A Prospective, Randomized Open-Label Phase II Study of the Safety and Tolerability of Metformin in Combination With Standard Antimicrobial Treatment of Pulmonary Tuberculosis in People Co-infected With HIV
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 112
- 试验地点
- 4
- 主要终点
- Number of Participants Experiencing Grade 3 or Higher Adverse Events
研究概览
简要总结
The METHOD study will examine whether adding metformin to standard antibiotic treatment for tuberculosis (TB) in people with HIV is safe and well tolerated. The study will also test if adding metformin clears the infection more quickly and with less lung damage. When enrolled, participants will have an equal chance of being in the group that takes standard TB medicines alone or in the group that also takes metformin. Participants will have a chance to be put on either: 1) standard TB medicines (isoniazid, rifampicin, ethambutol and pyrazinamide for two months, continuing isoniazid and rifampin for four more months) only; or 2) the same standard TB medicines plus metformin. Participants randomized to the metformin arm will take metformin for eleven weeks, starting one week after starting the standard TB medicines. In addition to monitoring for side effects, all participants will have studies of drug levels and lung and immune function.
详细描述
The METHOD trial is a Phase II A randomized, open-label trial of metformin added to standard anti-tuberculosis treatment (ATT) and anti-retroviral therapy (ART) in TB/HIV co-infected patients. HIV-positive adults (treated or ART-naïve) newly diagnosed with sputum culture-positive, drug-sensitive pulmonary TB will be recruited to and enrolled in the study. All participants in the interventional study will take standard ATT for drug-sensitive pulmonary TB starting at enrollment. Participants in the metformin arm will begin taking metformin 1 week later and metformin will be stopped on week-12. The total cohort is sample size N=112, comprising 56 participants each in two parallel study arms (standard therapy or standard therapy plus metformin) with the goal of retaining 100 participants with evaluable data for analysis. The duration of the METHOD trial is 5 years. The duration of individual participation in the interventional arms of the study is 36 weeks, not including an initial period of screening over an interval of up to 14 additional days prior to study enrollment. The final clinic visit coincides with the completion of ATT at week-24. The final follow-up contact is a phone interview at week-36. Ten consenting participants from each study arm (n=20 total) will have intensive pharmacokinetic/pharmacodynamic (PK/PD) sampling. The remaining 92 participants will have sparse PK/PD sampling.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Senior study leadership, Drs. Kornfeld, Wallis, Churchyard, Singhal will be blinded. Participants, study personnel and clinicians are not blinded.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18 through 65 years.
- •HIV-1 seropositive status prior to or after screening.
- •Chest radiograph compatible with pulmonary TB.
- •Positive sputum Xpert MTB/RIF or Xpert MTB/RIF Ultra with one cycle threshold (Ct) <25 or subsequent culture confirmation.
- •RIF susceptibility diagnosed by an approved TB diagnostic test e.g. Xpert MTB/RIF (Cepheid), Xpert MTB/RIF Ultra (Cepheid) or BD MAX (Becton-Dickinson).
- •Residence within study catchment area.
- •If female of childbearing potential, willing to use contraception for the duration of study participation (Criteria for childbearing potential and for acceptable contraception). If male, willing to use condoms for the duration of metformin treatment plus 3 months after stopping metformin.
- •Able and willing to provide informed consent.
排除标准
- •Any condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the participant or prevent, limit or confound protocol-specified assessments.
- •Is critically ill, and in the judgment of the investigator has a diagnosis likely to result in death during the trial or the follow-up period.
- •TB meningitis or other forms of severe TB with high risk of a poor outcome as judged by the investigator.
- •Pregnant or breastfeeding.
- •Resistance to any first-line ATT drug demonstrated by susceptibility testing.
- •More than 14 days ATT for the current episode of TB, prior to enrollment.
- •Taking any fluoroquinolone antibiotic.
- •History of diabetes mellitus or fasting blood glucose >7.0 mmol/L on screening evaluation.
- •History of congestive heart failure, chronic liver disease, diabetes, autoimmune disease or malignancy.
- •Consumption of >28 units (men) OR >21 units (women) of alcohol/week.
- •Use of metformin within 1 year prior to enrollment.
- •History of sensitivity to metformin.
- •Acute or chronic metabolic acidosis based on reported medical history or laboratory tests performed on screening.
