| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria |
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| E.1.1.1 | Medical condition in easily understood language |
| Chronic Spontaneous Hives |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020197 |
| E.1.2 | Term | Hives |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
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| 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 |
The primary objective of the study is to demonstrate biosimilar efficacy of TEV 45779 300 mg compared to XOLAIR 300 mg as determined by change in itch severity score of chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria (CSU) in patients who remain symptomatic despite antihistamine (H1) treatment to demonstrate relative potency of TEV 45779 compared to XOLAIR as determined by itch severity score of CIU/CSU in patients who remain symptomatic despite antihistamine (H1) treatment.
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| E.2.2 | Secondary objectives of the trial |
To compare further efficacy parameters between TEV 45779 and XOLAIR. The comparisons will be performed between the different doses (150 mg vs. 300 mg) as well as between TEV 45779 and XOLAIR.
To compare efficacy parameters between TEV 45779 and XOLAIR after the switch from XOLAIR to TEV 45779. The comparisons will be performed between the different doses (150 mg vs. 300 mg) as well as between TEV 45779 and XOLAIR.
To compare the safety and tolerability between TEV 45779 and XOLAIR -throughout the study
-after the switch from XOLAIR to TEV 45779.
-To compare pharmacokinetics between TEV 45779 and XOLAIR after multiple doses
-To compare pharmacodynamics between TEV 45779 and XOLAIR after multiple doses
-To assess the immunogenicity of TEV 45779 in comparison with XOLAIR
-throughout the study
-after the switch from XOLAIR to TEV 45779
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. Male or female patients aged ≥18 years and ≤75 years.
b. Diagnosis of CIU/CSU refractory to H1 antihistamines at the time of randomization, as defined by all of the following:
-The presence of itch and wheals for ≥8 consecutive weeks at any time prior to enrollment despite current use of H1 antihistamine treatment during this time period.
-Weekly urticaria activity score (UAS7; sum of the daily number of wheals score and itch severity score over 7 days) ≥16 (range 0 42) and itch component of UAS7 ≥8 (range 0 21) during 7 days prior to randomization.
-Urticaria activity score (UAS) ≥4 assessed by a clinician on ≥1 of the screening visit days.
-Patients must have been on an approved dose of an H1 antihistamine for CIU/CSU for ≥3 consecutive days immediately prior to the start of screening and must document current use on the day of the initial screening visit , OR, have their H1 antihistamine for CIU/CSU adjusted to an approved dose during the first 3 days of screening and have their adjusted use documented at the end of the dose adjustment.
-CIU/CSU diagnosis for ≥3 months.
c. Women may be included if they fulfill one of the following criteria:
-Women of non-childbearing potential who are either surgically (documented hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or congenitally sterile as assessed by a physician, or 1 year postmenopausal (no menses for 12 months without an alternative medical cause plus an increased concentration of follicle stimulating hormone [FSH] of more than 35 U/L) in women not using hormonal contraception or hormonal replacement therapy.
-Women of childbearing potential whose male partners are potentially fertile (ie, no vasectomy) must:
-have a negative beta human chorionic gonadotropin (β HCG) test at baseline;result at screening (visit 2); and
-use highly effective birth control methods for the duration of the study (ie, starting at screening) and for 5 half lives (20 weeks) after last dose of IMP.
Highly effective birth control methods are methods that can achieve a failure rate of less than 1% per year when used consistently and correctly:
- Combined estrogen and progestogen hormonal contraception (oral, intravaginal, transdermal) associated with inhibition of ovulation; these should be initiated at least 7 days before the first dose of IMP.
- Progestogen-only hormonal contraception (oral, injectable, or implantable) associated with inhibition of ovulation; these should be initiated at least 7 days before the first dose of IMP.
- Intrauterine device or intrauterine hormone-releasing system need to be in place at least 2 months before the start of screening.
- Bilateral tubal occlusion (for hysteroscopic "Essure®" a hysterosalpingogram is required 3 months post procedure to assess surgical success) or tubal ligation.
-Vasectomized partner provided he is the sole sexual partner and has received medical assessment of the surgical process success.
-Sexual abstinence is only considered a highly effective method if defined as refraining from heterosexual intercourse in the defined period. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
Unacceptable birth control methods:
-Periodic abstinence (eg, calendar, ovulation, symptothermal, post ovulation methods), declaration of abstinence for the duration of a study, and withdrawal are not acceptable methods of contraception (according to Medicines and Healthcare Products Regulatory Agency).
d. Male patients (including vasectomized men) with partners who are of childbearing potential (whether pregnant or not) must use condoms prior to IMP administration and until 20 weeks after last IMP dose.
e. Must be able to understand the requirements of the study and to provide their written informed consent to participate in the study.
f. Must be willing and able to comply with study requirements and procedures as specified in this protocol. In particular, the patient must be willing and able to complete a symptom diary twice daily (morning or evening) for the duration of the study. The patients must have diary entries during at least 4 of the 7 days prior to randomization. |
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| E.4 | Principal exclusion criteria |
a. Body weight <40 kg.
b. Clearly defined underlying etiology for chronic urticarias other than CIU/CSU.
c. Evidence of parasitic infection defined as meeting the following 3 criteria:
-Risk factors for parasitic disease (living in an endemic area, chronic gastrointestinal symptoms, travel within the last 6 months to an endemic area and/or chronic immunosuppression), and
-An absolute eosinophil count more >2× the upper limit of normal (ULN), and
-Evidence of parasitic colonization or infection on stool evaluation for ova and parasites. Note that stool ova and parasite evaluation will only be conducted in patients with risk factor(s) and an eosinophil count >2× the ULN.
d. Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, or other skin disease associated with itch.
e. Treatment with an investigational agent within 30 days or longer depending on half life (>5 half lives) prior to the start of screening.
f. Previous treatment with omalizumab or other Anti-IgE therapy within a year prior to the start of screening.
g. Routine (daily or every other day during 5 or more consecutive days) doses of the following medications within 30 days prior to screening: Systemic or cutaneous (topical) corticosteroids (prescription or over the counter), hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide.
h. Intravenous immunoglobulin G, or plasmapheresis within 30 days prior to the start of screening.
i. Regular (daily/every other day) doxepin (oral) use within 2 weeks prior to the start of screening.
j. Any H2 antihistamine use within 7 days prior to the start of screening.
k. Any LTRA (montelukast or zafirlukast) use within 7 days prior to the start of screening.
l. Any H1 antihistamines at greater than approved doses use from 3 days
after the start of screening.
m. Current malignancy, history of malignancy within 5 last years, or currently under work up for suspected malignancy except non melanoma skin cancer that has been treated or excised and is considered resolved.
n. Hypersensitivity to omalizumab or any component of the formulation.
o. History of anaphylactic shock.
p. Contraindications to diphenhydramine hydrochloride.
q. Pregnant or lactating woman, or plans to become pregnant during the study.
r. Presence of clinically significant cardiovascular, neurological, psychiatric, metabolic, or other pathological conditions that could interfere with the interpretation of the study results and or compromise the safety of the patients.
s. Evidence of current drug or alcohol abuse.
t. Patients taking either LTRAs or H2 blockers for diseases other than chronic idiopathic urticaria (CIU) (eg, asthma or gastroesophageal reflux disease, respectively) will be permitted to continue their use during the study. These diseases must be recorded as part of the medical history collected during the screening period. Inhaled asthma controllers, including corticosteroids, are also permitted during the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Change from baseline in the weekly itch severity score (ISS7; sum of the daily itch severity score for 7 days) at Week 12, TEV 45779 300 mg compared to XOLAIR 300 mg and
• Relative potency of 2 dose levels (300 mg and 150 mg) of TEV 45779 and XOLAIR as measured by change from baseline in ISS7 at Week 12 using a 4 point assay, ie, TEV 45779 300 mg, TEV 45779 150 mg, XOLAIR 300 mg and XOLAIR 150 mg.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints are as follows.
• Change from baseline in ISS7 at Week 12
• Change from baseline in the ISS7 at Week 4
• Change from baseline in the weekly urticaria activity score (UAS7; sum of the daily number of wheals score and itch severity score over 7 days) at Week 12
• Percentage of patients with UAS7 ≤6 at Week 12
• Percentage of complete responders (UAS7=0) at Week 12
• Change from baseline in the physician’s (in clinic) assessment of UAS7 at Week 12
• Change from baseline in the weekly number of wheals score at Week 12
• Change from baseline in the weekly size of the largest wheals score at Week 12
• Time to minimally important difference (MID; reduction from baseline in ISS7 of ≥5 points) response up to Week 12
• Percentage of ISS7 MID responders at Week 12 (percentage of patients with reduction of ≥5 points from baseline in ISS7 at Week 12).
• Percentage of angioedema free days from Week 4 to Week 12
• Change from Week 12 in ISS7 at Week 24
• Change from Week 12 in ISS7 at Week 40
• Change from Week 12 in UAS7 at Week 24
• Change from Week 12 in the physician’s (in clinic) assessment of urticaria activity score (UAS) at Week 24
• Change from Week 12 in the weekly number of wheals score at Week 24
• Change from Week 12 in the weekly number of wheals score at Week 40
• Change from Week 12 in the weekly size of the largest wheals score at Week 24
• Change from Week 12 in the weekly size of the largest wheals score at Week 40
• Percentage of angioedema free days from Week 12 to Week 24
The safety/tolerability parameters include:
• Adverse events (and the number of patients who withdraw from the study due to adverse events)
• Change from baseline in clinical laboratory measurements (serum chemistry, hematology, and urinalysis) and vital signs
• Physical examination findings
• Electrocardiogram fndings
• Local tolerability at the injection site after each investigational medicinal product (IMP) administration
• Use of concomitant medication (including use of rescue medication)
• Device-related adverse events and malfunctions
The pharmacokinetic parameter is:
• Omalizumab serum concentration before next dose (Ctrough)
• Omalizumab serum concentration following last dose at Week 24, 28, 32, 36 and 40
The pharmacodynamic parameters are:
• Free immunoglobulin E (IgE) serum concentration
• Total IgE serum concentration
The immunogenicity parameters are:
• Incidence of patients with a confirmed anti drug antibody (ADA) positive sample
• For confirmed positive samples, the ADA titer and the neutralizing potential will be tested
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Yes |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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 | 40 |
| 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 |
| Ukraine |
| Taiwan |
| Australia |
| Georgia |
| India |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| United States |
| Bulgaria |
| Czechia |
| Greece |
| Hungary |
| Poland |
| Slovakia |
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| 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
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| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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