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临床试验/NCT03222492
NCT03222492已完成1 期

Evaluation of Brentuximab Vedotin for Diffuse Cutaneous Systemic Sclerosis BRAVOS: A Phase 1/2 Multicenter Randomized, Double Blinded, Safety Study (ITN075AI)

National Institute of Allergy and Infectious Diseases (NIAID)15 个研究点 分布在 1 个国家目标入组 17 人开始时间: 2017年9月20日最近更新:
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适应症

试验速览

阶段
1 期
状态
已完成
入组人数
17
试验地点
15
主要终点
Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Week 48.
研究概览研究设计入排标准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

There is significant unmet need for effective treatment options for Diffuse Cutaneous Systemic Sclerosis (dcSSc). The present study will be a dose-escalation safety trial of brentuximab vedotin, a drug-antibody conjugate approved for the treatment of lymphoma and targeted to the protein CD30 molecule expressed on activated immune cells There is evidence for CD30 involvement in SSc. This study represents the first step in determining safety and tolerability of brentuximab vedotin in SSc.

详细描述

This is a multicenter prospective double blind placebo controlled dose escalation safety clinical trial with brentuximab vedotin and stable background immunosuppressive therapy in adult individuals with Diffuse Cutaneous Systemic Sclerosis (dcSSc). Adult male and female participants with dcSSc will be recruited by a collaborative group of clinical sites in the United States. Participants who meet the eligibility criteria will be enrolled without regard to gender, race, or ethnicity.

Eligible participants will be randomly assigned to study treatment, either brentuximab vedotin or placebo equivalent in a 6:2 ratio favoring brentuximab vedotin. Three dose cohorts are planned with 8 participants in each cohort, for a total of 24 participants who receive sufficient doses of the investigational medication to assess safety.

The doses planned for each ascending dose cohort include 0.6mg/kg, 1.2 mg/kg, and 1.8 mg/kg brentuximab vedotin or placebo equivalent. All cohorts will receive intravenous administration of study medication every 3 weeks for 21 weeks, for a total of eight doses. Following completion of treatment, participants will undergo follow-up visits at weeks 24, 28, 36 and 48.

研究设计

研究类型
Interventional
分配方式
Randomized
干预模型
Sequential
主要目的
Treatment
盲法
Triple (Participant, Care Provider, Investigator)

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

  • •Classification of Systemic Sclerosis (SSc), as defined using the 2013 American College of Rheumatology/European Union League Against Rheumatism classification of SSc;
  • •Diagnosis of Diffuse Cutaneous Systemic Sclerosis (dcSSc), as defined by LeRoy and Medsger, Criteria for the classification of early systemic sclerosis. J Rheumatol,
  • •28(7): p. 1573-6;
  • •Disease duration ≤ 60 months (defined as time from the first non-Raynaud phenomenon manifestation);
  • •Modified Rodnan Skin Score (mRSS) units ≥ 15 and ≤ 45, and both of the following:
  • •At least mild skin thickening (≥ 1+ mRSS) of the forearm, and
  • •At least moderate skin thickening (≥ 2+ mRSS) at the planned forearm skin biopsy site.
  • •Documentation of at least 12 weeks of ongoing immunosuppressive therapy for SSc at the time of enrollment, and at least 4 weeks at a stable dose, of one of the following:
  • •Methotrexate ≤ 25 mg/week, or
  • •Mycophenolate mofetil ≤3 grams/day or mycophenolate sodium ≤2.16 grams/day, or
  • •Azathioprine ≤3mg/kg/day.
  • •Ability to provide informed consent.

