PanACEA DElpazolid Dose-finding and COmbination DEvelopment (DECODE)

Phase 2

Completed

Conditions: Infections and Infestations
Pulmonary Tuberculosis

Interventions: Drug: Bedaquiline, Delamanid, Moxifloxacin
Drug: Delpazolid

Registration Number: NCT04550832

Lead Sponsor: LigaChem Biosciences, Inc.

Brief Summary: This trial is to describe the safety, tolerability and exposure-toxicity relationship of Depazolid given over 16 weeks, in combination with standard-dose Bedaquiline, Delamanid and Moxifloxacin, compared to standard-dose Bedaquiline, Delamanid and Moxifloxacin alone

Detailed Description: This will be an open label Phase IIb dose-finding, randomized, controlled study with a duration of 16 weeks of experimental therapy of Delpazolid(DZD) - Bedaquiline/Delamanid/ Moxifloxacin (BDM) in adult patients with newly diagnosed, smear positive, uncomplicated, drug sensitive pulmonary tuberculosis (TB) to evaluate the safety, efficacy, tolerability, pharmacokinetics and exposure/response-relationship of different doses of delpazolid in combination with bedaquiline, delamanid and moxifloxacin.

Participants will be randomized to one of five arms containing BDM standard dose with different doses of DZD.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 76

Inclusion Criteria

Provide written, informed consent prior to all trial-related procedures including HIV testing.
Male or female, aged between 18 and 65 years, inclusive.
Body weight between 40 and 90 kg, inclusive.
Newly diagnosed, previously untreated, drug susceptible pulmonary TB: presence of MTB complex and rapid molecular tests result confirming susceptibility to RIF and INH such as GeneXpert and/or HAIN MTBDR plus.
A chest X-ray (no older than 2 weeks) which, in the opinion of the Investigator, is consistent with TB.
Sputum positive on microscopy from concentrated sputum for acid-fast bacilli on at least one sputum sample (at least 1+ on the IUATLD/WHO scale).
The participant is willing to forgo consumption of foods high in tyramine for the period of taking study medication (See Appendix, section 20.2, page 92).
The participant is either unable to conceive/father children AND/OR his/her partner is unable to conceive/father children AND/OR they will consent to be using effective methods of contraception when engaging in heterosexual intercourse, as defined below:

a. Non-childbearing potential: i. Female participant/sexual partner of male participant: Bilateral oophorectomy, and/or hysterectomy or bilateral tubal ligation more than 12 months ago and/or has been postmenopausal with a history of no menses for at least 12 consecutive months ii. Male participant/sexual partner of female participant: Vasectomised or has had a bilateral orchidectomy minimally three months prior to screening iii. Male participants having a pregnant female partner or a male sexual partner: At least one barrier method has to be used in this case. b. Effective contraception methods: i. Female participants: Two methods, including methods that the patient's sexual partner(s) use. At least one must be a barrier method. Contraception must be practised for at least until 12 weeks after the last dose of DZD. ii. Male participants: Two methods, including methods that the patient's female sexual partner(s) use. At least one must be a barrier method. Effective contraception must be ensured for at least 16 weeks after the last dose of DZD.

Note: hormone-based contraception alone may not be reliable when taking RIF during continuation phase; therefore, hormone-based contraceptives alone cannot be used by female participants/female partners of male participants to prevent pregnancy.

