Introduction
Tuberculosis (TB), caused by the bacillus Mycobacterium tuberculosis, is the world’s first leading cause of death from a single infectious agent other than coronavirus disease 2019 (COVID-19) [1]. Globally, 7.5 million patients were diagnosed with TB and 1.3 million deaths were caused by TB in 2022. In South Korea, the TB incidence rate was 38.2 per 100,000 population and 19,540 TB cases were notified in 2023 [2]. Although TB represents a global health threat, the treatment success rate for drug-susceptible TB is still 85% [1].
The standard regimen for drug-susceptible TB has remained largely unchanged for decades [3]. The standard regimen comprises four drugs, isoniazid, rifampicin, pyrazinamide, and ethambutol, and requires a minimum treatment period of 6 months [4]. However, this prolonged treatment leads to increased risks of toxicity and poor adherence [5]. To improve adherence and reduce adverse events, several clinical trials have attempted to shorten the treatment duration. Despite these efforts, many trials have failed to demonstrate non-inferiority to the standard 6-month regimen, with the exception of rifapentine-moxifloxacin or bedaquiline-linezolid-based regimens [6,7]. However, in real-world clinical practice, one-half of patients receiving the rifapentine-moxifloxacin-based regimen prematurely discontinued the treatment [8].
Rifampicin has strong sterilizing activity against M. tuberculosis. Although this sterilizing activity increases with increasing dose [9], the dose of rifampicin remains limited to 10 mg/kg because of concerns regarding adverse events [10]. Nevertheless, doses of 20 to 35 mg/kg rifampicin have shown favorable sterilizing effects in patients without any significant safety issues, and the number of adverse events was independent of the dose [9,11]. Therefore, use of higher rifampicin doses has the potential to safely shorten the treatment duration for TB [12].
Based on these backgrounds, we performed a phase 3, multicenter, randomized, open-label non-inferiority clinical trial. The efficacy, safety, and tolerability of a three-drug therapy regimen involving high-dose rifampicin with isoniazid and pyrazinamide was compared with the standard 6-month regimen for TB.
Materials and Methods
1. Study design
We conducted a prospective, multicenter, randomized, open-label, two-arm non-inferiority clinical trial, comparing a shorter high-dose rifampicin regimen with the standard regimen. Participants were recruited from eight referral hospitals in South Korea. The study protocol was reviewed and approved by the Institutional Review Board of each institution: Seoul National University Hospital (approval number: H-2005-191-1128), Seoul National University Bundang Hospital (approval number: B-2008-628-404), Seoul Metropolitan Government Seoul National University Boramae Medical Center (approval number: 20-2020-101). National Medical Center (approval number: NMC-2007-040), Pusan National University Hospital (approval number: H-2008-005-107), Pusan National University Yangsan Hospital (approval number: 05-2020-172), Severance Hospital, Yonsei University College of Medicine (approval number: 4-2020-0755), and the Chonnam National University Hospital (approval number: CNUH-2020-243). The protocol was also approved by the Ministry of Food and Drug Safety, Republic of Korea. A Data and Safety Monitoring Board (DSMB) reviewed the data every 3 months during the trial and provided recommendations regarding protocol changes, continuation, or termination. The study is registered with ClinicalTrials.gov (NCT04485156), and the protocol has been published [13].
2. Participants
Participants aged 19 to 85 years with respiratory specimen (sputum or bronchoscopic sample) positivity by Xpert MTB/RIF assay or M. tuberculosis culture were included. Participants with drug-resistant TB or human immunodeficiency virus (HIV) were excluded. Other exclusion criteria were (1) taking any TB medications for >7 days at the time of enrollment; (2) chronic hepatitis or liver cirrhosis; (3) malignancy needing chemotherapy; (4) any contraindications for the study drugs; (5) current use of drugs contraindicated for combination with the study drugs; and (6) pregnancy, breastfeeding, or pregnancy planned within the following 6 months. All participants provided written informed consent. The participants were randomly assigned to the high-dose rifampicin regimen (investigational group) or standard regimen (control group) at a ratio of 1:1, stratified by acid-fast bacilli smear positivity and diabetes.
