Evaluation of High-Dose Rifampicin, Moxifloxacin, and Linezolid Regimen in Bacilliferous Pulmonary Tuberculosis: A Randomized Controlled Trial
- Trial ID
- 2023-509075-17-00
- Protocol
- RML-TB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the **efficacy** and **safety** of a treatment regimen based on high-dose **rifampicin**, high-dose **moxifloxacin**, and **linezolid** over an 8-week period compared to standard treatment in patients with smear-positive **pulmonary tuberculosis**. This is clinically relevant as it aims to determine whether the experimental regimen can offer improved outcomes in terms of bacterial clearance and patient safety, potentially leading to more effective treatment protocols for this infectious disease.
Secondary objectives include:
- Evaluating the tolerability of the experimental arm versus the standard treatment arm by monitoring any adverse events.
- Assessing the dynamics of efficacy through the decrease in bacterial load over time and the increase in time until sputum positivity.
- Analyzing the correlation between the area under the curve/minimum inhibitory concentration (AUC/MIC) of rifampicin, moxifloxacin, and linezolid with the efficacy results.
- Assessing the quality of life of study participants using specific questionnaires, such as the SF-12 and St George respiratory questionnaire.
- Conducting a cost-effectiveness study to explore the feasibility of implementing the experimental arm within the National Health System.
Participants
The clinical trial involves participants diagnosed with **bacilliferous pulmonary tuberculosis**. The study population includes both male and female subjects, aged over 18 years, who have been diagnosed with smear-positive pulmonary tuberculosis. The trial does not specifically target a vulnerable population. Participants were required to provide informed consent, and women of childbearing age were required to have a negative pregnancy test. The sponsor has not provided information regarding the total number of participants. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria include age, diagnosis confirmation, and consent, while exclusion criteria are not detailed in the provided data.
Plans and Procedures
The clinical trial is designed as a **randomized**, controlled, open, multicentric study to evaluate the efficacy and safety of a combination of anti-tuberculous drugs in patients with **bacilliferous pulmonary tuberculosis**. The trial will compare a regimen based on high-dose **rifampicin**, high-dose **moxifloxacin**, and **linezolid** over an 8-week period against the standard treatment. The primary objective is to assess the proportion of patients achieving sterilization of sputum culture in liquid medium after 8 weeks of treatment, alongside evaluating the safety profile by monitoring for grade 3 or higher adverse events as per CTCAE V5.
The trial will commence with a screening visit to confirm eligibility, which includes criteria such as age over 18 years, a confirmed diagnosis of smear-positive pulmonary tuberculosis, and a signed consent form. Women of childbearing potential must have a negative pregnancy test. Following randomization, participants will undergo regular follow-up visits to monitor treatment efficacy and safety, with assessments including sputum culture tests and adverse event evaluations. The end-of-study visit will occur at the conclusion of the 8-week treatment period, where final assessments will be conducted.
Participants are expected to be involved in the study for the full 8-week treatment duration, with conditions for early termination including the occurrence of severe adverse events or withdrawal of consent. Secondary endpoints include evaluating the tolerability of the experimental regimen, the dynamics of efficacy compared to the control arm, and the quality of life of participants. The trial will also analyze the immunological and inflammatory patterns of participants and conduct a cost-effectiveness study. The estimated recruitment start date was July 1, 2022, with an anticipated end date of June 30, 2025.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments to evaluate their efficacy and safety in patients with smear-positive pulmonary tuberculosis. The primary experimental medication is **RIMSTAR®**, a combination of **isoniazid, pyrazinamide, rifampicin, and ethambutol hydrochloride**. This medication is provided in the form of film-coated tablets and is administered orally. The maximum daily dose is 5 units, with a total maximum dose of 280 units over a treatment period of 8 weeks.
Another experimental medication used in the trial is **Zyvoxid 600 mg Filmtabletten**, containing the active substance **linezolid**. This medication is also in the form of film-coated tablets and is administered orally. The maximum daily dose is 1200 mg, with a total maximum dose of 16800 mg over a treatment period of 2 weeks. Linezolid is classified as an antibiotic and serves as a comparator in the study.
**Moxifloxacin Tillomed 400 mg film-coated tablets** is another test medication, containing **moxifloxacin hydrochloride**. It is administered orally in the form of film-coated tablets. The maximum daily dose is 600 mg, with a total maximum dose of 33600 mg over an 8-week treatment period. Moxifloxacin is categorized as an antibiotic.
**Rimactan 300 mg hörð hylki** is a hard capsule containing **rifampicin**. This medication is administered orally, with a maximum daily dose of 2400 mg and a total maximum dose of 134400 mg over an 8-week treatment period. Rifampicin is classified as an antimycobacterial agent.
