| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Chronic Spontaneous Urticaria | |
| E.1.1.1 | Medical condition in easily understood language | | Long-lasting hives with an unknown cause | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | •To evaluate efficacy of different dose regimens of CDX-0159, compared to placebo, in reducing urticaria activity as assessed by urticaria activity score (UAS) in patients with CSU refractory to H1AH therapy | |
| E.2.2 | Secondary objectives of the trial | •To evaluate the efficacy of different dose regimens of CDX-0159, compared to placebo, in reducing itch severity as assessed by itch severity score (ISS) in CSU patients
•To evaluate the efficacy of different dose regimens of CDX-0159, compared to placebo, in reducing hive severity as assessed by hive severity score (HSS) in CSU patients
•To evaluate the efficacy of different dose regimens of CDX-0159, compared to placebo, in reducing angioedema severity as assessed by angioedema activity score (AAS) in CSU patients
•To evaluate the long-term (up to 52 weeks) efficacy of different dose regimens of CDX-0159 in CSU patients
•To evaluate the safety profile of different dose regimens of CDX-0159, compared to placebo, in CSU patients
•To evaluate the long-term (up to 52 weeks) safety profile of different dose regimens of CDX-0159 in CSU patients
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives | | Additional PK/tryptase samples are being taken in U.S., Germany, and South Africa (optional particpation). For this CTA, this would apply to Germany. | |
| E.3 | Principal inclusion criteria | 1.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.
2.Male or female, ≥ 18 years of age at the time of signing the informed consent
3.Diagnosis of CSU ≥ 6 months prior to Screening Visit 1
4.CSU refractory to a stable regimen of second-generation non-sedating H1AH as defined by all of the following:
•Recurrent pruritic wheals with or without angioedema for ≥ 6 weeks at any time prior to Screening Visit 1 despite treatment with a H1AH
Note: Hives consistent with CSU should be documented and confirmed by the investigator prior to randomization
•Patients must have been on a stable regimen of daily use of a second-generation non-sedating H1AH at approved or increased (up to 4 times the approved) dose for the treatment of CSU for ≥ 4 weeks prior to randomization and which is expected to remain stable at the time of randomization and throughout the study
•Weekly urticaria activity score (UAS7, range: 0-42) ≥ 16 and weekly itch severity score (ISS7, range: 0-21) ≥ 8 during the 7-day period immediately prior to randomization
5.Hemoglobin, white blood count (WBC), absolute neutrophil count (ANC), and platelets ≥ the lower limit of normal (LLN) and ≤ than 1.5 X the upper limit of normal (ULN) range if the values between ULN and 1.5 X ULNare deemed to be not clinically significant by the Investigator, at Screening Visits 1 and 2*
6.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*.
*For 5 and 6 above, if test results do not meet the above criteria, a repeat test may be performed to establish eligibility.
7.Females must meet one of the following criteria:
If of childbearing potential, agree to use highly effective contraception from the time of Screening Visit 1 and for at least 150 days after receipt of study treatment. Highly effective methods of contraception include the following:
•combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, administered as oral, intravaginal or transdermal
•progestogen-only hormonal contraception associated with inhibition of ovulation administered as oral, injectable or by implantable means
•intrauterine device (IUD)
•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.
8.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 to be a highly effective method of contraception provided that the vasectomized patient has received medical assessment confirming surgical success..
9.Willing and able to comply with all study requirements and procedures, including the completion of a daily symptom diary during screening and throughout the study. Note: For study eligibility, patients need to complete the diary for at least 6 of 7 days immediately prior to randomization.
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| E.4 | Principal exclusion criteria | 1.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).
2.Active chronic inducible urticaria (CIndU) including symptomatic dermographism (urticaria factitia), cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, cholinergic-, or contact-urticaria that would confound CSU assessments based on the investigator’s clinical judgment.
3.Any other active pruritic skin diseases that would confound CSU assessments (e.g., atopic dermatitis, psoriasis, bullous pemphigoid, dermatitis herpetiformis, prurigo nodularis, chronic pruritus of unknown origin) based on the investigator's clinical judgment
4.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.
5.Phototherapy with ultraviolet (UV) A or UVB within 4 weeks of Screening Visit 1.
6.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), anticoagulants (e.g., warfarin), antifibrinolytic agents (e.g., tranexamic acid), mast cell stabilizers (e.g., cromolyn, ketotifen), and other investigational agents
7.Biologic therapy including approved or investigational biologic agents (e.g., omalizumab, ligelizumab, dupilumab, interleukin (IL)-1 inhibitor, tumor necrosis factor (TNF) inhibitor, B-cell depleting therapy (e.g., rituximab), or other investigational monoclonal antibodies, intravenous immunoglobulin (IVIG) therapy or plasmapheresis within 3 months prior to Screening Visit 1.
8.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.
9.Planned or anticipated use of any prohibited medications during screening and study treatment, and follow-up.
10.Diagnosis of idiopathic anaphylaxis or a history of anaphylaxes (such as those due to Hymenoptera venom or IgE-mediated food allergy), that in the opinion of the investigator, could 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.
11.Women who are pregnant or nursing. All female patients with reproductive potential must have a negative pregnancy test prior to starting study treatment.
12.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.
13. Patients with moderate-to-severe pulmonary or cardiovascular diseases, see Appendix 10 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 dos not increase their risk of study participation.
14. 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 interference with pharmacodynamic actions of epinephrine (e.g. beta blockers).
15.Known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
16.Patients with active COVID-19 infection.
17.History of malignancy within 5 years before Screening Visit 1, except fully treated carcinoma in-situ of the cervix, fully treated and resolved non-metastatic squamous or basal cell carcinoma of the skin
More criteria can be found in Synopsis (18 to 24)
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| E.5 End points |
| E.5.1 | Primary end point(s) | | Mean change from baseline to Week 12 in UAS7 | |
| E.5.2 | Secondary end point(s) | - Mean change from baseline to Week 12 for ISS7, HSS7, and AAS7.
- Safety as assessed by adverse events over the treatment periods to Week 16 and Week 52.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Belgium | | Bulgaria | | Estonia | | Georgia | | Germany | | Hungary | | Poland | | South Africa | | Spain | | United States | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
