A comparison of clinical development pathways to advance tuberculosis regimen development.

BACKGROUND: Current tuberculosis (TB) regimen development pathways are slow and in urgent need of innovation. We investigated novel phase IIc and seamless phase II/III trials utilizing multi-arm multi-stage and Bayesian response adaptive randomization trial designs to select promising combination regimens in a platform adaptive trial. METHODS: Clinical trial simulation tools were built using predictive and validated parametric survival models of time to culture conversion (intermediate endpoint) and time to TB-related unfavorable outcome (final endpoint). This integrative clinical trial simulation tool was used to explore and optimize design parameters for aforementioned trial designs. RESULTS: Both multi-arm multi-stage and Bayesian response adaptive randomization designs were able to reliably graduate desirable regimens in ≥ 95% of trial simulations and reliably stop suboptimal regimens in ≥ 90% of trial simulations. Overall, adaptive phase IIc designs reduced patient enrollment by 17% and 25% with multi-arm multi-stage and Bayesian response adaptive randomization designs respectively compared to the conventional sequential approach, while seamless designs reduced study duration by 2.6 and 3.5 years respectively (typically ≥ 8.5 years for standard sequential approach). CONCLUSIONS: In this study, we demonstrate that adaptive trial designs are suitable for TB regimen development, and we provide plausible design parameters for a platform adaptive trial. Ultimately trial design and specification of design parameters will depend on clinical trial objectives. To support decision-making for clinical trial designs in contemporary TB regimen development, we provide a flexible clinical trial simulation tool that can be used to explore and optimize design features and parameters.

Investigation of the efficacy of the short regimen for rifampicin-resistant TB from the STREAM trial.

BACKGROUND: The STREAM trial demonstrated that a 9-11-month "short" regimen had non-inferior efficacy and comparable safety to a 20+ month "long" regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation. METHODS: Firstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses. RESULTS: Cure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3-4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide. CONCLUSION: Five alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included.

Pretreatment chest x-ray severity and its relation to bacterial burden in smear positive pulmonary tuberculosis.

BACKGROUND: Chest radiographs are used for diagnosis and severity assessment in tuberculosis (TB). The extent of disease as determined by smear grade and cavitation as a binary measure can predict 2-month smear results, but little has been done to determine whether radiological severity reflects the bacterial burden at diagnosis. METHODS: Pre-treatment chest x-rays from 1837 participants with smear-positive pulmonary TB enrolled into the REMoxTB trial (Gillespie et al., N Engl J Med 371:1577-87, 2014) were retrospectively reviewed. Two clinicians blinded to clinical details using the Ralph scoring system performed separate readings. An independent reader reviewed discrepant results for quality assessment and cavity presence. Cavitation presence was plotted against time to positivity (TTP) of sputum liquid cultures (MGIT 960). The Wilcoxon rank sum test was performed to calculate the difference in average TTP for these groups. The average lung field affected was compared to log 10 TTP by linear regression. Baseline markers of disease severity and patient characteristics were added in univariable regression analysis against radiological severity and a multivariable regression model was created to explore their relationship. RESULTS: For 1354 participants, the median TTP was 117 h (4.88 days), being 26 h longer (95% CI 16-30, p < 0.001) in patients without cavitation compared to those with cavitation. The median percentage of lung-field affected was 18.1% (IQR 11.3-28.8%). For every 10-fold increase in TTP, the area of lung field affected decreased by 11.4%. Multivariable models showed that serum albumin decreased significantly as the percentage of lung field area increased in both those with and without cavitation. In addition, BMI and logged TTP had a small but significant effect in those with cavitation and the number of severe TB symptoms in the non-cavitation group also had a small effect, whilst other factors found to be significant on univariable analysis lost this effect in the model. CONCLUSIONS: The radiological severity of disease on chest x-ray prior to treatment in smear positive pulmonary TB patients is weakly associated with the bacterial burden. When compared against other variables at diagnosis, this effect is lost in those without cavitation. Radiological severity does reflect the overall disease severity in smear positive pulmonary TB, but we suggest that clinicians should be cautious in over-interpreting the significance of radiological disease extent at diagnosis.

Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis.

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).

Outcomes from patients with presumed drug resistant tuberculosis in five reference centers in Brazil.

BACKGROUND: The implementation of rapid drug susceptibility testing (DST) is a current global priority for TB control. However, data are scarce on patient-relevant outcomes for presumptive diagnosis of drug-resistant tuberculosis (pDR-TB) evaluated under field conditions in high burden countries. METHODS: Observational study of pDR-TB patients referred by primary and secondary health units. TB reference centers addressing DR-TB in five cities in Brazil. Patients age 18 years and older were eligible if pDR-TB, culture positive results for Mycobacterium tuberculosis and, if no prior DST results from another laboratory were used by a physician to start anti-TB treatment. The outcome measures were median time from triage to initiating appropriate anti-TB treatment, empirical treatment and, the treatment outcomes. RESULTS: Between February,16th, 2011 and February, 15th, 2012, among 175 pDR TB cases, 110 (63.0%) confirmed TB cases with DST results were enrolled. Among study participants, 72 (65.5%) were male and 62 (56.4%) aged 26 to 45 years. At triage, empirical treatment was given to 106 (96.0%) subjects. Among those, 85 were treated with first line drugs and 21 with second line. Median time for DST results was 69.5 [interquartile - IQR: 35.7-111.0] days and, for initiating appropriate anti-TB treatment, the median time was 1.0 (IQR: 0-41.2) days. Among 95 patients that were followed-up during the first 6 month period, 24 (25.3%; IC: 17.5%-34.9%) changed or initiated the treatment after DST results: 16/29 MDRTB, 5/21 DR-TB and 3/45 DS-TB cases. Comparing the treatment outcome to DS-TB cases, MDRTB had higher proportions changing or initiating treatment after DST results (p = 0.01) and favorable outcomes (p = 0.07). CONCLUSIONS: This study shows a high rate of empirical treatment and long delay for DST results. Strategies to speed up the detection and early treatment of drug resistant TB should be prioritized.

Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Factors associated with screening failure and study withdrawal in multidrug-resistant TB.

SETTING: Multidrug-resistant TB (MDR-TB) clinical trial in Lima, Peru and Cape Town, South Africa.OBJECTIVE: To identify baseline factors associated with screening failure and study withdrawal in an MDR-TB clinical trial.DESIGN: We screened patients for a randomized, blinded, Phase II trial which assessed culture conversion over the first 6 months of treatment with varying doses of levofloxacin plus an optimized background regimen (ClinicalTrials.gov: NCT01918397). We identified factors for screening failure and study withdrawal using Poisson regression to calculate prevalence ratios and Cox proportional hazard regression to calculate hazard ratios. We adjusted for factors with P < 0.2.RESULTS: Of the 255 patients screened, 144 (56.5%) failed screening. The most common reason for screening failure was an unsuitable resistance profile on sputum-based molecular susceptibility testing (n = 105, 72.9%). No significant baseline predictors of screening failure were identified in the multivariable model. Of the 111 who were enrolled, 33 (30%) failed to complete treatment, mostly for non-adherence and consent withdrawal. No baseline factors predicted study withdrawal in the multivariable model.CONCLUSION: No baseline factors were independently associated with either screening failure or study withdrawal in this secondary analysis of a MDR-TB clinical trial.

A systematic review of endpoint definitions in late phase pulmonary tuberculosis therapeutic trials.

