On sample size calculation in drug interaction trials.

Drug-drug interaction (DDI) trials are an important part of drug development as they provide evidence on the benefits and risks when two or more drugs are taken concomitantly. Sample size calculation is typically recommended to be based on the existence of clinically justified no-effect boundaries but these are challenging to define in practice, while the default no-effect boundaries of 0.8-1.25 are known to be overly conservative requiring a large sample size. In addition, no-effect boundaries are of little use when there is prior pharmacological evidence that a mild or moderate interaction between two drugs may be present, in which case effect boundaries would be more useful. We introduce precision-based sample size calculation that accounts for both the stochastic nature of the pharmacokinetic parameters and the anticipated width of (no-)effect boundaries, should these exist. The methodology is straightforward, requires considerably less sample size and has favorable operating characteristics. A case study on statins is presented to illustrate the ideas.

The individual-level surrogate threshold effect in a causal-inference setting with normally distributed endpoints.

In the meta-analytic surrogate evaluation framework, the trial-level coefficient of determination Rtrial2 quantifies the strength of the association between the expected causal treatment effects on the surrogate (S) and the true (T) endpoints. Burzykowski and Buyse supplemented this metric of surrogacy with the surrogate threshold effect (STE), which is defined as the minimum value of the causal treatment effect on S for which the predicted causal treatment effect on T exceeds zero. The STE supplements Rtrial2 with a more direct clinically interpretable metric of surrogacy. Alonso et al. proposed to evaluate surrogacy based on the strength of the association between the individual (rather than expected) causal treatment effects on S and T. In the current paper, the individual-level surrogate threshold effect (ISTE) is introduced in the setting where S and T are normally distributed variables. ISTE is defined as the minimum value of the individual causal treatment effect on S for which the lower limit of the prediction interval around the individual causal treatment effect on T exceeds zero. The newly proposed methodology is applied in a case study, and it is illustrated that ISTE has an appealing clinical interpretation. The R package surrogate implements the methodology and a web appendix (supporting information) that details how the analyses can be conducted in practice is provided.

On the relationship between association and surrogacy when both the surrogate and true endpoint are binary outcomes.

The relationship between association and surrogacy has been the focus of much debate in the surrogate marker literature. Recently, the individual causal association (ICA) has been introduced as a metric of surrogacy in the causal inference framework, when both the surrogate and the true endpoint are normally distributed and when both are binary. Earlier work on the normal case has demonstrated that, although the ICA and the adjusted association are related metrics, their relationship strongly depends on unidentifiable parameters and, consequently, the association between both endpoints conveys little information on the validity of the surrogate. In addition, in the normal setting, the magnitude of the ICA does not depend on the mean of the outcomes. The latter implies that identifiable parameters such as mean responses and treatment effects provide no information on the validity of the surrogate. In the present work it is shown that this is fundamentally different in the binary case. We demonstrate that the observed association between the outcomes as well as the success rates in both treatment groups are quite predictive for the ICA. It is shown that finding a good surrogate will be more likely when the association between the endpoints is large, there are sizeable treatment effects and the success rates for both endpoints are similar in both treatment groups. These results are demonstrated using extensive simulations and illustrated on a case study in multi-drug resistant tuberculosis.

Modelling Forced Vital Capacity in Idiopathic Pulmonary Fibrosis: Optimising Trial Design.

