A Study to Test Whether BI 655130 (Spesolimab) Prevents Flare-ups in Patients With Generalized Pustular Psoriasis

Study Overview
=================
Brief Summary
-----------------
This is a study in adolescents and adults with Generalized Pustular Psoriasis (GPP). People between 12 and 75 years old can take part in the study. The study is open to people who had GPP flare-ups in the past but whose skin is clear or almost clear when they join the study. The purpose of the study is to test 3 different doses of a medicine called spesolimab and to see whether it helps to prevent GPP flare-ups. Participants are put into 4 groups by chance. Three groups get different doses of spesolimab. The fourth group gets a placebo. Placebo looks like spesolimab but does not contain any medicine. Spesolimab and placebo are given as an injection under the skin. Participants are in the study for about 1 year and 4 months. During this time, they visit the study site about 15 times. For the first 11 months, participants get spesolimab or placebo injections every month. At the study visits, the doctors check participants' skin for signs of a new GPP flare-up. The doctors also check the general health of the participants. If a participant has a GPP flare-up during the study, more visits may be necessary. In case of a flare-up, participants get a dose of spesolimab as an infusion into a vein.

Official Title
-----------------
Effisayil™ 2: Multi-center, Randomized, Parallel Group, Double Blind, Placebo Controlled, Phase IIb Dose-finding Study to Evaluate Efficacy and Safety of BI 655130 (Spesolimab) Compared to Placebo in Preventing Generalized Pustular Psoriasis (GPP) Flares in Patients With History of GPP.

