Safety and Tolerability of Chlorquine in Addition to Anti-tuberculosis Therapy
- Conditions
- Tuberculosis Infection
- Interventions
- Drug: Nivaquine ® (Chloroquine)
- Registration Number
- NCT05443178
- Lead Sponsor
- University of Zurich
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 16
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 1 Nivaquine ® (Chloroquine) 100 mg Nivaquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days Cohort 2 Nivaquine ® (Chloroquine) 200 mg Chloroquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days Cohort 3 Nivaquine ® (Chloroquine) 300 mg Chloroquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days Dose extension group Nivaquine ® (Chloroquine) Dose escalation: XX mg Chloroquine (depending on results) and 4 Tabl Rimstar peroral once daily before breakfast for 14 days
- Primary Outcome Measures
Name Time Method Safety Laboratory samples Panel 5.1 day 1 Total Bilirubin (umol/l)
Vital Signs 3.2 day 7 temperature (°C)
Vital Signs 3.3 day 14 temperature (°C)
Physicial examination 1.1 day 14 Heart auscultation (normal/abnormal)
Physicial examination 2.2 day 30 lung auscultation (normal, abnormal)
Physicial examination 3.1 day 14 abdominal examination (normal, abnormal)
Physicial examination 3.2 day 30 abdominal examination (normal, abnormal)
Physicial examination 4.1 day 14 lymph node palpation (normal, abnormal)
Vital Signs 3.1 day 1 temperature (°C)
Vital Signs 3.5 day 30 temperature (°C)
Safety Laboratory samples Panel 1.1 day 1 Sodium (mmol/l)
Safety Laboratory samples Panel 1.3 day 14 Sodium (mmol/l)
Safety Laboratory samples Panel 2.2 day 7 Potassium (mmol/l)
Safety Laboratory samples Panel 3.1 day 1 Calcium (mmol/l)
Safety Laboratory samples Panel 4.1 day 1 Creatinine (umol/l)
Physicial examination 1.2 day 30 Heart auscultation (normal/abnormal)
Physicial examination 2.1 day 14 lung auscultation (normal, abnormal)
Physicial examination 4.2 day 30 lymph node palpation (normal, abnormal)
Physicial examination 5.1 day 14 reflex testing (normal, abnormal)
Physicial examination 5.2 day 30 reflex testing (normal, abnormal)
Physicial examination 6.2 day 30 test vibration sense with tuning fork (mallelor left and right X/8)
Vital Signs 1.3 day 14 heart rate (beats/min)
Vital Signs 1.4 day 15 heart rate (beats/min)
Vital Signs 1.5 day 30 heart rate (beats/min)
Vital Signs 2.1 day 1 blood pressure (mmHg)
Vital Signs 2.2 day 7 blood pressure (mmHg)
Vital Signs 2.4 day 15 blood pressure (mmHg)
Vital Signs 2.5 day 30 blood pressure (mmHg)
Vital Signs 3.4 day 15 temperature (°C)
Safety Laboratory samples Panel 1.2 day 7 Sodium (mmol/l)
Physicial examination 6.1 day 14 test vibration sense with tuning fork (mallelor left and right X/8)
Vital Signs 1.1 day 1 heart rate (beats/min)
Vital Signs 1.2 day 7 heart rate (beats/min)
Vital Signs 2.3 day 14 blood pressure (mmHg)
Safety Laboratory samples Panel 1.4 day 30 Sodium (mmol/l)
Safety Laboratory samples Panel 2.3 day 14 Potassium (mmol/l)
Safety Laboratory samples Panel 2.4 day 30 Potassium (mmol/l)
Safety Laboratory samples Panel 3.2 day 7 Calcium (mmol/l)
Safety Laboratory samples Panel 3.3 day 14 Calcium (mmol/l)
Safety Laboratory samples Panel 3.4 day 30 Calcium (mmol/l)
Safety Laboratory samples Panel 4.2 day 7 Creatinine (umol/l)
Safety Laboratory samples Panel 4.3 day 14 Creatinine (umol/l)
Safety Laboratory samples Panel 4.4 day 30 Creatinine (umol/l)
Safety Laboratory samples Panel 5.3 day 14 Total Bilirubin (umol/l)
Safety Laboratory samples Panel 5.4 day 30 Total Bilirubin (umol/l)
Safety Laboratory samples Panel 5.2 day 7 Total Bilirubin (umol/l)
Safety Laboratory samples Panel 7.1 day 1 Glucose (mmol/l)
Safety Laboratory samples Panel 8.4 day 30 CRP (mg/l)
Safety Laboratory samples Panel 10.4 day 30 Platlets (G/l)
Safety Laboratory samples Panel 12.2 day 30 Blood pregnancy test (Blood beta-hCG)
Urinanalysis 1.3 day 14 Dipstick: protein negative/+/++/+++
Urinanalysis 2.2 day 7 Dipstick: white blood cells negative/+/++/+++
Urinanalysis 2.3 day 14 Dipstick: white blood cells negative/+/++/+++
