Study to Assess the Efficacy, Safety, and Tolerability of Vixarelimab in Reducing Pruritus in Prurigo Nodularis

Study Overview
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Brief Summary
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Study of the efficacy, safety, tolerability, pharmacokinetics (PK), and immunogenicity of Vixarelimab (KPL-716) in subjects with prurigo nodularis.

Detailed Description
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This is a Phase 2a/b randomized, double-blind, placebo-controlled study to investigate the efficacy, safety, tolerability, PK and immunogenicity of Vixarelimab administered subcutaneously (SC) in subjects with prurigo nodularis experiencing pruritus. Phase 2a portion (completed): Forty-nine subjects with moderate to severe PN experiencing moderate to severe pruritus were treated in the Phase 2a portion of the study. At Baseline, subjects were randomized 1:1 to receive double-blind Vixarelimab or placebo: Vixarelimab 720 mg loading dose followed by 360 mg every week; Placebo loading dose followed by placebo every week. The treatment Period was 8 weeks or 16 weeks (treatment duration was reduced from 16 weeks to 8 weeks in a protocol amendment [Protocol Version 3]). Phase 2b portion (enrolling): The Phase 2b study (Figure 1) will consist of a 4-week Screening Period and a 16-week Double-Blind Period, followed by a 36-week Open-Label-Extension (OLE) Period. Approximately 180 subjects with PN, experiencing severe pruritus, will be randomized (at 1:1:1:1 ratio) into one of 4 arms (3 active arms and one placebo arm). A total of 4 doses of study drug will be administered during the Double-Blind Period to measure the efficacy, safety, and PK of Vixarelimab. After the Double-Blind Period, all subjects will have the option to receive Vixarelimab during the OLE Period to evaluate the long-term safety and PK.

Official Title
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A Phase 2a/b, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of KPL-716 in Reducing Pruritus in Subjects With Prurigo Nodularis

Conditions
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Prurigo Nodularis, Pruritis

