Open Label, Single Center, Phase 1 Dose Escalation and Extension Trial to Evaluate Safety and Tolerability of Chlorquine as Adjuvant Drug to Standard 4-drug Anti-tuberculosis Therapy in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Safety Laboratory samples Panel 1.3
研究概览
简要总结
In vitro and in vivo data show promising results of adjunctive use of Chloroquine to standard tuberculosis therapy as Chloroquine enhances animicrobial effectiveness against intracellular MTB. To date, no safety data of the concurrent use of both treatments is availble. In a phase I trial, the investigators aim to evaluate safety and tolerability of the concurrent use of Chloroquine and standard anti-TB drug in healthy volunteers.
详细描述
Even though tuberculosis (TB) remains one of the top 10 causes of death worldwide in 2019, there exists a gap in development of new diagnostics and treatments. There is a substantial need for new TB regimens, which would ideally be shorter, more tolerable and more efficient in eradicating all subpopulations of mycobacterium tuberculosis (MTB). In this regard, a promising TB drug pipeline emerges through re-use of marketed non TB-drugs, re-engineering of existing anti-TB compounds and discovery of new compounds. In vitro data showed that Chloroquine (CQ) inhibits an efflux pump expressed on macrophages. Inhibition of this pump increases intracellular concentration of Isoniazid and Pyrazinamide and enhances antimicrobial effectiveness against intracellular MTB. Recently published in vivo mouse model data confirmed the positive effect of CQ combined with the standard anti-TB therapy.
In line with global attempts to enhance effectiveness and shorten TB therapy, the investigators propose to evaluate this combination in a clinical setting. The absence of clinical study data showing safety and tolerability of CQ administered with first-line anti-TB drugs in humans shows the need for the research team to conduct this study. the investigators hypothesize that additional CQ to standard 4-drug anti-TB therapy is safe and increases the efficacy against intracellular MTB, leading to a pronounced reduction of the intracellularly hiding bacteria and overall to an accelerated reduction of bacterial load. The major advantages of this new combination with CQ and the 4-drug anti-TB therapy are, that all substances are long-term approved, commercially available drugs and that effective CQ concentrations are well achievable in humans.
Primary objective of the study is to investigate the safety and tolerability of a combination of standard doses of Nivaquine® (Chloroquine) with standard doses of Rimstar® (4-drug anti-TB therapy) in healthy volunteers.
Secondary objective of the study is to assess drug concentration of the new combination (Nivaquine® and Rimstar®) in healthy volunteers over time.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Cohort 1
100 mg Nivaquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days
干预措施: Nivaquine ® (Chloroquine) (Drug)
Cohort 2
200 mg Chloroquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days
干预措施: Nivaquine ® (Chloroquine) (Drug)
Cohort 3
300 mg Chloroquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days
干预措施: Nivaquine ® (Chloroquine) (Drug)
Dose extension group
Dose escalation: XX mg Chloroquine (depending on results) and 4 Tabl Rimstar peroral once daily before breakfast for 14 days
干预措施: Nivaquine ® (Chloroquine) (Drug)
结局指标
主要结局
Safety Laboratory samples Panel 1.3
时间窗: day 14
Sodium (mmol/l)
Safety Laboratory samples Panel 2.2
时间窗: day 7
Potassium (mmol/l)
Safety Laboratory samples Panel 3.1
时间窗: day 1
Calcium (mmol/l)
Safety Laboratory samples Panel 5.1
时间窗: day 1
Total Bilirubin (umol/l)
Vital Signs 3.2
时间窗: day 7
