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临床试验/NCT03371251
NCT03371251已完成1 期

A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of Care

Boston Pharmaceuticals67 个研究点 分布在 9 个国家目标入组 143 人开始时间: 2018年1月10日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
1 期
状态
已完成
入组人数
143
试验地点
67
主要终点
Phase 2: Number of Participants With an SLE Responder Index 4 (SRI-4) Response at Day 210
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This study will be conducted to assess the safety, tolerability, and immunogenicity of repeat doses of BOS161721 (20 milligrams [mg], 60 mg, and 120 mg) administered subcutaneously in adult participants with moderately to severely active Systemic Lupus Erythematosus (SLE) on limited background standard of care treatment, in order to estimate the optimal dose.

BOS161721 at the chosen dose will be compared to placebo for response on the SLE Responder Index 4, with sustained reduction of oral corticosteroids, in the same participant population.

研究设计

研究类型
Interventional
分配方式
Randomized
干预模型
Parallel
主要目的
Treatment
盲法
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

入排标准

年龄范围
18 Years 至 70 Years（Adult, Older Adult）
性别
All
接受健康志愿者
否

入选标准

  • •Men and women, ages 18 to 70 years, inclusive
  • •Participants must be mentally capable of giving consent and there must be evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study
  • •Participants must have Systemic Lupus Erythematosus (SLE) as defined by meeting 4 of the Systemic Lupus International Collaborating Clinics classification criteria for SLE (with at least 1 clinical and 1 immunologic criterion OR Lupus nephritis as the sole clinical criterion in the presence of anti-nuclear antibodies (ANA) or anti-double stranded deoxyribonucleic acid (dsDNA) antibodies), either sequentially or simultaneously
  • •At screening, participants must have at least 1 of the following:
  • •Elevated ANA ≥ 1:80 via immunofluorescent assay at the central laboratory
  • •Positive anti-dsDNA or anti-Smith (anti-Sm) above the normal level as determined by the central laboratory
  • •At screening, the total Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score must be ≥ 8, including points from at least 1 of the following clinical components:
  • •a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis Note: Points from lupus headache and organic brain syndrome will also be excluded from qualifying total and clinical SLEDAI-2K scores at screening and Day
  • •A clinical SLEDAI-2K score of ≥ 6 at screening at Day
  • •Clinical SLEDAI-2K score is defined as follows:
  • •Contains points from arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, or vasculitis
  • •Excludes parameters which require central laboratory results: hematuria, pyuria, urinary casts, proteinuria, positive anti-dsDNA, decreased complement, thrombocytopenia, and leukopenia Note: Points from lupus headache and organic brain syndrome will also be excluded from qualifying total and clinical SLEDAI-2K scores at screening and Day
  • •Participants must have at least 1 qualifying A or 2Bs from the following manifestations of SLE, as defined by the British Isles Lupus Assessment Group (BILAG) criteria as modified for use in this study, which must be confirmed by the central data reviewer:
  • •BILAG A or B score in the mucocutaneous body system. If a BILAG B score is due to BILAG number 6, mild skin eruption, the CLASI activity score including erythema and scale/hypertrophy must be ≥ 3 excluding points from mucosal ulcers and alopecia.
  • •BILAG A or B score in the musculoskeletal body system due to active polyarthritis Note: Hips, shoulders, back, neck, and temporomandibular joints do not count towards the total number of joints with active synovitis.
  • •If only one "B" and no "A" score is present in the mucocutaneous body system or in the musculoskeletal body system due to arthritis, then at least 1 "B" must be present in at least 1 other body system for a total of 2 "B" BILAG body system scores.
  • •Participants must be currently receiving at least 1 of the following:
  • •Administration for a minimum of 12 weeks, and a stable dose for at least 56 days (8 weeks prior to Day 0) of the following permitted steroid sparing agents: azathioprine (AZA), mycophenolate mofetil or mycophenolic acid, chloroquine, hydroxychloroquine, or methotrexate
  • •If AZA, myocophenolate mofetil, mycophenolic acid, hydroxychloroquine, or MTX were discontinued prior to screening, the washout period must be ≥ 12 weeks.
  • •Corticosteroids (CSs) (prednisone or prednisone-equivalent) at a stable dose of up to 30 mg/day for at least 6 weeks prior to Day 0
  • •i. For participants whose only SLE treatment is CSs, the stable CS dose must be ≥ 10 mg/day for at least 6 weeks prior to Day 0 and no more than 30 mg/day at the time of randomization.
  • •ii. Topical steroids may be used, but the dose must be stable for at least 6 weeks prior to Day
  • •PRN topical steroids are not permitted.
  • •Women of childbearing potential (WOCBP):
  • •Must have a negative serum pregnancy test at screening. Urine pregnancy test must be negative prior to first dose
  • •Must not be breastfeeding
  • •Must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 52 weeks
  • •Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 52 weeks
  • •Participants must demonstrate willingness and ability to comply with the scheduled study visits, treatment plans, laboratory tests, and other procedures