Intervention / Treatment
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* Drug: vixarelimab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (apply to both Phase 2a and Phase 2b unless otherwise specified): Male or female aged 18 to 75 years (Phase 2a), 18 to 80 years (Phase 2b) Have clinical diagnosis of prurigo nodularis for at least 6 months Have at least 10 nodules (Phase 2a), 20 nodules (Phase 2b) at the Screening Visit and Day 1 Moderate to severe pruritus (Phase 2a); severe pruritus (Phase 2b) Female subjects of childbearing potential must have a negative pregnancy test, be nonlactating, and having agreed to use a highly effective method of contraception, as specified in the protocol, from the Screening Visit until 16 weeks after final study drug administration Able to comprehend and willing to sign an Informed Consent Form and able to abide by the study restrictions and comply with all study procedures for the duration of the study Exclusion Criteria (apply to both Phase 2a and Phase 2b unless otherwise specified): Use of prohibited medications within the indicated timeframe from Day 1 Is currently using medication known to cause pruritus Presence of any inflammatory, pruritic, and/or fibrotic skin condition other than moderate to severe prurigo nodularis or atopic dermatitis unless approved by the Sponsor Laboratory abnormalities that fall outside the windows specified in the protocol at the Screening Visit Has an active infection, including skin infection Any medical or psychiatric condition which, in the opinion of the Investigator or the Sponsor, may place the subject at increased risk as a result of study participation, interfere with study participation or study assessments, affect compliance with study requirements, or complicate interpretation of study results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 2a (completed): 2 arms; Phase 2b (enrolling): 5 arms (4 arms during Double Blind Period and 1 arm during Open Label Extension)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2a - Vixarelimab 360 mg SC QW<br>Vixarelimab 720 mg loading dose followed by 360 mg weekly for 8 weeks (Protocol Version 3) or 16 weeks (Protocol Version 2) | Drug: vixarelimab<br>* solution for injection<br>* Other names: KPL-716;|
| Placebo Comparator: Phase 2a - Placebo SC QW<br>Placebo loading dose followed by placebo weekly for 8 weeks (Protocol Version 3) or 16 weeks (Protocol Version 2) | Drug: Placebo<br>* solution for injection<br>|
| Experimental: Phase 2b - Vixarelimab 540 mg SC Q4W (DBL)<br>Vixarelimab 540 mg SC, every 4 weeks for 16 weeks during Double Blind Period | Drug: vixarelimab<br>* solution for injection<br>* Other names: KPL-716;|
| Experimental: Phase 2b - Vixarelimab 360 mg SC, Q4W (DBL)<br>Vixarelimab 360 mg SC, every 4 weeks for 16 weeks during Double Blind Period | Drug: vixarelimab<br>* solution for injection<br>* Other names: KPL-716;|
| Experimental: Phase 2b - Vixarelimab 120 mg SC, Q4W (DBL)<br>Vixarelimab 120 mg SC, every 4 weeks for 16 weeks during Double Blind Period | Drug: vixarelimab<br>* solution for injection<br>* Other names: KPL-716;|
| Placebo Comparator: Phase 2b - Placebo SC, Q4W (DBL)<br>Placebo SC, every 4 weeks for 16 weeks during Double Blind Period | Drug: Placebo<br>* solution for injection<br>|
| Experimental: Phase 2b - Vixarelimab 360 mg SC, Q2W (OLE)<br>Vixarelimab 360 mg SC, every 2 weeks for 36 weeks during Open Label Extension | Drug: vixarelimab<br>* solution for injection<br>* Other names: KPL-716;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2a & 2b: Percent change from baseline in Worst Itch Numeric Rating Scale (WI-NRS) | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | at Week 8 (Phase 2a); at Week 16 (Phase 2b) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| *Phase 2a: Proportion of subjects achieving at least a 4-point reduction from baseline in weekly average WI-NRS | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | at Week 8 | 
| Phase 2a: Percent change from baseline in pruritus visual analog scale (VAS) | At every visit, subjects rate intensity of their average pruritus over previous 3 days on 0-10 line scale (0=no pruritis, 10=worst imaginable pruritis) | at Week 8 | 
| Phase 2a: Change from baseline in weekly average of WI-NRS (Worst Itch [pruritis] - Numerical Rating Scale; 0=no pruritis, 10=worst imaginable pruritis) over time | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Percent change from baseline in weekly average of WI-NRS (Worst Itch [pruritis] - Numerical Rating Scale; 0=no pruritis, 10=worst imaginable pruritis) over time | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Change from baseline in pruritis visual analog scale (VAS) over time | At every visit, subjects rate intensity of their average pruritus over previous 3 days on 0-10 line scale (0=no pruritis, 10=worst imaginable pruritis) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Percent change from baseline in pruritis visual analog scale (VAS) over time | At every visit, subjects rate intensity of their average pruritus over previous 3 days on 0-10 line scale (0=no pruritis, 10=worst imaginable pruritis) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Change from baseline in 5-D Pruritus total score over time | Administered every 2 visits, the 5-D Pruritus Scale evaluates pruritus in five domains: duration, degree, direction, disability and distribution. The scores from each domain are added together to obtain a total 5-D score ranging from 5 (no pruritus) and 25 (most severe pruritus) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Percent change from baseline in 5-D Pruritus total score over time | Administered every 2 visits, the 5-D Pruritus Scale evaluates pruritus in five domains: duration, degree, direction, disability and distribution. The scores from each domain are added together to obtain a total 5-D score ranging from 5 (no pruritus) and 25 (most severe pruritus) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Proportion of subjects achieving at least a 4-point reduction from baseline in weekly average WI-NRS (Worst Itch [pruritis] - Numerical Rating Scale; 0=no pruritis, 10=worst imaginable pruritis) over time | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Change from baseline in Sleep Loss VAS over time | At every visit, subjects rate intensity of their average sleeplessness over previous 3 days on 0-10 line scale (0=no sleeplessness, 10=worst imaginable sleeplessness) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Percent change from baseline in Sleep Loss VAS over time | At every visit, subjects rate intensity of their average sleeplessness over previous 3 days on 0-10 line scale (0=no sleeplessness, 10=worst imaginable sleeplessness) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Change from baseline in weekly average of difficulty falling asleep NRS over time | Subjects rate difficulty falling asleep daily on Numerical Rating Scale (0=no difficulty, 10=extremely difficult) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Percent change from baseline in weekly average of difficulty falling asleep NRS over time | Subjects rate difficulty falling asleep daily on Numerical Rating Scale (0=no difficulty, 10=extremely difficult) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Change from baseline in weekly average of sleep quality NRS over time | Subjects rate daily sleep quality on Numerical Rating Scale (0=best possible sleep, 10=worst possible sleep) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Percent change from baseline in weekly average of sleep quality NRS over time | Subjects