temperature (°C)
Physicial examination 1.1
时间窗: day 14
Heart auscultation (normal/abnormal)
Physicial examination 2.2
时间窗: day 30
lung auscultation (normal, abnormal)
Vital Signs 3.5
时间窗: day 30
temperature (°C)
Physicial examination 3.1
时间窗: day 14
abdominal examination (normal, abnormal)
Physicial examination 3.2
时间窗: day 30
abdominal examination (normal, abnormal)
Physicial examination 4.1
时间窗: day 14
lymph node palpation (normal, abnormal)
Vital Signs 3.1
时间窗: day 1
temperature (°C)
Safety Laboratory samples Panel 1.1
时间窗: day 1
Sodium (mmol/l)
Safety Laboratory samples Panel 4.1
时间窗: day 1
Creatinine (umol/l)
Physicial examination 1.2
时间窗: day 30
Heart auscultation (normal/abnormal)
Physicial examination 2.1
时间窗: day 14
lung auscultation (normal, abnormal)
Physicial examination 4.2
时间窗: day 30
lymph node palpation (normal, abnormal)
Physicial examination 5.1
时间窗: day 14
reflex testing (normal, abnormal)
Physicial examination 5.2
时间窗: day 30
reflex testing (normal, abnormal)
Physicial examination 6.2
时间窗: day 30
test vibration sense with tuning fork (mallelor left and right X/8)
Vital Signs 1.3
时间窗: day 14
heart rate (beats/min)
Vital Signs 1.4
时间窗: day 15
heart rate (beats/min)
Vital Signs 1.5
时间窗: day 30
heart rate (beats/min)
Vital Signs 2.1
时间窗: day 1
blood pressure (mmHg)
Vital Signs 2.2
时间窗: day 7
blood pressure (mmHg)
Vital Signs 2.4
时间窗: day 15
blood pressure (mmHg)
Vital Signs 2.5
时间窗: day 30
blood pressure (mmHg)
Vital Signs 3.3
时间窗: day 14
temperature (°C)
Vital Signs 3.4
时间窗: day 15
temperature (°C)
Safety Laboratory samples Panel 1.2
时间窗: day 7
Sodium (mmol/l)
Physicial examination 6.1
时间窗: day 14
test vibration sense with tuning fork (mallelor left and right X/8)
Vital Signs 1.1
时间窗: day 1
heart rate (beats/min)
Vital Signs 1.2
时间窗: day 7
heart rate (beats/min)
Vital Signs 2.3
时间窗: day 14
blood pressure (mmHg)
Safety Laboratory samples Panel 1.4
时间窗: day 30
Sodium (mmol/l)
Safety Laboratory samples Panel 2.3
时间窗: day 14
Potassium (mmol/l)
Safety Laboratory samples Panel 2.4
时间窗: day 30
Potassium (mmol/l)
Safety Laboratory samples Panel 3.2
时间窗: day 7
Calcium (mmol/l)
Safety Laboratory samples Panel 3.3
时间窗: day 14
Calcium (mmol/l)
Safety Laboratory samples Panel 3.4
时间窗: day 30
Calcium (mmol/l)
Safety Laboratory samples Panel 4.2
时间窗: day 7
Creatinine (umol/l)
Safety Laboratory samples Panel 4.3
时间窗: day 14
Creatinine (umol/l)
Safety Laboratory samples Panel 4.4
时间窗: day 30
Creatinine (umol/l)
Safety Laboratory samples Panel 5.3
时间窗: day 14
Total Bilirubin (umol/l)
Safety Laboratory samples Panel 5.4
时间窗: day 30
Total Bilirubin (umol/l)
Safety Laboratory samples Panel 5.2
时间窗: day 7
Total Bilirubin (umol/l)
Safety Laboratory samples Panel 7.1
时间窗: day 1
Glucose (mmol/l)
Safety Laboratory samples Panel 8.4
时间窗: day 30
CRP (mg/l)
Safety Laboratory samples Panel 10.4
时间窗: day 30
Platlets (G/l)
Safety Laboratory samples Panel 12.2
时间窗: day 30
Blood pregnancy test (Blood beta-hCG)
Urinanalysis 1.3
时间窗: day 14
Dipstick: protein negative/+/++/+++
Urinanalysis 2.2
时间窗: day 7
Dipstick: white blood cells negative/+/++/+++
Urinanalysis 2.3
时间窗: day 14
Dipstick: white blood cells negative/+/++/+++
Urinanalysis 2.4
时间窗: day 30
Dipstick: white blood cells negative/+/++/+++
Urinanalysis 3.1
时间窗: day 1
Dipstick: red blood cells negative/+/++/+++
Urinanalysis 3.2
时间窗: day 7
Dipstick: red blood cells negative/+/++/+++
Safety Laboratory samples Panel 2.1
时间窗: day 1
Potassium (mmol/l)
Safety Laboratory samples Panel 6.3
时间窗: day 14
ALT (U/l)
Safety Laboratory samples Panel 6.4
时间窗: day 30
ALT (U/l)
Safety Laboratory samples Panel 7.2
时间窗: day 7
Glucose (mmol/l)
Safety Laboratory samples Panel 7.3
时间窗: day 14
Glucose (mmol/l)
Safety Laboratory samples Panel 7.4
时间窗: day 30
