Study to Evaluate the Therapeutic Equivalence of SYN008 Versus Xolair® in the Treatment of Patients With Refractory Chronic Spontaneous Urticaria

A Multicenter Randomized, Double-blind, Parallel, Positive-controlled Phase III Clinical Trial to Evaluate the Therapeutic Equivalence of SYN008 Versus Xolair® in the Treatment of Patients With Refractory Chronic Spontaneous Urticaria

• This study is a multicenter, randomized, double-blind, parallel-group, positive-controlled phase III study to evaluate the therapeutic equivalence of SYN008 versus omalizumab for injection (Xolair®) in the treatment of CSU patients who remain symptomatic despite antihistamine treatment.

A total of approximately 340 patients with H1 antihistamines (H1AH) refractory CSU will be randomized into two treatments arms (SYN008 300 mg s.c., and omalizumab 300 mg s.c.) at a 1:1 ratio. Both SYN008 and omalizumab will be injected every 4 weeks as an add-on therapy on top of H1AH treatment.

The study will consist of three distinct epochs over 27 weeks, as follows:

• Screening epoch: Day -21 to Day -1
• Randomized-treatment epoch: Day 1 to Week 12
• Post-treatment follow-up epoch: Week 1

Inclusion Criteria:

1. Diagnosis of CSU refractory to H1AH at the time of randomization, as defined by all of the following:

   • CSU diagnosis for ≥ 6 months;
   • The presence of itch and hives for ≥ 6 consecutive weeks within one year prior to randomization despite use of H1AH treatment during this time period;
   • UAS7 score (range 0-42) ≥ 16 and itch component of UAS7 (range 0-21) ≥ 8 during 7 days prior to randomization (Day 1);
   • In-clinic UAS ≥ 4 on at least one of the screening visit days;
   • Patients must have been on an approved dose of an H1AH for CSU for at least the 3 consecutive days immediately prior to the screening visit and must have documented current use on the day of the initial screening visit.

2. Voluntarily sign the informed consent form. Willing and able to complete a daily symptom diary for the duration of the study, and comply with the protocol requirements.

3. Patients must not have had any missing diary entries in the 7 days prior to randomization.

4. Both male and female patients must agree to practice contraception from the signing of informed consent to 6 months after the last dose of study drugs.

Exclusion Criteria:

1. Previous treatment with omalizumab within one year prior to signing the informed consent.

2. Hypersensitivity to omalizumab, study drug excipients or other biosimilars, or have a history of severe drug allergy or anaphylactic shock.

3. Clearly defined underlying etiology for chronic urticarias other than CSU. This includes but is not limited to:

   1. dermatographism (factitious urticaria);
   2. cold, heat, solar, delayed pressure, aquagenic, cholinergic or contact urticarias;
   3. Any of the following diseases, which may have symptoms of urticaria and/or angioedema: urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary or acquired angioedema, lymphoma, leukemia, etc.

4. Patients with a stool examination positive for ova or parasites at screening. {Stool ova and parasite evaluation will only be conducted in patients with BOTH risk factors for parasitic disease (living in an endemic area, and/or chronic gastrointestinal (GI) symptoms and chronic immunosuppression, travel within the last 6 months to an endemic area) AND an absolute eosinophil count more than twice the upper limit of normal.}

5. Suffer from other chronic pruritic dermatosis that may confound the results: atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, etc.

6. CSU patients who had difficulty breathing episodes due to angioedema in the past six months.

7. Active infections requiring treatment at screening, include but not limited to pulmonary infection and tuberculosis.

8. Patients with platelet count ≤100*109/L at screening.

9. A history of malignancy of any organ or system within 5 years prior to screening, regardless of local recurrence or metastasis {except for basal cell carcinoma, actinic keratosis, or Bowen's disease (squamous cell carcinoma in situ) that have been treated and have not recurred in the past 12 weeks; Cervical carcinoma in situ or non-invasive malignant colonic polyps that have been resected and have not recurred within the last 5 years}

10. Presence of clinically significant unstable diseases:

    • High risk of severe ventricular arrhythmias, such as significant left ventricular dysfunction, NYHA class III / IV;
    • Myocardial infarction occurred within 6 months before screening. History of unstable angina, acute coronary syndrome or other high-risk coronary heart disease;
    • Poorly controlled hypertension [Hypertension diagnosis of grade II or III, high risk, and systolic blood pressure (SBP) ≥ 160 mmHg or diastolic blood pressure (DBP) ≥ 100 mmHg while taking one or two antihypertensive drugs].

11. Presence of clinically significant cardiovascular, neurological, psychiatric, metabolic, hepatic, or other pathological conditions that could interfere with the interpretation of the study results and or compromise the safety of the patients, e.g.:

    • Abnormal liver function [AST or ALT ≥ 1.5 x ULN, or total bilirubin ≥ 1.5 x ULN]; abnormal renal function [elevated serum creatinine > 1.5 x ULN];
    • HBsAg positive and HBV DNA quantitative value exceeds the upper limit of the normal value range of each research site, or positive in any one of the tests of hepatitis C virus antibody, HIV antibody and Treponema pallidum antibody;
    • ECG abnormalities of clinical significance, e.g., clinically significant II-III degree atrioventricular (AV) block without a pacemaker, QTc interval≥480 ms, or sustained tachycardia requiring treatment.

12. History of alcohol or drug abuse, within the last 6 months prior to screening.

13. Currently participating in other clinical trials, or have received any experimental intervention within 3 months prior to signing the informed consent.

14. Pregnant or nursing (lactating) women.

15. Currently taking or plan to take medications prohibited by the protocol at screening.

16. Other conditions deemed by investigator as unsuitable for this trial.