Optimizing (O) rifapentine-based (RI) regimen and shortening (EN) the treatment of drug-susceptible tuberculosis (T) (ORIENT) using an adaptive seamless design: study protocol of a multicenter randomized controlled trial | BMC Infectious Diseases

Study objectives

ORIENT is a phase II/III, multicenter, open-label, randomized controlled clinical trial of non-inferiority design, recruiting DS-TB patients susceptible to rifampicin, isoniazid, pyrazinamide, ethambutol, and fluoroquinolones. The purpose of this study is to a) Evaluate the safety, tolerability, and PK/PD of a high-dose rifapentine regimen; b) Evaluate whether the regimen containing high-dose rifapentine and moxifloxacin may reduce the duration of DS-TB treatment to 17 weeks; c) define the optimal dose of rifapentine in the Chinese population.

Study design

The study is composed of two stages in a seamless progression, which means only after the decision has been taken following the analysis of stage 1 primary endpoint, the participant recruitment of stage 2 will start. Figure 1 shows the flowchart of ORIENT trial. The WHO standardized regimen for DS-TB is used as a control arm for two stages.

Stage 1 corresponds to the phase II trial, aiming to evaluate the safety of investigational regimens in patients with DS-TB. Recruited participants are randomly assigned to the Short Regimen with Rifapentine 10 mg/kg, Short Regimen with Rifapentine 15 mg/kg, and Short Regimen with Rifapentine 20 mg/kg as investigational arms and the WHO Standardized Regimen as a control arm.

If at least two investigational arms meet the safety conditions in the stage 1 analysis, the two investigational arms with the higher conversion rate of liquid culture in 8 weeks and the control arm will enter stage 2. The subsequently enrolled patients will be expanded and be allocated to the 3 arms at a random ratio of 1:1:1. If only one arm meets the safety conditions in stage 1, the participants with DS-TB will be expanded and be 1:1 randomly assigned to this certain investigational arm and the control arm. If all investigational arms in stage 1 fail to meet the safety conditions, stage 2 will be canceled.

Study regimens and comparator

The rifapentine regimens are composed of two periods of 17 to 26 weeks. The first phase is an 8-week intensive phase, including rifapentine (P), isoniazid (H), pyrazinamide (Z), and moxifloxacin (M) for daily use. This is followed by a 9-week continuation phase with the following agents every day: rifapentine, isoniazid, and moxifloxacin (8wHPZM/9wHPM) (The continuation phase should be extended to maximum of 18 weeks for patients who have lung cavitation at the end of 17 weeks treatment on chest radiography or positive sputum culture in liquid medium at the end of 8 weeks treatment (8wHPZM/18wHPM)). The control regimen is the WHO standardized regimen with two phases of treatment for 26 weeks. The first is an intensive phase using rifampicin, isoniazid, pyrazinamide, and ethambutol (E) every day for 8 weeks. This is followed by a continuation phase of 18 weeks with the following agents for daily use: rifampicin and isoniazid (8wHRZE/18wHR). Table 1 shows the doses and usage of each drug in the WHO standardized regimen and the short regimen with rifapentine.

Enrollment termination criteria and safety conditions in stage 1 analysis

The primary aim of stage 1 is to choose drug regimens for the assessment of stage 2, based on the 8-week efficacy and safety endpoint evaluation. Any study arm will be terminated early when any of the following conditions are present: 1) The number of patients with serious adverse events(SAEs) related to the study drug is more than 2, and the proportion exceeds 20% of the number of enrolled people in this arm; 2) More than 1 case of liver failure or death related to the study drug and the proportion exceeds 10% of the enrolled population in this arm; 3) Other situations require discontinuation of arm decided by the Safety Reviewer Committee (SRC).

Stage 2, equivalent to a phase III trial, will expand subsequent enrollment, if the safety evaluation in stage 1 meets all the following three conditions:1) The arm has not stopped in advance due to safety; 2) The trial has been assessed as tolerable (defined as the upper bound of the 90% one-sided confidence interval of the percentage of participants permanently discontinuing treatment < 30%); 3) There is no other situation that warrants discontinuation of the study arm after the decision by the SRC.

Site selection

This trail is under the guidance of the China National Tuberculosis Defense Association, sponsored by the National Medical Center for Infectious Diseases (NMCID is a national medical center established based on Huashan Hospital, Fudan University, aiming to create a highland of medical treatment technology and improve the overall and regional medical service capacity of the country). The recruiting-cooperative units are 12 hospitals in four provinces in China, namely Huashan Hospital, Hangzhou Red Cross Hospital, Wenzhou Central Hospital, Hunan Chest Hospital, First People’s Hospital of Hangzhou Xiaoshan District, First People’s Hospital of Linping District, Guiyang Public Health Clinical Center, The Third People’s Hospital of Bijie City, People’s Hospital of Anshun City Guizhou Province, Guizhou Aerospace Hospital, Liupanshui Third People’s Hospital, Affiliated Hospital of Zunyi Medical University. The special audit team will carry out quality control for the cooperative unit every month.

Patient eligibility criteria

In addition to volunteering to participate in this clinical trial, the main eligibility criterion is pulmonary TB caused by Mycobacterium tuberculosis susceptible to rifampicin detected by molecular or phenotypic susceptibility testing. Participants must have a respiratory specimen, that is either positive for acid-fast bacilli on smear microscopy or positive for Mycobacterium tuberculosis by Xpert® MTB/RIF (Cepheid, Sunnyvale, CA, USA). Besides, patients aged between 18 to 60 years and weighed between 40 to 80 kg are eligible for the trial. An individual meeting any of the following exclusion criteria will be excluded from screening: resistance to isoniazid, pyrazinamide, ethambutol, or fluoroquinolones, and patients with extrapulmonary TB or with an extensive lesion (extent of disease greater than 50% or the aggregate diameter of all lung cavities greater than 6 cm). In addition, considering the safety of the regimen, patients will be excluded if they suffer from impaired liver function, their estimated glomerular filtration rate is smaller than 90 mL/min/1.73m², or live with human immunodeficiency virus (HIV). Patients will also be excluded if they are taking drugs that affected the efficacy or contraindications with this study drugs. Moreover, pregnant or breastfeeding women are excluded. Detailed inclusion and exclusion criteria are shown in Table 2.

Recruitment process

DS-TB patients identified by Xpert® MTB/RIF are being screened to determine whether they meet other eligibility criteria for inclusion. The screening information in this trial includes medical history, signed informed consent, results of physical examination, clinical evaluation, sputum smear, Xpert® MTB/RIF, liver function, renal function, blood routine, blood glucose, blood potassium, hepatitis B and C, HIV testing, pregnancy testing, electrocardiogram, chest radiography, and ophthalmologic examination, including assessment of visual acuity and color vision. After screening procedures, these eligible patients without evidence of resistance to isoniazid, pyrazinamide, ethambutol, and fluoroquinolones will be recruited into this trial.

Treatment allocation

Online registers will be applied to the patients satisfying the eligibility criteria. To balance the bias of each center from different regions, the randomization is conducted through the online central randomization system stratified by the study sites (sponsored by REDCap) and the presence of lung cavitation. In stage 1, participants will be 1:1:1:1 randomly assigned to the study regimens. In stage 2, if 3 regimens are enrolled, participants will be 1:1:1 randomly assigned into the 3 arms; If 2 arms are enrolled, participants will be assigned with a random ratio of 1:1.

Duration of follow-up

After screening and baseline assessment, follow-up visits will be conducted every 3 days to 2 weeks in the 8-week intensive phase, every 4 to 5 weeks until the end of treatment, every 12 to 14 weeks at the period of post-treatment until 78 weeks after treatment initiation, and the last follow-up visit is 104 weeks after treatment initiation. All patients undergo intensive monitoring of liver function and blood routine, especially for the first two weeks after the first dose. During the follow-up, physical examination, clinical assessment, weight measurement, sputum smear, sputum culture, blood routine, liver function, renal function, electrocardiogram, ophthalmologic examination, and other adjuvant examinations will be done according to schedule (the Additional file). Study enrollment began in November 2022.

Sample size assumptions

According to previous studies, the percentage of participants with regimen discontinuation at 8 weeks after the first dose is estimated to be 20%. Using the PASS 15 system (NCSS, Version: 15.0.5), we assumed α = 0.1 and β = 0.2 and calculated that a sample size of 96 cases in each group was required for safety assessment in stage 1. Considering a 4% lost follow-up rate, the number of cases per arm to show safety was calculated as 100 (400 in total).

This sample size of stage 2 was also calculated using the PASS 15 system. Assuming α = 0.05, β = 0.2, according to previous studies, the success rate of the control group was 85.4%, and the success rate of the test group was 84.5%, σ = 6.6%. If stage 2 included three arms for research, according to Bonferroni correction α₁ = α/2 = 0.025, according to PASS 15 non-inferiority test system, 618 samples were required for each arm. In consideration of 12% of patients not satisfying the criteria for microbiological eligibility and 12% of patients not being assessed, 814 patients were required for each arm, so the total sample size of the two arms was considered to be 2442. If stage 2 was divided into two arms for the study, the significance level was set as α = 0.05 with no correction required. According to the PASS15 non-inferiority test system, 487 samples per arm were required. Considering that 12% of patients did not meet the microbiological eligibility criteria and 12% of patients could not be evaluated, thus the total number was considered to be 1282 with 641 samples needed per group.