排除标准

  • •Participants presenting with any of the following will not be included in this study:
  • •Drug-induced SLE, rather than "idiopathic" SLE
  • •Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid arthritis [RA], multiple sclerosis [MS], systemic sclerosis, or vasculitis not related to SLE). RA-Lupus overlap (Rupus), and secondary Sjogren syndrome are allowed.
  • •Any major surgery within 6 weeks of study drug administration (Day 0) or any elective surgery planned during the course of the study
  • •Any history or risk for tuberculosis (TB), specifically those with:
  • •Current clinical, radiographic, or laboratory evidence of active TB
  • •History of active TB
  • •Latent TB defined as positive QuantiFERON-TB Gold In Tube or other diagnostic test in the absence of clinical manifestations. Latent TB is not excluded if the participant has documented completion of adequate course of prophylactic treatment with regimen recommended by local health authority guideline, or the participant has started treatment with isoniazid, or other regimen recommended by local health authority guidelines for at least 1 month before Day 0 and continues to receive the prophylactic treatment during study until the treatment course is completed
  • •Active or unstable lupus neuropsychiatric manifestations, including but not limited to any condition defined by BILAG A criteria, with the exception of mononeuritis multiplex and polyneuropathy, which are allowed
  • •Severe proliferative lupus nephritis (World Health Organization Class III, IV), which requires or may require induction treatment with cytotoxic agents or high dose CSs
  • •Concomitant illness that, in the opinion of the investigator or the Sponsor or their designee, is likely to require additional systemic glucocorticosteroid therapy during the study, (eg, asthma), is exclusionary. However, treatment for asthma with inhalational CSs therapy is allowed.
  • •Use or planned use of concomitant medication outside of standard of baseline treatment for SLE from Day -1 or for any time during the study
  • •Active and clinically significant infection (bacterial, fungal, viral, or other) within 60 days prior to first dose of study drug. Clinically significant is defined as requiring systemic parenteral antibiotics or hospitalization
  • •A history of opportunistic infection, or a history of recurrent or severe disseminated herpes zoster or disseminated herpes simplex within the last 3 years
  • •Chronic viral hepatitis B (HBV) and hepatitis C (HCV), unless participant received curative treatment for HCV and has a documented negative viral load, known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness
  • •Cryptosporidium in the stool sample at screening
  • •White blood cells < 1,200/millimeters cubed (mm^3) (1.2 × 10^9/Liter [L]) at screening
  • •Absolute neutrophil count < 500/mm^3 at screening
  • •CD4+ count < 150/microliter (µL) at screening
  • •Platelets < 50,000/mm^3 (50 × 10^9/L) or < 35,000/mm^3 (35 × 10^9/L) if related to SLE, at screening
  • •Hemoglobin < 8 grams per deciliter (g/dL) or < 7 g/dL at screening if related to SLE
  • •Proteinuria > 3.0 g/day (3000 milligrams per day [mg/day]) at screening or equivalent level of proteinuria as assessed by protein/creatinine ratio (3 mg/mg or 339 milligrams per millimole [mg/mmol])
  • •Serum creatinine > 2.0 mg/dL at screening or creatinine clearance < 40 milliliters per minute (mL/minute) based on Cockcroft-Gault calculation
  • •Serum alanine aminotransferase and/or serum aspartate aminotransferase > 2 × the upper limit of normal (ULN) at screening, unless explicitly related to lupus based on the investigator's judgment
  • •Creatinine kinase > 3.0 × ULN at screening unless related to lupus myositis
  • •Total bilirubin > 1.5 × ULN at screening (unless related to Gilbert's syndrome)
  • •Any other laboratory test results that, in the opinion of the Investigator or the Sponsor or Sponsor's designee, might place a participant at unacceptable risk for participating in this study
  • •History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibodies (mAb) (eg, IgG protein) or molecules made of components of mAbs
  • •History substance and/or alcohol abuse, or dependence within the past 1 year, at the investigator's judgment
  • •History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell cancer, or cervical cancer in situ resolved by excision)
  • •Any other severe acute or chronic medical or psychiatric condition, including recent (within the past year) medical conditions (eg, cardiovascular conditions, respiratory illnesses) that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, Sponsor, or Sponsor's designee, would make the participant inappropriate for entry into this study
  • •Investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the investigator, or participants who are employees of the sponsor or directly involved in the conduct of the trial
  • •Currently participating in, or who have participated in other interventional (drug or device) clinical study within 30 days or 5 half-lives of baseline, whichever is longer
  • •Recent (within the past 12 months) or active suicidal ideation or behavior based on participant responding "yes" to question 3, 4, or 5 on the Columbia Suicide severity Rating Scale
  • •Current or pending incarceration
  • •Current or pending compulsory detainment for treatment of either a psychiatric or physical (eg, infectious disease) illness
  • •Currently taking a total daily dose of > 30 mg morphine or morphine equivalent
  • •Body mass index (BMI) ≥ 40.0