3. Procedure
The investigational group received high-dose rifampicin (30 mg/kg), isoniazid, and pyrazinamide until culture conversion in liquid medium was confirmed, followed by high-dose rifampicin and isoniazid for an additional 12 weeks. The control group received the standard regimen recommended by the World Health Organization [14] and in the South Korea guidelines [15] (Tables 1, 2). In case of adverse events, temporary use of secondary anti-TB drugs was permitted for up to 4 weeks.
After enrollment, the participants visited the hospital every 2 weeks until 8 weeks and every 4 weeks thereafter until the end of treatment. Mycobacterial culture using liquid medium was performed at each visit. A simple chest X-ray was conducted every 4 weeks. After the end of treatment, visits were made every 3 months until 18 months after randomization. Mycobacterial culture and chest X-ray were carried out at each visit.
4. Outcomes
The primary outcome was the proportion of unfavorable outcomes at 18 months after randomization. The secondary outcomes were time to unfavorable treatment outcomes, time to culture conversion, treatment success rate at the end of treatment, and adverse events of grade 3 or higher during the treatment.
Culture conversion was defined when two or more consecutive cultures in liquid medium were negative. If a participant could not produce sputum after the first negative culture, culture conversion was considered to have been achieved. Treatment failure was accepted when participants failed to achieve culture conversion within 6 months after randomization or the duration of secondary anti-TB drugs exceeded 4 weeks. Recurrence was determined when M. tuberculosis was isolated in sputum two or more times after the end of treatment. The sum of treatment failure, recurrence, loss to follow-up, death during treatment (except for accidents and suicide), and withdrawal from the protocol was assigned as “unfavorable outcomes” [16].
The severity of adverse events was determined in accordance with the Common Terminology Criteria for Adverse Events version 5.0 [17]. Adverse events resulting in death, life-threatening conditions, hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, or a congenital anomaly or birth defect were classified as serious adverse events.
5. Statistical analysis
The hypothesis was that the shorter high-dose rifampicin regimen was non-inferior to the standard regimen at 18 months after randomization in terms of the proportion of unfavorable outcomes. A 10% rate of unfavorable outcomes for the standard regimen [18,19] and a 0% difference from the investigational group were assumed. Using α=0.025 for significance (one-sided test), 80% power, <6% difference in unfavorable outcome rates as a non-inferiority margin, and 15% dropout rate, a total of 926 participants were planned to be enrolled in the study.
The efficacy outcomes in the trial were analyzed using both modified intention-to-treat (mITT) and per-protocol (PP) approaches, with primary consideration given to the mITT analysis. The mITT group included participants who were randomized and received the study drugs at least once. The PP group included participants in the mITT group who completed at least 20 of the 24 weeks for the standard regimen in the control group or at least 10 of the 12 weeks for the high-dose rifampicin regimen in the investigational group. A safety analysis was performed in the group of participants who received at least one dose of the investigational drugs.
For the primary outcome analysis, the frequencies of unfavorable outcomes in the control and investigational groups were analyzed. The incidence rate of unfavorable outcomes and the 95% confidence interval (CI) were estimated. For the analyses of time to unfavorable outcomes and time to culture conversion, the median times in each group were estimated using the Kaplan-Meier method and compared using the log-rank test. Treatment success rate at the end of treatment and recurrence rate were compared using the chi-square test or Fisher’s exact test. Safety was assessed by the occurrence of adverse events. The frequencies and proportions of all adverse events, serious adverse events, and adverse events of grade 3 or higher were compared using the chi-square test or Fisher’s exact test.
Results
1. Participants
Between November 4, 2020 and January 3, 2022, 79 participants were enrolled. The trial was stopped earlier than planned because participant enrollment was much slower than expected owing to the COVID-19 pandemic [20]. Enrollment was also suspended from January 24, 2021 to March 2, 2021 after 1-methyl-4-nitrosopiperazine (MNP), which has carcinogenic potential, was detected in rifampicin [21]. Therefore, based on a recommendation from the DSMB, the study enrollment was stopped on January 3, 2022.
