Early Bactericidal Activity of Rifampin + Meropenem + Amoxicillin/Clavulanate in Adults With Pulmonary TB
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| ClinicalTrials.gov Identifier: NCT03174184 |
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Recruitment Status :
Completed
First Posted : June 2, 2017
Last Update Posted : June 10, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Tuberculosis, Pulmonary | Drug: Rifampin Drug: MEROPENEM 2 grams TID Drug: MEROPENEM 1 gram TID Drug: MEROPENEM 3 grams QD Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet Drug: Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet | Phase 2 |
This is a proof-of-concept study to determine whether, in humans infected with M. tuberculosis that is resistant or susceptible to rifampin based on conventional drug susceptibility testing, the combination of meropenem, amoxicillin/clavulanate, and rifampin has activity that is sufficiently promising to proceed with further drug development along these lines. Rifampin has an incompletely understood but critical role in eradication of M. tuberculosis persisters and consequently the shortening of the duration of treatment for 'rifampin susceptible' tuberculosis (TB). For Multi-Drug Resistant (MDR) / Extensively Drug Tuberculosis (XDR) TB, the ability to recoup rifampin's antituberculosis activity through rational combination with a carbapenem and a β-lactamase inhibitor with or without amoxicillin could transform the treatment of this disease.
This proof-of-concept study is designed such that a negative outcome would refute the hypothesis that the combination of a carbapenem and amoxicillin/clavulanate with rifampin will have greater activity than either component alone against M. tuberculosis strains having Minimum Inhibitory Concentrations (MIC) in the range considered resistant to rifampin. A positive study outcome would catalyze further research to identify optimal dosing strategies for all regimen components as well as development of carbapenems optimized for TB treatment with respect to targets of activity, stability against hydrolysis, and oral formulation.
The study hypothesis cannot be tested satisfactorily in traditional animal models of tuberculosis chemotherapy due to the rapid inactivation of carbapenems (as well as other beta-lactams) by dehydropeptidases that are expressed at high levels in mouse, rabbit, and guinea pig tissues. However, all of the study drugs are Food and Drug Administration (FDA) -approved for various infectious disease indications, are in routine clinical use, and have good safety profiles, such that proceeding with the proposed clinical trial based on in vitro data is justified.
This study will also characterize the relationship between meropenem exposure (in combination with amoxicillin/clavulanate) and early bactericidal activity in order to identify the pharmacokinetic drivers of activity and pharmacokinetic targets for desired effects. This will inform the identification of more feasible meropenem dosing strategies in the near term, as well as the dose selection for novel oral carbapenems that may be available for tuberculosis treatment in the future. The proportion of the dosing interval for which free drug concentrations exceed MIC (T>MIC) is the pharmacokinetic (PK) / pharmacodynamic(PD) parameter most closely correlated with efficacy of carbapenems against common fast-growing bacteria such as Enterobacteriaceae that cause infections for which meropenem is currently approved. A commonly accepted target for efficacy in these infections is 40% T>MIC, which requires multiple daily doses to achieve. Whether this PK/PD parameter and target value is optimal for carbapenem treatment of infections with M. tuberculosis, which has a much longer doubling time, is unknown. In the trial by Diacon et al, meropenem 2 grams thrice daily plus amoxicillin/clavulanate resulted in a median T>MIC of 76% [90% Confidence Interval (CI): 66-93] whereas faropenem sodium 600 mg thrice daily plus amoxicillin/clavulanate resulted in T>MIC of 13% (90% CI: 0-33), indicating that if T>MIC is the single parameter most strongly linked to efficacy in tuberculosis, then the target for bactericidal effect is between 13% and 76%, and lower and/or less frequent doses (or use of oral carbapenems with lower bioavailability) may still have significant efficacy. If T>MIC is not the efficacy-linked PK/PD parameter, less frequent administration of the same total dose is likely to remain equally effective.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 112 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 2a Study of the Early Bactericidal Activity of Rifampin (RIF) in Combination With Meropenem Plus Amoxicillin/Clavulanate Among Adults With Rifampin-resistant or Rifampin-susceptible Pulmonary Tuberculosis |
| Actual Study Start Date : | August 23, 2017 |
| Actual Primary Completion Date : | May 13, 2022 |
| Actual Study Completion Date : | May 13, 2022 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Rifampin resistant A