INTRODUCTION: Forced vital capacity is the only registrational endpoint in idiopathic pulmonary fibrosis clinical trials. As most new treatments will be administered on top of standard of care, estimating treatment response will become more challenging. We developed a simulation model to quantify variability associated with forced vital capacity decline. METHODS: The model is based on publicly available clinical trial summary and home spirometry data. A single, illustrative trial setting is reported. Model assumptions are 400 subjects randomised 1:1 to investigational drug or placebo over 52 weeks, 50% of each group receiving standard of care (all-comer population), and a 90-mL treatment difference in annual forced vital capacity decline. Longitudinal profiles were simulated and the impact of varying clinical scenarios evaluated. RESULTS: Power to detect a significant treatment difference was 87-97%, depending on the analysis method. Repeated measures analysis generally outperformed analysis of covariance and mixed linear models, particularly with missing data (as simulated data were non-linear). A 15% yearly random dropout rate led to 0.6-5% power loss. Forced vital capacity decline-related dropout introduced greater power loss (up to 12%), as did subjects starting/stopping standard of care or investigational drug. Power was substantially lower for a 26-week trial due to the smaller assumed treatment effect at week 26 (sample size would need doubling to reach a power similar to that of a 52-week trial). CONCLUSIONS: Our model quantifies forced vital capacity decline and associated variability, with all the caveats of background therapy, permitting robust power calculations to inform future idiopathic pulmonary fibrosis clinical trial design. FUNDING: Galapagos NV (Mechelen, Belgium).

A reflection on the possibility of finding a good surrogate.

Surrogate endpoints need to be statistically evaluated before they can be used as substitutes of true endpoints in clinical studies. However, even though several evaluation methods have been introduced over the last decades, the identification of good surrogate endpoints remains practically and conceptually challenging. In the present work, the question regarding the existence of a good surrogate is addressed using information-theoretic concepts, within a causal-inference framework. The methodology can help practitioners to assess, given a clinically relevant true endpoint and a treatment of interest, the chances of finding a good surrogate endpoint in the first place. The methodology focuses on binary outcomes and is illustrated using data from the Initial Glaucoma Treatment Study. Furthermore, a newly developed and user friendly R package Surrogate is provided to carry out the necessary calculations.

Assessing the predictive value of a binary surrogate for a binary true endpoint based on the minimum probability of a prediction error.

The individual causal association (ICA) has recently been introduced as a metric of surrogacy in a causal-inference framework. The ICA is defined on the unit interval and quantifies the association between the individual causal effect on the surrogate (ΔS) and true (ΔT) endpoint. In addition, the ICA offers a general assessment of the surrogate predictive value, taking value 1 when there is a deterministic relationship between ΔT and ΔS, and value 0 when both causal effects are independent. However, when one moves away from the previous two extreme scenarios, the interpretation of the ICA becomes challenging. In the present work, a new metric of surrogacy, the minimum probability of a prediction error (PPE), is introduced when both endpoints are binary, ie, the probability of erroneously predicting the value of ΔT using ΔS. Although the PPE has a more straightforward interpretation than the ICA, its magnitude is bounded above by a quantity that depends on the true endpoint. For this reason, the reduction in prediction error (RPE) attributed to the surrogate is defined. The RPE always lies in the unit interval, taking value 1 if prediction is perfect and 0 if ΔS conveys no information on ΔT. The methodology is illustrated using data from two clinical trials and a user-friendly R package Surrogate is provided to carry out the validation exercise.

Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial.

The emergence of multidrug resistant-tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis strains with in vitro resistance to at least isoniazid and rifampicin, has necessitated evaluation and validation of appropriate surrogate endpoints for treatment response in drug trials for MDR-TB. The trial that has demonstrated efficacy of bedaquiline, a diarylquinoline that inhibits mycobacterial ATP synthase, possesses the requisite features to conduct this evaluation. Approval of bedaquiline for use in MDR-TB was based primarily on the results of the controlled C208 Stage II study (ClinicalTrials.gov number, NCT00449644) including 160 patients randomized 1:1 to receive bedaquiline or placebo for 24 weeks when added to an 18-24-month preferred five-drug background regimen. Since randomization in C208 Stage II was preserved until study end, the trial results allow for the investigation of the complex relationship between sustained durable outcome with either Week 8 or Week 24 culture conversion as putative surrogate endpoints. The relationship between Week 120 outcome with Week 8 or Week 24 culture conversion was investigated using a descriptive analysis and with a recently developed statistical methodology for surrogate endpoint evaluation using methods of causal inference. The results demonstrate that sputum culture conversion at 24 weeks is more reliable than sputum culture conversion at 8 weeks when assessing the outcome of adding one new drug to a MDR-TB regimen.

