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Background: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. Methods: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). Findings: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21–11·53, p

Starting in December 2013, West Africa was overwhelmed with the deadliest outbreak of Ebola virus known to date, resulting in more than 27,500 cases and 11,000 deaths. In response to the epidemic, development of a heterologous prime-boost vaccine regimen was accelerated and involved preparation of a phase 3 effectiveness study. While individually randomized controlled trials are widely acknowledged as the gold standard for demonstrating the efficacy of a candidate vaccine, there was considerable debate on the ethical appropriateness of these designs in the context of an epidemic. A suitable phase 3 trial must convincingly ensure unbiased evaluation with sufficient statistical power. In addition, efficient evaluation of a vaccine candidate is required so that an effective vaccine can be immediately disseminated. This manuscript aims to present the statistical and modeling considerations, design rationale and challenges encountered due to the emergent, epidemic setting that led to the selection of a cluster-randomized phase 3 study design under field conditions.

The ability to dose antiretroviral agents once daily simplifies the often complex therapeutic regimens required for the successful treatment of HIV infection. Thus, once-daily dosing can lead to improved patient adherence to medication and, consequently, sustained virological suppression and reduction in the risk of emergence of drug resistance. Several trials have evaluated once-daily darunavir/ritonavir in combination with other antiretrovirals (ARTEMIS and ODIN trials) or as monotherapy (MONET, MONOI and PROTEA trials) in HIV-1-infected adults. Data from ARTEMIS and ODIN demonstrate non-inferiority of once-daily darunavir/ritonavir against a comparator and, together with pharmacokinetic data, have established the suitability of once-daily darunavir/ritonavir for treatment-naive and treatment-experienced patients with no darunavir resistance-associated mutations. The findings of ARTEMIS and ODIN have led to recent updates to treatment guidelines, whereby once-daily darunavir/ritonavir, given with other antiretrovirals, is now a preferred treatment option for antiretroviral-naive adult patients and a simplified treatment option for antiretroviral-experienced adults who have no darunavir resistance-associated mutations. Once-daily dosing with darunavir/ritonavir is an option for treatment-naive and for treatment-experienced paediatric patients with no darunavir resistance-associated mutations based on the findings of the DIONE trial and ARIEL substudy. This article reviews the pharmacokinetics, efficacy, safety and tolerability of once-daily boosted darunavir. The feasibility of darunavir/ritonavir monotherapy as a treatment approach for some patients is also discussed. Finally, data on a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily are presented, showing comparable darunavir bioavailability to that obtained with 800/100 mg of darunavir/ritonavir once daily.

In hierarchical data settings, be it of a longitudinal, spatial, multi-level, clustered, or otherwise repeated nature, often the association between repeated measurements attracts at least part of the scientific interest. Quantifying the association frequently takes the form of a correlation function, including but not limited to intraclass correlation. Vangeneugden et al. (2010) derived approximate correlation functions for longitudinal sequences of general data type, Gaussian and non-Gaussian, based on generalized linear mixed-effects models. Here, we consider the extended model family proposed by Molenberghs et al. (2010). This family flexibly accommodates data hierarchies, intrasequence correlation, and overdispersion. The family allows for closed-form means, variance functions, and correlation function, for a variety of outcome types and link functions. Unfortunately, for binary data with logit link, closed forms cannot be obtained. This is in contrast with the probit link, for which such closed forms can be derived. It is therefore that we concentrate on the probit case. It is of interest, not only in its own right, but also as an instrument to approximate the logit case, thanks to the well-known probitlogit ‘conversion.’ Next to the general situation, some important special cases such as exchangeable clustered outcomes receive attention because they produce insightful expressions. The closed-form expressions are contrasted with the generic approximate expressions of Vangeneugden et al. (2010) and with approximations derived for the socalled logistic-beta-normal combined model. A simulation study explores performance of the method proposed. Data from a schizophrenia trial are analyzed and correlation functions derived. Financial support from the IAP research network #P6/03 of the Belgian Government (Belgian Science Policy) is gratefully acknowledged. The fourth author is supported by CNPq, a Brazilian Science Funding Agency.

