Clinical trial NCT05443178: Safety and Tolerability of Chlorquine in Addition to Anti-tuberculosis Therapy
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Tuberculosis Infection
Keywords: Safety and tolerability
Chloroquin as adjuvant to standard 4-drug anti-TB therapy
Healthy volunteers
Phase I trial
Lead sponsor: University of Zurich
Sponsor class: OTHER
First posted: 2022-07-05
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Physicial examination 1.1
timeFrame: day 14
measure: Physicial examination 1.2
timeFrame: day 30
measure: Physicial examination 2.1
timeFrame: day 14
measure: Physicial examination 2.2
timeFrame: day 30
measure: Physicial examination 3.1
timeFrame: day 14
measure: Physicial examination 3.2
timeFrame: day 30
measure: Physicial examination 4.1
timeFrame: day 14
measure: Physicial examination 4.2
timeFrame: day 30
measure: Physicial examination 5.1
timeFrame: day 14
measure: Physicial examination 5.2
timeFrame: day 30
measure: Physicial examination 6.1
timeFrame: day 14
measure: Physicial examination 6.2
timeFrame: day 30
measure: Vital Signs 1.1
timeFrame: day 1
measure: Vital Signs 1.2
timeFrame: day 7
measure: Vital Signs 1.3
timeFrame: day 14
measure: Vital Signs 1.4
timeFrame: day 15
measure: Vital Signs 1.5
timeFrame: day 30
measure: Vital Signs 2.1
timeFrame: day 1
measure: Vital Signs 2.2
timeFrame: day 7
measure: Vital Signs 2.3
timeFrame: day 14
measure: Vital Signs 2.4
timeFrame: day 15
measure: Vital Signs 2.5
timeFrame: day 30
measure: Vital Signs 3.1
timeFrame: day 1
measure: Vital Signs 3.2
timeFrame: day 7
measure: Vital Signs 3.3
timeFrame: day 14
measure: Vital Signs 3.4
timeFrame: day 15
measure: Vital Signs 3.5
timeFrame: day 30
measure: Safety Laboratory samples Panel 1.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 1.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 1.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 1.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 2.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 2.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 2.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 2.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 3.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 3.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 3.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 3.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 4.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 4.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 4.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 4.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 5.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 5.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 5.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 5.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 6.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 6.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 6.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 6.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 7.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 7.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 7.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 7.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 8.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 8.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 8.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 8.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 9.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 9.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 9.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 9.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 10.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 10.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 10.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 10.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 11.1
timeFrame: day 1
measure: Safety Laboratory samples Panel 11.2
timeFrame: day 7
measure: Safety Laboratory samples Panel 11.3
timeFrame: day 14
measure: Safety Laboratory samples Panel 11.4
timeFrame: day 30
measure: Safety Laboratory samples Panel 12.1
timeFrame: day 7
measure: Safety Laboratory samples Panel 12.2
timeFrame: day 30
measure: Urinanalysis 1.1
timeFrame: day 1
measure: Urinanalysis 1.2
timeFrame: day 7
measure: Urinanalysis 1.3
timeFrame: day 14
measure: Urinanalysis 1.4
timeFrame: day 30
measure: Urinanalysis 2.1
timeFrame: day 1
measure: Urinanalysis 2.2
timeFrame: day 7
measure: Urinanalysis 2.3
timeFrame: day 14
measure: Urinanalysis 2.4
timeFrame: day 30
measure: Urinanalysis 3.1
timeFrame: day 1
measure: Urinanalysis 3.2
timeFrame: day 7
measure: Urinanalysis 3.3
timeFrame: day 14
measure: Urinanalysis 3.4
timeFrame: day 30
measure: Urinanalysis 4.1
timeFrame: day 1
measure: Urinanalysis 4.2
timeFrame: day 7
measure: Urinanalysis 4.3
timeFrame: day 14
measure: Urinanalysis 4.4
timeFrame: day 30
measure: Safety 12 lead ECG 1.1
timeFrame: day 7
measure: Safety 12 lead ECG 1.2
timeFrame: 30
measure: Safety 12 lead ECG 2.1
timeFrame: day 7
measure: Safety 12 lead ECG 2.2
timeFrame: day 30
measure: Safety 12 lead ECG 3.1
timeFrame: day 7
measure: Safety 12 lead ECG 3.3
timeFrame: day 30
measure: Safety 12 lead ECG 4.1
timeFrame: day 7
measure: Safety 12 lead ECG 4.2
timeFrame: day 30
measure: Safety 12 lead ECG 5.1
timeFrame: day 7
measure: Safety 12 lead ECG 5.2
timeFrame: day 30
measure: Safety ophtalmological examination 1.1
timeFrame: day 30
measure: Safety ophtalmological examination 1.2
timeFrame: day 30
measure: Safety ophtalmological examination 1.3
timeFrame: day 30
measure: Safety ophtalmological examination 1.4
timeFrame: day 30
measure: Safety ophtalmological examination 1.5
timeFrame: day 30
measure: Occurence of adverse events and serious adverse events 1.1
timeFrame: day 1
measure: Occurence of adverse events and serious adverse events 1.2
timeFrame: day 7
measure: Occurence of adverse events and serious adverse events 1.3
timeFrame: day 14
measure: Occurence of adverse events and serious adverse events 1.4
timeFrame: day 15
measure: Occurence of adverse events and serious adverse events 1.5
timeFrame: day 30
measure: Occurence of adverse events and serious adverse events 1.6
timeFrame: day 256
Secondary outcomes:
measure: Drug concentration over time measured by the pharmacokinetics
timeFrame: day 14 prior to dosing (-15 until -5 minutes) and 1, 2, 4, 6 and 24 hours after dosing
Other outcomes:
Locations:
city: Zurich
country: Switzerland
facility: Clinical Trial Center
Study officials:
affiliation: University of Zurich
name: Marisa Kaelin, Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: