Safety and Efficacy of Blocking IL-4 With Pascolizumab in Patients Receiving Standard Combination Therapy for Pulmonary Tuberculosis (TB): a Randomized, Double-blind, Placebo-controlled, Proof-of-concept Clinical Trial
试验速览
- 阶段
- 2 期
- 入组人数
- 32
- 试验地点
- 7
- 主要终点
- Efficacy - Time to detection on liquid culture of sputum on Week 8
研究概览
简要总结
New approaches are needed to achieve more rapid elimination of dormant mycobacteria and thereby shorten treatment for drug-sensitive and drug-resistant tuberculosis (TB). Dormant mycobacteria are relatively resistant to antibacterial drugs and approaches that enhance immune clearance have the potential to be more effective. Interleukin-4 (IL-4) is a key cytokine in the immune response to TB that may impair the clearance of mycobacteria. We hypothesize that pascolizumab, an anti-IL-4 monoclonal antibody, might be of value as an adjunct to standard treatment.
The aims of this trial are to determine whether administration of pascolizumab as an adjunct to standard combination treatment for drug-sensitive TB produces changes in one or more parameters of bacterial or host response (including bacterial clearance, host clinical status, immune response, bacterial and host transcriptomics, lung imaging) that may indicate potential for enhanced sterilization and to confirm the safety of blocking IL-4 (previously demonstrated in healthy volunteers and patients with asthma) in patients with TB.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 21 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged 21 -75 years of age
- •Male or female: females eligible only if not of childbearing potential or agree to remain abstinent or use an appropriate contraceptive method during the study.
- •Confirmed pulmonary TB by smear microscopy and Gene Xpert™
- •Absence of rifampicin resistance on molecular probe (Gene Xpert™)
- •Estimated to be able to produce at least 5ml of sputum per 24 hour period.
- •No previous history of anti-TB therapy for active disease (treatment for latent disease acceptable).
- •Willing to comply with the study visits and procedures
- •Willing and able to provide written informed consent
排除标准
- •More than 28 days of standard anti-TB chemotherapy at the time of randomization.
- •Disseminated TB (lymphadenopathy is acceptable)
- •Underlying serious chronic diseases such as those of the liver, kidney disease, blood disorders and Type I diabetes (controlled Type II diabetes is acceptable) or any significant organ dysfunction.
- •History of myocardial infarction, congestive heart failure or arrhythmia within 6 months of screening
- •History or evidence of chronic alcohol consumption or drug abuse
- •Current autoimmune disease or history of autoimmune disease.
- •Known or suspected hypersensitivity to any component of the trial medication (sodium phosphate, sodium chloride, glycine, sucrose, polysorbate 80)
- •Chronic use of an immunosuppressant
- •Treatment with any monoclonal antibody within 6 months of randomization
- •Vaccination within the 6 weeks prior to randomization (patients who have received influenza vaccination can enroll at 2 weeks following vaccination).
- •Seropositive for human immunodeficiency virus-1 or 2; hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at screening
- •Creatinine > 1.4 times upper limit of normal or ALT greater than 2.5 times upper limit of normal on screening blood tests
- •QTc >450 msec on ECG performed at screening
- •Women who are currently pregnant or breastfeeding
- •Any other significant condition that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial.
- •Participation in other clinical intervention trial or research protocol (Participation in other studies that do not involve an intervention may be allowed, but this must be discussed and approved by Chief Investigator )
研究组 & 干预措施
Pascolizumab
The dose of study medication will be calculated using the patient's body weight and the appropriate dosing regimen based on the cohort of enrollment. The medication will be administered by slow intravenous infusion over 1 hour under close medical supervision.
干预措施: Pascolizumab (Drug)
Placebo
For patients randomized to placebo, Sterile 0.9% w/v Sodium Chloride will be used for Injection, using the same volume that would have been prepared if the patient had been randomized to receive pascolizumab.
干预措施: Placebo (Drug)
结局指标
主要结局
Efficacy - Time to detection on liquid culture of sputum on Week 8
时间窗: 8 weeks post intervention
Co-primary outcome measure - safety
时间窗: Upto 24 weeks via follow-up visits/assessments and 24-96 weeks via phone assessments
Adverse events considered at least possibly related to study medication and that are classified by the site investigator as serious and/or grade IV severity
次要结局
- Sputum culture status (positive or negative) on liquid culture at week 8(8 weeks)
- Rate of change (area under the curve) from baseline to week 8 in the time to positivity in liquid culture of sputum(8 weeks)
- Rate of change of RPF-dependent serial sputum colony counts from baseline to week 8(8 weeks)
- Resolution of PET/MRI changes at week 8 and week 24(24 weeks)
- Rate of change in serial sputum colony counts on solid cultures from baseline to week 8(8 weeks)
- Serum IL-4 levels (free and drug-bound)(24 weeks)
- Time to resolution of all TB symptoms(24 weeks)
- Anti-pascolizumab antibodies(24 weeks)
- Sputum culture status (positive or negative) on solid culture at week 8(8 weeks)
- Rate of change of sputum smear lipid-body positive mycobacteria from baseline to week 8(8 weeks)
- Time to resolution of fever(24 weeks)
- Resolution of chest X-ray changes at week 24(24 weeks)
- TB relapse at any time up to week 96(96 weeks)