Safety and Tolerability of Chlorquine in Addition to Anti-tuberculosis Therapy

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Tuberculosis Infection

Intervention / Treatment
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* Drug: Nivaquine ® (Chloroquine)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Informed study-specific consent (including possible pharmacogenetic analysis) as documented by signature Healthy volunteers aged between 18 and 50 years of age (significantly increased risk of side effects from 50 years of age with Rimstar®) Exclusion criteria: Lack of highly effective contraception during the study treatment and for 8 months after the last dose of study treatment (until Day 254, visit 7) according to 11.4 with the following consideration for participating women: From Day 1 (visit 2) up to Day 30 (visit 6) hormonal contraception is insufficient due to lower concentrations of estrogen and/or gestagen during and up to 14 days after Rimstar® intake. The hormonal contraception must be supplemented with a barrier method (preferably male condom). From Day 30 (visit 6) up to Day 254 (visit 7) hormonal contraceptive methods can be used and are considered highly effective. Pregnant or lactating females Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product, glucose-6-phosphate dehydrogenase insufficiency (favism) Regular treatment with drugs in the last 14 days prior to first intake of study drug (except for Paracetamol and Vitamin B6 (pyridoxine), see 8.7). History of or concurrent, clinically significant cardiac, immunological, pulmonary, neurological, renal, gastrointestinal, dermatological, endocrinological or other major disease as determined by the Investigator and/or his representative History of or presence of any clinically significant abnormality in vital signs, ECG, or laboratory test results or has any medical or psychiatric condition that, in the opinion of the Investigator, may interfere with the study procedures or compromise subject safety History of or currently present retinopathy or other disturbances of the field of vision or the retina according to the Investigator History of alcohol or substance abuse for the last 3 months prior to Screening, as determined by the Investigator Weight less than 55kg Intake of grapefruit juice or grapefruits within 2 weeks before the first study drug administration and during treatment phase Donation of blood or blood products within a 30-day period prior to Screening Current enrolment or a plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy for investigational use is administered within 3 months of participation to the Clear trial. Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant The investigator, his/her family members, employees and other dependent persons

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3 subjects are planned to enter each cohort. No more than 3 subjects will receive the same dose during the dose escalation phase. 3 participants are initially enrolled into the first dose cohort (100mg daily). If there is no DLT observed at Day 30, the investigators enroll 3 additional subjects into the second dose cohort (200mg daily). The targeted maximum dose of Nivaquine® is 300mg (cohort 3). Development of DLTs in ≥ 1 subject(s) in a specific dose cohort suggests that the RP2D has been exceeded, and further dose escalation is not pursued. In this case, the preceding dose level will be assumed to be the dose level for another 7 participants in the extension part of the study. If in cohort 3, no DLT is observed, an additional 7 participants will receive 300 mg chloroquine daily in the dose extension phase.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>100 mg Nivaquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days | Drug: Nivaquine ® (Chloroquine)<br>* dose escalation and extension trial<br>* Other names: Rimstar ® (Rifampicin, Isoniazid, Ethambutol, Pyrazinamid);|
| Experimental: Cohort 2<br>200 mg Chloroquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days | Drug: Nivaquine ® (Chloroquine)<br>* dose escalation and extension trial<br>* Other names: Rimstar ® (Rifampicin, Isoniazid, Ethambutol, Pyrazinamid);|
| Experimental: Cohort 3<br>300 mg Chloroquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days | Drug: Nivaquine ® (Chloroquine)<br>* dose escalation and extension trial<br>* Other names: Rimstar ® (Rifampicin, Isoniazid, Ethambutol, Pyrazinamid);|