Participants with the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive RIFAMPIN 20mg/kg once daily (QD), MEROPENEM 2 grams (G) thrice daily (TID) intravenously, Amoxicillin/Clavulanate Potassium 500 milligrams (MG)-125 MG Oral Tablet once daily for 14 days
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Drug: Rifampin
Oral administration of rifampin at a dosage of 20 mg/kg daily
Other Name: Rifamycins Drug: MEROPENEM 2 grams TID Intravenous administration at a dosage of 2 grams thrice daily
Other Name: Merrem Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily
Other Name: Augmentin |
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Experimental: Rifampin resistant B
Participants with the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive MEROPENEM 2 grams TID (thrice daily) intravenously, Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet once daily for 14 days
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Drug: MEROPENEM 2 grams TID
Intravenous administration at a dosage of 2 grams thrice daily
Other Name: Merrem Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily
Other Name: Augmentin |
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Experimental: Rifampin susceptible C
Participants without the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive RIFAMPIN 20mg/kg once daily, MEROPENEM 2 grams TID (thrice daily) intravenously, Amx/Clv orally at a dose of 500 mg/125 mg thrice daily for 14 days
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Drug: Rifampin
Oral administration of rifampin at a dosage of 20 mg/kg daily
Other Name: Rifamycins Drug: MEROPENEM 2 grams TID Intravenous administration at a dosage of 2 grams thrice daily
Other Name: Merrem Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily
Other Name: Augmentin |
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Experimental: Rifampin susceptible D
Participants without the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive MEROPENEM 2 grams TID intravenously, Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet once daily for 14 days
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Drug: MEROPENEM 2 grams TID
Intravenous administration at a dosage of 2 grams thrice daily
Other Name: Merrem Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily
Other Name: Augmentin |
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Experimental: Rifampin susceptible E
Participants without the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive MEROPENEM 1 gram TID intravenously, Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet once daily for 14 days
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Drug: MEROPENEM 1 gram TID
Intravenous administration at a dosage of 1 gram thrice daily
Other Name: Merrem Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily
Other Name: Augmentin |
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Experimental: Rifampin susceptible F
Participants without the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive MEROPENEM 3 grams QD intravenously, Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet once daily for 14 days
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Drug: MEROPENEM 3 grams QD
Intravenous administration at a dosage of 3 grams once daily
Other Name: Merrem Drug: Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily
Other Name: Augmentin |
- Estimate of the 14-day Early Bactericidal Activity (EBA), based on colony forming unit counts, of the combination of meropenem and amoxicillin/clavulanate, without versus with rifampin [ Time Frame: 14 days ]The Early Bactericidal Activity (EBA) over a 14 days period (EBA0-14), as determined by the rate of change in log10 Colony Forming Units (CFU) per mL sputum, described with at most three parameters from a linear, bi-linear, or non-linear regression of log10 CFU on time.
- Equivalence testing between arms [ Time Frame: 14 days ]Equivalence tests will be conducted to examine whether the EBA0-14 CFU of Arm A is different from the EBA0-14 CFU of Arm B. A similar comparison will be done comparing Arm C to Arm D, Arm A to Arm C, Arm D to Arm E, Arm D to Arm F, and Arm E to Arm F.
- Evaluation of relationship between the Area Under the Curve/Minimum Inhibitory Concentration (AUC/MIC) for rifampin [ Time Frame: 14 days ]Relationship between the AUC/MIC for rifampin (value of zero in Arms B and D; experimentally determined in Arms A and C) and the EBA will be evaluated
- Frequency of Grade 2 or higher Adverse Events [ Time Frame: From the time a study participant receives the first dose of study drug through the final study visit ]Grade 2 or higher Adverse Events (AE) that constitute any untoward medical occurrence in a study participant and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
- Distribution of Minimum Inhibitory Concentration (MIC) of rifampin, meropenem, and meropenem plus amoxicillin/clavulanate [ Time Frame: 14 days ]The distribution of rifampin, meropenem, and meropenem plus amoxicillin/clavulanate MIC against M. tuberculosis will be reported for participants with drug-sensitive TB (Arms A and B) and drug-resistant TB (Arms C and D).
