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

NCT05443178 | Recruiting Phase 1 DMC

• 1 other identifier: Clear TB
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Tuberculosis Infection

Keywords

Safety and tolerability; Chloroquin as adjuvant to standard 4-drug anti-TB therapy; Healthy volunteers; Phase I trial

Outcome Measures

Primary Outcomes (110)

• 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 Outcomes (1)

• 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

Study Arms (4)

Cohort 1

EXPERIMENTAL

100 mg Nivaquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days

Drug: Nivaquine ® (Chloroquine)

Cohort 2

EXPERIMENTAL

200 mg Chloroquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days

Drug: Nivaquine ® (Chloroquine)

Cohort 3

EXPERIMENTAL

300 mg Chloroquine and 4 Tabl Rimstar peroral once daily before breakfast for 14 days

Drug: Nivaquine ® (Chloroquine)

Dose extension group

EXPERIMENTAL

Dose escalation: XX mg Chloroquine (depending on results) and 4 Tabl Rimstar peroral once daily before breakfast for 14 days

Drug: Nivaquine ® (Chloroquine)

Interventions

Nivaquine ® (Chloroquine) DRUG

dose escalation and extension trial

Also known as: Rimstar ® (Rifampicin, Isoniazid, Ethambutol, Pyrazinamid)

Cohort 1; Cohort 2; Cohort 3; Dose extension group

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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®)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Zurich: lead

Study Sites (1)

Clinical Trial Center

Zurich, 8091, Switzerland

RECRUITING

MeSH Terms

Conditions

Latent Tuberculosis

Interventions

Chloroquine; Rifampin; Isoniazid; Ethambutol; Pyrazinamide

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Ethylenediamines; Diamines; Polyamines; Amines; Pyrazines

Study Officials

• Marisa Kaelin, Dr. med.

  University of Zurich

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Khadija M'Rabet, Dr. med.

CONTACT

+41 44 255 13 65; Khadija.MRabet-Bensalah@usz.ch

Jean Marc Hoffmann, Dr med.

CONTACT

+41432532749; Jean-Marc.Hoffmann@usz.ch

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: August 20, 2020
• First Posted: July 5, 2022
• Study Start: January 4, 2022
• Primary Completion: October 4, 2024
• Study Completion: June 1, 2025
• Last Updated: July 1, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)