| 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 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10072757 |
| E.1.2 | Term | Chronic spontaneous urticaria |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
| 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 |
Efficacy Objectives:
The primary objective of the study will be to characterize the efficacy of lirentelimab SC in omalizumab-naïve and omalizumab-exposed adult subjects with H1-AH refractory CSU as assessed by the absolute change from baseline in UAS7 at Week 12.
Safety Objectives:
To evaluate the safety and tolerability of lirentelimab in adult subjects with H1-AH refractory CSU by determining AE incidence and severity, study withdrawals due to AE, changes in vital signs and laboratory tests including immunogenicity, changes in concomitant medication beginning on or after the first injection of study drug, and other safety parameters. |
|
| E.2.2 | Secondary objectives of the trial |
To further characterize the efficacy of lirentelimab SC in adult subjects with CSU as measured by the following:
1) Improvement of severity of hives assessed as absolute change from baseline in Hives Severity Score (HSS7) at Weeks 12.
2) Improvement of severity of itch assessed as absolute change from baseline in Itch Severity Scale (ISS7) at Weeks 12.
3) Complete absence of hives and itch at Weeks 12, assessed as proportion of subjects achieving UAS7=0.
4) Occurrence of treatment-emergent adverse events (TEAE) and serious adverse events (SAE), laboratory values, vital signs, and physical examinations during the study. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects with CSU are eligible to enroll in the study if they meet all of the following criteria:
1) Subject is able to understand the information on the study, has the capacity to consent, and has provided written informed consent.
2) Male and female subjects ≥18 years of age at the time of screening.
3) CSU diagnosis for ≥6 months.
4) Diagnosis of moderate-severe CSU refractory to H1-AH at a minimum of the licensed dose at the licensed frequency at the time of randomization as defined by the following:
− Presence of hives and itch for ≥6 consecutive weeks prior to Screening Visit 1.
− UAS7 score (range 0–42) ≥16 and HSS7 score (range 0–21) ≥8 during the 7 days prior to randomization.
5) Subjects that are omalizumab-naïve or omalizumab-exposed. Omalizumab-exposed subjects are those that have demonstrated secondary loss of response, intolerance, or lack of access to biologics due to economic reasons.
6) Subjects must be on a stable dose of H1-AH, between 1× and 4× of the licensed dose and at the licensed dosing frequency, for treatment of CSU for at least 1 week prior to screening and willing to remain on a stable dose throughout the study.
7) Able and compliant with completing a daily symptom eDiary for the duration of the study and adherent to the study visit schedules.
8) Female subjects must be either postmenopausal (defined as no menses for 12 months without an alternative medical cause) with FSH level >30 mIU/mL at screening or surgically sterile (tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 3 months or, if of childbearing potential, have a negative pregnancy test and agree to use a highly effective method of contraception as defined in this protocol or abstain from sexual activity, if compliant with preferred and usual lifestyle of the subject from screening until the end of the study or for 120 days following the last dose of study drug, whichever is longer.
9) Male subjects with female partners of childbearing potential must agree to use a highly effective method of contraception from screening until the end of the study or for 120 days following the last dose of study drug, whichever is longer. All fertile men with female partners of childbearing potential should be instructed to contact the Investigator immediately if they suspect their partner might be pregnant (e.g., missed or late menstrual period) at any time during study participation. |
|
| E.4 | Principal exclusion criteria |
1) History of hypersensitivity to the study drugs or their excipients or to drugs of similar chemical classes.
2) Current use of biologics for any indication.
3) Demonstrated lack of primary response to treatment with a biologic therapy (e.g., omalizumab) for the treatment of CSU, defined as no response to treatment despite complete adherence to a prescribed regimen (e.g., a stable dose of omalizumab at ≥300 mg/kg per month) for at least 3 months, based on interview at screening.
4) Use of any of the following treatments within 4 weeks prior to the baseline visit or any condition that in the opinion of the Investigator is likely to require such treatment(s) during the first 4 weeks of study treatment:
− Immunosuppressive or immunomodulatory drugs, including but not limited to systemic calcineurin inhibitors, mTOR inhibitors, anti-metabolites, alkylating agents (e.g., cyclophosphamide), and eosinophil-depleting drugs (e.g., pramipexole).
− Routine (daily or every other day during 5 or more consecutive days) doses of systemic hydroxychloroquine
− Plasmapheresis
5) Use of oral Janus kinase (JAK) inhibitors within 8 weeks of the baseline visit (requires discussion with Allakos Medical Monitor prior to subject enrolling in study).
