A Phase 2, Open-label Multi-center Study to Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Efficacy of Apremilast in Subjects With Recalcitrant Plaque-type Psoriasis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 31
- 试验地点
- 4
- 主要终点
- Treatment Emergent Adverse Events (TEAEs) During the Treatment Phase
研究概览
简要总结
The study will test the safety and tolerability of Apremilast twice a day in participants with recalcitrant plaque type psoriasis.
详细描述
This is a phase 2, multicenter, open-label, study to evaluate the safety, tolerability, pharmacodynamics, pharmacokinetics and efficacy of Apremilast in participants with recalcitrant plaque-type psoriasis.
Approximately 31 participants were enrolled and received 20 mg apremilast orally BID and, in participants who are non-responders after 84 days of apremilast, 30 mg Apremilast over the course of the two study treatment phases. The study consisted of four phases: Screening Phase - up to 35 days, Treatment Phase of 84 days, Extension Phase of 84 days and a Observational Follow-up Phase of 28 days.
During the Treatment Phase, participants received two 20 mg Apremilast capsules each day. Following the Treatment Phase, participants had the option to continue on treatment during the Extension Phase. During the Extension Phase, participants either continued to take two 20 mg or dose escalated to two 30 mg of Apremilast each day. Participants who were considered responders (achieved a Psoriasis Area and Severity Index (PASI-75) at the beginning of the Extension Phase continued on 20 mg twice per day (BID) while the remaining participants received 30 mg capsules BID. The Extension Phase was introduced after some participants had already completed the study; therefore, there were several participants who never had the opportunity to continue into the Extension Phase. All participants were asked to participate in a 4-week post-treatment observational follow-up phase either upon completion of the study or upon discontinuation of study drug for those participants who terminated the study early.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must understand and voluntarily sign an informed consent form
- •Must be male or female subject of any ethnic origin or race that is >18 years at time of consent
- •Must have a documented history of plaque-type psoriasis for at least 6 months prior to screening visit
- •Subjects must fulfill criteria outlined in at least one of the following clinical categories:
- •Unresponsive to standard systemic therapy, as defined by clinical history, in the investigator's opinion, i.e. inadequate response to one or more adequate treatment course (s) of standard systemic therapy
- •Intolerant to or cannot receive (e.g., contraindication to prescribe) standard systemic therapy or biological interventions for psoriasis
- •Must have a Static Physician Global Assessment (sPGA) score of at least 3 and a Body surface area (BSA) ≥ 10% at screening
- •Must meet the specified laboratory criteria:
- •o Must be able to adhere to the study visit schedule and study protocol requirements
- •Females of childbearing potential (FCBP) must have a negative urine pregnancy test at screening (Visit 1). In addition, FCBP must agree to use two of the following adequate forms of contraception methods such as oral, injectable, or implantable hormonal contraception; tubal ligation; intrauterine device; barrier contraceptive with spermicide or vasectomized partner while on study. A FCBP must agree to have pregnancy tests every 4 weeks while on study medication.
- •Males (including those who have had a vasectomy) must agree to use barrier contraception (latex condoms) when engaging in sexual activity with FCBP
排除标准
- •History of clinically significant (as determined by the investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic, or other major disease
- •Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
- •Pregnant or lactating females
- •History of active tuberculosis (TB) infection within 3 years prior to the screening visit. Infections which occurred > 3 years prior to entry must have been effectively treated
- •History of incompletely treated latent (as indicated by a positive PPD [purified protein derivative] skin results) TB infection
- •Clinically significant abnormality on the chest x-ray (CXR) at screening
- •Psoriasis flare within 30 days of screening, as defined by protocol
- •Use of systemic therapy for psoriasis within 28 days of Visit 2 (Baseline).