This 2-part, phase 1, open-label, randomized, crossover study (NCT00752310) assessed ritonavir-boosted darunavir bioavailability (oral suspension vs. tablets), and steady-state darunavir pharmacokinetics (suspension). Part 1: 20 healthy adults randomly received 3 treatments with a ≥7-day washout between treatments; twice-daily ritonavir (100 mg, days 1-5) with darunavir (600 mg, day 3) as 2 × 300-mg tablets (fed, reference), or 6 mL of a 100-mg/mL suspension (fed or fasted, test). Part 2: 18 healthy volunteers received twice-daily darunavir (suspension, 600 mg days 1-6, one dose day 7) with twice-daily ritonavir (100 mg, days 1-9). Darunavir pharmacokinetics were evaluated (part 1 day 3; part 2 day 7). Safety/tolerability were assessed. In part 1, 90% confidence intervals for darunavir Cmax and AUC were all within 80-125% for suspension (fed or fasted) versus tablets (fed). Steady-state darunavir (suspension) pharmacokinetics in part 2 were similar to historic controls (tablets). No clinically relevant differences in adverse events or laboratory abnormalities occurred between treatments. Darunavir administered as an oral suspension or tablets (both with low-dose ritonavir) showed comparable bioavailability in healthy adults after a single dose. Steady-state darunavir pharmacokinetics (suspension, 600/100 mg twice daily) were consistent with historic controls; this formulation is considered suitable for pediatric use and for adults who cannot swallow tablets.

Background Declining incidence and spatial heterogeneity complicated the design of phase 3 Ebola vaccine trials during the tail of the 2013–16 Ebola virus disease (EVD) epidemic in West Africa. Mathematical models can provide forecasts of expected incidence through time and can account for both vaccine efficacy in participants and effectiveness in populations. Determining expected disease incidence was critical to calculating power and determining trial sample size. Methods In real-time, we fitted, forecasted, and simulated a proposed phase 3 cluster-randomized vaccine trial for a prime-boost EVD vaccine in three candidate regions in Sierra Leone. The aim was to forecast trial feasibility in these areas through time and guide study design planning. Results EVD incidence was highly variable during the epidemic, especially in the declining phase. Delays in trial start date were expected to greatly reduce the ability to discern an effect, particularly as a trial with an effective vaccine would cause the epidemic to go extinct more quickly in the vaccine arm. Real-time updates of the model allowed decision-makers to determine how trial feasibility changed with time. Conclusions This analysis was useful for vaccine trial planning because we simulated effectiveness as well as efficacy, which is possible with a dynamic transmission model. It contributed to decisions on choice of trial location and feasibility of the trial. Transmission models should be utilised as early as possible in the design process to provide mechanistic estimates of expected incidence, with which decisions about sample size, location, timing, and feasibility can be determined.

Vangeneugden et al. [15] derived approximate correlation functions for longitudinal sequences of general data type, Gaussian and non-Gaussian, based on generalized linear mixed-effects models (GLMM). Their focus was on binary sequences, as well as on a combination of binary and Gaussian sequences. Here, we focus on the specific case of repeated count data, important in two respects. First, we employ the model proposed by Molenberghs et al. [13], which generalizes at the same time the Poisson-normal GLMM and the conventional overdispersion models, in particular the negative-binomial model. The model flexibly accommodates data hierarchies, intra-sequence correlation, and overdispersion. Second, means, variances, and joint probabilities can be expressed in closed form, allowing for exact intra-sequence correlation expressions. Next to the general situation, some important special cases such as exchangeable clustered outcomes are considered, producing insightful expressions. The closed-form expressions are co...

The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25- O -desacetylrifabutin (desRFB), on day 13. The DRV and ritonavir areas under the plasma concentration-time curve from zero to 12 h (AUC 12h ) increased by 57% and 66%, respectively, in the presence of RFB. The RFB exposure was comparable between treatment with RFB QD alone (treatment B) and treatment with DRV/r plus RFB QOD (treatment C); however, based on least-square means ratios, the minimum plasma concentration ( C min ) increased by 64% and the maximum plasma concentration ( C max ) decreased by 28%, respectively. The exposure (AUC within the dosage interval and at steady state [AUC τ ]) to desRFB was considerably increased (by 881%) following treatment with DRV/r/RFB. The exposure to the parent drug plus the metabolite increased 1.6-fold in the presence of DRV/r. Adverse events (AEs) were more commonly reported during combined treatment (83% versus 44% for RFB and 28% for DRV/r); similarly, grade 3-4 AEs occurred in 17% versus 11% and 0%, respectively, of volunteers. Eighteen of 27 volunteers (66.7%) prematurely discontinued the trial; all volunteers discontinuing for safety reasons ( n = 9) did so during RFB treatment phases. These results suggest that DRV/r may be coadministered with RFB with a dose adjustment of RFB to 150 mg QOD and increased monitoring for RFB-related AEs. Based on the overall safety profile of DRV/r, no dose adjustment of DRV/r is considered to be warranted. Given the safety profile seen with the combination of RFB with a boosted protease inhibitor in this and other studies, it is not recommended to conduct further studies with this combination in healthy volunteers.