Additionally, **Hidroxil B1-B6-B12 comprimidos recubiertos con película** is used as an auxiliary treatment. It contains **thiamine hydrochloride, cyanocobalamin, and pyridoxine hydrochloride**. This film-coated tablet is administered orally, with a maximum daily dose of 250 mg and a total maximum dose of 3500 mg over a 2-week treatment period. This combination is categorized under vitamin B1 in combination with vitamin B6 and/or vitamin B12.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess the efficacy and safety of these medications in comparison to standard treatment protocols for pulmonary tuberculosis.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **sterilization of sputum culture** in liquid medium 8 weeks after the initiation of treatment. This primary endpoint will determine the proportion of patients achieving this outcome, providing a direct measure of the treatment's effectiveness in patients with smear-positive pulmonary tuberculosis. The trial will also include secondary endpoints to further assess efficacy, such as the dynamics of efficacy between the experimental and control arms, measured by the time until positive culture and the time until sputum becomes negative. Additionally, the trial will analyze the correlation between pharmacokinetic parameters and evaluate the quality of life of the patients. The efficacy assessments will be conducted at specified timepoints, with the primary endpoint evaluated at the 8-week mark. The trial will utilize validated laboratory tests to collect and analyze sputum samples, ensuring the reliability and accuracy of the efficacy data collected throughout the study period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age >18 years 2. Diagnosis of smear-positive pulmonary tuberculosis 3. Signature of consent form 4. Negative pregnancy test in women of childbearing age (defined as a woman who has had menarche and has not yet had menopause, with the exception of infertile women, which includes, among other situations, women with a hysterectomy, women with a double salpingectomy and women with double oophorectomy).
Exclusion Criteria
- Recent contact with a patient with multidrug-resistant tuberculosis 2. Multidrug-resistant tuberculosis or monoresistance to any of the first-line drugs (except ethambutol) 3. Positive smear microscopy with negative mycobacterial culture. 4. Barthel <60 or the investigator considers that there is a risk of poor prognosis in the following months 5. Weight less than 40kg 6. Treatment with drugs that can prolong QT in the last month before randomization for more than 7 days (azithromycin, chloroquine, chlorpromazine, cisapride, clarithromycide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, lumefantrine, mefloquine, methadone, pentamidine, procainamide, quinidine, quinine, sotalol, sparfloxine, thioridazine, amiodarone). 7. Cirrhosis Child C 8. User of drugs of abuse according to the researcher's criteria 9. Patient with solid organ or bone marrow transplant. 10. Patient on treatment with anti-TNF or other immunosuppressive drugs 11. Patients with oncohematological diseases Advanced lung disease according to the researcher 13. Epilepsy or non-stable psychiatric illness. 14. History of ischemic coronary heart disease or severe arrhythmia in the previous 6 months 15. Long QT syndrome or family history of sudden death 16. Patient with HIV diagnosis 17. Women who breastfeed 18. Allergy or intolerance to any of the study drugs 19. History of TB in the previous year 20. Any of the following laboratory alterations: AST or ALT > 3 times the upper limit of normal b Total Bi > 3 times the upper limit of normal c Hb< 6.5 g/dl d Platelets < 40,000/mm^3 e Potassium < 3.2 mmol/L f GFR<30 ml/min/1.73m^2 21. Any of the following alterations in the ECG: at QTcF>0.5sec b Other clinically relevant changes in the ECG according to the investigator. 22. Treatment with any of the drugs included in the trial for more than 7 days in the last month. 23. Participants who are being treated with serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5HT1 receptor agonists (triptans), direct or indirect acting sympathomimetics (including adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), vasopressors (e.g. epinephrine, norepinephrine), dopaminergic medications (e.g. dopamine, dobutamine), pethidine or buspirone and cannot be removed or replaced by drugs of another class at the discretion of the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 01 Jul 2022 | 120 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Rimactan 300 mg hörð hylki. | Test | HÖRÐ HYLKI | ORAL | 2400 | 8 | PRD1668239 |
Moxifloxacin Tillomed 400 mg film coated tablets | Test | FILM COATED TABLETS | ORAL | 600 | 8 | PRD10226326 |
LINEZOLID | Test | — | ORAL | 600 | 6 | SUB08520MIG |
RIMSTAR®, COMPRIMIDOS RECUBIERTOS CON PELÍCULA | Comparator | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL | 5 | 8 | PRD796716 |
Hidroxil B1-B6-B12 comprimidos recubiertos con película | Other | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL | 250 | 2 | PRD2202502 |
Zyvoxid 600 mg Filmtabletten | Test | FILMTABLETTEN | ORAL | 1200 | 2 | PRD1759191 |