排除标准

  • •Rheumatic disease other than Diffuse Cutaneous Systemic Sclerosis (dcSSc); it is acceptable to include patients with osteoarthritis, fibromyalgia, sicca symptoms, and scleroderma-associated myopathy;
  • •Limited cutaneous Systemic Sclerosis (SSc) or sine scleroderma;
  • •Pulmonary disease with Forced Vital Capacity (FVC) ≤60% of predicted, or Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) (corrected for hemoglobin) ≤60% of predicted;
  • •Pulmonary hypertension (PH) or moderate to severe left ventricular dysfunction, defined as one of the following:
  • •Transthoracic echocardiography demonstrating at least one of the following (unless subsequent right heart catheterization does not demonstrate PH; or unless prior right heart catheterization within one year did not demonstrate PH and echocardiography results are not significantly changed):
  • •Tricuspid regurgitation jet >2.8 m/sec or estimated right ventricular systolic pressure > 42 mm Hg. or
  • •At least one of the following:
  • •Abnormality of right atrial size, shape, or wall thickness consistent with PH, or
  • •Abnormality of right ventricular size, shape, or wall thickness consistent with PH, or
  • •Abnormal septal wall shape consistent with PH.
  • •Left Ventricular Ejection Fraction (LVEF) <50%.
  • •Right heart catheterization showing mean pulmonary artery pressure ≥25 mm Hg at rest;
  • •Current use of approved medications for PH. It is acceptable to use phosphodiesterase type 5 (PDE-5) inhibitors for Raynaud's, digital ulcers, and intermittently for erectile dysfunction.
  • •Active scleroderma renal crisis within the 4 months prior to enrollment;
  • •History of moderate-to-severe lower gastrointestinal dysmotility such as current use of parenteral nutrition and/or recent history of intestinal pseudo-obstruction within 3 months prior to enrollment;
  • •The following medications:
  • •Oral corticosteroids >10 mg/day of prednisone or equivalent within 2 weeks prior to enrollment;
  • •Treatment with Intravenous Immunoglobulin (IVIG) within 12 weeks prior to enrollment;
  • •Treatment with cyclophosphamide within 6 months prior to enrollment;
  • •Use of investigational biologic or non-biologic medication within the past 90 days, or 5 half-lives prior to enrollment, whichever is greater;
  • •Use of anti-TNF medication or other biologic medications within the past 90 days, or 5 half-lives prior to enrollment, whichever is greater;
  • •Prior treatment with anti-CD20 if either of the following are true:
  • •B cells ≤ lower limit of normal (LLN), or
  • •Treatment with anti-CD20 has been within 12 months prior to enrollment.
  • •Any prior treatment with cell-depleting therapies other than anti-CD20, including investigational agents, including but not limited to, CAMPATH(R), anti- CD4, anti-CD5, anti-CD3, anti-CD19; or
  • •Any prior treatment with chlorambucil, bone marrow transplantation, or total lymphoid irradiation.
  • •Receipt of a live-attenuated vaccine within 3 months of study enrollment;
  • •Concomitant malignancies or a history of malignancy, with the exception of adequately treated basal and squamous cell carcinoma of the skin, or carcinoma in situ of the cervix;
  • •Major surgery (including joint surgery) within 8 weeks prior to enrollment;
  • •History of solid organ or hematopoietic stem cell transplantation;
  • •History of primary immunodeficiency;
  • •Comorbidities requiring systemic corticosteroid therapy, including those which have required three or more courses of systemic corticosteroids within the 12 months prior to enrollment;
  • •Current substance abuse or history of substance abuse within 12 months prior to enrollment;
  • •History of severe depression or severe psychiatric condition;
  • •Lack of peripheral venous access;
  • •Known hypersensitivity to brentuximab vedotin, a component thereof, or the excipient contained in the drug formulation;
  • •Severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, or neurological disease (or, in the investigator's opinion, any other concomitant medical condition that places the participant at risk by participating in this study), including but not limited to:
  • •Uncompensated congestive heart failure (New York Heart Association Class III or VI);
  • •Clinically significant active coronary artery disease (e.g., unstable angina or acute myocardial infarction within 6 months prior to enrollment);
  • •Recently active cerebrovascular disease (e.g., stroke or transient ischemic attack within 6 months prior to enrollment);
  • •Uncontrolled systemic hypertension;
  • •Confirmed diagnosis of diabetes mellitus;
  • •Pancreatitis within 30 days prior to enrollment; or
  • •History or presence of peripheral neuropathy, such as mononeuritis multiplex, acute or chronic inflammatory demyelinating polyneuropathy, axonal sensorimotor neuropathies, or drug related neuropathy or neuritis.
  • •Evidence of infection:
  • •Any infected ulcer at enrollment;
  • •Active bacterial, viral, fungal, or opportunistic infections requiring systemic anti-infective therapy;
  • •Evidence of current or prior infection with tuberculosis:
  • •Positive QuantiFERON® - TB Gold or TB Gold Plus test results.
  • •Note: Purified protein derivative (PPD) tuberculin test may be substituted for QuantiFERON® - TB Gold or TB fold Plus test.
  • 另有 24 项未显示

结局指标

主要结局

Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Week 48.

时间窗: Baseline through end of study (48 weeks)

Adverse events were graded using the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, except for the grading of liver chemistry abnormalities. The scale ranges from grade 1 through 5, with grade 1 being the least severe and grade 5 being the most severe. Liver chemistry abnormalities were graded, from 1 through 4 (with 1 being least severe and 4 being most severe) relative to the upper limit of normal (ULN) with different grades depending on whether there was an increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), or blood bilirubin.