- Estimate the antimycobacterial activity based on liquid culture time-to-positivity [ Time Frame: 14 days ]Change in time-to-positivity in Mycobacteria Growth Indicator Tube (MGIT) liquid media over 14 days of treatment (EBA0-14(TTP)) (time to positivity) for the study treatments
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| Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- New or recurrent pulmonary TB with one or both of the following:
- sputum positive for acid-fast bacilli on direct microscopy of at least grade 1+ (International Union Against Tuberculosis and Lung Disease (IUATLD) scale) on at least one pre-treatment sputum sample
- sputum positive for M. tuberculosis by Xpert® MTB/RIF testing, with semiquantitative result of 'medium' or 'high' on at least one pre-treatment sputum sample
- Age ≥18 and ≤65 years at study screening
- Ability and willingness to provide informed consent
- Body weight 40 kg to 90 kg, inclusive
- Laboratory values obtained within 30 days prior to or at study screening:
- Absolute neutrophil count (ANC) > 750 cells/mm3
- Hemoglobin 7.0 g/dL
- Platelet count 50,000/mm3
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 X upper limit of normal (ULN)
- Total bilirubin ≤ 2.5 X ULN
- Creatinine < 1.5 X ULN
- HIV infection must be documented as either absent or present
- For HIV-positive candidates only: CD4+ cell count of ≥ 100 cells/cu mm, performed within 30 days prior to or at study screening
- For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to or at study screening. Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal method of contraception (condoms or an IUD), or another method (diaphragm or cervical cap) if it is approved by the national regulatory authority and used according to package insert, while receiving study medications.
- Willingness to be hospitalized for a minimum of 16 consecutive days
- Ability to produce an overnight sputum sample of sufficient quality and quantity. As a guideline, this should be 10 ml or more during a 16-hour collection period. Volume is clinically estimated from a spot sample provided at screening and verified upon the first overnight collection (which can be repeated upon retraining).
- Xpert® MTB/RIF result performed on sputum within 14 days prior to or at study screening that shows EITHER 'Rifampin resistance detected' OR 'Rifampin resistance not detected'
Exclusion Criteria:
- Treatment with any drug active against M. tuberculosis within the 3 months prior to study screening.
- Breast-feeding
- Known allergy or sensitivity to any of the study drugs
- Participants receiving valproate sodium or probenecid
- Karnofsky score < 60 OR poor general condition such that, in the opinion of the investigator at screening, any delay in initiation of definitive TB treatment cannot be tolerated
- Known current neurological TB or seizure disorder
- Any condition as determined by physical examination, medical history, laboratory data, or chest x-ray which, in the opinion of the investigator, would interfere with safety or endpoint assessments in the study.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03174184
| South Africa | |
| Task Applied Science and Stellenbosch University | |
| Stellenbosch, South Africa, 7505 | |
| Principal Investigator: | Kelly Dooley, MD | Associate Professor of Medicine |
| Responsible Party: | Johns Hopkins University |
| ClinicalTrials.gov Identifier: | NCT03174184 |
| Other Study ID Numbers: |
IRB00119017 FD-R-05724 ( Other Grant/Funding Number: FDA OOPD ) |
| First Posted: | June 2, 2017 Key Record Dates |
| Last Update Posted: | June 10, 2022 |
| Last Verified: | June 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Tuberculosis Tuberculosis, Pulmonary Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Respiratory Tract Infections Lung Diseases Respiratory Tract Diseases Amoxicillin Rifampin Meropenem Clavulanic Acid |
Clavulanic Acids Amoxicillin-Potassium Clavulanate Combination Rifamycins Anti-Bacterial Agents Anti-Infective Agents Antibiotics, Antitubercular Antitubercular Agents Leprostatic Agents Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 Enzyme Inducers Cytochrome P-450 CYP2C8 Inducers Cytochrome P-450 CYP2C19 Inducers |