A Phase 2, Open-Label, Dose-finding Study to Evaluate the Safety, Tolerability, and Activity of KD025 in Subjects With Psoriasis Vulgaris Who Failed First-line Therapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 38
- 试验地点
- 9
- 主要终点
- Efficacy: Percentage of Subjects With ≥ 75% Decrease or ≥ 50% Decrease in PASI Score at EOT---ITT Population
研究概览
简要总结
This study was performed to evaluate the safety, tolerability, activity, pharmacokinetics (PK), and daily dose regimen of KD025 administered orally (PO) for 12 weeks to subjects with psoriasis vulgaris who failed at least one line of systemic therapy.
详细描述
Study KD025-206 was a phase 2, open-label, dose-finding, safety, tolerability, activity, and PK study of KD025 in subjects with psoriasis who had failed at least 1 line of systemic therapy or phototherapy.
Subjects received KD025 PO for 12 weeks. Planned enrollment was 36 subjects in 3 cohorts, 12 subjects per cohort:
- Cohort 1 (12 subjects): KD025 400 mg once daily (QD) PO for 12 weeks
- Cohort 2 (12 subjects): KD025 200 mg PO twice daily (BID) for 12 weeks
- Cohort 3 (12 subjects): KD025 400 mg BID PO for 12 weeks
Subjects were initially enrolled simultaneously in Cohort 1 and Cohort 2 according to a randomization schedule, with safety reviewed before any subjects. If safety guidelines were met, Cohort 3 was added to explore the efficacy and safety of KD025 at a dose of 400 mg PO BID.
Subjects underwent safety evaluations: medical history evaluations; physical examinations (PEs); vital sign measurements; weight measurements; adverse event (AE) assessments; concomitant medication assessments; blood sample collection for hematology, chemistry, and coagulation; lipid panel; thyroid-stimulating hormone; measurements of antinuclear antibody; anti-double-stranded deoxyribonucleic acid; Complement C; antiphospholipid antibody; liver ultrasound (US); pregnancy testing for females of childbearing potential; PK sampling (subset of subjects only); urinalysis; and electrocardiogram (ECG).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to provide written informed consent prior to the performance of any study specific procedures
- •Diagnosis of moderately severe plaque psoriasis that has been moderately stable for 6 months and failed at least 1 line of systemic or phototherapy and is a candidate for additional systemic therapy
- •PASI of ≥ 12 within the 24-hour period prior to the first dose of study drug
- •At least 10% of body surface area affected by plaque psoriasis within the 24-hour period prior to the first dose of study drug
- •Willing to avoid tanning devices
- •Willing to forgo other systemic and topical treatments for psoriasis during the course of the study
- •Adequate bone marrow function: absolute neutrophil count > 1500/mm^3; hemoglobin > 9.0 g/dL; platelets > 100,000/mm^3
- •Negative urine pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of study drug
- •Agree to use a highly effective method of birth control (< 1% per year failure rate) during the study and for 1 month after the termination of the study. Effective birth control included implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence, or vasectomized partner
- •Willing to complete all study measurements and assessments in compliance with the protocol
排除标准
- •Non-plaque or drug-induced (antimalarials, lithium) psoriasis (If subject is taking angiotensin II receptor blockers or beta blockers doses had to be stable for 6 months prior to study entry)
- •Use of corticosteroid or immunosuppressive therapy within 4 weeks prior to study entry except for Class 5 or weaker topical corticosteroids or immunosuppressive therapies to the face, groin, or scalp.
- •Use of methotrexate, acitretin, or cyclosporine within 4 weeks prior to study entry
- •Use of phototherapy within 4 weeks prior to study entry
- •Use of biologic therapies, including antibodies to IL-17, within 3 months prior to study entry
- •Concomitant condition requiring treatment with moderate to high dose steroids in the 12 weeks prior to screening
- •Viral, fungal, or bacterial skin infection
- •Pregnant or lactating
- •History of gastrointestinal (GI) surgery including bariatric surgery, or any GI condition that might interfere with drug absorption
- •Currently participating in another study with an investigational drug or within 28 days of study entry
- •History or other evidence of severe illness or any other conditions that would make the subject, in the opinion of the investigator, unsuitable for the study (such as poorly controlled psychiatric disease or coronary artery disease)
- •Regular and excessive use of alcohol within the 2 years prior to study entry defined as alcohol intake > 14 drinks per week in a man or > 7 drinks per week in a woman. Approximately 10 g of alcohol equals one "drink" unit. One unit equals 1 ounce of distilled spirits, one 12-ounce beer, or one 4-ounce glass of wine
- •History or presence of any of the following:
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 × the upper limit of normal (ULN) at screening. (Subjects with an isolated AST elevation of any magnitude, or a ratio of AST:ALT > 1.5 interviewed regarding use of alcohol, have levels repeated and participation in the study should be discussed with the medical monitor.)
- •Renal disease and/or serum creatinine > 1.5 × ULN at screening
- •QTc(F) interval (QT interval data corrected using Fridericia's formula) > 450 msec at the screening or predose ECG
- •Previous exposure to KD025 or known allergy/sensitivity to KD025 or any other ROCK-2 inhibitor
研究组 & 干预措施
Cohort 1
KD025 400 mg QD PO for 12 weeks
干预措施: KD025 (Drug)
Cohort 2
KD025 200 mg BID PO for 12 weeks
干预措施: KD025 (Drug)
Cohort 3
KD025 400 mg BID PO for 12 weeks
干预措施: KD025 (Drug)
结局指标
主要结局
Efficacy: Percentage of Subjects With ≥ 75% Decrease or ≥ 50% Decrease in PASI Score at EOT---ITT Population
时间窗: 12 weeks
Percentage of available subjects who achieved at least a 75% reduction (PASI 75) or at least a 50% reduction from baseline in Psoriasis Area and Severity Index (PASI) score after 12 weeks of treatment with belumosudil or at the end of treatment with belumosudil in the Intent-to-Treat Population. \[The Psoriasis Area and Severity Index (PASI) is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The severity of each sign is assessed using a 5-point scale, where 0=no symptoms, 1=slight, 2=moderate, 3=marked, 4=very marked. The PASI score ranges from 0 to 72, where 0 indicates no psoriasis and 72 indicates very severe psoriasis.\]
Efficacy: Percentage of Subjects With ≥ 75% Decrease or ≥ 50% Decrease With PASI Score at EOT---Evaluable Population
时间窗: 12 weeks
Percentage of available subjects who achieved at least a 75% reduction and a 50% reduction from baseline in Psoriasis Area and Severity Index score at end of treatment with belumosudil in the Evaluable Population. \[The Psoriasis Area and Severity Index (PASI) is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The severity of each sign is assessed using a 5-point scale, where 0=no symptoms, 1=slight, 2=moderate, 3=marked, 4=very marked. The PASI score ranges from 0 to 72, where 0 indicates no psoriasis and 72 indicates very severe psoriasis.\]
Safety: Percentage of Subjects With AEs by Severity and Relationship to Belumosudil--ITT Population
时间窗: 12 weeks
Percentage of subjects who had an adverse event by severity in the Intent-to-Treat Population: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. Percentage of subjects who had an adverse event by relationship to belumosudil in the Intent-to-Treat Population as assessed by the investigator: definitely related, probably related, possibly related, and not related to belumosudil.
次要结局
- Efficacy: Mean Change in PASI Score at 12 Weeks From Baseline--ITT Population(12 weeks)
- Efficacy: Mean Changes in DLQI at 12 Weeks--Evaluable Population(12 weeks)
- Pharmacokinetics: Cmax of Parent Drug KD025, KD025m1, and KD025m2(24 hours)
- Pharmacokinetics: AUC of Parent Drug KD025, KD025m1, and KD025m2(24 hours)
- Efficacy: Mean Change in PASI Score at 12 Weeks From Baseline--Evaluable Population(12 weeks)
- Efficacy: Percentage of Subjects With a Decrease in PASI After 4 Weeks---ITT Population(4 weeks)
- Efficacy: Percentage of Subjects With a Decrease in PASI Score After 8 Weeks---ITT Population(8 weeks)
- Efficacy: Percentage of Subjects With a Decrease in PASI Score at EOT---ITT Population(12 weeks)
- Efficacy: Mean Change in PASI Score After 4 Weeks---ITT Population(4 weeks)
- Efficacy: Mean Change in PASI Score After 8 Weeks---ITT Population(8 weeks)
- Efficacy: Mean Change in PASI Score at 4 and 8 Weeks---Evaluable Population(8 weeks)
- Efficacy: Percentage of Subjects With a Decrease in PASI Score After 4 Weeks, 8 Weeks, and 12 Weeks---Evaluable Population(12 weeks)
- Efficacy: Percentage of Subjects With Improvement in PGA af 4 Weeks---ITT Population(4 weeks)
- Efficacy: Percentage of Subjects With Improvement in PGA af 8 Weeks---ITT Population(8 weeks)
- Efficacy: Mean Changes in DLQI at EOT--ITT Population(12 weeks)
- Efficacy: Percentage of Subjects With Improvement in PGA af EOT--ITT Population(12 weeks)
- Efficacy: Percentage of Subjects With Improvement in PGA af 4, 8, and 12 Weeks---Evaluable Population(12 weeks)
- Pharmacokinetics: t(1/2) of KD025(24 hours)
- Pharmacokinetics: MR C(Max) and MR AUC(0-t) for KD025m1 and KD025m2(24 hours)