Of the 79 participants, 76 were randomly assigned to the control group (38 participants) or investigational group (38 participants). Fifty-eight participants (7.3%) were included in the mITT analysis (32 in control group and 26 in investigational group), and 38 participants (50.0%) were included in the PP analysis (21 in control group and 17 in investigational group). Sixty-six participants (38 in control group and 28 in investigational group) who received at least one dose of the study drugs were included in the safety analysis (Figure 1).
Among the 58 participants included in the mITT analysis, 36 (62.1%) were male and the median age was 60 years (Table 3). The median treatment durations were 175.5 days (range, 14 to 360) in the control group and 97.5 days (range, 10 to 145) in the investigational group (p<0.001).
2. Efficacy
In the mITT analysis, unfavorable outcomes were reported in 10 (31.3%) of 32 participants in the control group and 10 (38.5%) of 26 participants in the investigational group. The difference between the two groups was 7.2% (95% CI, ∞ to 31.9%), and the shorter high-dose rifampicin regimen failed to show non-inferiority to the standard regimen (Table 4). In the PP analysis, no participants in the control group and one participant (5.9%) in the investigational group had unfavorable outcomes. The between-group difference was 5.9% (95% CI, ∞ to 17.1%), and the non-inferiority of the shorter regimen was not proven. The times to unfavorable outcomes did not differ in the mITT (p=0.523) and PP (p=0.266) analyses.
M. tuberculosis was isolated in liquid medium at the baseline visit in 24 (75.0%) of 32 participants in the control group and 23 (88.5%) of 26 participants in the investigational group in the mITT analysis. The time to negative culture conversion in liquid medium did not differ between the control group (14 days [95% CI, 14 to 26]) and the investigational group (14 days [95% CI, 14 to 16]) (p=0.628). Similarly, the time to negative culture conversion did not differ between the two groups in the PP analysis (p=0.563) (Figure 2).
In the mITT analysis, 28 (87.5%) of 32 participants in the control group and 24 (92.3%) of 26 participants in the investigational group achieved treatment success at the end of treatment (p=0.681). No patients in the control group and two participants in the investigational group experienced relapse after treatment (p=0.113). In the PP analysis, the treatment success rate was 100% in both groups. No significant difference was observed in terms of relapse in the PP analysis, with no patients in the control group and one participant in the investigational group experiencing relapse (p=0.266).
3. Safety
Sixty-six participants who received at least one dose of the study drugs were included in the safety analysis (38 in control group and 28 in investigational group). Thirty-four out of 66 patients (51.5%) were older than 60 years. No significant difference observed in the proportions of participants who experienced any adverse events between the control group (35 [92.1%] of 38 participants) and the investigational group (25 [89.3%] of 28 participants) (p=0.693). There were 182 adverse events reported in the control group and 105 in the investigational group. The most frequently reported adverse events were pruritus (22 cases: 14 in the control group, eight in the study group), nausea (21 cases: 13 in the control group, eight in the study group), and elevated uric acid levels (18 cases: 10 in the control group, eight in the study group). The proportions of serious adverse events and adverse events of grade 3 or more also did not differ between the two groups (Table 5). The 10 serious adverse events (six in the control group and four in the investigation group) that occurred in eight participants are shown in Table 6. No participants died during the study period.
Discussion
This trial aimed to determine whether a high-dose rifampicin regimen could shorten the treatment duration for drug-susceptible TB. The participants in the investigational group received high-dose rifampicin with isoniazid and pyrazinamide until culture conversion, followed by high-dose rifampicin and isoniazid for 12 weeks, and this regimen was compared with the standard 6-month regimen to demonstrate non-inferiority. Owing to the COVID-19 pandemic and the detection of MNP in rifampicin, the study was terminated early after enrollment of <10% of the planned participants, potentially resulting in insufficient power.
We compared predefined outcomes between the two groups. The high-dose rifampicin regimen failed to show non-inferiority in terms of unfavorable outcomes measured at 18 months after randomization. Nevertheless, the time to culture conversion, treatment success rate at the end of treatment, and safety profiles did not differ between the high-dose rifampicin regimen and the standard regimen.
Since rifampicin was first approved for treatment of TB in 1971, the dosage of rifampicin has been fixed at 10 mg/kg [10]. However, the evidence supporting this dosage is limited. When rifampicin was initially introduced, its high production cost due to its semisynthetic nature [10,22] limited attempts to use higher dose of the drug. There were also concerns regarding adverse events associated with an increased dose [10]. Consequently, the rifampicin dose has remained unchanged for a long time. Although the standard 600-mg dose of rifampicin has reduced the treatment duration for TB to 6 months, there has been no further shortening of the treatment duration [23,24].
Animal studies have shown that higher doses of rifampicin can shorten the treatment duration by enhancing the sterilizing activity [25,26]. Similarly, in patients, higher doses of rifampicin exerted sterilizing activity in a dose-dependent manner with no significant increase in adverse events [9,11,27]. Based on these findings, several clinical trials have been conducted to assess whether high-dose rifampicin can shorten the duration of TB treatment. In the TRUNCATE-TB trial, an initial 8-week regimen of high-dose rifampicin (35 mg/kg) and linezolid failed to demonstrate non-inferiority to the standard 6-month regimen [7]. Similarly, in the RIFASHORT study, administration of rifampicin at 1,200 or 1,800 mg for 4 months failed to show non-inferiority to the standard regimen [28].
In this study, high-dose rifampicin combined with isoniazid and pyrazinamide also failed to demonstrate non-inferiority to the standard regimen. The difference in unfavorable outcomes in the mITT analysis was 7.2%. Although all patients in the investigational group achieved culture conversion, two of them (6.3%) experienced relapses. Taken together, we failed to demonstrate non-inferiority in the investigational group, and there were two cases of recurrence that were not observed in the control group. Therefore, our study did not provide evidence that our high-dose rifampicin regimen could shorten the treatment duration.
However, the present study suggested that high-dose rifampicin was relatively safe in terms of adverse events. In the RIFASHORT study, grade 4 alanine transaminase increases and grade 3 or 4 bilirubin increases were more common in the group receiving 1,800 mg of rifampicin [28]. In this study, rifampicin was administered at 30 mg/kg with doses reaching up to 2,400 mg/day. Although there are concerns about the small sample size, the safety profile of the higher dose did not differ from that of the standard regimen. Hepatic adverse events occurred in three of 28 patients in the investigational group, all of which were grade 1. Four serious adverse events were reported in four patients in the investigational group, but none were related to the study drugs. These findings indicate that the safety of high-dose rifampicin may be acceptable.
High-dose rifampicin is increasingly being used to shorten the duration of latent TB. A recent study demonstrated that rifampicin at 20 mg/kg for 2 months can be safely used to treat latent TB [29]. However, there has been no reported clinical experience with high-dose rifampicin in South Korea. The safety of high-dose rifampicin demonstrated in this study may serve as a reference for future high-dose rifampicin studies in South Korea.
To properly appreciate the results of the present study, the limitations of the study should be recognized. First, the patient recruitment was stopped earlier than planned. Therefore, the failure to show non-inferiority of the high-dose rifampicin regimen could have been caused by insufficient power from the smaller sample size than calculated. Second, because of the low prevalence of HIV in South Korea (0.02% of the national population) [30], we did not enroll patients with HIV in the study. The lack of these patients could limit the generalizability of our findings.
In conclusion, although the administration of high-dose rifampicin with isoniazid and pyrazinamide until culture conversion, followed by administration of high-dose rifampicin and isoniazid for 12 weeks, failed to demonstrate non-inferiority to the standard regimen, it showed a relatively safe profile in terms of adverse events.
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