Clinical trial NCT05807399: PanACEA - STEP2C -01
Official title: A Multiple Arm, Multiple Stage (MAMS), Phase 2B/C, Open Label, Randomized, Controlled Platform Trial to Evaluate Experimental Arms Including an Increased Dose of Rifampicin, an Optimized Dose of Pyrazinamide, Moxifloxacin and BTZ-043, in Adults With Newly Diagnosed, Drug Sensitive, Smear-positive Pulmonary Tuberculosis.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Pulmonary Tuberculosis
Other Specified Pulmonary Tuberculosis
Keywords: Tuberculosis, Pulmonary
Tuberculosis
Antitubercular Agents
Safety
Tolerability
Pharmacokinetics (PK)
Moxifloxacin
BTZ-043
Rifampicin
Lead sponsor: Ludwig-Maximilians - University of Munich
Sponsor class: OTHER
Collaborators: name: Radboud University Medical Center
name: University of California, San Francisco
name: University College, London
First posted: 2023-04-11
Enrollment: 270
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study will compare the efficacy, safety of 3 experimental regimens with a standard control regimen in participants with newly diagnosed, drug sensitive pulmonary tuberculosis.

In stage 1, participants will be randomly allocated to the control or one of the 2 rifampicin-containing experimental regimens in the ratio 1:1:1. In stage 2, the experimental arm 4 containing BTZ-043 will be added. The allocation ratio will be changed to co-enrol the remaining participants in arms 1- 3 simultaneously with arm 4. When arms 1-2 are fully enrolled and arm 4 is not, further participants will be randomized 1:1 to control and experimental arm 4. Not all countries will participate in stage 2.
Primary purpose: TREATMENT

Brief summary: This is a phase 2B/C, open label platform study that will compare the efficacy, safety of 3 experimental regimens with a standard control regimen in participants with newly diagnosed, drug sensitive pulmonary tuberculosis. In stage 1, participants will be randomly allocated to the control or one of the 2 rifampicin-containing experimental regimens in the ratio 1:1:1. In stage 2, the experimental arm 4 containing BTZ-043 will be added. The allocation ratio will be changed to co-enrol the remaining participants in arms 1- 3 simultaneously with arm 4. When arms 1-2 are fully enrolled and arm 4 is not, further participants will be randomized 1:1 to control and experimental arm 4. Not all countries will participate in stage 2.

Detailed description: This open label, phase 2B/C , randomized, controlled platform trial, will evaluate experimental arms including an increased dose of rifampicin, on optimized dose of pyrazinamide, moxifloxacin and BTZ-043, in adults with newly diagnosed, drug sensitive, smear-positive pulmonary tuberculosis A total of up to 270 adult (≥ 18 years of age) participants will be enrolled. In case of a high number of dropouts or non-evaluable participants, it may be necessary to recruit more participants into the study. Also, if the stage 2 starts later than stage 1, it may be necessary to increase the number of control arm participants to achieve a 1:1 ratio of concomitantly recruited control and arm 4 participants until the recruitment for arm 4 is completed (see sample size considerations).

Eligibility criteria: Inclusion Criteria:

1. Provide written, informed consent prior to all trial-related procedures including HIV testing.
2. Male or female, aged between 18 and 65 years, inclusive.
3. Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
4. 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.
5. A chest X-ray (no older than 2 weeks) which, in the opinion of the Investigator, is consistent with TB.
6. 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).
7. The participant understands the interaction between the study drugs and certain foods and is willing to forgo the consumption of foods high in tyramine for the period of study medication, which will be necessary if randomized to arm 4.
8. The participant is not of child-bearing potential or is willing to use effective methods of contraception when engaging in heterosexual intercourse, as defined below:

   1. 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 seen prior to 76 weeks after randomization 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.
   2. Effective contraception methods: i. Female participants: Two methods, including methods that the participant'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 experimental treatment. ii. Male participants: Two methods, including methods that the participant'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 experimental treatment.