- •Topical therapy as defined in the protocol Adalimumab, etanercept, efalizumab or infliximab use within 56 days of Visit 2 (Baseline)
- •Alefacept use within 180 days of Visit 2 (Baseline)
- •Phototherapy Ultraviolet light A (UVA), Ultraviolet light B (UVB), Psoralens and long-wave ultraviolet radiation (PUVA) within 28 days of Visit 2 (Baseline)
- •Use of any investigational drug within 28 days of Visit 2 (Baseline), or 5 half lives if known (whichever is longer) Clinically significant abnormality on 12-lead Electrocardiogram (ECG) at screening
研究组 & 干预措施
Apremilast 20 mg BID/ 30 mg BID
Apremilast 20 mg or 30 mg orally twice per day
干预措施: Apremilast (Drug)
结局指标
主要结局
Treatment Emergent Adverse Events (TEAEs) During the Treatment Phase
时间窗: Week 0 to Week 12
TEAE = any AE occurring or worsening on or after the first treatment with any study drug. Related = suspected by investigator to be related to study treatment. National Cancer Institute \[NCI\] Common Toxicity Criteria for Adverse Events \[CTCAE\], Version 3.0, grades: 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, 5 = death. Adverse event (AE) = any noxious, unintended, or untoward medical occurrence occurring at any dose that may appear or worsen in a participant during the course of a study, including new intercurrent illness, worsening concomitant illness, injury, or any concomitant impairment of participant's health, including laboratory test values, regardless of etiology. Serious adverse event (SAE) = any AE which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; constitutes an important medical event.
Treatment Emergent Adverse Events (TEAEs) During the Extension Phase
时间窗: Week 12 to Week 24
TEAE = any AE occurring or worsening on or after the first treatment with any study drug. Related = suspected by investigator to be related to study treatment. National Cancer Institute \[NCI\] Common Toxicity Criteria for Adverse Events \[CTCAE\], Version 3.0, grades: 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, 5 = death. Adverse event (AE) = any noxious, unintended, or untoward medical occurrence occurring at any dose that may appear or worsen in a participant during the course of a study, including new intercurrent illness, worsening concomitant illness, injury, or any concomitant impairment of participant's health, including laboratory test values, regardless of etiology. Serious adverse event (SAE) = any AE which: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event.
次要结局
- Percentage of Participants Who Achieved a PASI-75 Score at Week 12(Baseline to Week 12)
- Percentage of Participants Who Achieved a PASI-50 Score at Week 12(Baseline to Week 12)
- Time to Achieve PASI-75 During Treatment Phase
- Peak (Maximum) Plasma Concentration of Medication (Cmax)(Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose)
- Trough Plasma Concentration (Cmin)(Day 85 Pre-dose)
- Time to Maximum Plasma Concentration (Tmax) During the Treatment Phase(Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose)
- Percentage of Participants With at Least a 1 Point Reduction on 0 to 5 Point Scale From Baseline in Static Physician Global Assessment (sPGA) at Week 12(Baseline and Week 12)
- Percent Change From Baseline in Psoriasis Area Severity Index (PASI) Score at Week 12(Baseline and Week 12)
- Percent Change From Baseline in the Psoriasis Affected Body Surface Area (BSA) Involvement at Week 12(Baseline to Week 12)
- Time to Relapse of Psoriatic Arthritis During the Observational Follow-up Phase(Observational follow up phase; Days 168 to Day 196)
- Area Under the Plasma Concentration Time-curve From 0 to 12 Hours Post Dose (AUC 0-12)(Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose)
- Maximal PASI Response Documented for Each Participant During Treatment Phase(Baseline to Week 12)
- Time to Clinically Relevant Response (Time to Achieve PASI-50) During Treatment Phase
- Time to Relapse of Psoriasis (50% Loss of Maximal PASI Score Improvement in Participants Who Achieved at Least PASI-50 During the Treatment Phase) During the Observational Follow up Phase(28-day Observational Follow-up Phase; Days 168 to Day 196.)
