The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB

• Status: Active, not recruiting
• Trial end date: 2022-08-01
• Target enrollment: 0
• Participant gender: All

Summary

Tuberculosis (TB) is a common, infectious, bacterial disease that is spread when an infected person transmits their saliva through the air by coughing or sneezing. Despite the availability and effectiveness of affordable six-month treatments for tuberculosis (TB), the worldwide control of this disease is currently being impacted by the emergence of multidrug resistant TB (MDR-TB). MDR-TB refers to TB that is resistant to at least isoniazid and rifampicin. These are the two most powerful first-line drugs used to treat pulmonary TB. MDR-TB usually develops while a person is taking TB treatment due to either inappropriate treatment or failure of patients to comply with their treatment. This strain of drug-resistant bacteria can also be spread to other people through the air. With the incident rate of MDR-TB on the rise, there is a need to investigate optimal treatment regimens using effective drugs.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: IUATLD, Inc
• Collaborators: Institute of Tropical Medicine, Belgium; Liverpool School of Tropical Medicine; Medical Research Council; Rede TB
• Treatments: Antitubercular Agents; Bedaquiline; Clofazimine; Diarylquinolines; Ethambutol; Isoniazid; Kanamycin; Levofloxacin; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination; Ofloxacin; Prothionamide; Pyrazinamide

Criteria

Inclusion Criteria:

1. Consent: Is willing and able to give informed consent to participate in the trial treatment and follow-up (signed or witnessed consent if the patient is illiterate). If the patient is below the age of consent (according to local regulations), the parent/caregiver should be able and willing to give consent, and the patient be informed about the study and asked to give positive assent, if feasible

2. Age: Is aged 18 years or older (Stage 1) or 15 years or older (Stage 2)

3. AFB or GeneXpert results: Has a positive AFB sputum smear result at screening (at least scanty), or a positive GeneXpert result (with a cycle threshold (Ct) value of 25 or lower) from a test performed at screening or from a test performed within the four weeks prior to screening

4. Has evidence of resistance to rifampicin either by line probe assay (Hain Genotype), GeneXpert or culture-based drug susceptibility testing (DST), from a test performed at screening or from a test performed within the four weeks prior to screening

5. Is willing to have an HIV test and, if positive, is willing to be treated with ART in accordance with the national policies but excluding ART contraindicated for use with bedaquiline

6. Is willing to use effective contraception: pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilised must agree to use a barrier method or an intrauterine device unless their partner has had a vasectomy; men who have not had a vasectomy must agree to use condoms. In Stage 2 pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilised must agree to use two methods of contraception, for example a hormonal method and a barrier method

7. Resides in the area and expected to remain for the duration of the study.

8. Has had a chest X-ray that is compatible with a diagnosis of pulmonary TB (if such a chest X-ray taken within 4 weeks of randomisation is available, a repeat X-ray is not required)

9. Has normal K+, Mg2+ and corrected Ca2+ at screening.

Exclusion Criteria:

1. Is infected with a strain of M. tuberculosis resistant to second-line injectables by line probe assay (Hain Genotype) from a test performed at screening or from a test performed within the four weeks prior to screening

2. Is infected with a strain of M. tuberculosis resistant to fluoroquinolones by line probe assay (Hain Genotype) from a test performed at screening or from a test performed within the four weeks prior to screening

3. Has tuberculous meningitis or bone and joint tuberculosis

4. Is critically ill, and in the judgment of the investigator, unlikely to survive more than 4 months

5. Is known to be pregnant or breast-feeding

6. Is unable or unwilling to comply with the treatment, assessment, or follow-up schedule

7. Is unable to take oral medication

8. Has AST or ALT more than 5 times the upper limit of normal for Stage 1, and AST or ALT more than 3 times the upper limit of normal for Stage 2

9. Has any condition (social or medical) which in the opinion of the investigator would make study participation unsafe

10. In the investigator's opinion the patient is likely to be eligible for treatment with bedaquiline according to local guidelines due to a pre-existing medical condition such as hearing loss or renal impairment

11. Is taking any medications contraindicated with the medicines in any trial regimen

12. Has a known allergy to any fluoroquinolone antibiotic

13. Is currently taking part in another trial of a medicinal product

14. Has a QT or QTcF interval at screening or immediately prior to randomisation of more than or equal to 500 ms for Stage 1, and more than or equal to 450 ms for Stage 2

In addition to the criteria above, for Stage 2 only, a patient will not be eligible for randomisation to the study if he/she:

15. Has experienced one or more of the following risk factors for QT prolongation:

• A confirmed prolongation of the QT or QTcF more than or equal to 450 ms in the screening ECG (retesting to reassess eligibility will be allowed once using an unscheduled visit during the screening phase)

• Pathological Q-waves (defined as Q-wave more than 40 ms or depth more than 0.4-0.5 mV)

• Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome)

• Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block

• Evidence of second or third degree heart block

• Intraventricular conduction delay with QRS duration more than 120 ms

• Bradycardia as defined by sinus rate less than 50 bpm

• Personal or family history of Long QT Syndrome

• Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, with the exception of sinus arrhythmia

• Syncope (i.e. cardiac syncope not including syncope due to vasovagal or epileptic causes)

• Risk factors for Torsades de Pointes (e.g., heart failure, hypokalaemia, or hypomagnesemia)

16. Has received treatment for MDR-TB in the 12 weeks prior to screening, other than the maximum permitted treatment specified in Section 5.2.1

17. Has a history of cirrhosis and classified as Child's B or C at screening or a bilirubin more than 1.5 times upper limit of normal.

18. Has an estimated creatinine clearance (CrCl) less than 30 mL/min based on the Cockcraft-Gault equation

19. Is HIV positive and has a CD4 count less than 50 cells/mm3

20. Has pancreatic amylase elevation more than two times above the upper limit of normal

21. Has a history of alcohol and/or drug abuse

22. Has had previous treatment with bedaquiline

23. Has taken rifampicin in the seven days prior to randomisation

24. There has been a delay of more than four weeks between the screening consent and randomisation

25. Is an employee or family member of the investigator or study site staff with direct involvement in the proposed study.