Assessing a surrogate predictive value: a causal inference approach.

Several methods have been developed for the evaluation of surrogate endpoints within the causal-inference and meta-analytic paradigms. In both paradigms, much effort has been made to assess the capacity of the surrogate to predict the causal treatment effect on the true endpoint. In the present work, the so-called surrogate predictive function (SPF) is introduced for that purpose, using potential outcomes. The relationship between the SPF and the individual causal association, a new metric of surrogacy recently proposed in the literature, is studied in detail. It is shown that the SPF, in conjunction with the individual causal association, can offer an appealing quantification of the surrogate predictive value. However, neither the distribution of the potential outcomes nor the SPF are identifiable from the data. These identifiability issues are tackled using a two-step procedure. In the first step, the region of the parametric space of the distribution of the potential outcomes, compatible with the data at hand, is geometrically characterized. Further, in a second step, a Monte Carlo approach is used to study the behavior of the SPF on the previous region. The method is illustrated using data from a clinical trial involving schizophrenic patients and a newly developed and user friendly R package Surrogate is provided to carry out the validation exercise. Copyright © 2016 John Wiley & Sons, Ltd.

Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis.

Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo-controlled, phase 2 trial (TMC207-C208; NCT00449644). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871) reported here was conducted to confirm the safety and efficacy of bedaquiline.Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24 weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120 weeks after starting bedaquiline.Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB-related events. Adverse events were generally those commonly associated with MDR-TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120 weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively.Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB.

Multidrug-resistant tuberculosis and culture conversion with bedaquiline.

BACKGROUND: Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks. METHODS: In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline. RESULTS: Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P<0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P=0.008) and at 120 weeks (62% vs. 44%, P=0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P=0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident. CONCLUSIONS: The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.).

Antiviral activity, pharmacokinetics, and safety of the HIV-1 protease inhibitor TMC310911, coadministered with ritonavir, in treatment-naive HIV-1-infected patients.

OBJECTIVES: TMC310911 is a novel HIV type-1 (HIV-1) protease inhibitor with broad in vitro antiviral activity. In this phase 2a, open-label randomized study, the antiviral activity, pharmacokinetics, and safety and tolerability of ritonavir-boosted TMC310911 was assessed. METHODS: In this study, treatment-naive HIV-1 patients (aged 18-60 years) received 1 of the 4 dosing regimens of TMC310911: 150 mg twice-daily (bid) (n = 8), 300 mg bid (n = 8), 75 mg bid (n = 9), or 300 mg once-daily (qd) (n = 8), for 14 days, all coadministered with 100 mg of ritonavir, as only antiretroviral therapy. RESULTS: The mean change from baseline in HIV-1 RNA (log10 copies per milliliter; primary efficacy endpoint) was -1.30 (75 mg bid), -1.14 (150 mg bid), -1.07 (300 mg bid), and -1.06 (300 mg qd) on day 8 and -1.53 (75 mg bid), -1.79 (150 mg bid), -1.69 (300 mg bid), and -1.55 (300 mg qd) on day 15. At steady state (day 14), the mean maximum plasma concentration and mean area under the plasma concentration-time curve from 0 to 12 hours tended to increase dose proportionally for bid doses; TMC310911 daily exposures for the 300 mg qd treatment and 150 mg bid treatment were comparable. The most common (≥ 10%) treatment-emergent adverse events were fatigue (27.3%) and nausea (12.1%); no deaths or serious treatment-emergent adverse events were reported in this study. CONCLUSIONS: Combination treatment with TMC310911 and ritonavir showed potent antiviral activity (>1.5 log10 copies/mL decrease in plasma HIV-1 RNA) at all evaluated doses, and treatment was generally safe and well tolerated.

Safety and pharmacokinetics of the HIV-1 protease inhibitor TMC310911 coadministered with ritonavir in healthy participants: results from 2 phase 1 studies.

