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

NCT ID: NCT05443178

Last Updated: 2024-07-01

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-01-04
• Study Completion Date: 2025-06-01

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.

Conditions

Tuberculosis Infection

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1

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

Group Type: EXPERIMENTAL

Nivaquine ® (Chloroquine)

Intervention Type: DRUG

dose escalation and extension trial

Cohort 2

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

Group Type: EXPERIMENTAL

Nivaquine ® (Chloroquine)

Intervention Type: DRUG

dose escalation and extension trial

Cohort 3

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

Group Type: EXPERIMENTAL

Nivaquine ® (Chloroquine)

Intervention Type: DRUG

dose escalation and extension trial

Dose extension group

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

Group Type: EXPERIMENTAL

Nivaquine ® (Chloroquine)

Intervention Type: DRUG

dose escalation and extension trial

Interventions

Nivaquine ® (Chloroquine)

dose escalation and extension trial

Intervention Type: DRUG

Other Intervention Names

Rimstar ® (Rifampicin, Isoniazid, Ethambutol, Pyrazinamid)

Eligibility Criteria

Inclusion Criteria

1. Informed study-specific consent (including possible pharmacogenetic analysis) as documented by signature

2. 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

1. 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.

2. Pregnant or lactating females

3. 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)

4. 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).

5. 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

6. 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

7. History of or currently present retinopathy or other disturbances of the field of vision or the retina according to the Investigator

8. History of alcohol or substance abuse for the last 3 months prior to Screening, as determined by the Investigator

9. Weight less than 55kg

10. Intake of grapefruit juice or grapefruits within 2 weeks before the first study drug administration and during treatment phase

11. Donation of blood or blood products within a 30-day period prior to Screening

12. 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.

13. Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant

14. The investigator, his/her family members, employees and other dependent persons

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Zurich

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marisa Kaelin, Dr. med.

Role: PRINCIPAL_INVESTIGATOR

University of Zurich

Locations

Clinical Trial Center

Zurich, , Switzerland

Site Status: RECRUITING

Countries

Switzerland

Central Contacts

Khadija M'Rabet, Dr. med.

Role: CONTACT

Khadija.MRabet-Bensalah@usz.ch

+41 44 255 13 65

Jean Marc Hoffmann, Dr med.

Role: CONTACT

Jean-Marc.Hoffmann@usz.ch

+41432532749

Facility Contacts

Khadija M'Rabet, Dr.med.

Role: primary

Khadija.MRabet-Bensalah@usz.ch

+41442551365

Jean Marc Hoffmann, Dr.med

Role: backup

Jean-Marc.Hoffmann@usz.ch

+41 43 253 27 49

Other Identifiers

Clear TB

Identifier Type: -

Identifier Source: org_study_id