OPTIMA: Efficacy of Optimized Re-treatment and Step-up Therapy With Omalizumab in Chronic Spontaneous Urticaria (CSU) Patients

Phase 3

Completed

Conditions: Chronic Spontaneous Urticaria

Interventions: Drug: omalizumab

Registration Number: NCT02161562

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This trial assessed the efficacy of optimized re-treatment therapy with omalizumab (150mg or 300mg) after relapse, in participants with Chronic Spontaneous Urticaria who were clinically well-controlled following their first course of treatment with omalizumab (150mg or 300mg). The study also assessed the benefit of uptitrating to 300mg dose in participants who were not well-controlled following their initial course of treatment with omalizumab 150mg, as well as the benefit of treatment extension of those patients who were not well-controlled following their initial course of treatment with omalizumab 300mg.

Detailed Description: The study consisted of 5 phases.

Phase 1 (Screening): At the first visit (Screening Visit), the participant was provided informed consent and then completed all screening visit assessments. During this visit, all CIU/CSU treatments taken by the participant were documented. Any protocol-defined prohibited CIU/CSU treatments were stopped at this visit, and the participant underwent a wash-out period of 1-5weeks (refer to study protocol for medication wash-out times) prior to Phase 2 Visit1. Only non-sedating H1- antihistamines, at locally-approved dosages, were allowed to be continued during the Screening Period and throughout the rest of the study. All participants also needed to complete daily diary during the entire screening period.

Phase 2 (Initial Dosing Period): Following completion of Phase 1, eligible participants were randomly assigned (in a 4:3 ratio) to either Group A or Group B. Participants in Group A were treated with omalizumab 150mg by subcutaneous (SC) injection every 4 weeks during the 24-week Phase 2 (Initial Dosing Period), while participants in Group B were treated with omalizumab 300mg every 4 weeks during this period. Randomization to treatment groups was stratified at Phase 2 Visit 1 by geographic location of the study site (i.e. Canada or Latin America), baseline presence/absence of angioedema and baseline UAS7 score (collected at Phase 2 Visit 1). At the end of Phase 2, all participants with a UAS7 score ≤ 6 entered Phase 3 (Study Treatment Withdrawal Period). Group A participants who had a UAS7 \> 6 at any visit of Phase 2 starting at Week 8 (Phase2-Visit3) skipped Phase 3 and moved directly to Phase 4 (Second Dosing Period) and received 300 mg Omalizumab (step-up). Group B participants who had a UAS7 \>6 at the end of Phase 2 skipped Phase 3 and moved directly to Phase 4.

Phase 3 (Study Treatment Withdrawal Period): During Phase 3 (Study Treatment Withdrawal Period), no study treatment (omalizumab) was given and participants continued to visit the study center at 4-week intervals (to a maximum of 8 weeks). If a UAS7 score ≥16 was observed during Phase 3 (Study Treatment Withdrawal Period), the participant moved directly to Phase 4 (Second Dosing Period). If a participant completed the full 8 weeks of Phase 3 (Study Treatment Withdrawal Period) with a UAS7 score \<16, the participant was moved directly to Phase 5 (Follow-up Period).

Phase 4 (Second Dosing Period)

* Group A participants who relapsed (UAS7 ≥16) during Phase 3 (Study Treatment Withdrawal Period) were retreated with omalizumab 150mg by SC injection every 4 weeks during the 12-week Phase 4 (Second Dosing Period)

* Group A participants who were not clinically well-controlled at week 8 of Phase 2 (Initial Treatment Period) or any subsequent visit in Phase 2 moved to Phase 4 (Second Dosing Period) immediately during which their study treatment was up-titrated to 300mg by SC injection every 4 weeks for 12 weeks.

* Group A participants who had their symptoms well controlled at week 24 (UAS7≤6) but did not relapse during the 8 weeks Study Treatment withdrawal period (UAS7\<16) moved directly to Phase 5, Follow up period.