6) Use of any of the following treatments within 3 weeks prior to the baseline visit:
− H2-AH
− Routine (daily or every other day during 5 or more consecutive days) doses of systemic corticosteroids
− Regular (daily or every other day) doxepin (oral)
− Leukotriene Receptor Antagonists (LTRA) (e.g., montelukast, zafirlukast)
7) H1-AH use at greater than approved doses or greater than local CSU guideline recommended doses after Screening Visit 1.
8) Previous treatment with biologics or intravenous immunoglobulin:
− Any cell-depleting agents including but not limited to rituximab; within 6 months prior to the baseline visit or until lymphocyte count returns to normal, whichever is longer.
− Other biologics, including investigational biologics (e.g., dupilumab, omalizumab, benralizumab, etc.) and TNF inhibitors (e.g., infliximab, adalimumab) within 5 half-lives if known or 8 weeks prior to baseline visit, whichever is longer.
- Intravenous immunoglobulin (IVIG) within 5 half-lives
9) Planned or anticipated use of any prohibited medication.
10) Subjects having causes other than CSU for their urticaria including symptomatic dermographism, cholinergic urticaria, or any inducible urticaria.
11) Diseases other than chronic urticaria with urticarial or angioedema symptoms, including chronic itching, that in the Investigator’s opinion might influence study evaluations and results.
12) Subjects with known or suspected urticarial vasculitis.
13) Subjects with known or suspected hereditary angioedema.
14) Any other skin disease associated with chronic itch, including atopic dermatitis, that in the Investigator’s opinion might influence study outcome and subject’s interpretation of symptoms caused by CSU.
15) A helminth parasitic infection diagnosed within 6 months prior to the date that informed consent is obtained and has not been treated with or has failed to respond to standard-of-care therapy.
16) Evidence of active HIV infection at screening based on serology or evidence of active hepatitis B or C at screening based on serology.
17)Presence of an abnormal screening laboratory value considered to be clinically significant by the Investigator.
18) Known or suspected history of alcohol, drug, or other substance abuse or dependence that in the opinion of the Investigator may interfere with study participation or assessments.
19) Treatment with chemotherapy or radiotherapy in the preceding 6 months.
20) History of malignancy except carcinoma in situ in the cervix, early-stage prostate cancer, or non-melanoma skin cancers.
21) Women who are pregnant, breastfeeding, or planning to become pregnant while participating in the study.
22) Participation in a concurrent interventional study with the last intervention occurring within 30 days prior to study drug administration (or 90 days or 5 half-lives, whichever is longer, for biologic products).
23) Subjects who weigh <40 kg at screening.
24) Any other reason that in the opinion of the Investigator or the Medical Monitor makes the subject unsuitable for enrollment.
25) Vaccination with live attenuated vaccines within 30 days prior to initiation of treatment in the study, during the treatment period, or vaccination expected within 5 half-lives (4 months) of study drug administration.
26) Employees or relatives of the Sponsor or the Investigator, or other persons dependent on the Sponsor or the Investigator.
27) Commitment to an institution by order issued either by the judicial or the administrative authorities.
28) Presence of a SARS-CoV-2 infection and/or have not completed an authorized/approved COVID-19 primary immunization series as per national recommendations at the time of screening (Germany only). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint in the study will be the absolute change in UAS7 at Week 12 compared with baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be assessed at Week 12, i.e., 2 weeks after the last dose in the double-blind period of the study. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
1) Improvement of severity of hives assessed as absolute change from baseline in HSS7 at Week 12.
2) Improvement of severity of itch assessed as absolute change from baseline in ISS7 at Week 12.
3) Complete absence of hives and itch at Weeks 12 assessed as proportion of subjects achieving UAS7 = 0.
4) Occurrence of TEAE and SAE, laboratory values, vital signs, and physical examinations during the study.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoint will be assessed at Week 12, i.e., 2 weeks after the last dose in the double-blind period of the study. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 2 |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| United States |
| Germany |
| Poland |
|
| 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
|
The end of the double-blind, placebo-controlled period of the study is defined as the completion of the last follow-up visit of the last enrolled subject who elects not to participate in the OLE period of the study.
For subjects electing to enter the OLE period of the study, the end of the OLE period of the study is defined as the completion of the last follow-up visit for the last subject.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 3 |
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