| Experimental: Dose extension group<br>Dose escalation: XX mg Chloroquine (depending on results) and 4 Tabl Rimstar peroral once daily before breakfast for 14 days | Drug: Nivaquine ® (Chloroquine)<br>* dose escalation and extension trial<br>* Other names: Rimstar ® (Rifampicin, Isoniazid, Ethambutol, Pyrazinamid);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physicial examination 1.1 | Heart auscultation (normal/abnormal) | day 14 | 
| Physicial examination 1.2 | Heart auscultation (normal/abnormal) | day 30 | 
| Physicial examination 2.1 | lung auscultation (normal, abnormal) | day 14 | 
| Physicial examination 2.2 | lung auscultation (normal, abnormal) | day 30 | 
| Physicial examination 3.1 | abdominal examination (normal, abnormal) | day 14 | 
| Physicial examination 3.2 | abdominal examination (normal, abnormal) | day 30 | 
| Physicial examination 4.1 | lymph node palpation (normal, abnormal) | day 14 | 
| Physicial examination 4.2 | lymph node palpation (normal, abnormal) | day 30 | 
| Physicial examination 5.1 | reflex testing (normal, abnormal) | day 14 | 
| Physicial examination 5.2 | reflex testing (normal, abnormal) | day 30 | 
| Physicial examination 6.1 | test vibration sense with tuning fork (mallelor left and right X/8) | day 14 | 
| Physicial examination 6.2 | test vibration sense with tuning fork (mallelor left and right X/8) | day 30 | 
| Vital Signs 1.1 | heart rate (beats/min) | day 1 | 
| Vital Signs 1.2 | heart rate (beats/min) | day 7 | 
| Vital Signs 1.3 | heart rate (beats/min) | day 14 | 
| Vital Signs 1.4 | heart rate (beats/min) | day 15 | 
| Vital Signs 1.5 | heart rate (beats/min) | day 30 | 
| Vital Signs 2.1 | blood pressure (mmHg) | day 1 | 
| Vital Signs 2.2 | blood pressure (mmHg) | day 7 | 
| Vital Signs 2.3 | blood pressure (mmHg) | day 14 | 
| Vital Signs 2.4 | blood pressure (mmHg) | day 15 | 
| Vital Signs 2.5 | blood pressure (mmHg) | day 30 | 
| Vital Signs 3.1 | temperature (°C) | day 1 | 
| Vital Signs 3.2 | temperature (°C) | day 7 | 
| Vital Signs 3.3 | temperature (°C) | day 14 | 
| Vital Signs 3.4 | temperature (°C) | day 15 | 
| Vital Signs 3.5 | temperature (°C) | day 30 | 
| Safety Laboratory samples Panel 1.1 | Sodium (mmol/l) | day 1 | 
| Safety Laboratory samples Panel 1.2 | Sodium (mmol/l) | day 7 | 
| Safety Laboratory samples Panel 1.3 | Sodium (mmol/l) | day 14 | 
| Safety Laboratory samples Panel 1.4 | Sodium (mmol/l) | day 30 | 
| Safety Laboratory samples Panel 2.1 | Potassium (mmol/l) | day 1 | 
| Safety Laboratory samples Panel 2.2 | Potassium (mmol/l) | day 7 | 
| Safety Laboratory samples Panel 2.3 | Potassium (mmol/l) | day 14 | 
| Safety Laboratory samples Panel 2.4 | Potassium (mmol/l) | day 30 | 
| Safety Laboratory samples Panel 3.1 | Calcium (mmol/l) | day 1 | 
| Safety Laboratory samples Panel 3.2 | Calcium (mmol/l) | day 7 | 
| Safety Laboratory samples Panel 3.3 | Calcium (mmol/l) | day 14 | 
| Safety Laboratory samples Panel 3.4 | Calcium (mmol/l) | day 30 | 
| Safety Laboratory samples Panel 4.1 | Creatinine (umol/l) | day 1 | 
| Safety Laboratory samples Panel 4.2 | Creatinine (umol/l) | day 7 | 
| Safety Laboratory samples Panel 4.3 | Creatinine (umol/l) | day 14 | 
| Safety Laboratory samples Panel 4.4 | Creatinine (umol/l) | day 30 | 
| Safety Laboratory samples Panel 5.1 | Total Bilirubin (umol/l) | day 1 | 
| Safety Laboratory samples Panel 5.2 | Total Bilirubin (umol/l) | day 7 | 
| Safety Laboratory samples Panel 5.3 | Total Bilirubin (umol/l) | day 14 | 
| Safety Laboratory samples Panel 5.4 | Total Bilirubin (umol/l) | day 30 | 
| Safety Laboratory samples Panel 6.1 | ALT (U/l) | day 1 | 
| Safety Laboratory samples Panel 6.2 | ALT (U/l) | day 7 | 
| Safety Laboratory samples Panel 6.3 | ALT (U/l) | day 14 | 
| Safety Laboratory samples Panel 6.4 | ALT (U/l) | day 30 | 
| Safety Laboratory samples Panel 7.1 | Glucose (mmol/l) | day 1 | 
| Safety Laboratory samples Panel 7.2 | Glucose (mmol/l) | day 7 | 
| Safety Laboratory samples Panel 7.3 | Glucose (mmol/l) | day 14 | 
| Safety Laboratory samples Panel 7.4 | Glucose (mmol/l) | day 30 | 
| Safety Laboratory samples Panel 8.1 | CRP (mg/l) | day 1 | 
| Safety Laboratory samples Panel 8.2 | CRP (mg/l) | day 7 | 
| Safety Laboratory samples Panel 8.3 | CRP (mg/l) | day 14 | 
| Safety Laboratory samples Panel 8.4 | CRP (mg/l) | day 30 | 
| Safety Laboratory samples Panel 9.1 | Haemoglobin (g/l) | day 1 | 
| Safety Laboratory samples Panel 9.2 | Haemoglobin (g/l) | day 7 | 