Glucose (mmol/l)
Safety Laboratory samples Panel 8.2
时间窗: day 7
CRP (mg/l)
Safety Laboratory samples Panel 10.1
时间窗: day 1
Platlets (G/l)
Safety Laboratory samples Panel 11.3
时间窗: day 14
White blood cell (G/l)
Safety Laboratory samples Panel 6.1
时间窗: day 1
ALT (U/l)
Safety Laboratory samples Panel 6.2
时间窗: day 7
ALT (U/l)
Safety Laboratory samples Panel 8.1
时间窗: day 1
CRP (mg/l)
Safety Laboratory samples Panel 9.1
时间窗: day 1
Haemoglobin (g/l)
Safety Laboratory samples Panel 9.2
时间窗: day 7
Haemoglobin (g/l)
Safety Laboratory samples Panel 9.3
时间窗: day 14
Haemoglobin (g/l)
Safety Laboratory samples Panel 9.4
时间窗: day 30
Haemoglobin (g/l)
Safety Laboratory samples Panel 10.2
时间窗: day 7
Platlets (G/l)
Safety Laboratory samples Panel 10.3
时间窗: day 14
Platlets (G/l)
Safety Laboratory samples Panel 11.1
时间窗: day 1
White blood cell (G/l)
Safety Laboratory samples Panel 11.2
时间窗: day 7
White blood cell (G/l)
Safety ophtalmological examination 1.2
时间窗: day 30
Refraction both sides (+/-)
Safety ophtalmological examination 1.5
时间窗: day 30
Color sense test according to Panel D-15 bilateral (normal/abnormal)
Occurence of adverse events and serious adverse events 1.1
时间窗: day 1
according to GCP Guideline
Occurence of adverse events and serious adverse events 1.2
时间窗: day 7
according to GCP Guideline
Occurence of adverse events and serious adverse events 1.3
时间窗: day 14
according to GCP Guideline
Occurence of adverse events and serious adverse events 1.4
时间窗: day 15
according to GCP Guideline
Occurence of adverse events and serious adverse events 1.5
时间窗: day 30
according to GCP Guideline
Occurence of adverse events and serious adverse events 1.6
时间窗: day 256
according to GCP Guideline
Safety Laboratory samples Panel 8.3
时间窗: day 14
CRP (mg/l)
Safety Laboratory samples Panel 11.4
时间窗: day 30
White blood cell (G/l)
Urinanalysis 1.1
时间窗: day 1
Dipstick: protein negative/+/++/+++
Urinanalysis 2.1
时间窗: day 1
Dipstick: white blood cells negative/+/++/+++
Urinanalysis 4.2
时间窗: day 7
Dipstick: Glucose negative/+/++/+++
Safety Laboratory samples Panel 12.1
时间窗: day 7
Blood pregnancy test (Blood beta-hCG)
Urinanalysis 1.2
时间窗: day 7
Dipstick: protein negative/+/++/+++
Urinanalysis 1.4
时间窗: day 30
Dipstick: protein negative/+/++/+++
Urinanalysis 3.3
时间窗: day 14
Dipstick: red blood cells negative/+/++/+++
Urinanalysis 3.4
时间窗: day 30
Dipstick: red blood cells negative/+/++/+++
Urinanalysis 4.1
时间窗: day 1
Dipstick: Glucose negative/+/++/+++
Urinanalysis 4.3
时间窗: day 14
Dipstick: Glucose negative/+/++/+++
Urinanalysis 4.4
时间窗: day 30
Dipstick: Glucose negative/+/++/+++
Safety 12 lead ECG 1.1
时间窗: day 7
Rate/min
Safety 12 lead ECG 1.2
时间窗: 30
Rate/min
Safety 12 lead ECG 2.1
时间窗: day 7
Rhythm (regular/irregular)
Safety 12 lead ECG 2.2
时间窗: day 30
Rhythm (regular/irregular)
Safety 12 lead ECG 3.1
时间窗: day 7
PQ interval (ms)
Safety 12 lead ECG 3.3
时间窗: day 30
PQ interval (ms)
Safety 12 lead ECG 4.1
时间窗: day 7
QRS interval (ms)
Safety 12 lead ECG 4.2
时间窗: day 30
QRS interval (ms)
Safety 12 lead ECG 5.1
时间窗: day 7
ST Segment (normal/elevation/depression)
Safety 12 lead ECG 5.2
时间窗: day 30
ST Segment (normal/elevation/depression)
Safety ophtalmological examination 1.1
时间窗: day 30
Slit lamp examaniation both sides (normal/abnormal)
Safety ophtalmological examination 1.3
时间窗: day 30
Biomicroscopy of the central fundus both sides(normal/abnormal)
Safety ophtalmological examination 1.4
时间窗: day 30
Applanation tonometry and stereoscopic papilla evaluation bilateral (normal/abnormal), Color sense test according to Panel D-15 right and left side (normal/abnormal)
次要结局
- Drug concentration over time measured by the pharmacokinetics(day 14 prior to dosing (-15 until -5 minutes) and 1, 2, 4, 6 and 24 hours after dosing)