BACKGROUND: Safe, more efficacious treatments are needed to address the considerable morbidity and mortality associated with pulmonary tuberculosis (TB). However, the current practice in TB therapeutics trials is to use composite binary outcomes, which in the absence of standardization may inflate false positive and negative errors in evaluating regimens. The lack of standardization of outcomes is a barrier to the identification of highly efficacious regimens and the introduction of innovative methodologies METHODS: We conducted a systematic review of trials designed to advance new pulmonary TB drugs or regimens for regulatory approval and inform practice guidelines. Trials were primarily identified from the WHO International Clinical Trial Registry Platform (ICTRP). Only trials that collected post-treatment follow-up data and enrolled at least 100 patients were included. Protocols and Statistical Analysis Plans (SAP) for eligible trials from 1995 to the present were obtained from trial investigators. Details of outcome data, both explicit and implied, were abstracted and organized into three broad categories: favorable, unfavorable, and not assessable. Within these categories, individual trial definitions were recorded and collated, and areas of broad consensus and disagreement were identified and described. RESULTS: From 2205 trials in any way related to TB, 51 were selected for protocol and SAP review, from which 31 were both eligible and had accessible documentation. Within the three designated categories, we found broad consensus in the definitions of favorable and unfavorable outcomes, although specific details were not always provided, and when explicitly addressed, were heterogeneous. Favorable outcomes were handled the most consistently but were widely variable with respect to specification. In some cases, the same events were defined differently by different protocols, particularly in distinguishing unfavorable from not assessable events. Death was often interpreted as conditional on cause. Patients who did not complete the study because of withdrawal or loss to follow-up presented a particular challenge to consistent interpretation and analytic treatment of outcomes. CONCLUSIONS: In a review of 31 clinical trials, we found that outcome definitions were heterogeneous, highlighting the need to establish clearer specification and a move towards universal standardization of outcomes across pulmonary TB trials. The ICH E9 (R1) addendum provides guidelines for undertaking and achieving this goal. PROSPERO REGISTRATION: PROSPERO CRD42020197993 . Registration 11 August 2020.

Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial.

BACKGROUND: Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. METHODS: endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. DISCUSSION: The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Cost minimization analysis of line probe assay for detection of multidrug-resistant tuberculosis in Arkhangelsk region of Russian Federation.

BACKGROUND: The development of new diagnostic tools allows for faster detection of both tuberculosis (TB) and multidrug-resistant (MDR) TB and should lead to reduced transmission by earlier initiation of anti TB therapy. The research conducted in the Arkhangelsk region of the Russian Federation in 2012-14 included economic evaluation of Line Probe Assay (LPA) implementation in MDR-TB diagnostics compared to existing culture-based diagnostics of Löwenstein Jensen (LJ) and BacTAlert. Clinical superiority of LPA was demonstrated and results were reported elsewhere. STUDY AIM: The PROVE-IT Russia study aimed to report the outcomes of the cost minimization analysis. METHODS: Costs of LPA-based diagnostic algorithm (smear positive (SSm+) and for smear negative (SSm-) culture confirmed TB patients by Bactec MGIT or LJ were compared with conventional culture-based algorithm (LJ-for SSm- and SSm+ patients and BacTAlert-for SSm+ patients). Cost minimization analysis was conducted from the healthcare system, patient and societal perspectives and included the direct and indirect costs to the healthcare system (microscopy and drug susceptibility test (DST), hospitalization, medications obtained from electronic medical records) and non-hospital direct costs (patient's travel cost, additional expenses associated with hospitalization, supplementary medicine and food) collected at the baseline and two subsequent interviews using the WHO-approved questionnaire. RESULTS: Over the period of treatment the LPA-based diagnostic corresponded to lesser direct and indirect costs comparing to the alternative algorithms. For SSm+ LPA-based diagnostics resulted in the costs 4.5 times less (808.21 US$) than LJ (3593.81 US$) and 2.5 times less than BacTAlert liquid culture (2009.61 US$). For SSm- LPA in combination with Bactec MGIT (1480.75 US$) vs LJ (1785.83 US$) showed the highest cost minimization compared to LJ (2566.09 US$). One-way sensitivity analyses of the key parameters and threshold analyses were conducted and demonstrated that the results were robust to variations in the cost of hospitalization, medications and length of stay. CONCLUSION: From the perspective of Russian Federation healthcare system, TB diagnostic algorithms incorporating LPA method proved to be both more clinically effective and less expensive due to reduction in the number of hospital days to the correct MDR-TB diagnosis and treatment initiation. LPA diagnostics comparing conventional culture diagnostic algorithm MDR-TB was a cost minimizing strategy for both patients and healthcare system.

Methodological considerations in clinical trials for new MDR-TB treatment regimens.