OBJECTIVES: To evaluate safety, tolerability, and pharmacokinetics of TMC310911, a novel human immunodeficiency virus type-1 protease inhibitor. METHODS: Healthy participants aged 18-55 years with body mass index 18-30 kg/m were enrolled in 2 phase 1 studies. In the first-in-human, single-dose study, 18 participants received placebo or TMC310911 (75-2000 mg) in the double-blind phase and 8 participants received 300 or 600 mg of TMC310911 [administered alone or with 100 mg ritonavir twice daily (bid)] in the subsequent open-label phase. The multiple-dose double-blind study included 5 successive treatment sessions wherein healthy participants received placebo or TMC310911 [300 mg bid, 600 mg once daily or 150 mg bid (plus 100 mg ritonavir bid), 900 mg bid (alone) or 300 mg bid (plus ritonavir 50 mg bid)]; in all sessions, TMC310911 and ritonavir were administered for 6 and 9 days, respectively. RESULTS: In the single-dose study, no dose-limiting toxicity was observed up to 2000 mg of TMC310911. Systemic exposure to TMC310911 generally increased in a dose-proportional manner after the single- or multiple-dose administrations. Coadministration of ritonavir increased the systemic exposure to TMC310911. The mean Cmax and area under plasma concentration-time curve values (single-dose: 1200 mg TMC310911) were higher under fasted conditions than in fed condition. In both studies, most treatment-emergent adverse events were related to gastrointestinal system. CONCLUSIONS: TMC310911 exhibited a linear pharmacokinetic profile after the single- (up to 2000 mg) and multiple-dose (up to 900 mg) administrations; ritonavir improved the pharmacokinetic profile of TMC310911. TMC310911 was generally safe and tolerable when administered with or without ritonavir.

Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial.

BACKGROUND: Antiviral activity of TMC435, an oral, once-daily, HCV NS3/4A protease inhibitor, was evaluated with pegylated interferon-α2a/ribavirin (P/R) in HCV genotype-1 patients. METHODS: Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA-1; TMC435-C201; NCT00561353) is a Phase IIa, randomized, placebo-controlled study. Treatment-naive patients (n=74) received 25, 75 or 200 mg TMC435 once daily, or placebo for 7 days followed by 21 days of triple therapy with P/R, or triple therapy for 28 days. Treatment-experienced patients (n=37; 56.8% with cirrhosis) received 75, 150 or 200 mg TMC435 once daily, or placebo with P/R for 28 days. Patients continued P/R up to week 48. RESULTS: Treatment-naive patients who received initial monotherapy had a rapid decline in HCV RNA by day 3. At day 7, HCV RNA reductions were greatest for the 75 and 200 mg doses (0.02, -2.63, -3.43 and -4.13 log(10) IU/ml for placebo, and TMC435 25, 75 and 200 mg, respectively). At day 28, all patients who received triple therapy with TMC435 75 or 200 mg had HCV RNA<25 IU/ml versus 4/9 for placebo. In total, 18/28 treatment-experienced patients (9/9 prior relapsers, 9/19 non-responders) who received TMC435 had HCV RNA<25 IU/ml at day 28 versus 0/9 for placebo; similar results were observed for the 150 and 200 mg doses. Most adverse events were grade 1/2. No relevant changes in laboratory parameters occurred, except mild and reversible bilirubin elevations, mostly at the 200 mg dose. CONCLUSIONS: Once-daily TMC435 with P/R showed potent, dose-dependent antiviral activity over 28 days, and had a favourable tolerability profile.

Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients.

