Evaluation of SQ109, High-dose Rifampicin, and Moxifloxacin in Adults With Smear-positive Pulmonary TB in a MAMS Design
Information source: Ludwig-Maximilians - University of Munich
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Tuberculosis, Pulmonary
Intervention: SQ109 (Drug); Rifampicin (Drug); Moxifloxacin (Drug); isoniazid (Drug); pyrazinamide (Drug); ethambutol (Drug); pyridoxine (Dietary Supplement)
Phase: Phase 2
Status: Active, not recruiting
Sponsored by: Michael Hoelscher Official(s) and/or principal investigator(s): Michael Hoelscher, MD, Study Chair, Affiliation: Klinikum of the University of Munich Martin Boeree, MD, Principal Investigator, Affiliation: Radboud University
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.
Clinical Details
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
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Sputum culture conversion (2 negative cultures) using liquid media
Secondary outcome: Frequency of Adverse EventsMycobacteriology Identification and Characterization by PCR and MIC Pharmacokinetics including AUC, Cl, t1/2, Vd, and protein binding Pharmacodynamics including AUC0‐24/MIC (h*ng/mL) and Cmax/MIC (ng/mL) Time to first negative culture on liquid and solid media Proportion of negative sputum cultures Rate of change in time to positivity Rate of change in quantitative PCR during therapy Occurence of treatment failure (relapse or emergence of drug-resistance) Changes in baseline laboratory safety parameters during treatment and follow-up
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria
1. 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.
2. 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.
3. 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.
4. 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.
5. The patient is aged at least 18 years at the day of informed consent.
6. The patient has a body weight in light clothing and without shoes of at least 35 kg,
but not more than 90 kg.
7. 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).
8. 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).
9. 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
1. Circumstances that raise doubt about free, uncoerced consent to study participation
(e. g. in a prisoner or mentally handicapped person)
2. Poor General Condition where delay in treatment cannot be tolerated or death within
three months is likely.
3. The patient is pregnant or breast‐feeding.
4. 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.
5. 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.
6. 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.
7. History of previous TB within the last five years.
8. 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;
9. 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.
10. 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
11. 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.
12. 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.
13. 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.
Locations and Contacts
TASK Applied Science, Bellville 7530, South Africa
University of Cape Town, Centre for Tuberculosis Research Innovation, Cape Town 7700, South Africa
The Aurum Institute for Health Research, Johannesburg 2193, South Africa
Wits Health Consortium, Johannesburg 2092, South Africa
Ifakara Health Institute, Bagamoyo P.O.Box 74, Tanzania
NIMR - Mbeya Medical Research Programme, Mbeya P.O. Box 2410, Tanzania
Kilimanjaro Christian Medical Centre (KCMC) / Kilimanjaro Clinical Research Institute (KCRI) (with affiliated field sites such as Kibong'oto National Tuberculosis Hospital Same, Mererani, Chekereni and Mawenzi Regional Hospital), Moshi 2236, Tanzania
Additional Information
Starting date: April 2013
Last updated: October 10, 2014
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