- •Body mass index (BMI) <17kg/m^2 on screening evaluation.
- •Peripheral blood CD4 + T cell count <50 cells/mm^3 on screening evaluation.
- •Hemoglobin <9 g/dL for males, and <8 g/dL (women) for females on screening evaluation.
- •Platelet count <50,000/mm^3 on screening evaluation.
- •Absolute neutrophil count <750 cells/mm^3 on screening evaluation.
- •Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m^2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
- •Serum bicarbonate <18 mmol/L on screening evaluation.
- •Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 times the upper limit of normal (ULN) on screening evaluation.
- •Hepatitis B surface antigen positive.
- •Enrollment in another interventional study at any time during participation in the METHOD trial.
- •Imprisonment at the time of or after enrollment in the METHOD trial.
- •Diagnosis of active Coronavirus Disease 2019 (COVID-19) at the time of screening or high suspicion of active COVID-19 disease during screening.
研究组 & 干预措施
Standard Tuberculosis Medicines
Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months.
干预措施: Ethambutol (Drug)
Standard Tuberculosis Medicines
Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months.
干预措施: Isoniazid (Drug)
Standard Tuberculosis Medicines
Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months.
干预措施: Rifampicin (Drug)
Standard Tuberculosis Medicines and Metformin
Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) only, in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months. They also take Metformin hydrochloride, one 500 mg tablet, daily starting one week after the initiation of tuberculosis medicines, increasing to one 500 mg tablet twice daily through study week-12 for a total of 11 weeks of metformin exposure.
干预措施: Isoniazid (Drug)
Standard Tuberculosis Medicines and Metformin
Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) only, in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months. They also take Metformin hydrochloride, one 500 mg tablet, daily starting one week after the initiation of tuberculosis medicines, increasing to one 500 mg tablet twice daily through study week-12 for a total of 11 weeks of metformin exposure.
干预措施: Metformin hydrochoride (Drug)
Standard Tuberculosis Medicines
Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months.
干预措施: Pyrazinamide (Drug)
Standard Tuberculosis Medicines and Metformin
Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) only, in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months. They also take Metformin hydrochloride, one 500 mg tablet, daily starting one week after the initiation of tuberculosis medicines, increasing to one 500 mg tablet twice daily through study week-12 for a total of 11 weeks of metformin exposure.
干预措施: Rifampicin (Drug)
Standard Tuberculosis Medicines and Metformin
Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) only, in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months. They also take Metformin hydrochloride, one 500 mg tablet, daily starting one week after the initiation of tuberculosis medicines, increasing to one 500 mg tablet twice daily through study week-12 for a total of 11 weeks of metformin exposure.
干预措施: Ethambutol (Drug)
Standard Tuberculosis Medicines and Metformin
Participants are randomized to receive standard tuberculosis medicines (Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) only, in a combination pill pack taken by mouth daily for 2 months. This is followed by Isoniazid and Rifampicin for 4 months. They also take Metformin hydrochloride, one 500 mg tablet, daily starting one week after the initiation of tuberculosis medicines, increasing to one 500 mg tablet twice daily through study week-12 for a total of 11 weeks of metformin exposure.
干预措施: Pyrazinamide (Drug)
结局指标
主要结局
Number of Participants Experiencing Grade 3 or Higher Adverse Events
时间窗: Up to 24 weeks
The cumulative number of participants in each arm experiencing grade 3 or higher adverse events, assessed on every visit from week-1 to week-24.
次要结局
- Time to Sputum Liquid Culture Conversion(Up to 24 weeks)
- Change in Radiographic Severity Score From Baseline to TB Treatment Completion(Baseline and 24 weeks)
- Change in 6-minute Walk Test Distance From Baseline to TB Treatment Completion(Baseline and 24 weeks)
- Change in 6-minute Walk Test Distance-saturation Product From Baseline to TB Treatment Completion(Baseline and 24 weeks)
- Change in FVC From Baseline to TB Treatment Completion(Baseline and 24 weeks)
- Change in FEV1% From Baseline to TB Treatment Completion(Baseline and 24 weeks)
- Change in St. George's Respiratory Questionnaire Score From Baseline to TB Treatment Completion(Baseline and 24 weeks)
- Number of Participants Experiencing One or More Adverse Event of Any Grade(Up to 24 weeks)
研究者
Hardy Kornfeld, MD
Professor
University of Massachusetts, Worcester