In contrast to the treatment of drug-susceptible tuberculosis (TB), the evidence base underpinning global guidelines for the treatment of multidrug-resistant (MDR) TB is very poor. This, combined with the lack of experience from previous trials and the nature of the disease, means that a number of methodological aspects are specific only to trials for new MDR-TB regimens. These aspects include the weight of evidence required to change policy and practice, the flexibility to make adaptations to an ongoing trial, the choice of patient population, the importance of internal control, the duration and frequency of follow-up, and safety monitoring of novel combinations of new and repurposed drugs.

Adaptive clinical trials in tuberculosis: applications, challenges and solutions.

Drug development for tuberculosis (TB) faces numerous practical obstacles, including the need for combination treatment with at least three drugs, reliance on possibly unrepresentative animal models which may not reproduce key features of human disease and the lack of a well-validated surrogate endpoint for stable cure. Pivotal Phase III trials are large, lengthy and expensive, and the funding and capacity to conduct them are limited worldwide. More rational methods for the selection of priority regimens for Phase III are urgently needed to avoid costly late-stage failures. We examine the suitability of adaptive clinical trial designs for drug development in TB, focusing on designs for Phase IIB and III trials, where we believe the biggest gains in efficiency can be made. Key areas that may be addressed by such designs are improvements in the selection of doses and combinations of drugs in early clinical development and in maximising the power of confirmatory trials in multidrug-resistant TB, where patient numbers and complexity pose practical limitations. We encourage trialists and regulators in this area to consider the advantages that may be offered by these designs and their potential to more effectively and rapidly identify better treatment regimens for TB patients worldwide.

Is a 4-month regimen adequate to cure patients with non-cavitary tuberculosis and negative cultures at 2 months?

A recent trial evaluating a 4-month regimen of standard drugs in adults with non-cavitary tuberculosis (TB) and negative cultures at 2 months failed to demonstrate equivalence compared to the same regimen given for 6 months. To contribute further evidence, data from two trials conducted by the British Medical Research Council (BMRC) comparing 4 and 6 month regimens were re-analysed. The results from the BMRC trials in patients with non-cavitary TB and negative cultures at 2 months were consistent with those from the recent trial. However, given that there was no acquired drug resistance, the estimated 6.6% relapse rate (95%CI 4.3-10.1) across all three trials might be considered acceptable for a 4-month regimen in patients with non-cavitary pulmonary TB.

Timing of relapse in short-course chemotherapy trials for tuberculosis.

We have reviewed the results from 15 tuberculosis treatment trials initiated by the British Medical Research Council between 1970 and 1983 in Africa and East Asia. Of 574 relapses, 447 (78%) occurred within 6 months of stopping treatment and 525 (91%) within 12 months. We suggest that investigators should consider terminating follow-up after the last enrolled patient completes 6 months following treatment, while continuing to follow patients enrolled earlier until that time. Compared to following all patients to 24 months, the total trial duration could be reduced by 18 months, with no increase in patient numbers in a non-inferiority design.

Radiological cavitation, sputum mycobacterial load and treatment response in pulmonary tuberculosis.

SETTING: Royal Free Hospital, London. OBJECTIVE: To investigate the relationship between sputum mycobacterial load, assessed by time to positivity (TTP) in liquid culture, radiological cavitation and change in sputum bacterial load in response to anti-tuberculosis treatment. DESIGN: The study was conducted on 95 patients treated for sputum culture-positive pulmonary tuberculosis (TB), with pre-treatment TTP and baseline chest X-ray (CXR). Of these, 31 had chest computed tomography scans assessed for number and volume of cavities. The microbiological treatment response was measured in 56 patients with serial TTP, and related to baseline radiological cavitation. RESULTS: Cavitation was present in 48% of patients, and was associated with a shorter TTP at baseline (P < 0.001). Patients with more cavities and greater total cavitary volume had a shorter TTP (P < 0.001 for both). No difference was demonstrated in the rate of change in TTP on treatment (P = 0.36) between patients with and without cavities. CONCLUSION: This study confirms that cavitation is associated with higher baseline sputum mycobacterial load. The rate of decline in bacterial load in response to treatment is similar in patients with and without radiologically demonstrable cavities, suggesting that response to, and hence duration of, effective treatment may be predicted by the initial number of organisms present in the sputum.