Exclusion Criteria

Circumstances that raise doubt about free, unconstrained consent to study participation (e.g. prisoner or mentally handicapped person)
Poor general condition where delay in treatment cannot be tolerated or death within four months is likely.
Poor social condition which would make it unlikely that the patient would be able to complete follow-up
The patient is pregnant or breast-feeding.
The patient is infected with HIV with a CD4 count <220 cells/mm3. If >220 cells/mm3, patients will be included only if any of the following is applicable:
- The patient is antiretroviral (ARV) naïve and able to postpone commencing HIV treatment for 2 months after the trial has started and then restrict regimens to those containing dolutegravir (see section 12.6.2 on ARVs) or The patient is ARV experienced (has been on ARV´s a minimum of 5 months) and able to switch to a dolutegravir-based regimen.
- The patient is treated with nucleosidic reverse transcriptase inhibitors (are permitted as concomitant medication).
- The patient is treated with protease inhibitors as part of antiretroviral treatment regimens, which will be stopped at least 3 days before the start of study treatment (WK01, day1) for a patient to be eligible.
- The patient is treated with Efavirenz as part of antiretroviral treatment regimens which would have to be stopped 14 days before the start of study treatment (WK00, Day 01) for a patient to be eligible.
The patient has a known intolerance to any of the study drugs or concomitant disorders or conditions for which study drugs or standard TB treatment are contraindicated
The patient has a history of, or current evidence of clinically relevant cardiovascular metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or any other condition that will influence treatment response, study adherence or survival in the judgement of the investigator, especially:
1. Neuropathy, or significant psychiatric disorder like depression or schizophrenia; especially if treatment for those has ever been required or is anticipated to be required
2. Clinically significant evidence of extra-pulmonary TB (e.g. miliary TB, TB meningitis, but not limited lymph node involvement)
3. Serious lung conditions other than TB, or significant respiratory impairment in the discretion of the investigator
4. Any diabetes mellitus
5. Cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension
6. Arterial hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure of ≥90 mmHg on two occasions during screening).
7. Long QT syndrome or family history of long QT syndrome or sudden death of unknown or cardiac-related cause
8. Alcohol or other drug abuse that is sufficient to significantly compromise the safety or cooperation of the patient, that includes substances prohibited by the protocol or has led to significant organ damage at the discretion of the investigator.
Any of the following laboratory findings at screening:
1. Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) >3x the upper limit of normal (ULN),
2. Serum alkaline phosphatase or y-glutamyl transferase > 2.5x the ULN,
3. Serum total bilirubin level >1.5x the ULN
4. Estimated creatinine clearance (eCrCl; using the Cockroft and Gault formula [57] lower than 30 ml/min
5. Serum albumin < 2.8 mg/dl
6. Haemoglobin level <7.0 g/dl
7. Platelet count <50,000/mm3
8. Serum potassium below the lower level of normal for the laboratory
9. Blood glucose at screening of less than 70mg/dL (3.9mmol/L)
ECG findings in the screening ECG: (one or more):
1. QTcF of >0.450 s
2. Atrioventricular (AV) block with PR interval > 0.20 s,
3. QRS complex > 120 milliseconds
4. Any other changes in the ECG that are clinically relevant as per discretion of the investigator
Restricted medication:
1. Treatment with any other investigational drug within 1 month prior to enrolment or enrolment into other clinical (intervention) trials during participation.
2. Previous anti-TB treatment with drugs active against MTB within the last 3 months prior to screening.
3. Unable or unwilling to abide by the requirements regarding restricted medication or have taken restricted medication as described under section 12.6, page 58. Restricted medication includes the following drug classes:
  - Anti-TB drugs other than study drugs
  - Medication that lowers the threshold for epileptic seizures
  - Medication that prolongs the QTc interval
  - Drugs that affect monoaminooxidase or serotonin metabolism
  - CYP 450 inhibitors or inducers, including grapefruit containing foods / beverages and St. John's Wort

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm1(D0)	Bedaquiline, Delamanid, Moxifloxacin	Participants receive the following medication for the duration of 16weeks together with food. * Delpazolid : Will not administered * Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week. * Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg. * Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
Arm2(D400)	Bedaquiline, Delamanid, Moxifloxacin	Participants receive the following medication for the duration of 16weeks together with food. * Delpazolid : Will be dosed 400 mg orally once daily * Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week. * Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg. * Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
Arm3(D800-OD)	Bedaquiline, Delamanid, Moxifloxacin	Participants receive the following medication for the duration of 16weeks together with food. * Delpazolid : Will be dosed 800 mg orally once daily * Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week. * Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg. * Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
Arm4(D1200)	Bedaquiline, Delamanid, Moxifloxacin	Participants receive the following medication for the duration of 16weeks together with food. * Delpazolid : Will be dosed 1200 mg orally once daily * Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week. * Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg. * Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
Arm5(D800-BD)	Bedaquiline, Delamanid, Moxifloxacin	Participants receive the following medication for the duration of 16weeks together with food. * Delpazolid : Will be dosed 800 mg orally twice daily * Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week. * Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg. * Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
Arm2(D400)	Delpazolid	Participants receive the following medication for the duration of 16weeks together with food. * Delpazolid : Will be dosed 400 mg orally once daily * Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week. * Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg. * Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
Arm3(D800-OD)	Delpazolid	Participants receive the following medication for the duration of 16weeks together with food. * Delpazolid : Will be dosed 800 mg orally once daily * Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week. * Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg. * Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
Arm4(D1200)	Delpazolid	Participants receive the following medication for the duration of 16weeks together with food. * Delpazolid : Will be dosed 1200 mg orally once daily * Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week. * Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg. * Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
Arm5(D800-BD)	Delpazolid	Participants receive the following medication for the duration of 16weeks together with food. * Delpazolid : Will be dosed 800 mg orally twice daily * Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week. * Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg. * Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily

Primary Outcome Measures

Name	Time	Method
Safety Outcome : Proportion of Patients Experiencing Adverse Event	week0 - week52	Participants with ≥ 1 TEAE, by severity, related Adverse events: possibly, probably, or definitely related to study drugs
Efficacy Outcome: Exposure-response Analysis With TTP (Time to Positive)_AUC0-24	Week 0 - Week 16	The efficacy of DZD was evaluated by measuring the change in mycobacterial load over time on treatment as quantified by TTP (Time to positive) in BD MGIT960® liquid culture described by non linear mixed effects methodology. A population PK model was developed using NONMEM version 7.4.1. DZD PK is well-described by a two-compartment model with first-order absorption, first-order elimination and a proportional residual error. The final model included allometric scaling based on FFM.
Efficacy Outcome: Exposure-response Analysis With TTP (Time to Positive)_Cmax	Week 0 - Week 16	The efficacy of DZD was evaluated by measuring the change in mycobacterial load over time on treatment as quantified by TTP (Time to positive) in BD MGIT960® liquid culture described by non linear mixed effects methodology. A population PK model was developed using NONMEM version 7.4.1. DZD PK is well-described by a two-compartment model with first-order absorption, first-order elimination and a proportional residual error. The final model included allometric scaling based on FFM.
Efficacy Outcome: Exposure-response Analysis With TTP (Time to Positive)_Cmin	Week 0 - Week 16	The efficacy of DZD was evaluated by measuring the change in mycobacterial load over time on treatment as quantified by TTP (Time to positive) in BD MGIT960® liquid culture described by non linear mixed effects methodology. A population PK model was developed using NONMEM version 7.4.1. DZD PK is well-described by a two-compartment model with first-order absorption, first-order elimination and a proportional residual error. The final model included allometric scaling based on FFM.

Secondary Outcome Measures

Name	Time	Method
Efficacy Outcome: Changes in Mycobacterial Load Over Time on Treatment as Quantified by Time to Positivity in BD MGIT960® Liquid Media	Week 0 - Week 16	The efficacy of DZD was evaluated by measuring the change in mycobacterial load over time on treatment as quantified by time to positivity (TTP) in BD MGIT 960® liquid culture described by nonlinear mixed-effects methodology. Sputum samples were collected for BD MGIT960® Liquid Media culture at all time points during the treatment and follow-up phases, and this table shows TTP results.
Efficacy Outcome: BD MGIT960® Liquid Media Culture Results	Week 0 - Week 16	Summary of Changes in Mycobacterial Load Over Time on Treatment as Quantified by Time to Positivity in BD MGIT960® Liquid Media - Intent to Treat Population Sputum samples were collected for BD MGIT960® Liquid Media culture at all time points during the treatment and follow-up phases, and this table shows culture results, which are reported as: Positive, Negative, Contaminated, Missing. Note: Contaminated cultures are shown as contaminated for the purpose of the overall result but are counted as missing for calculating summary statistics. The data recorded as 'Positive for MTB Complex with Contamination' are included as 'Positive' for MGIT result. However, the data from mean and median calculations for TTP (Time to positive) due to contamination.
Efficacy Outcome: Loewenstein-Jensen Solid Media Culture Results	Week 0 - Week 16	Summary of Changes in Mycobacterial Load Over Time on Treatment as Quantified by Time to Culture Conversion in Loewenstein-Jensen Solid Media - Intent-to-Treat Population Sputum samples were collected for Loewenstein-Jensen Solid Media culture at at Week 0, Week 8, Week 12, Week 6 during the treatment and follow-up phases, and this table shows culture results, which are reported as: Positive, Negative, Contaminated, Missing.
Efficacy Outcome: The Proportion Converted by Day Corresponding to End of Each Week	Week 0 - Week 16	Culture conversion was defined as 2 negative cultures without an intervening positive culture. Time was measured as time on treatment until the first negative culture (up to Week 16 Visit). 'Converted by Week x' shows proportion converted by day corresponding to end of each week, e.g., Week 2 = Day 14.
Efficacy Outcome: Time to Culture Conversion	Week 0 - Week 16	Time to culture conversion was defined as 2 negative cultures without an intervening positive culture. Time was measured as time on treatment until the first negative culture (up to Week 16 Visit).
Efficacy Outcome : Relapse or Reinfection	Week0 - Week52	A participant was positive for relapse or reinfection if they converted to culture negative by Week 8 and had 2 consecutive positive cultures after Week 16 of randomization, without an intervening negative.

Trial Locations

Locations (5): Ifakara Health Institute
🇹🇿
Bagamoyo, Tanzania
The Aurum Institute Tembisa Clinical Research Centre
🇿🇦
Tembisa, Gauteng, South Africa
Clinical HIV Research Unit (CHRU) University of the Witwatersrand
🇿🇦
Johannesburg, South Africa
National Institute for Medical Research (NIMR-MMRC)
🇹🇿
Mbeya, Tanzania
Ki'bongoto Infectious Disease Hospital (KIDH) Kilimanjaro Clinical Research Institute (KCRI)
🇹🇿
Moshi, Tanzania