Efficacy and Safety of Ixekizumab in a Randomized, Double-blinded, Placebo-controlled Phase IIIb Study of Patients With Moderate-to-severe Genital Psoriasis

C. Ryan; A. Menter; L. Guenther; A. Blauvelt; R. Bissonnette; K. Meeuwis; J. Sullivan; J.C. Cather; G. Yosipovitch; A.B. Gottlieb; J.F. Merola; K. Callis Duffin; S. Fretzin; O.O. Osuntokun; R. Burge; A.N. Naegeli; F.E. Yang; C.-Y. Lin; K. Todd; A. Potts Bleakman; on behalf of the IXORA-Q Study Group

Disclosures

The British Journal of Dermatology. 2018;179(4):844-852. 

In This Article

Patients and Methods

Participants

Participants were ≥ 18 years old; had chronic plaque psoriasis for ≥ 6 months prior to baseline; had moderate-to-severe genital (sPGA-G ≥ 3) and overall psoriasis (overall sPGA ≥ 3); had plaque psoriasis in a nongenital area; had BSA involvement of ≥ 1% (up to 40% of enrolled patients could have BSA < 10%); were candidates for phototherapy or systemic therapy; had previously failed to respond to, or were intolerant of, at least one topical therapy for GenPs; and had agreed to use a reliable method of birth control.

Patients were excluded if they had forms of psoriasis other than plaque psoriasis, had pustules or vesicles in the genital area, or had previously received treatment with interleukin–17 antagonists. Additional key exclusion criteria included prior exposure to agents targeting α–4 integrin, live vaccination within 12 weeks prior to baseline, current or prior history of lymphoproliferative disease or malignant disease within 5 years prior to baseline, a recent history of suicide attempt (≤ 30 days) or a score of 3 on item 12 (thoughts of death or suicide) on the Quick Inventory of Depressive Symptomatology Self-Report (16 items) at screening or baseline or a history of histoplasmosis, coccidioidomycosis or any other infection typical of an immunocompromised host. Complete inclusion and exclusion criteria are available in Appendix S1 (see Supporting Information).

Study Design

Participants were randomized 1 : 1 to ixekizumab (160 mg at week 0, then 80 mg every 2 weeks through week 12) or placebo during a 12–week blinded treatment period. Participants then entered a currently ongoing open-label treatment period through week 52.

IXORA-Q (Clinicaltrials.gov listing NCT02718898) was conducted in accordance with the ethical principles of the Declaration of Helsinki. All patients provided written informed consent before undergoing study-related procedures.

Outcomes

Efficacy. The primary end point was to determine whether ixekizumab was superior to placebo at week 12 as determined by the percentage of patients achieving 0 or 1 (clear or minimal) on the sPGA-G.[13] The major secondary end points were to determine whether ixekizumab was superior to placebo at week 12 as determined by the percentage of patients achieving 0 or 1 (clear or minimal) on the overall sPGA, a clinically meaningful (≥ 3–point) improvement from baseline for patients with ≥ 3 at baseline on the GenPs itch numerical rating scale (NRS),[14] and a GenPs Sexual Frequency Questionnaire (GenPs-SFQ)[15] item 2 score of 0 or 1 for patients with a score ≥ 2 at baseline. Additional secondary end points included mean change from baseline in the modified GenPs Area and Severity Index (mGPASI)[1,9] and in the Dermatology Life Quality Index (DLQI) at week 12. The percentage of patients achieving 0 or 1 on the DLQI at week 12 was also measured.

The GenPs-SFQ[15] is a two-item, patient-reported outcome measure to assess the impact of GenPs on the frequency of sexual activity (including nonintercourse activities such as masturbation). Item 1 assesses the overall frequency of sexual activity by asking how often in the last week patients engaged in sexual activity (none/zero, once, or two or more times). Item 2 assesses the impact of GenPs on the frequency of sexual activity by asking how often during the last week GenPs symptoms limited the frequency of sexual activity; responses include never (0), rarely (1), sometimes (2), often (3) or always (4). Additional details on outcome measures are described in Appendix S1 (see Supporting Information).

Investigators were trained in the use of the sPGA-G for clinical assessment of GenPs through either an in-person or online training module, which was accompanied by a certification examination. Details on the training module and examination are described in Merola et al.[13] The GenPs-SFQ item 2 and genital itch NRS were collected using an electronic diary that included instructions and guidance for self-assessment.

Safety. Safety was evaluated by monitoring of adverse events (AEs) for all enrolled patients. Treatment-emergent AEs (TEAEs) were defined as any unfavourable or unintended sign (including laboratory results), symptom or disease that first occurred or worsened on or after baseline. TEAEs were classified by severity, relationship with study drug or procedure, and association with patient discontinuation. AEs of special interest included cytopenias, liver function test changes or enzyme elevations, infections, injection-site reactions, allergic reactions or hypersensitivities, cerebrocardiovascular events, malignancies, inflammatory bowel disease and depression.

Statistical Analysis

Sample-size determination. Study enrolment was planned for approximately 146 patients randomized 1 : 1 into treatment groups. As no biological drug had been evaluated in a large-scale, randomized, phase III clinical trial and no prior data existed for the sPGA-G, the sample size was calculated based on data from the assessment of DLQI item 9 (sexual difficulties due to skin) from phase II and phase III studies of ixekizumab in plaque psoriasis. Assumptions based on data from these studies included rates of 2% and 20% for skin-related sexual difficulties for the ixekizumab and placebo treatment groups, respectively. Power calculations used a two-sided Fisher's exact test at a 0·05 level of significance. With 146 patients (73 per treatment group) the study was calculated to have 94% power.

Efficacy and safety analysis. Efficacy analyses were performed for all randomized patients according to the treatment group to which they were assigned (intent-to-treat population). A gatekeeping strategy for testing the primary and major secondary end points was implemented to control the overall type I error rate at a two-sided alpha level of 0·05 (details are described in Appendix S1; see Supporting Information). There was no adjustment for multiple comparisons for any other secondary end points or time points.

Categorical efficacy and health outcome variables were analysed using a logistic regression model accounting for missing data using nonresponder imputation, in which patients were defined as nonresponders if they did not meet the clinical response criteria or had missing clinical response data for any reason including discontinuation at the analysis time point, unless otherwise specified. Continuous variables were analysed using a mixed-effects model for repeated measures (MMRM). Type III tests for the least square mean (LSM) were used for statistical comparisons between treatment groups for continuous variables. Both the logistic and MMRM models included baseline BSA category (1 to < 10% vs. ≥ 10%) as a covariate. Subgroup analysis for sPGA-G 0/1 response at week 12 using nonresponder imputation within each BSA subgroup (baseline BSA of 1 to < 10% or ≥ 10%) and sex (male or female) was performed.

Safety outcomes were summarized for all randomized patients who received at least one dose of investigational product according to the treatment group to which they were assigned. Safety data were summarized as the frequency of events in each treatment group.

Additional details of the statistical methods are described in Appendix S1.

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