研究组 & 干预措施

Phase 1b: BOS161721 20, 60, 120 mg

Experimental

Participants will be randomized to receive a 20 milligram (mg), 60 mg, or 120 mg subcutaneous (SC) dose of BOS161721. Participants may receive a total of 7 SC monthly doses of BOS161721 on Days 0, 30, 60, 90, 120, 150, and 180, followed by safety follow-up visits on at Days 210, 240, and 270.

干预措施: BOS161721 (Drug)

Phase 1b: Placebo 20, 60, 120 mg

Placebo Comparator

Participants will be randomized to receive a 20 mg, 60 mg, or 120 mg SC dose of placebo. Participants may receive a total of 7 SC monthly doses of placebo on Days 0, 30, 60, 90, 120, 150, and 180, followed by safety follow-up visits on at Days 210, 240, and 270.

干预措施: Placebo (Drug)

Phase 2: BOS161721

Experimental

Participants will be randomized to receive a 120 mg SC dose of BOS161721 (as determined from Phase 1b of the study). Participants may receive a total of 7 SC monthly doses of BOS161721 on Days 0, 30, 60, 90, 120, 150, and 180, followed by safety follow-up visits on at Days 210, 240, and 270.

干预措施: BOS161721 (Drug)

Phase 2: Placebo

Placebo Comparator

Participants will be randomized to receive a 120 mg SC dose of placebo (as determined from Phase 1b of the study). Participants may receive a total of 7 SC monthly doses of placebo on Days 0, 30, 60, 90, 120, 150, and 180, followed by safety follow-up visits on at Days 210, 240, and 270.

干预措施: Placebo (Drug)

结局指标

主要结局

Phase 2: Number of Participants With an SLE Responder Index 4 (SRI-4) Response at Day 210

时间窗: Day 210

The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from the SLE Disease Activity Index 2000 (SLEDAI-2K), the British Isles Lupus Assessment Group (BILAG) 2004 Index and the Physician's Global Assessment (PGA). Response based on the SRI-4 is defined by: 1) ≥ 4-point reduction in the SLEDAI-2K total score; 2) no new severe disease activity (BILAG A organ score) or more than 1 new moderate organ score (BILAG B) compared with baseline; and 3) no deterioration from baseline in the PGA by ≥ 30 millimeters. The SLEDAI-2K total score falls between 0 and 105, with higher scores representing increased disease activity.The SRI-4 response in participants with moderate to severe SLE is associated with broad improvements in clinical and participant-reported outcomes.

Phase 1b: Number of Participants With Adverse Events (AEs)

时间窗: Up to Day 270

The safety, tolerability, and immunogenicity of repeat doses of BOS161721 (20, 60, and 120 mg) administered SC were assessed in adult participants with moderate to severe SLE on limited background standard of care treatment, in order to estimate the optimal dose.