Urinanalysis 2.4 day 30 Dipstick: white blood cells negative/+/++/+++
Urinanalysis 3.1 day 1 Dipstick: red blood cells negative/+/++/+++
Urinanalysis 3.2 day 7 Dipstick: red blood cells negative/+/++/+++
Safety Laboratory samples Panel 2.1 day 1 Potassium (mmol/l)
Safety Laboratory samples Panel 6.3 day 14 ALT (U/l)
Safety Laboratory samples Panel 6.4 day 30 ALT (U/l)
Safety Laboratory samples Panel 7.2 day 7 Glucose (mmol/l)
Safety Laboratory samples Panel 7.3 day 14 Glucose (mmol/l)
Safety Laboratory samples Panel 7.4 day 30 Glucose (mmol/l)
Safety Laboratory samples Panel 8.2 day 7 CRP (mg/l)
Safety Laboratory samples Panel 10.1 day 1 Platlets (G/l)
Safety Laboratory samples Panel 11.3 day 14 White blood cell (G/l)
Safety Laboratory samples Panel 6.1 day 1 ALT (U/l)
Safety Laboratory samples Panel 6.2 day 7 ALT (U/l)
Safety Laboratory samples Panel 8.1 day 1 CRP (mg/l)
Safety Laboratory samples Panel 9.1 day 1 Haemoglobin (g/l)
Safety Laboratory samples Panel 9.2 day 7 Haemoglobin (g/l)
Safety Laboratory samples Panel 9.3 day 14 Haemoglobin (g/l)
Safety Laboratory samples Panel 9.4 day 30 Haemoglobin (g/l)
Safety Laboratory samples Panel 10.2 day 7 Platlets (G/l)
Safety Laboratory samples Panel 10.3 day 14 Platlets (G/l)
Safety Laboratory samples Panel 11.1 day 1 White blood cell (G/l)
Safety Laboratory samples Panel 11.2 day 7 White blood cell (G/l)
Safety ophtalmological examination 1.2 day 30 Refraction both sides (+/-)
Safety ophtalmological examination 1.5 day 30 Color sense test according to Panel D-15 bilateral (normal/abnormal)
Occurence of adverse events and serious adverse events 1.1 day 1 according to GCP Guideline
Occurence of adverse events and serious adverse events 1.2 day 7 according to GCP Guideline
Occurence of adverse events and serious adverse events 1.3 day 14 according to GCP Guideline
Occurence of adverse events and serious adverse events 1.4 day 15 according to GCP Guideline
Occurence of adverse events and serious adverse events 1.5 day 30 according to GCP Guideline
Occurence of adverse events and serious adverse events 1.6 day 256 according to GCP Guideline
Safety Laboratory samples Panel 8.3 day 14 CRP (mg/l)
Safety Laboratory samples Panel 11.4 day 30 White blood cell (G/l)
Urinanalysis 1.1 day 1 Dipstick: protein negative/+/++/+++
Urinanalysis 2.1 day 1 Dipstick: white blood cells negative/+/++/+++
Safety Laboratory samples Panel 12.1 day 7 Blood pregnancy test (Blood beta-hCG)
Urinanalysis 1.2 day 7 Dipstick: protein negative/+/++/+++
Urinanalysis 1.4 day 30 Dipstick: protein negative/+/++/+++
Urinanalysis 3.3 day 14 Dipstick: red blood cells negative/+/++/+++
Urinanalysis 3.4 day 30 Dipstick: red blood cells negative/+/++/+++
Urinanalysis 4.1 day 1 Dipstick: Glucose negative/+/++/+++
Urinanalysis 4.2 day 7 Dipstick: Glucose negative/+/++/+++
Urinanalysis 4.3 day 14 Dipstick: Glucose negative/+/++/+++
Urinanalysis 4.4 day 30 Dipstick: Glucose negative/+/++/+++
Safety 12 lead ECG 1.1 day 7 Rate/min
Safety 12 lead ECG 1.2 30 Rate/min
Safety 12 lead ECG 2.1 day 7 Rhythm (regular/irregular)
Safety 12 lead ECG 2.2 day 30 Rhythm (regular/irregular)
Safety 12 lead ECG 3.1 day 7 PQ interval (ms)
Safety 12 lead ECG 3.3 day 30 PQ interval (ms)
Safety 12 lead ECG 4.1 day 7 QRS interval (ms)
Safety 12 lead ECG 4.2 day 30 QRS interval (ms)
Safety 12 lead ECG 5.1 day 7 ST Segment (normal/elevation/depression)
Safety 12 lead ECG 5.2 day 30 ST Segment (normal/elevation/depression)
Safety ophtalmological examination 1.1 day 30 Slit lamp examaniation both sides (normal/abnormal)
Safety ophtalmological examination 1.3 day 30 Biomicroscopy of the central fundus both sides(normal/abnormal)
Safety ophtalmological examination 1.4 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)
- Secondary Outcome Measures
Name Time Method 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 drug concentration (mg/l) of Rifampicin, Isoniazid, 25-O-Desacetylrifampicin, Ethambutol, Pyrazinamide, Chloroquine, Desethylchloroquine
Trial Locations
- Locations (1)
Clinical Trial Center
🇨🇭Zurich, Switzerland