Exclusion Criteria:

1. Circumstances that raise doubt about free, unconstrained consent to study participation (e.g., prisoner or mentally handicapped person)
2. Poor general condition where delay in treatment cannot be tolerated or death within four months is likely.
3. Poor social condition which would make it unlikely that the participant would be able to complete follow-up:
4. The participant is pregnant or breast-feeding or planning to become pregnant in the study period.
5. The participant is infected with HIV with a CD4 count \<220 cells/mm3. If \>22 cells/mm3 participants will be included only if any of the following is applicable:

   * The participant 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 mentioned in section on ARVs Antiretroviral Therapy or
   * The participant is ARV experienced (has been on ARV´s a minimum of 5 months), AND:

   ARV treatment is compliant to, or can be modified as described in the section on Antiretroviral Therapy
6. The participant 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.
7. The participant 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. Evidence of clinically significant 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. Uncontrolled diabetes mellitus.
   5. Cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension
   6. Uncontrolled arterial hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure of ≥95 mmHg on two occasions during screening).
   7. Long QT syndrome or family history of long QT syndrome or family history of sudden death of unknown or cardiac-related cause
   8. Alcohol, regular opiate, or other drug abuse that is sufficient to significantly compromise the safety or cooperation of the participant, that includes substances prohibited by the protocol or has led to significant organ damage at the discretion of the investigator.
8. 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. 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
10. 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. Restricted medication includes the following drug classes, with relevant timing of intake. Exceptions may be permissible after discussion with the sponsor medical expert. Anti-TB drugs other than study drugs Medication that increases the risk for serious cardiac arrhythmia (see 8.5.4). Drugs that affect monoamine oxidase or serotonin metabolism CYP 450 inhibitors or inducers.

Primary outcomes:
measure: Time to stable culture conversion to negative in liquid media
timeFrame: Day 01- Week 26
Secondary outcomes:
measure: Relapse - free survival at 12 months after randomization
timeFrame: Day 01-364
measure: Frequency of all adverse events (serious and non-serious)
timeFrame: Day 01-182
measure: Frequency of adverse events of Grade 3 severity (severe) or higher
timeFrame: Day 01-182
measure: Frequency of adverse events possibly, probably or definitely related to study drug
timeFrame: Day 01-182
measure: Frequency of treatment discontinuations or interruptions related to adverse events/serious adverse event
timeFrame: Day 01-182
measure: Changes in ECG intervals of PR, RR, QRS, QT, Fridericia-corrected QT [QTcF]
timeFrame: Day 01-182
measure: Area under the plasma concentration curve from dosing to the end of the dosing interval (AUC 0-24) predicted from limited pharmacokinetic sampling.
timeFrame: Day 14
measure: The observed maximum concentration (Cmax)
timeFrame: Day 14
measure: Time to reach Cmax (Tmax)
timeFrame: Day 14
measure: Minimum observed plasma concentration 24 hours following the last dose (Cmin)
timeFrame: Day 14.
measure: DTG and TFD concentration
timeFrame: Day 01-15
measure: Identification of M. tuberculosis complex and Rifampicin (RIF) resistance by PCR (GeneXpert Ultra MTB/RIF®/GeneXpert XDR/HAIN MTBDRplus or similar)
timeFrame: Day 01-182
measure: Identification of M. tuberculosis complex and Isoniazid (INH) resistance by PCR (GeneXpert Ultra MTB/RIF®/GeneXpert XDR/HAIN MTBDRplus or similar)
timeFrame: Day 01-182
measure: Minimum inhibitory concentrations (MIC) of study drugs the patient was receiving
timeFrame: Day 01-182
Other outcomes:
Locations:
city: Lambaréné
country: Gabon
facility: Centre de Recherches Médicales de Lambaréné (CERMEL)
city: Blantyre
country: Malawi
facility: Kamuzu College of Health Sciences (formerly College of Medicine)
city: Maputo
country: Mozambique
facility: Instituto Nacional de Saúde (INS)
city: Cape Town
country: South Africa
facility: TASK Applied Sciences Clinical Research Centre
city: Bagamoyo
country: Tanzania
facility: Ifakara Health Institute (IHI)
city: Mbeya
country: Tanzania
facility: National Institute for Medical Research (NIMR-MMRC)
city: Moshi
country: Tanzania
facility: Kilimanjaro Clinical Research Institute (KCRI)
city: Kampala
country: Uganda
facility: Makerere University Lung Institute Limited
Study officials:
affiliation: LMU University Hospital
name: Michael Hoelscher, Prof Dr
role: STUDY_DIRECTOR
affiliation: Radbouc University Medical Center, Nijmegen
name: Martin Boeree, Prof Dr
role: PRINCIPAL_INVESTIGATOR
References: