Evaluation of SQ109, High-dose Rifampicin, and Moxifloxacin in Adults With Smear-positive Pulmonary TB in a MAMS Design

Study Overview
=================
Brief Summary
-----------------
This study is a multiple-arm, multiple-stage (MAMS), phase 2, open label, randomized, controlled clinical trial that will compare the efficacy and safety of four experimental four drug regimens with a standard control regimen in patients with smear positive, pulmonary tuberculosis (TB). Patients will be randomly allocated to the control or one of the four experimental regimens in the ratio 2:1:1:1:1. Experimental regimens will be given for 12 weeks. Thereafter, participants in the experimental arms will receive continuation phase treatment for 14 weeks containing standard-dose rifampicin and isoniazid. All participants will receive 25 mg of vitamin B6 (pyridoxine) with every dose of INH to prevent INH-related neuropathy. Interim analyses will be conducted during the trial for efficacy, with the aim of identifying experimental arms that perform below a pre-specified efficacy threshold; these arms will then be stopped from further recruitment. Following the first scheduled interim analysis on March 3rd, the Trial Steering Committee (TSC) followed a recommendation of the independent data monitoring committee (IDMC) and has stopped the enrolment into two of the arms in the MAMS-TB trial: HRZQ and HR20ZQ, based on these arms not meeting the pre-specified gain in efficacy over control. Importantly, there was no safety concern that prompted stopping recruitment to these arms. They recommended that recruitment to arm 2 (HRZQ) and 3 (HR20ZQ) be terminated as there was insufficient evidence that these regimens could shorten treatment. Importantly, there was no evidence that either arm was inferior to standard treatment (the control arm) with regards to efficacy. There was, however, sufficient evidence that the other intervention arms HR35ZE and HR20ZM could shorten treatment to continue enrolling patients.

Detailed Description
-----------------
This Phase II, multi-arm, multi-stage, open label, prospectively randomized, controlled clinical trial will compare the efficacy and safety of four experimental regimens with the control, standard treatment regimen in patients with smear positive, pulmonary tuberculosis (TB). There will be four experimental regimens. Participants will be randomly allocated to control or one of the four experimental intensive phase regimens in the ratio 2:1:1:1:1. The control and 4 experimental regimens are: Control: HRZE isoniazid, rifampicin standard, pyrazinamide, ethambutol Arm 1: HRZQlow isoniazid, rifampicin standard, pyrazinamide, SQ109 150 mg Arm 2: HRZQhigh isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg Arm 3: HR20ZQhigh isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg Arm 4: HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400mg Up to 372 participants will be randomized into this study, with 124 participants being randomized to the control arm and 62 participants to each experimental arm. With an expected loss to follow-up of 5%, the final power of the study to detect a hazard ratio of 1.8 for culture conversion to negative will be 90%, at the 5% significance level. Participants will be randomised using a probabilistic minimisation algorithm based on site, baseline bacterial load as measured by GeneXpert MTB/RIF®, and HIV status. The allocated intensive phase of the four experimental arms will be administered daily for twelve weeks. During this time, participants will visit the study clinic on a weekly basis for sputum collection, safety monitoring and receipt of study medication. After the completion of the experimental treatment, participants in the experimental arms will receive daily standard continuation phase treatment for 14 weeks containing standard-dose RIF and INH to complete their TB treatment course. Participants in the control arm will receive eight weeks of intensive four-drug treatment (HRZE, followed by 18 weeks of the HR continuation phase treatment in line with the current WHO recommendations. All participants will receive 25mg of Vitamin B6 (pyridoxine) with every dose of treatment in order to prevent INH-related neuropathy. Interim analyses will be conducted during the trial for efficacy at predetermined times, with the aim of identifying experimental arms that perform below a pre-specified efficacy threshold. There will be no further recruitment to these arms.

Official Title
-----------------
A Multiple Arm, Multiple Stage, Phase 2, OL, Randomized, Controlled Trial to Evaluate 4 Treatment Regimens of SQ109, Increased Doses of Rifampicin, and Moxifloxacin in Adults With Newly Diagnosed, Smear-positive Pulmonary Tuberculosis

Conditions
-----------------
Tuberculosis, Pulmonary

Intervention / Treatment
-----------------
* Drug: SQ109
* Drug: Rifampicin
* Drug: Moxifloxacin
* Drug: isoniazid
* Drug: pyrazinamide
* Drug: ethambutol
* Dietary Supplement: pyridoxine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria The patient has given free, signed written or witnessed oral informed consent for study participation prior to all trial-related procedures, including HIV testing if HIV serostatus is not known or the last documented negative is more than four weeks ago. The patient has a diagnosis of pulmonary tuberculosis from a health clinic established by sputum smear and/or GeneXpert MTB/RIF® and/or chest X-ray. An adequate sputum bacterial load is confirmed by a Ziehl-Neelsen stained smear in the study laboratory, done from concentrated sputum found at least 1+ on the IUATLD/WHO scale. The patient has a valid rapid test result (GeneXpert MTB/RIF®) from the sputum positive for MTB complex, and indicating susceptibility to Rifampicin. This test must be done in the study laboratory. The patient is aged at least 18 years at the day of informed consent. The patient has a body weight in light clothing and without shoes of at least 35 kg, but not more than 90 kg. Female patients of childbearing potential must have a negative serum pregnancy test, and consent to practise an effective method of birth control until week 26. Effective birth control for female patients has to include two methods, including methods that the patient's sexual partner(s) use. At least one must be a barrier method. Female patients are considered not to be of childbearing potential if they are post-menopausal with no menses for the last 12 months, or surgically sterile (this condition is fulfilled by bilateral oophorectomy, hysterectomy, and by tubal ligation which is done at least 12 months prior to enrolment). Male patients must consent to use an effective contraceptive method, if their sexual partner(s) is/are of childbearing potential, and if they are not surgically sterile (see 6.). Contraception by male participants must be practised until at least week 24 to cover the period of spermatogenesis. Contraceptive methods used by male participants may include hormonal methods used by the partner(s). The patient has a firm home address that is readily accessible for visiting and willingness to inform the study team of any change of address during trial participation, or will be compliant to study schedule, in the discretion of the investigator. Exclusion Criteria Circumstances that raise doubt about free, uncoerced consent to study participation (e.g. in a prisoner or mentally handicapped person) Poor General Condition where delay in treatment cannot be tolerated or death within three months is likely. The patient is pregnant or breast-feeding. The patient has an HIV infection and is receiving antiretroviral treatment (ART), and/or is likely to require ART during the twelve weeks of experimental study treatment as per local guidelines. The patient has a known intolerance to any of the study drugs, or concomitant disorders or conditions for which SQ109, rifampicin, moxifloxacin, or standard TB treatment are contraindicated. The patient has an history or evidence of clinically relevant 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: clinically significant evidence of severe TB (e.g. miliary TB, TB meningitis. Limited lymph node involvement will not lead to exclusion); serious lung conditions other than TB or severe respiratory impairment in the discretion of the investigator; neuropathy, epilepsy or significant psychiatric disorder; uncontrolled and/or insulin-dependent diabetes; cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure of ≥100 mmHg on two occasions), arrhythmia, or tachyarrhythmia; long QT syndrome (see criterion 9.), or family history of long QT syndrome or sudden death of unknown or cardiac-related cause; Plasmodium spp. parasitemia as indicated by thick blood smear or a positive rapid test present at screening; Alcohol or other drug abuse that is sufficient to significantly compromise the safety or cooperation of the patient, includes substances prohibited by the protocol, or has led to significant organ damage at the discretion of the investigator. History of previous TB within the last five years. Laboratory: at screening one or more of the following abnormalities were observed for the patient in screening laboratory: Serum amino aspartate transferase (AST) and/or serum alanine aminotransferase (ALT) activity >3x the upper limit of normal; Serum total bilirubin level >2.5 times the upper limit of normal; Creatinine clearance (CrCl) level lower than 30 mls/min; Complete blood count with hemoglobin level <7.0 g/dL; Platelet count <50,000/mm3; Serum potassium below the lower level of normal; ECG findings in the screening ECG: QTcB and/or QTcF of >0.450 s; atrioventricular (AV) block with PR interval > 0.20 s; prolongation of the QRS complex over 120 milliseconds; other changes in the ECG that are clinically relevant as per discretion of the investigator. The patient has had treatment with any other investigational drug within 1 month prior to enrolment, or enrolment into other clinical (intervention) trials is planned during week 1-26 Previous anti-TB treatment: the patient has had previous treatment with drugs active against M. tuberculosis within the last 3 months, including but not limited to INH, EMB, RIF, PZA, amikacin, cycloserine, rifabutin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, capreomycin, fluoroquinolones, thioamides. QT prolonging medications: Administration within 30 days prior to study start, anticipated administration during the study period, or during the 12 weeks of experimental treatment, of any QT-prolonging agents such as, but not limited to, azithromycin, bepridil chloroquine, chlorpromazine, cisapride, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, lumefantrine, mefloquine, mesoridazine, methadone, moxifloxacin, pentamidine, pimozide, procainamide, quinidine, quinine, roxithromycin, sotalol, sparfloxacin, terfenadine, thioridazine. Exceptions may be made for participants who have received 3 days or less of one of these drugs or substances, if there has been a wash-out period equivalent to at least 5 half-lives of that drug or substance. Patients who have ever received amiodarone will be excluded from study participation. CYP 450 inducers/inhibitors: administration within 30 days prior to dosing, or planned administration until the end of week 12, of any drug(s) or substance(s) known to be strong inhibitors or inducers of cytochrome P450 enzymes, or specific inhibitors/inducers of SQ109-metabolizing enzymes as Exceptions may be made for subjects that have received 3 days or less of one of these drugs or substances, if a wash-out period equivalent to at least 5 half-lives of that drug or substance prior to study treatment is granted.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (R35)<br>Arm 1 (R35): HR35ZE isoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol | Drug: Rifampicin<br>* Rifampicin 10 to 35 mg/kg<br>Drug: isoniazid<br>* isoniazid 75 mg<br>Drug: pyrazinamide<br>* pyrazinamide 400 mg<br>Drug: ethambutol<br>* ethambutol 275 mg<br>Dietary Supplement: pyridoxine<br>* pyridoxine 25 mg<br>|
| Experimental: HRZQ<br>Arm 2 (Q): HRZQ isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg | Drug: SQ109<br>* SQ109 300 mg<br>Drug: Rifampicin<br>* Rifampicin 10 to 35 mg/kg<br>Drug: isoniazid<br>* isoniazid 75 mg<br>Drug: pyrazinamide<br>* pyrazinamide 400 mg<br>Dietary Supplement: pyridoxine<br>* pyridoxine 25 mg<br>|
| Experimental: HR20ZQ<br>Arm 3 (R20Q): HR20ZQ isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg | Drug: SQ109<br>* SQ109 300 mg<br>Drug: Rifampicin<br>* Rifampicin 10 to 35 mg/kg<br>Drug: isoniazid<br>* isoniazid 75 mg<br>Drug: pyrazinamide<br>* pyrazinamide 400 mg<br>Dietary Supplement: pyridoxine<br>* pyridoxine 25 mg<br>|
| Experimental: HR20ZM<br>Arm 4 (R20M): HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400 mg | Drug: Rifampicin<br>* Rifampicin 10 to 35 mg/kg<br>Drug: isoniazid<br>* isoniazid 75 mg<br>Drug: pyrazinamide<br>* pyrazinamide 400 mg<br>Dietary Supplement: pyridoxine<br>* pyridoxine 25 mg<br>|
| Active Comparator: HRZE<br>HRZE: Isoniazid, rifampicin standard, pyrazinamide, ethambutol | Drug: Rifampicin<br>* Rifampicin 10 to 35 mg/kg<br>Drug: Moxifloxacin<br>* Moxifloxacin 400mg<br>Drug: isoniazid<br>* isoniazid 75 mg<br>Drug: pyrazinamide<br>* pyrazinamide 400 mg<br>Drug: ethambutol<br>* ethambutol 275 mg<br>Dietary Supplement: pyridoxine<br>* pyridoxine 25 mg<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sputum Culture Conversion (2 Negative Cultures) Using Liquid Media | From enrollment, the time to stable culture conversion (2 consecutive negative weekly cultures) in liquid media. | 0 - 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Events | All Adverse Events (AE), and AEs considered to be drug-related will coded using standard AE dictionaries. | 0 - 12 weeks | 
| Mycobacteriology Identification and Characterization by PCR and MIC | Cultures grown from the screening period, and the last sputum sample with mycobacteriological growth will be assessed as follows: Identification of M. tuberculosis complex and RIF resistance by PCR (GeneXpert MTB/RIF®), First-line drug susceptibility testing of the M. tuberculosis isolates using the MGIT system for sensitivity to rifampicin; isoniazid, pyrazinamide, moxifloxacin or ethambutol. Minimum inhibitory concentrations (MIC) of SQ109, rifampicin and moxifloxacin. Typing of the infecting strain(s) by molecular methods. | 0 - 12 weeks | 
| Pharmacokinetics Including AUC, Cl, t1/2, Vd, and Protein Binding | Pharmacokinetic parameters will be assessed for rifampicin, moxifloxacin and SQ109: area under the plasma concentration curve from dosing to the end of the dosing interval (AUC 0-24) (in h*ng/mL) the observed maximum concentration (Cmax( (in ng/mL) time to reach Cmax (Tmax)(in hours) the minimum observed plasma concentration 24 hours following the last dose (Cmin) (in hours), clearance (Cl) (in mL/minute), volume of distribution (Vd) (in L), elimination half-life (T1/2,) (in hours) free (protein-unbound) fraction (for rifampicin only) (in percent). | 0 - 12 weeks | 
| Pharmacodynamics Including AUC0-24/MIC (h*ng/mL) and Cmax/MIC (ng/mL) | By combining pharmacokinetic parameters and MIC values (see below), the pharmacodynamic indices AUC0-24/MIC (h*ng/mL) and Cmax/MIC (ng/mL) will be calculated for individual patients for experimental drugs administered. Pharmacokinetic parameters and pharmacodynamic indices will be related to efficacy and safety/tolerability endpoints. | 0 - 12 weeks | 
| Time to First Negative Culture on Liquid and Solid Media | Time to a convert to a single negative culture on liquid and solid media | 0 - 12 weeks | 
| Proportion of Negative Sputum Cultures | Proportion of patients converting to negative sputum culture (2 consecutive weekly cultures) in liquid and solid media | 0 - 12 weeks | 
| Rate of Change in Time to Positivity | Rate of change in time to positivity in BD MGIT 960® liquid culture | 0 - 12 weeks | 
| Rate of Change in Quantitative PCR During Therapy | GeneXpert MTB/RIF (Xpert) quantitative PCR results (counts per week | 0 - 12 weeks | 
| Occurence of Treatment Failure (Relapse or Emergence of Drug-resistance) | Frequency of treatment failures (number of patients with relapse and/or development of drug resistance) will be recorded | 0 - 12 weeks | 
| Changes in Baseline Laboratory Safety Parameters During Treatment and Follow-up | Frequency tables will be generated for visual acuity tests, 12 lead ECGs, clinical chemistry metrics, haematology, and urinalysis | 0 - 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TB, Tuberculosis, MAMS - Multiple-arm, multiple-stage, Pulmonary, SQ109, High dose rifampicin, moxifloxacin