* Group B participants who relapsed during Phase 3 (Study Treatment Withdrawal Period) were retreated with omalizumab 300mg by SC injection every 4 weeks during the 12- week Phase 4 (Second Dosing Period)

* Group B participants who were not clinically well-controlled at week 24 of Phase 2 (Initial Treatment Period) moved to Phase 4 (Second Dosing Period) immediately during which their study treatment remained 300mg by SC injection every 4 weeks for 12 weeks. In case the treating physician and the participant decided not to extend treatment, they could move directly from Phase 2 (Initial Treatment Period) to Phase 5 (Follow- up Period).

* Group B participants who had their symptoms well controlled at week 24 (UAS7≤6) but did not relapse during the 8 weeks Study Treatment withdrawal period (UAS7\<16) moved directly to Phase 5, Follow up period.

Phase 5 (Follow-up Period)

* Participants who did not relapse (UAS7 \<16) following completion of Phase 3 (Study Treatment Withdrawal Period) entered the 4-week Phase 5 (Follow-up Period).

* Group B participants who did not respond during their initial 24-week treatment period (Phase 2), and who did not wish to extend their treatment into Phase 4 (Second Dosing Phase) were allowed to move directly into the 4-week Phase 5 (Follow-up Period).

* All participants who completed Phase 4 (Second Dosing Period) entered the 4-week Phase 5 (Follow-up Period).

During Phase 5 (Follow-up Period), participants continued to only receive non-sedating H1- antihistamines at approved dosages. Omalizumab was not allowed to be administered during this period.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 314

Inclusion Criteria

Men or women at least 18 years of age at time of screening.
Having a diagnosis of CSU and the presence of symptoms for ≥6 months prior to the screening visit.
Presence of itch and hives for ≥6 consecutive weeks at any time prior to the screening visit despite concurrent use of non-sedating H1-antihistamine treatment
Patient must have been on an approved dose of non-sedating H1-antihistamine for CSU, and no other concomitant CSU treatment, for at least the 7 consecutive days immediately prior to the randomization visit and must document current use on the day of the randomization visit.

Key

Exclusion Criteria

Patients having a clearly defined underlying etiology for chronic urticaria other than CSU including the following urticarias: acute, solar, cholinergic, heat, cold, aquagenic, delayed pressure or contact
Patients with other skin disease associated with itch that could interfere with study outcomes and/or compromise the safety of the patient
Patients with evidence of parasitic infection
Patients with a history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
Pregnant or nursing (lactating) women,
Women of child-bearing potential, unless they are using effective methods of contraception during dosing of study treatment.
Patients who are unable or unwilling to comply with study procedures, attend scheduled study visits, complete questionnaires and daily diaries, or who may otherwise be unable to comply with the study requirements.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
omalizumab 150mg	omalizumab	Participants received 150mg omalizumab every 4 weeks during the initial dosing phase (24 weeks). A second dosing period (at 150mg or 300mg) may have been implemented based on protocol-defined assessment criteria.
omalizumab 300mg	omalizumab	Participants received 300mg omalizumab every 4 weeks during the initial dosing phase (24 weeks). A second dosing period may have been implemented based on protocol-defined assessment criteria.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Were Clinically Well-controlled (UAS7<=6) After the Initial Dosing Period, Relapsed (UAS7>=16) When Treatment Was Discontinued, and Who Achieved a UAS7 Score <=6 at the End of the Second Dosing Period (Retreatment A2 and B2)	Last 7 days of second dosing period, 44 weeks	The UAS7 is a 7-day composite self-reported evaluation of itch (daily score 0-3) plus number of hives (daily score 0-3). The worst possible daily UAS score is 6, and the worst possible UAS7 score is 42. For this outcome, the participant's self-reported UAS7 score will be drawn from the last 7 days of the second dosing period.