BACKGROUND & AIMS: The search for targeted anti-hepatitis C virus (HCV) drugs is driven by the adverse effect profile and limited efficacy of the current standard of care (pegylated interferon-alpha/ribavirin). In a first-in-human trial, we tested the safety, tolerability, and pharmacokinetics of the macrocyclic HCV NS3/4A protease inhibitor TMC435 in healthy volunteers, followed by HCV genotype 1-infected patients to assess antiviral activity. METHODS: The TMC435350-C101 study was a phase I, randomized, double-blind, placebo-controlled trial in 49 healthy volunteers, followed by an open-label, nonplacebo-controlled panel in 6 genotype 1 hepatitis C patients. Healthy volunteers received oral, single, ascending doses (up to 600 mg) or 5-day multiple ascending doses (200 mg twice daily or 100, 200, or 400 mg once daily). Patients received 200 mg once daily for 5 days. Pharmacokinetics and safety were evaluated for all panels, and plasma HCV-RNA levels were determined in patients. RESULTS: There were no serious adverse events, no grade 3 reactions, and no treatment-related discontinuations; pharmacokinetics supported a once daily dosing regimen. Plasma HCV-RNA levels dropped rapidly in all patients, with a median maximal reduction of 3.9-log(10) IU/mL and a median of 6 days to maximal reduction. The initial steep reduction of HCV-RNA (median 3.5-log(10) IU/mL at day 3) was followed by a more gradual decline that was maintained over the dosing period. No viral breakthroughs (>1-log(10) IU/mL HCV-RNA increase from nadir) were observed during treatment nor in the 3 days posttreatment; HCV-RNA returned to pretreatment levels by week 4. CONCLUSIONS: Once daily TMC435 given orally was generally safe and well tolerated and demonstrated potent antiviral activity.

The diarylquinoline TMC207 for multidrug-resistant tuberculosis.

BACKGROUND: The diarylquinoline TMC207 offers a new mechanism of antituberculosis action by inhibiting mycobacterial ATP synthase. TMC207 potently inhibits drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro and shows bactericidal activity in patients who have drug-susceptible pulmonary tuberculosis. METHODS: In the first stage of a two-stage, phase 2, randomized, controlled trial, we randomly assigned 47 patients who had newly diagnosed multidrug-resistant pulmonary tuberculosis to receive either TMC207 (400 mg daily for 2 weeks, followed by 200 mg three times a week for 6 weeks) (23 patients) or placebo (24 patients) in combination with a standard five-drug, second-line antituberculosis regimen. The primary efficacy end point was the conversion of sputum cultures, in liquid broth, from positive to negative. RESULTS: The addition of TMC207 to standard therapy for multidrug-resistant tuberculosis reduced the time to conversion to a negative sputum culture, as compared with placebo (hazard ratio, 11.8; 95% confidence interval, 2.3 to 61.3; P=0.003 by Cox regression analysis) and increased the proportion of patients with conversion of sputum culture (48% vs. 9%). The mean log(10) count of colony-forming units in the sputum declined more rapidly in the TMC207 group than in the placebo group. No significant differences in average plasma TMC207 concentrations were noted between patients with and those without culture conversion. Most adverse events were mild to moderate, and only nausea occurred significantly more frequently among patients in the TMC207 group than among patients in the placebo group (26% vs. 4%, P=0.04). CONCLUSIONS: The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis. (ClinicalTrials.gov number, NCT00449644.)

Levetiracetam intravenous infusion as an alternative to oral dosing in patients with partial-onset seizures.

PURPOSE: This multicenter, open-label study evaluated the short-term tolerability of intravenously (IV)-infused levetiracetam (LEV; 500-1,500 mg/100 ml, 15 min, b.i.d.) as a substitute for the same oral dose. METHODS: The study consisted of screening, 4-day IV LEV and 1-7 days of follow-up, and was conducted in 25 adults with partial-onset seizures receiving adjunctive oral LEV. RESULTS: During the 4-day IV LEV, 11 (44%) subjects experienced at least one treatment-emergent adverse event (TEAE), with headache and fatigue being the most frequently reported. Five (20%) subjects experienced TEAEs considered to be related to the study drug. The tolerability profile was consistent with that of oral LEV, with all events judged mild or moderate in severity, no discontinuations, and no serious AEs or deaths reported. No AE related to seizure worsening was reported during IV LEV or brief follow-up. CONCLUSIONS: LEV IV appears to be a well-tolerated, practical alternative in patients with partial-onset seizures temporarily unable to take the drug orally.