo-controlled, dose-ranging format. The placebo used in the study serves as a comparator treatment to assess the therapeutic effects of Barzolvolimab. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the outcomes of the treatment.

Efficacy

The efficacy of the investigational product, **Barzolvolimab**, will be assessed in a Phase 2 randomized, double-blind, placebo-controlled, dose-ranging study involving patients with Chronic Inducible Urticaria (CIndU), specifically the ColdU and SD subtypes. The primary efficacy endpoint is the proportion of patients achieving a negative provocation test at Week 12. For ColdU patients, a negative provocation test is defined as the absence of wheals at the provocation site within 10 minutes at temperatures ≤ 4°C using TempTest®. For SD patients, it is defined as the absence of wheals at the provocation site within 10 minutes at 0 pins using the FricTest®.

Secondary efficacy endpoints include the mean change from baseline to Week 12 in ColdU Threshold Temperature (CTT) and SD Friction Threshold (CFT), as well as the mean change in Wheal Intensity Numeric Rating Scale provocation (WI-NRSprovo) scores for both ColdU and SD subtypes. Additionally, the study will evaluate the proportion of patients with a negative provocation test at Week 12 in the combined CIndU subtype cohorts and the mean change in WI-NRSprovo in these cohorts. The proportion of patients experiencing treatment-emergent adverse events (TEAEs) over the 20-week treatment period will also be assessed by subtype cohort and in the combined CIndU subtype cohorts.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Read, understood, and provided written informed consent, and Health Insurance Portability and Accountability Act (HIPAA) authorization if applicable, after the nature of the study has been fully explained.
Male or female, ≥ 18 years of age at the time of signing the informed consent
Diagnosis of ColdU or SD for ≥ 3 months prior to Screening Visit 1
Patients with chronic ColdU or SD whose urticaria remains uncontrolled despite a stable regimen of a second-generation non-sedating H1AH as defined by all of the following: Recurrent pruritic wheals with or without angioedema due to ColdU or SD for ≥ 6 weeks prior to Screening Visit 1 despite treatment with a H1AH Patients must have been on a stable regimen of daily use of a single second-generation non-sedating H1AH at approved or increased (up to 4 times the approved) dose for the treatment of ColdU or SD for ≥ 4 weeks prior to randomization and which is expected to remain stable at the time of randomization and throughout the study UCT < 12 at Screening Visit 1 and the randomization visit (Visit 3)
Provocation tests that meet the following criteria: For ColdU patients: developing a wheal at the provocation site within 10 min after provocation using TempTest® at any temperature at both screening (Visit 1) and randomization (Visit 3) For SD patients, developing a wheal at the provocation site within 10 min after provocation using FricTest® with ≥ 3 pins at both screening (Visit 1) and randomization (Visit 3)
Hemoglobin, white blood count (WBC), absolute neutrophil count (ANC), and platelets must be > the lower limit of normal (LLN) and < 1.5 X the upper limit of normal (ULN) range if the higher values between ULN and 1.5 X ULN are deemed to be not clinically significant by the Investigator, at Screening Visits 1 and 2*
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2 x ULN, and total bilirubin < ULN (unless elevated bilirubin is related to Gilbert’s Syndrome), at Screening Visits 1 and 2*
Females must meet one of the following criteria: (X) Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, administered as oral, intravaginal or transdermal (X) progestogen-only hormonal contraception associated with inhibition of ovulation administered as oral, injectable or by implantable means (X) Intrauterine device (IUD) (X) Intrauterine hormone-releasing system (IUS) Females of non-childbearing potential, who are surgically sterile (i.e., had undergone complete hysterectomy, salpingectomy and bilateral oophorectomy) or in a menopausal state (at least 1 year without menses), as confirmed by FSH levels, are eligible.
Male patients must agree that while participating in the study and for at least 150 days after receipt of the study treatment, they will use highly effective methods of contraception with female partners of childbearing potential, and they will not donate sperm. Vasectomy is considered as a highly effective method of contraception provided that the vasectomized patient has received medical assessment confirming the surgical success.
Willing and able to comply with all study requirements and procedures, including the completion of a daily diary during screening and throughout the study. Note: For study eligibility, patients need to complete the diary for at least 6 of the 7 days immediately prior to randomization.

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Exclusion Criteria

Diseases with possible symptoms of urticaria or angioedema such as urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa), autoimmune syndromes with urticarial lesions (e.g., Schnitzler Syndrome) and hereditary or acquired angioedema (e.g., due to C1 inhibitor deficiency).
Active chronic spontaneous urticaria (CSU) or other forms of CIndU including cholinergic-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, or contact-urticaria that would confound assessments of ColdU or SD, respectively, based on the investigator’s clinical judgment.
Familial cold urticaria (FCU), also known as familial cold autoinflammatory syndrome (FCAS).
Any other active pruritic skin diseases that would confound CIndU assessments (e.g., atopic dermatitis, psoriasis, bullous pemphigoid, dermatitis herpetiformis, prurigo nodularis, chronic pruritus of unknown origin) based on the investigator's clinical judgment
Regular (3 or more days a week) use of topical corticosteroid, topical calcineurin inhibitors or topical antihistamines, first-generation sedating antihistamines (e.g., diphenhydramine, hydroxyzine, doxylamine) and other sedatives/hypnotics (e.g., doxepin), within 1 week of Screening Visit 1.
Phototherapy with ultraviolet (UV) A or UVB within 4 weeks of Screening Visit 1.
Non-biologic systemic (oral or injectable) agents listed below, including investigational agents, within 4 weeks or 5 half-lives, whichever is longer, prior to Screening Visit 1. Note: Non-biologic systemic (oral or injectable) agents: corticosteroids, non-steroidal immunosuppressants (e.g., methotrexate, cyclosporin, tacrolimus, mycophenolate mofetil, azathioprine, cyclophosphamide), and other immunomodulators (e.g., dapsone, sulfasalazine, hydroxychloroquine, and colchicine, Jak inhibitors, Bruton's kinase [BTK] inhibitors), mast cell stabilizers (e.g., cromolyn, ketotifen), anabolic steroid (e.g., danazol), and other investigational agents; and trigger desensitization protocol
Biologic therapy including investigational agents (e.g., omalizumab, ligelizumab, dupilumab, IL-1 inhibitor, interferon gamma, TNF inhibitor, B-cell depleting therapy (e.g., rituximab), or other investigational monoclonal antibodies) within 3 months prior to Screening Visit 1.
Trigger desensitization within 4 weeks of Screening Visit 1.
Planned or anticipated use of any prohibited medications during screening and study treatment, and follow-up
Receipt of a live vaccine within 2 months prior to the Baseline (Day 1) Visit (patients must agree to avoid live vaccination during study treatment and within 3 months thereafter). Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally inactivated virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. Currently authorized COVID-19 vaccines are allowed.
Diagnosis of idiopathic anaphylaxis or exercise-induced anaphylaxis, or a history of anaphylaxis (such as those due to Hymenoptera venom or IgE-mediated food allergy), that in the opinion of the investigator, would increase the patient’s risk for systemic hypersensitivity reactions; or any known contraindications or hypersensitivity to any component of study treatments, drugs of similar chemical classes (i.e., to murine, chimeric, or human antibodies) or antihistamines. Note: ColdU patients with a history of cold-induced anaphylaxis due to cold exposure over a large body surface area (such as swimming in cold water) are not excluded
Women who are pregnant or nursing. All female patients with reproductive potential must have a negative pregnancy test prior to starting study treatment.
Severe or uncontrolled chronic diseases (e.g., chronic hepatic or renal disease, diabetes mellitus) that might interfere with the evaluation of the clinical effect or safety of study treatment.
Patients with moderate-to-severe pulmonary or cardiovascular diseases, see Appendix 23 for guidelines. Note: patients with symptomatic cardiovascular or pulmonary disease that requires medication should be carefully assessed and discussed with the medical monitor to assure their cardiovascular and/or pulmonary status does not increase their risk of study participation.
Patients with contraindications for use of epinephrine (e.g., history of closed angle glaucoma, significant arrhythmias, myocardial infarction, or cardiomyopathy) or are taking medications that might interfere with the pharmacodynamic actions of epinephrine (e.g., beta blockers)
Known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
Patients with active COVID-19 infection.
History of malignancy within 5 years before Screening Visit 1, except fully treated carcinoma in situ of the cervix, full treated and resolved non-metastatic squamous or basal cell carcinoma of the skin.
Other screening laboratory or electrocardiogram (ECG) findings that are considered clinically significant.
Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antifungals, antiparasitics or antiprotozoals during the Screening period.
Any other acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with study participation or could interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into the study.
Procedures requiring general or epidural anaesthesia within 8 weeks prior to study treatment, minor procedures (e.g., dental) within 14 days prior to study treatment, or anticipation of procedures requiring general anaesthesia during study participation.
Prior receipt of CDX-0159
Patients who live in detention on court order or on regulatory action will not be enrolled.
Sponsor or contract research organization (CRO) staff directly involved in the conduct of the study, and site staff supervised by the investigator, and their respective family members.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	01 Aug 2022	10
Germany	Not Recruiting	01 Aug 2022	32
Hungary	Not Recruiting	01 Aug 2022	1
Latvia	Not Recruiting	01 Aug 2022	10
Lithuania	Not Recruiting	01 Aug 2022	27
Poland	Not Recruiting	01 Aug 2022	27
Spain	Not Recruiting	01 Aug 2022	7