Data collection and quality management

Dedicated websites and data collection forms will be applied by collaborating hospitals or centers for research management to record data. Unique usernames and passwords will control all data access on websites, so staff only have access to the functionality and data that are appropriate for their role in the study restrictedly. The responsibility of the Central Coordinating Office (CCO) staff will be the provision of the relevant website and case report forms. The eligibility of patients and follow-up data completeness will be also checked by CCO regularly. The database will be locked after the completion of the whole follow-up schedule and data review.

Adverse event management

SRC is established in this trial to review and discuss the existing safety and efficacy data to determine whether the arm is suitable to continue to the next stage and provide professional advice on clinical management strategy. SRC is composed of a powerful clinical team of TB specialists, pulmonologists, infectious disease experts, nephrologists, psychiatrists, cardiologists, hematologists, and rheumatologists. SRC meetings are divided into regular and urgent meetings. Regular SRC meetings will be held for routine safety data review every 2 months. Any SAE must be reported by investigators to the SRC within 24 h, meanwhile, the urgent SRC meeting will be triggered to decide the execution of the related cases and treatment arms, including adjustment of anti-TB regimens, discontinuation of treatment arms, etc. AEs are defined and reported by the site investigator according to the Common Terminology Criteria for Adverse Events 5.0 (CTCAE) [26]. An SAE is classified if it led to death, life threatening, prolonged hospitalization, permanent or serious disability, malformation or congenital defect of the offspring, or required hospital admission for management. All AEs and the adjustment or withdrawal of drugs in this trial will be recorded and checked by CCO.

Assessment and analysis of outcome

The primary safety outcome of stage 1 is the proportion of participants with regimen discontinuation for safety reasons at the end of the first 8 weeks of treatment (regimen discontinuation is defined as greater than or equal to one drug permanent withdrawal from the assigned regimen). The safety outcomes measured in both stages include the AEs and SAEs assessment, the proportion of participants with grade 3 or higher AEs during the period of treatment.

The primary efficacy endpoint is the proportion of favorable outcomes at 78 weeks after the first dose for both stages. Besides, the secondary outcomes of stage 1 include liquid culture conversion rate at the 8 weeks of treatment, the proportion of participants with favorable outcomes at 104 weeks after the first dose, and incidence of acquired resistance during treatment and follow-up. The secondary outcomes of stage 2 include the percentage of participants with favorable outcomes at 104 weeks after the first dose, recurrence rate after treatment completion, proportion of sputum solid and liquid culture conversion at 8 weeks and at the end of the treatment, median time of sputum solid and liquid culture conversion, and rate of acquired resistance during treatment and follow-up.

For each participant, treatment outcomes includes favorable outcome, unfavorable outcome and not assessable outcome, as described in Table 3.

All subjects who have taken at least one dose of the treatment will be included in the safety analysis. The analysis for efficacy in this study will be conducted with modified intention-to-treat (mITT), assessable, and per-protocol populations with primary consideration for mITT results. For the primary outcome measurement in stage 2, the upper bound of the 95% confidence interval for the difference in favorable outcome between the control arm and the rifapentine arms must be less than 6.6% (the margin of non-inferiority) in the mITT populations for the rifapentine regimen to be declared non-inferior to the WHO standardized regimen.

Pharmacokinetic sampling

Sampling for pharmacokinetic analysis of anti-TB drugs is performed for all participants with rifapentine regimens in stage 1. Pharmacokinetic sampling is divided into intensive and sparse sampling, and 20 to 30 people in each rifapentine group perform intensive sampling and all other participants undergo sparse sampling.

An intensive sampling scheme includes two samplings. The first intensive sampling is at the first dose after randomization, and 4 ml venous blood is obtained at 0 h before administration and 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, and 96 h after administration, respectively. The second intensive sampling will be permitted at any time between the 11th study drug dose and the week 8 visit, and blood samples, 4 ml each, is collected over a 96-h period at the same time as the first intensive sampling. Subjects do not take any anti-TB drugs during the intensive sampling period. For patients participating in intensive sampling, the first administration is not included in the course of treatment, meaning that the treatment period begins with completing the first sampling (the fourth day of the first sampling).

Patients participating in sparse sampling are sampled during routine follow-ups between week 2 and week 8 visits. The volume of venous blood collected at each follow-up for sparse sampling is approximately 4 ml, and the collection time will be recorded. Blood specimens will be shipped to the designated laboratory, in which concentrations of moxifloxacin, rifapentine, and metabolites of rifapentine are measured.

Confidentiality

The personal information of participants is restricted to information required for the assessment of trial outcomes with laws on privacy protection and guaranteeing confidentiality. Cooperative hospitals need to have an exclusive office to lock paper documents recording participants’ data. We also conduct password-protected files to store digital documents on the website. Access to these research files is restricted to authorized personnel only.