| Safety Laboratory samples Panel 9.3 | Haemoglobin (g/l) | day 14 | 
| Safety Laboratory samples Panel 9.4 | Haemoglobin (g/l) | day 30 | 
| Safety Laboratory samples Panel 10.1 | Platlets (G/l) | day 1 | 
| Safety Laboratory samples Panel 10.2 | Platlets (G/l) | day 7 | 
| Safety Laboratory samples Panel 10.3 | Platlets (G/l) | day 14 | 
| Safety Laboratory samples Panel 10.4 | Platlets (G/l) | day 30 | 
| Safety Laboratory samples Panel 11.1 | White blood cell (G/l) | day 1 | 
| Safety Laboratory samples Panel 11.2 | White blood cell (G/l) | day 7 | 
| Safety Laboratory samples Panel 11.3 | White blood cell (G/l) | day 14 | 
| Safety Laboratory samples Panel 11.4 | White blood cell (G/l) | day 30 | 
| Safety Laboratory samples Panel 12.1 | Blood pregnancy test (Blood beta-hCG) | day 7 | 
| Safety Laboratory samples Panel 12.2 | Blood pregnancy test (Blood beta-hCG) | day 30 | 
| Urinanalysis 1.1 | Dipstick: protein negative/+/++/+++ | day 1 | 
| Urinanalysis 1.2 | Dipstick: protein negative/+/++/+++ | day 7 | 
| Urinanalysis 1.3 | Dipstick: protein negative/+/++/+++ | day 14 | 
| Urinanalysis 1.4 | Dipstick: protein negative/+/++/+++ | day 30 | 
| Urinanalysis 2.1 | Dipstick: white blood cells negative/+/++/+++ | day 1 | 
| Urinanalysis 2.2 | Dipstick: white blood cells negative/+/++/+++ | day 7 | 
| Urinanalysis 2.3 | Dipstick: white blood cells negative/+/++/+++ | day 14 | 
| Urinanalysis 2.4 | Dipstick: white blood cells negative/+/++/+++ | day 30 | 
| Urinanalysis 3.1 | Dipstick: red blood cells negative/+/++/+++ | day 1 | 
| Urinanalysis 3.2 | Dipstick: red blood cells negative/+/++/+++ | day 7 | 
| Urinanalysis 3.3 | Dipstick: red blood cells negative/+/++/+++ | day 14 | 
| Urinanalysis 3.4 | Dipstick: red blood cells negative/+/++/+++ | day 30 | 
| Urinanalysis 4.1 | Dipstick: Glucose negative/+/++/+++ | day 1 | 
| Urinanalysis 4.2 | Dipstick: Glucose negative/+/++/+++ | day 7 | 
| Urinanalysis 4.3 | Dipstick: Glucose negative/+/++/+++ | day 14 | 
| Urinanalysis 4.4 | Dipstick: Glucose negative/+/++/+++ | day 30 | 
| Safety 12 lead ECG 1.1 | Rate/min | day 7 | 
| Safety 12 lead ECG 1.2 | Rate/min | 30 | 
| Safety 12 lead ECG 2.1 | Rhythm (regular/irregular) | day 7 | 
| Safety 12 lead ECG 2.2 | Rhythm (regular/irregular) | day 30 | 
| Safety 12 lead ECG 3.1 | PQ interval (ms) | day 7 | 
| Safety 12 lead ECG 3.3 | PQ interval (ms) | day 30 | 
| Safety 12 lead ECG 4.1 | QRS interval (ms) | day 7 | 
| Safety 12 lead ECG 4.2 | QRS interval (ms) | day 30 | 
| Safety 12 lead ECG 5.1 | ST Segment (normal/elevation/depression) | day 7 | 
| Safety 12 lead ECG 5.2 | ST Segment (normal/elevation/depression) | day 30 | 
| Safety ophtalmological examination 1.1 | Slit lamp examaniation both sides (normal/abnormal) | day 30 | 
| Safety ophtalmological examination 1.2 | Refraction both sides (+/-) | day 30 | 
| Safety ophtalmological examination 1.3 | Biomicroscopy of the central fundus both sides(normal/abnormal) | day 30 | 
| Safety ophtalmological examination 1.4 | Applanation tonometry and stereoscopic papilla evaluation bilateral (normal/abnormal), Color sense test according to Panel D-15 right and left side (normal/abnormal) | day 30 | 
| Safety ophtalmological examination 1.5 | Color sense test according to Panel D-15 bilateral (normal/abnormal) | day 30 | 
| Occurence of adverse events and serious adverse events 1.1 | according to GCP Guideline | day 1 | 
| Occurence of adverse events and serious adverse events 1.2 | according to GCP Guideline | day 7 | 
| Occurence of adverse events and serious adverse events 1.3 | according to GCP Guideline | day 14 | 
| Occurence of adverse events and serious adverse events 1.4 | according to GCP Guideline | day 15 | 
| Occurence of adverse events and serious adverse events 1.5 | according to GCP Guideline | day 30 | 
| Occurence of adverse events and serious adverse events 1.6 | according to GCP Guideline | day 256 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug concentration over time measured by the pharmacokinetics | drug concentration (mg/l) of Rifampicin, Isoniazid, 25-O-Desacetylrifampicin, Ethambutol, Pyrazinamide, Chloroquine, Desethylchloroquine | day 14 prior to dosing (-15 until -5 minutes) and 1, 2, 4, 6 and 24 hours after dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety and tolerability, Chloroquin as adjuvant to standard 4-drug anti-TB therapy, Healthy volunteers, Phase I trial