Abatacept for the Treatment of Common Variable Immunodeficiency With Interstitial Lung Disease
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 38
- 试验地点
- 12
- 主要终点
- High Resolution CT Scan of the chest (HRCT)
研究概览
简要总结
There is no standard of care therapy for patients with granulomatous-lymphocytic interstitial lung disease (GLILD) seen in common variable immunodeficiency (CVID). Abatacept has recently looked promising for the treatment of patients with complex CVID. This study is a multi-site, phase II, randomized, blinded/placebo-controlled clinical trial in pediatric and adult subjects to determine the efficacy of abatacept compared to placebo for treatment of subjects with GLILD in the context of CVID.
Funding Source - FDA OOPD
详细描述
There is no standard of care therapy for patients with granulomatous-lymphocytic interstitial lung disease (GLILD) seen in common variable immunodeficiency (CVID). Abatacept is a recombinant, human fusion protein of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and human IgG1 that blocks T cell activation by binding to CD80 and CD86, thereby blocking CD28 engagement- the "second signal" needed for T cell activation. Abatacept has recently looked promising for the treatment of patients with complex CVID.
This study is a multi-site, phase II, randomized, blinded/placebo-controlled clinical trial in pediatric subjects ≥50 kg and adult subjects (cohort 1), with an additional cohort (#2) of pediatric subjects <50 kg tested as a single arm, receiving open-label abatacept. Cohort 1 utilizes a 'delayed-start' design to obtain maximum statistical power from this cohort. Cohort 2 will be open label due to the lack of a suitable placebo for pediatric dose abatacept syringes. A total of 21-30 evaluable subjects will be treated in cohort 1 and 8 evaluable subjects in cohort 2.
Following the initial 12 months of treatment, patients will have the option of continuing abatacept for up to 3 years. Patients will have the option of continuing abatacept any time after the initial 12 months of treatment (does not have to be immediately). A separate consent form will be utilized to document a patient's decision to continue. Abatacept will be provided by BMS. Patients who decide to continue abatacept will be monitored for safety, including infections, approximately every 3 months.
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
- 4 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of CVID according to the international consensus document (ICON)
- •Age 4 years or above
- •Serum IgG at least 2 standard deviations below the age adjusted normal
- •Decreased serum IgA and/or serum IgM
- •Abnormal specific antibody response to immunization
- •Exclusion of secondary immunodeficiency
- •On replacement immunoglobulin for at least 6 months and willing to maintain throughout study
- •Granulomatous-lymphocytic interstitial lung disease with a lymphocytic component diagnosed by lung biopsy prior to study entry, wedge biopsy preferred.
- •Persistence or worsening of interstitial lung disease measured on serial CT imaging of the lung at least 6 months apart, with the latest assessment within 3 months of study entry.
- •Signed written informed consent
- •Willing to allow storage of biological specimens for future use in medical research.
- •Female subjects of childbearing potential must agree to an effective form of birth control such as hormone based contraceptive, intrauterine device, condoms/barrier, surgically sterile partner, or abstinence.
- •Fertile, non-vasectomized males with a female partner of childbearing potential should use condoms throughout the study and for 3 months after the last dose
排除标准
- •History of hypersensitivity to abatacept or any of its components
- •Has received any lymphocyte depleting agents including anti-CD20 monoclonal antibodies, alemtuzumab, ATG in the preceding 6 months
- •Has received abatacept, cyclophosphamide, tumor necrosis factor inhibitors, or pulse steroids (defined as >15mg/kg/day of methylprednisone or corticosteroid equivalent) within the past 3 months
- •Have started or increased any of the following immune modulating drugs within 3 months of enrolling and 3 months from initial CT chest: azathioprine, cyclosporine, tacrolimus, mercaptopurine, methotrexate, mycophenolate mofetil, or sirolimus
- •History of HIV infection (positive PCR)
- •Chronic untreated hepatitis B or C (positive PCR)
- •Active tuberculosis (TB) by positive QuantiFERON gold. If history of latent TB, then must supply evidence of completing treatment.
- •Persistent Epstein-Barr Virus (EBV) load ≥ 1,000 units/mL blood checked twice at least 1 month apart
- •Other uncontrolled infections
- •Live vaccine given within 6 weeks of the start of the trial
- •Malignancy or treated for malignancy within the past year
- •Currently pregnant or breast feeding
- •Life expectancy less than 1 month
- •Subjects unwilling to self-administer or have a parent/caregiver self-administer subcutaneous injections at home
- •Other conditions that the investigators feel contraindicate participation in the study
- •Inclusion criteria for Extended Treatment Plan:
- •Patients must have completed the abatacept for the treatment of Interstitial Lung Disease in Common Variable Immunodeficiency (ABCVILD) trial
- •Patients must have demonstrated positive response to abatacept.
- •Patients must provide informed consent to participate in the Extended Treatment Plan.
- •Exclusion criteria for Extended Treatment Plan:
- •Patients who experienced SAEs during the original trial, and such SAEs were determined as related to treatment, or patients who in the opinion of the investigator would not benefit from the extended treatment option.
研究组 & 干预措施
Abatacept
Pediatric subjects weighing <50 kg will be placed in an single arm with abatacept with dosing based on weight. Pediatric subjects weighing ≥50kg and adult subjects will enter a double blinded, randomization in a 1:2 ratio of subjects to the abatacept treatment group (arm 1) or to the placebo group (arm 2) treated weekly through month 6. After month 6, all subjects will begin receiving abatacept weekly.
Pediatric dosing:
Abatacept subcutaneous every week:
10-25 kg: 50 mg; 25-50 kg: 87.5 mg; >50 kg: 125 mg
Adult dosing:
Abatacept: 125 mg subcutaneous every week
干预措施: Abatacept (Drug)
Placebo
Pediatric subjects weighing ≥50kg and adult subjects will enter a double blinded, randomization in a 1:2 ratio of subjects to the abatacept treatment group (arm 1) or to the placebo group (arm 2) treated weekly through month 6. The composition of the placebo is the same as the active study drug without the abatacept. To maintain the blind, injection volumes will be the same as the active treatment. After month 6, all subjects will begin receiving abatacept weekly.
干预措施: Placebo (Other)
结局指标
主要结局
High Resolution CT Scan of the chest (HRCT)
时间窗: 6 months
Proportion of subjects achieving a significant response (defined as \>30 percent change in lung tissue disease burden by GLILD) on HRCT after 6 months of abatacept therapy.
次要结局
- Forced vital capacity (FVC)(6 months, 12 months)
- Diffusion capacity of carbon monoxide (DLCo)(6 months, 12 months)
- Incidence(6 months, 12 months)
- Change in PedsQL (Pediatric Quality of Life) Generic Core scores(6 months, 12 months)
- Pediatric growth - change in height(6 months, 12 months)
- Pediatric growth - change in weight(6 months, 12 months)
- Additional Immune Agents(6 months, 12 months)
- Adverse Events/Serious Adverse Events(6 months, 12 months)
- Dropout rate(6 months, 12 months)
- Forced expiratory volume (FEV)(6 months, 12 months)
- Resolution(6 months, 12 months)
- Steroid usage(6months, 12 months)
- Change in Short Form-36 scores(6 months, 12 months)
- Change in King's Interstitial Lung Disease scores(6 months, 12 months)
- Survival(6 months, 12 months)
- Incidence of concurrent infections(6 months, 12 months)
- Treatment of concurrent infections(6 months, 12 months)
- Complications of concurrent infections(6 months, 12 months)