次要结局

  • Phase 1b: Terminal Elimination Half-life (t1/2)(Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180)
  • Phase 1b: Apparent Plasma Clearance After Extravascular Administration (CL/F)(Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180)
  • Phase 1b: Mean Change From Baseline in Antiphospholipid (APL) Autoantibodies (Beta 2 Glycoprotein, Cardiolipin IgG)(Baseline (Day 0); Day 180)
  • Phase 2: Mean Change From Baseline in PGA(Baseline, Day 210)
  • Phase 1b: Mean Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (pSTAT3)(Baseline (Day 0); Days 30, 44, 60, and 90 (pre-dose [trough] samples only))
  • Phase 2: Number of Participants With an SRI-4, SRI-5, and SRI-6 Response at Each Visit(Days 30, 60, 90, 120, 150, 180, 210, 240, and 270)
  • Phase 1b: The Area Under the Plasma Concentration Versus Time Curve, From Time 0 to the Last Quantifiable Concentration (AUClast)(Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180)
  • Phase 1b: Mean Change From Baseline in Complement 3 (C3) and Complement (C4) Levels(Baseline (Day 0); Day 210)
  • Phase 1b: Mean Change From Baseline in Anti-Smith Antibody (Sm)(Baseline (Day 0); Day 180)
  • Phase 2: Number of Participants With Medication Failures(Days 30, 60, 90, 120, 150, 180, and 210)
  • Phase 2: Time to First BILAG Flare (≥ 1 New or Recurrent BILAG A or > 1 New or Recurrent BILAG B) Relative to Baseline Through Day 210(Baseline; Day 210)
  • Phase 2: Number of Participants With AEs(Up to Day 270)
  • Phase 1b: Maximum Observed Concentration (Cmax)(Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180)
  • Phase 1b: First Time to Maximum Concentration (Tmax)(Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180)
  • Phase 1b: Mean Change From Baseline in Anti-double-stranded DNA (dsDNA) Autoantibodies at Each Visit(Baseline (Day 0); Days 30, 60, 90, 120, 150, 180, 210, 240, and 270)
  • Phase 1b: Mean Change From Baseline in Anti-Sjögren's Syndrome A and B (SSA, SSB)(Baseline (Day 0); Day 180)
  • Phase 2: Number of Participants With a BILAG-based Composite Lupus Assessment (BICLA) Response at Day 210(Day 210)
  • Phase 2: Mean Change From Baseline in CLASI at Day 210(Baseline, Day 210)
  • Phase 2: Mean Change From Baseline in SLEDAI-2K at Day 210(Baseline, Day 210)
  • Phase 1b: Apparent Volume of Distribution After Extravascular Administration (Vz/F)(Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180)
  • Phase 1b: Mean Change From Baseline in Leukocyte Immunophenotype(Baseline (Day 0); Day 180)
  • Phase 1b: Mean Change From Baseline in Abrogation of IL-21 Gene Signature(Baseline (Day 0); Days 15, 90, 180, and 270)
  • Phase 2: Number of Participants With a Sustained Reduction From Baseline of Oral Corticosteroid (CS) (≤ 7.5 mg/Day and < Day 0 Dose) Between Day 150 and Day 210(Day 150 to Day 210)
  • Phase 2: Number of Participants With a Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) Response at Day 210(Day 210)
  • Phase 2: Mean Change From Baseline in the Total Number of Swollen Joints, Tender Joints, and Active Joints (Swelling and Tenderness in the Same Joint) in the American College of Rheumatology-28 (ACR-28) Joint Count(Baseline, Day 210)
  • Phase 2: Mean Change From Baseline in Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index(Baseline; Day 180)
  • Mean Percent Change in CS Administration From the Baseline Day 0 Dose Through Day 210 in Participants Receiving ≥ 7.5 mg/Day Prednisone Equivalent at Day 0(Baseline; Day 210)
  • Phase 2: Number of Participants With New or Recurrent BILAG Flares (≥ 1 Qualifying BILAG A or > 1 Qualifying BILAG B) Through Day 210(Days 30, 60, 90, 120, 150, 180, 210)
  • Phase 2: Number of Participants With Physician's Global Assessment (PGA) Worsening(Days 30, 60, 90, 120, 150, 180, and 210)
  • Phase 2: Time to Medication Failure(Up to Day 270)
  • Phase 2: Duration of Longest SRI-4 Response(Up to Day 270)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (67)

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