rate daily sleep quality on Numerical Rating Scale (0=best possible sleep, 10=worst possible sleep) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Change from baseline in quality of life (QoL) measures (DLQI and Itchy QoL) over time | QoL is assessed at designated visits and includes the Dermatology QoL Index (DLQI) whereby 0=no effect on quality of life; 30= extremely large effect on QoL; and Itchy QoL, administered as designated visits, which contains 22 items focused on the impact of pruritus on daily activities and on the level of psychological stress. The frequency items are scored using a 5-point Likert scale ranging from never to all the time. The bother items are scored from 1 (not bothered) to 5 (severely bothered) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Percent change from baseline in quality of life (QoL) measures (DLQI and Itchy QoL) over time | QoL is assessed at designated visits and includes the Dermatology QoL Index (DLQI) whereby 0=no effect on quality of life; 30= extremely large effect on QoL; and Itchy QoL, administered as designated visits, which contains 22 items focused on the impact of pruritus on daily activities and on the level of psychological stress. The frequency items are scored using a 5-point Likert scale ranging from never to all the time. The bother items are scored from 1 (not bothered) to 5 (severely bothered) | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Change from baseline in Prurigo Nodularis Nodule Assessment Tool (PN-NAT) over time | PN-NAT, assessed at designated visits, is a novel exploratory tool for the evaluation of disease severity based on estimate of the number of nodules over the whole body, estimate of hardness of nodules over the whole body, estimate of extent of excoriation over the whole body, distribution of nodules, exact number of nodules in the representative area. | to end of treatment, assessed up to 24 weeks | 
| Phase 2a: Proportion of subjects with improvement in Prurigo Nodularis Investigator Global Assessment (PN-IGA) by 2 categories over time | PN-IGA, assessed at designated visits, is a novel exploratory tool for the overall investigator assessment of PN disease severity based on the size of the nodules as defined by their elevation. The IGA utilizes a 5-point scale that ranges from 0 (clear) to 4 (severe disease) | to end of treatment, assessed up to 24 weeks | 
| Phase 2b: Proportion of subjects achieving at least a 6-point reduction from baseline in weekly average WI-NRS (Worst Itch [pruritis] - Numerical Rating Scale; 0=no pruritis, 10=worst imaginable pruritis) | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Proportion of subjects achieving at least a 4-point reduction from baseline in weekly average WI-NRS (Worst Itch [pruritis] - Numerical Rating Scale; 0=no pruritis, 10=worst imaginable pruritis) | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | at Week 16 | 
| Phase 2b: Proportion of subjects achieving 0 or 1 from baseline in PN-IGA | PN-IGA, assessed at designated visits, is a novel exploratory tool for the overall investigator assessment of PN disease severity based on the size of the nodules as defined by their elevation. The IGA utilizes a 5-point scale that ranges from 0 (clear) to 4 (severe disease) | at Week 16 | 
| Phase 2b: Change from baseline in weekly average of WI-NRS (Worst Itch [pruritis] - Numerical Rating Scale; 0=no pruritis, 10=worst imaginable pruritis) over time | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Percent change from baseline in weekly average of WI-NRS (Worst Itch [pruritis] - Numerical Rating Scale; 0=no pruritis, 10=worst imaginable pruritis) over time | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Proportion of subjects achieving at least a 6-point reduction from baseline in weekly average WI-NRS (Worst Itch [pruritis] - Numerical Rating Scale; 0=no pruritis, 10=worst imaginable pruritis) over time | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Proportion of subjects achieving at least a 4-point reduction from baseline in weekly average WI-NRS (Worst Itch [pruritis] - Numerical Rating Scale; 0=no pruritis, 10=worst imaginable pruritis) over time | Subjects rate pruritus daily on Worst Itch [pruritis] Numerical Rating Scale (0=no pruritus; 10=worst imaginable pruritus) | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Proportion of subjects achieving 0 or 1 in PN-IGA over time | PN-IGA is a novel exploratory tool for the overall investigator assessment of PN disease severity based on the size of the nodules as defined by their elevation. The IGA utilizes a 5-point scale that ranges from 0 (clear) to 4 (severe disease) | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Proportion of subjects with at least 2-point improvement from baseline in PN-IGA over time | PN-IGA, assessed at designated visits, is a novel exploratory tool for the overall investigator assessment of PN disease severity based on the size of the nodules as defined by their elevation. The IGA utilizes a 5-point scale that ranges from 0 (clear) to 4 (severe disease) | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Proportion of subjects achieving 0 or 1 in Investigator's Global Assessment for Prurigo Nodularis-Stage (IGA-CNPG-S) over time | IGA-CNPG-S, administered at designated visits, is a novel tool for the investigator assessment of PN disease severity based on the number of palpable nodules and utilizes a 5-point scale that ranges from 0 (clear) to 4 (severe). A score is assigned based on the appearance of the disease at the time of the evaluation without referring to the baseline state. | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Proportion of subjects with at least 2-point improvement from baseline in IGA-CNPG-S over time | IGA-CNPG-S, administered at designated visits, is a novel tool for the investigator assessment of PN disease severity based on the number of palpable nodules and utilizes a 5-point scale that ranges from 0 (clear) to 4 (severe). A score is assigned based on the appearance of the disease at the time of the evaluation without referring to the baseline state. | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Change from baseline in weekly average of Sleep Loss VAS over time | At every visit, subjects rate intensity of their average sleeplessness over previous 3 days on 0-10 line scale (0=no sleeplessness, 10=worst imaginable sleeplessness) | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Percent change from baseline in weekly average of Sleep Loss VAS over time | At every visit, subjects rate intensity of their average sleeplessness over previous 3 days on 0-10 line scale (0=no sleeplessness, 10=worst imaginable sleeplessness) | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Change from baseline in ItchyQoL over time | Itchy QoL, administered as designated visits, contains 22 items focused on the impact of pruritus on daily activities and on the level of psychological stress. The frequency items are scored using a 5-point Likert scale ranging from never to all the time. The bother items are scored from 1 (not bothered) to 5 (severely bothered) | to end of treatment, assessed up to 52 weeks | 
| Phase 2b: Percent change from baseline in ItchyQoL over time | Itchy QoL, administered as designated visits, contains 22 items focused on the impact of pruritus on daily activities and on the level of psychological stress. The frequency items are scored using a 5-point Likert scale ranging from never to all the time. The bother items are scored from 1 (not bothered) to 5 (severely bothered) | to end of treatment, assessed up to 52 weeks |