次要结局

  • Proportion of Participants That Experience at Least One Grade 2 or Higher Adverse Event at or Before Weeks 48.(Baseline through the Week 48 study visit or 48 weeks on study if the visit was missed.)
  • Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Weeks 36.(Baseline through Week 36 study visit or 36 weeks on study if the visit was missed.)
  • Proportion of Participants That Experience at Least One Grade 2 or Higher Adverse Event at or Before Weeks 12, 24, 36, and 48.(Baseline thru Week 12 visit or 12 weeks on study if visit was missed/thru Week 24 visit or 24 weeks on study if visit was missed/thru Week 36 visit or 36 weeks on study if visit was missed/thru Week 48 visit or 48 weeks on study if visit was missed)
  • Proportion of Participants With Grade 2 or Higher Peripheral Neuropathy at or Before Weeks 12(Baseline through the Week 12 study visit or 12 weeks on study if the visit was missed.)
  • Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Weeks 12, 24, and 36.(Baseline through Week 12 study visit or 12 weeks on study if the visit was missed. Baseline through Week 24 study visit or 24 weeks on study if the visit was missed. Baseline through Week 36 study visit or 36 weeks on study if the visit was missed)
  • Proportion of Participants That Experience at Least One Grade 2 or Higher Adverse Event at or Before Weeks 24.(Baseline through the Week 24 study visit or 24 weeks on study if the visit was missed.)
  • Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Week12(Baseline through Week 12 study visit or 12 weeks on study if the visit was missed.)
  • Proportion of Participants With Grade 2 or Higher Peripheral Neuropathy at or Before Weeks 24.(Baseline through the Week 24 study visit or 24 weeks on study if the visit was missed.)
  • Proportion of Participants With Grade 2 or Higher Peripheral Neuropathy at or Before Weeks 36.(Baseline through the Week 36 study visit or 36 weeks on study if the visit was missed.)
  • Proportion of Participants With Grade 3 or Higher Neutropenia at or Before Weeks 48.(Baseline through the Week 48 study visit or 48 weeks on study if the visit was missed.)
  • Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Weeks 24.(Baseline through Week 24 study visit or 24 weeks on study if the visit was missed.)
  • Proportion of Participants That Experience at Least One Grade 2 or Higher Adverse Event at or Before Weeks 36.(Baseline through the Week 36 study visit or 36 weeks on study if the visit was missed.)
  • Proportion of Participants With Grade 2 or Higher Peripheral Neuropathy at or Before Weeks 12, 24, 36, and 48.(Baseline thru Week 12 visit or 12 weeks on study if visit was missed/thru Week 24 visit or 24 weeks on study if visit was missed/thru Week 36 visit or 36 weeks on study if visit was missed/thru Week 48 visit or 48 weeks on study if visit was missed)
  • Proportion of Participants With Grade 3 or Higher Neutropenia at or Before Weeks 12(Baseline through the Week 12 study visit or 12 weeks on study if the visit was missed.)
  • Proportion of Participants With Grade 3 or Higher Neutropenia at or Before Weeks 24.(Baseline through the Week 24 study visit or 24 weeks on study if the visit was missed.)
  • Proportion of Participants That Experience at Least One Grade 2 or Higher Adverse Event at or Before Weeks 12(Baseline through the Week 12 study visit or 12 weeks on study if the visit was missed)
  • Proportion of Participants With Grade 2 or Higher Peripheral Neuropathy at or Before Weeks 48.(Baseline through the Week 48 study visit or 48 weeks on study if the visit was missed.)
  • Proportion of Participants With Grade 3 or Higher Neutropenia at or Before Weeks 12, 24, 36, and 48.(Baseline thru Week 12 visit or 12 weeks on study if visit was missed/thru Week 24 visit or 24 weeks on study if visit was missed/thru Week 36 visit or 36 weeks on study if visit was missed/thru Week 48 visit or 48 weeks on study if visit was missed)
  • Proportion of Participants With Any of the Following Grade 3 or Higher AEs at or Before Week 48: Peripheral Neuropathy, Neutropenia, Infectious Adverse Events, Infusions Reactions, or Progressive Multifocal Leukoencephalopathy.(Baseline through the Week 48 study visit or 48 weeks on study if the visit was missed.)
  • Proportion of Participants With Grade 3 or Higher Neutropenia at or Before Weeks 36.(Baseline through the Week 36 study visit or 36 weeks on study if the visit was missed.)

研究者

申办方类型
Nih
责任方
Sponsor

研究点 (15)

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