Secondary Outcome Measures

Name	Time	Method
The Difference in Urticaria Activity Score Over 7 Days (UAS7) Between the Start and End of the Second Dosing Period, in Participants That Step-up Treatment Dose During the Initial Dosing Period (Step-up A3)	7 days prior to start of second dosing period and last 7 days of Second Dosing Period	The UAS7 is a 7-day composite self-reported evaluation of itch (daily score 0-3) plus number of hives (daily score 0-3). The worst possible daily UAS score is 6, and the worst possible UAS7 score is 42. For this outcome, the participant's self-reported UAS7 score will be drawn from the 7 days prior to the second dosing period, and the last 7 days of the second dosing period. A negative change indicates improvement.
Time to Relapse (Urticaria Activity Score Over 7 Days (UAS7) ≥ 16) After Drug Withdrawal in Participants Who Responded to Initial Dosing Period (Retreatment A2 and B2)	study drug withdrawal period, weeks 24 through 32	The UAS7 is a 7-day composite self-reported evaluation of itch (daily score 0-3) plus number of hives (daily score 0-3). The worst possible daily UAS score is 6, and the worst possible UAS7 score is 42. For this outcome, the time between end of initial dosing period to first occurence of UAS7 ≥ 16 will be evaluated.
The Change in Urticaria Activity Score Over 7 Days (UAS7) From Baseline to Week 24 in Group B Participants	7 days prior to Baseline visit, and last 7 days prior to week 24 of the initial dosing period	The UAS7 is a 7-day composite self-reported evaluation of itch (daily score 0-3) plus number of hives (daily score 0-3). The worst possible daily UAS score is 6, and the worst possible UAS7 score is 42. For this outcome, the participant's self-reported UAS7 score will be drawn from the 7-day period prior to Baseline visit and the last 7 days prior to the week 24 visit of initial dosing period. A negative change from baseline indicates improvement.
Number of Participants With Urticaria Activity Score Over 7 Days (UAS7)≤6 at the End of the Second Dosing Period, in Participants Who Stepped-up Treatment Dosing (Step-up A3)	Last 7 days of the second dosing period	The UAS7 is a 7-day composite self-reported evaluation of itch (daily score 0-3) plus number of hives (daily score 0-3). The worst possible daily UAS score is 6, and the worst possible UAS7 score is 42. For this outcome, the participant's self-reported UAS7 score will be drawn from the last 7 days of the second dosing period.
Difference in Urticaria Activity Score Over 7 Days (UAS7) Between End of Initial Dosing Period and the End of the Second Dosing Period, in Group B3 Participants Who Did Not Respond to the Initial Dosing Period	last 7 days of initial dosing period, week 24, and last 7 days of second dosing period, week 36	The UAS7 is a 7-day composite self-reported evaluation of itch (daily score 0-3) plus number of hives (daily score 0-3). The worst possible daily UAS score is 6, and the worst possible UAS7 score is 42. For this outcome, the participant's self-reported UAS7 score will be drawn from the last 7 days of the initial dosing period and the last 7 days of the second dosing period. A negative change indicates improvement.
Change in Urticaria Activity Score Over 7 Days (UAS7) Between Baseline and End of Second Dosing Period	7 days prior to Baseline visit, and last 7 days of second dosing period	The UAS7 is a 7-day composite self-reported evaluation of itch (daily score 0-3) plus number of hives (daily score 0-3). The worst possible daily UAS score is 6, and the worst possible UAS7 score is 42. For this outcome, the participant's self-reported UAS7 score will be drawn from the 7 days before Baseline and the last 7 days of the second dosing period.
The Number of Participants Who Remained Well-controlled (UAS7<=6) or Who Had Achieved UAS=0 at Phase 4 (Second Dosing Period) Week 8 During Retreatment After Being Well Controlled or Achieving UAS7=0 at Phase 2 (Initial Dosing Period) Week 8	Week 8 of initial dosing phase and week 8 of second dosing phase	The UAS7 is a 7-day composite self-reported evaluation of itch (daily score 0-3) plus number of hives (daily score 0-3). The worst possible daily UAS score is 6, and the worst possible UAS7 score is 42. For this outcome, the participant's self-reported UAS7 score will be drawn from week 8 of initial dosing phase and week 8 of second dosing phase.