Conditions
-----------------
Generalized Pustular Psoriasis

Intervention / Treatment
-----------------
* Drug: Spesolimab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with a known and documented history of GPP per ERASPEN criteria (see Section 3.3.1) regardless of IL36RN mutation status, with at least 2 presentations of moderate to severe GPP flares with fresh pustulation (new appearance or worsening) in the past. Patients with a GPPGA score of 0 or 1 at screening and randomization. Patients who are not on concomitant GPP treatment at time of randomization (V2) must have had at least two presentations of moderate to severe GPP flare in the past year, at least one of which had evidence of either fever and/or elevated CRP and/or elevated WBC, and/or asthenia and/or myalgia. Patients who are not on concomitant GPP treatment at time of randomization (V2) but who were on concomitant GPP treatment until shortly before randomization (V2) (≤ 12 weeks before randomization), these patients must have a history of flaring while on concomitant treatment for GPP or in case of dose reduction or discontinuation of their concomitant medication. Patients who are on concomitant treatment regimen with retinoids and/or methotrexate and/or cyclosporine must stop at the day of randomization (V2). These patients must have a history of flaring while on concomitant treatment for GPP or in case of dose reduction or discontinuation of these concomitant medications. Male or female patients, aged 12 to 75 years at screening. For all patients, a minimum weight of 40 kg is required. Signed and dated written informed consent and assent in accordance with ICH-GCP and local legislation prior to admission in the trial. Women of childbearing potential (WOCBP)1 must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the CTP as well as in the patient, parent(s) (or patient's legal guardian) information. Exclusion Criteria: Patients with SAPHO (Synovitis-acne-pustulosis-hyperostosis-osteitis) syndrome. Patients with primary erythrodermic psoriasis vulgaris. Severe, progressive, or uncontrolled hepatic disease, defined as >3-fold Upper Limit of Normal (ULN) elevation in Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) or alkaline phosphatase, or >2-fold ULN elevation in total bilirubin. Treatment with: Any restricted medication as specified in the CTP, or any drug considered likely to interfere with the safe conduct of the study, as assessed by the investigator. Any prior exposure to BI 655130 or another IL36R inhibitor biologic. Increased risk of infectious complications (e.g. recent pyogenic infection, any congenital or acquired immunodeficiency (e.g. HIV), past organ or stem cell transplantation), as assessed by the investigator. Relevant chronic or acute infections including active tuberculosis, human immunodeficiency virus (HIV) infection or viral hepatitis at the time of randomization. A patient can be re-screened if the patient was treated and is cured from the acute infection. Active or Latent Tuberculosis (TB): Patients with active tuberculosis should be excluded Patients with a positive QuantiFERON® (or if applicable, T-Spot®) TB test during screening are excluded, unless the patient had previous diagnosis of active or latent TB and has completed appropriate treatment per the discretion of the local investigator within the last 3 years and at the latest at the time of screening (i.e. 2 to 4 weeks before study drug administration); patients may be re-screened once to meet this criterion) Patients with suspected false positive or indeterminate QuantiFERON® (or if applicable, T-Spot®) TB result may be re-tested once If QuantiFERON® (or if applicable, T-Spot®) TB testing is not available or provides indeterminate results after repeat testing, a tuberculin skin test (TST) can be performed: A TST reaction of ≥10mm (≥5mm if receiving ≥15mg/d prednisone or its equivalent) is considered positive. History of allergy/hypersensitivity to the systemically administered trial medication agent or its excipients. Further exclusion criteria apply.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Spesolimab SC low dose<br> | Drug: Spesolimab<br>* Solution for injection<br>|
| Experimental: Spesolimab SC medium dose<br> | Drug: Spesolimab<br>* Solution for injection<br>|
| Experimental: Spesolimab SC high dose<br> | Drug: Spesolimab<br>* Solution for injection<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Solution for injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Generalized Pustular Psoriasis (GPP) Flare | A GPP flare was defined as increase in Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score by ≥ 2 from baseline and the pustular component of GPPGA ≥ 2) up to week 48. Use of rescue medication, or investigator-prescribed Standard of Care (SoC) for GPP worsening, was considered to represent a GPP flare onset. GPPGA relied on clinical assessment of the Generalized Pustular Psoriasis (GPP) patient's skin presentation. The GPPGA total score was calculated by taking the mean of the erythema subscore, pustules subscore and scaling/crusting subscore. The severity of each subscore was assessed using a 5 point scale score ranging from 0 to 4 (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe). The final GPPGA score is assigned as follows: 0 , if scores for all three subscores are 0, 1, if 0 < mean < 1.5, 2, if 1.5 ≤ mean < 2.5, 3, if 2.5 ≤ mean < 3.5, 4, if mean ≥ 3.5. | GPPGA was regularly assessed at baseline (Week 1) and up to Week 48 (at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48). Patients could come to site for flare confirmation anytime as unscheduled visit. Visit window was ±7 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Key Secondary Endpoint: The Occurrence of at Least One Generalized Pustular Psoriasis (GPP) Flare up to Week 48 | Proportion of patients with at least one GPP flare up to Week 48 is reported. Proportions were rounded up to three decimal places. A GPP flare was defined as increase in Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score by ≥ 2 from baseline and the pustular component of GPPGA ≥ 2. Any use of rescue medication, or investigator-prescribed SoC for GPP worsening, prior to week 48 was considered to represent the onset of a GPP flare. Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) relied on the clinical assessment of GPP patient's skin presentation. The total score is calculated by taking the mean of the three subscores: 1) erythema; 2) pustules and 3) scaling/crusting which were assessed using a scale score 0 to 4 (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe). The final GPPGA score: 0 , if scores for all three subscores are 0, if 0 < mean < 1.5; if 1.5 ≤ mean < 2.5; if 2.5 ≤ mean < 3.5; if mean ≥ 3.5. | GPPGA was regularly assessed at baseline (Week 1) and up to Week 48 (at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48). Patients could come to site for flare confirmation anytime as unscheduled visit. Visit window was ±7 days. | 
| Time to First Worsening of Psoriasis Symptom Scale (PSS) up to Week 48 | Worsening of Psoriasis Symptom Scale (PSS) was defined as a 4-point increase in total score from baseline. Intake of rescue medication, or investigator-prescribed SoC for GPP worsening, was considered as onset of a worsening. The PSS is a 4-item patient-reported outcome (PRO) instrument that was developed to assess the severity of 4 psoriasis symptoms in patients with moderate to severe psoriasis. The symptoms included are: pain, redness, itching, and burning. Current symptom severity is assessed using a 5-point scale ranging from 0 (none) to 4 (very severe). The symptom scores are added to an unweighted total score (range: 0 (no symptoms) to 16 (severe symptoms)). | PSS assessments were performed at: Baseline (Week 1) and up to Week 48 (at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48). Visit window was ±7 days. | 
| Time to First Worsening of Dermatology Quality of Life Index (DLQI) up to Week 48 | Worsening of DLQI up to week 48 was defined as a 4-point increase in total score from baseline. Intake of rescue medication, or investigator-prescribed SoC for GPP worsening, was considered as onset of a worsening. The DLQI is a patient-administered, ten-question, quality of life questionnaire that covers six domains including symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment. Response categories include not relevant (score of 0), not at all (score of 0), a little (score of 1), a lot (score of 2) and very much (score of 3). Question 7 is a yes/ no question where yes is scored as 3. DLQI total score is calculated by summing the scores of each question resulting in a range of 0 (no effect on patient's life) to 30 (extremely large effect on patient's life). | DLQI assessments were performed at: Baseline (Week 1) and up to Week 48 (at Week 4, 8, 12, 24, 36 and 48). Visit window was ±7 days. Time window for Week 48 was from Week 46 to Week 50. | 
| Sustained Remission | Proportion of patients with sustained remission at all visits up to Week 48. Proportions were rounded up to three decimal places. Remission was defined as a patient with a GPPGA score of 0 or 1 (clear or almost clear) at all visits up to week 48, without intake of rescue medication, or investigator-prescribed SoC for GPP worsening. GPPGA relied on clinical assessment of the Generalized Pustular Psoriasis (GPP) patient's skin presentation. The GPPGA total score was calculated by taking the mean of the erythema subscore, pustules subscore and scaling/crusting subscore. The severity of each subscore was assessed using a 5 point scale score ranging from 0 to 4 (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe). The final GPPGA score is assigned as follows: 0 , if scores for all three subscores are 0, 1, if 0 < mean < 1.5, 2, if 1.5 ≤ mean < 2.5, 3, if 2.5 ≤ mean < 3.5, 4, if mean ≥ 3.5. | GPPGA was regularly assessed at baseline (Week 1) and up to Week 48 (at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48). Patients could come to site for flare confirmation anytime as unscheduled visit. Visit window was ±7 days. | 
| The Occurrence of Treatment Emergent Adverse Events (TEAEs) | Percentage of patients with treatment emergent adverse events (TEAEs) is reported. Percentages were rounded up to one decimal places. Time Frame: Placebo, Spesolimab (Speso) SC low, medium, high: From randomized study treatment start until the first use of rescue medication with IV spesolimab or until last dose + 16 weeks, up to 62 weeks. Speso IV SD and Speso IV DD: From first use of rescue medication with IV spesolimab until OL maintenance spesolimab SC or until last dose of spesolimab IV + 16 weeks, up to 17 weeks. Speso OL SC: From the first dose of OL spesolimab SC treatment until last dose + 16 weeks, up to 62 weeks. | Up to 62 weeks (for detailed timeframe see description). |