- Terminal Phase Elimination Half Life of Apremilast (t½)(Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose)
- Percent of Participants With Psoriatic Arthritis Who Achieved an American College of Rheumatology 20% Improvement (ACR-20) Response at Week 12(Baseline to Week 12)
- Apparent Total Clearance of Apremilast From Plasma After Extravascular Administration (CLz/F) During the Treatment Phase(Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose)
- Apparent Total Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) During the Treatment Phase(Day 85)
- Accumulation Index (R)(Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose)
- Mean Residence Time (MRT) During the Treatment Phase(Day 85 Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours after the AM dose)
- Change From Baseline in Peripheral Blood T Cell, B Cell, and NK Cell Subsets at Week 12(Baseline and Week 12)
- Percent Change From Baseline of CD3 in the Dermis of the Psoriatic Skin Biopsy at Week 12(Baseline and Week 12)
- Percent Change From Baseline of CD3 in the Epidermis of the Psoriatic Skin Biopsy at Week 12(Baseline and Week 12)
- Percent Change From Baseline of CD 11c in the Dermis of the Psoriatic Skin Biopsy at Week 12(Baseline and Week 12)
- Percent Change From Baseline of CD56 in the Epidermis of the Psoriatic Skin Biopsy at Week 12(Baseline and Week 12)
- Percent Change From Baseline of CD11c in the Epidermis of the Psoriatic Skin Biopsy at Week 12(Baseline and Week 12)
- Percent Change From Baseline in the Defensin Beta 4 (DEFB4) Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the keratin16 (K16) Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the pluripotent19 (P19) Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline of CD56 in the Dermis of the Psoriatic Skin Biopsy at Week 12(Baseline and Week 12)
- Percent Change From Baseline of Langerin in the Dermis of Psoriatic Skin Biopsy at Week 12(Baseline and Week 12)
- Percent Change From Baseline of Langerin in the Epidermis of the Psoriatic Skin Biopsy at Week 12(Baseline and Week 12)
- Percent Change From Baseline of Epidermal Thickness in the Psoriatic Skin Biopsy at Week 12(Baseline and Week 12)
- Percent Change From Baseline in the Inducible Nitric Oxide (iNOS) Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the Interleukin (IL) IL-22 Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the p40 Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the IL8 Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the MX1 (Gene That Encodes the Interferon-induced p78 Protein) Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the IL10 Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Change From Baseline in the Medical Outcome Study Short Form 36-item Health Survey (SF-36) Scores, Mental and Physical Components to Week 12(Baseline to Week 12)
- Area Under the Plasma Concentration Time-curve From 0 to 12 Hours Post Dose (AUC 0-12) During the Extension Phase(Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose)
- Percent Change From Baseline in the IL17A Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the Tumor Necrosing Factor (TNF) Alpha Inflammatory Marker in Psoriatic Skin Biopsies(Week 0 to Week 12)
- Percent Change From Baseline in the Interferon (INF) Gamma Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the Chemokine Ligand (CXCL9) Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the IL2 Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Percent Change From Baseline in the Dendritic Cell (CD83) Inflammatory Marker in Psoriatic Skin Biopsies(Baseline and Week 12)
- Accumulation Index During the Extension Phase(Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose)
- Mean Residence Time (MRT) During the Extension Phase(Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose)
- Change From Baseline in the Dermatology Life Quality Index (DLQI) at Week 12(Baseline to Week 12)
- Peak (Maximum) Plasma Concentration of Apremilast (Cmax) During the Extension Phase(Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose)
- Time to Maximum Plasma Concentration (Tmax) During the Extension Phase(Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose)
- Terminal Phase Elimination Half Life of Apremilast (t½) During the Extension Phase(Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose)
- Apparent Total Clearance of Apremilast From Plasma After Extravascular Administration (CL/F) During the Extension Phase(Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose)
- Apparent Total Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) During the Extension Phase(Day 169 pre-dose, 0.5, 1, 2, 4, 8 12, 24 and 36 hours after AM dose)