Longitudinal studies are permeating clinical trials in psychiatry. Therefore, it is of utmost importance to study the psychometric properties of rating scales, frequently used in these trials, within a longitudinal framework. However, intrasubject serial correlation and memory effects are problematic issues often encountered in longitudinal data. In the present work the authors study, via simulation, the impact of uncontrolled sources of serial correlation on newly proposed measures, designed to evaluate reliability in a longitudinal scenario. This study also addresses the relationship between serial correlation and memory effect. The simulations illustrate that ignoring serial correlation can have a severe impact on the estimates of reliability and on inferences related to it. Importantly, the authors show that the underlying modeling framework used in this new approach allows correcting for this type of correlation and avoiding bias. Moreover, it can adjust for the presence of a memory effect. Nevertheless, to achieve that, a careful model building is required. The authors disclosed receipt of the following financial support for the research and/or authorship of this article: IAP research Network P6/03 of the Belgian Government (Belgian Science Policy).

Background Long-term (96-week) efficacy and safety of the protease inhibitor (PI) darunavir coadministered with low-dose ritonavir (DRV/r) was evaluated in HIV type-1 (HIV-1)-infected patients with extensive prior treatment experience in the POWER 1, 2 and 3 trials. Methods Patients with HIV-1 RNA≥1,000 copies/ml and ≥1 primary PI mutation were randomized to receive either DRV/r 600/100 mg twice daily plus an optimized background regimen (OBR), or an investigator- selected control PI (CPI) plus OBR (POWER 3 was a DRV/r 600/100 mg twice daily single-arm study). The proportion of patients with HIV-1 RNAResults In total, 467 patients received DRV/r 600/100 mg twice daily; 124 patients received CPI(s). At week 96, 39% of DRV/r patients in POWER 1 and 2 (pooled analysis) versus 9% of CPI patients achieved HIV-1 RNA+ T-cell count increase for DRV/r at 96 weeks was 133 cells/mm3 in POWER 1 and 2 and 103 cells/mm3 in POWER 3. Grade 2–4 treatment-emergent adverse events at least possibly related to DRV/r (≥2% incidence, excluding laboratory abnormalities) were diarrhoea (3%), vomiting (3%), nausea (2%) and headache (2%). Conclusions Treatment with DRV/r 600/100 mg twice daily was well tolerated and led to sustained virological and immunological responses in treatment-experienced HIV-1-infected patients over 96 weeks.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The protease inhibitor (PI) darunavir with low-dose ritonavir (DRV/r) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) are used in combination with other antiretroviral agents and they may be co-administered for the treatment of HIV-1 infection. • There is the potential for a pharmacokinetic interaction between NVP and DRV/r, since these drugs use similar metabolic pathways. WHAT THIS STUDY ADDS • This study assesses for the first time the extent of the drug–drug interaction between NVP and DRV/r in the relevant population of HIV-1-infected patients. AIM To investigate the pharmacokinetic interaction between darunavir/ritonavir (DRV/r) and nevirapine (NVP) in 19 HIV-infected patients. METHODS An open-label, randomized, crossover study. Patients received Treatment A [NVP 200 mg b.i.d. plus ≥2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)] and Treatment B [A plus DRV/r 300/100 mg b.i.d. (DRV oral solution)] or Treatment B2 [A plus DRV/r 400/100 mg b.i.d. (DRV tablet)] in two 14-day sessions. RESULTS Mean NVP AUC12h increased by 27% [least square means ratio 1.27 (95% confidence interval 1.02, 1.58)]. Mean DRV and ritonavir exposures were similar to historical data. Co-administration was well tolerated. CONCLUSIONS DRV/r and NVP have no clinically relevant interaction. No dose adjustments are required.

Tibotec BVBA, Mechelen, BelgiumBackgroundDarunavir (TMC114) is a new HIV protease inhibitor (PI).DesignThis Phase I, randomized, open-label trial compared the effects of darunavir plus low-dose ritonavir(RTV) (darunavir/RTV) with those of atazanavir/RTV on lipid and glucose parameters.MethodsForty-nine HIV-negative, healthy male volunteers received RTV 100mg once a day (qd) for 7 days,followed by either darunavir/RTV 800/100mg qd (n525) or atazanavir/RTV 300/100mg qd (n524)for 21 days. Mean changes in fasting lipid and glucose parameters at day 28 were calculated usingpost-RTV alone (day 7) and baseline (day 1) values as references. Short-term safety, tolerabilityand RTV pharmacokinetic parameters were evaluated.ResultsAfter 7 days of RTV treatment, the mean triglyceride concentration increased by approximately30mg/dL in both groups, changes in other lipid and glucose parameters were relatively small. Meanconcentrations of lipids and glucose over the treatment period were mostly similar between thetreatment groups. Mean changes from day 7 to day 28 for the darunavir/RTV and atazanavir/RTVgroups, respectively, were 3.6 and 0.5mg/dL for high-density lipoprotein cholesterol; 5.0 and5.3mg/dL for low-density lipoprotein cholesterol; 4.9 and 1.2 mg/dL for total cholesterol; 6.4 and14.0 mg/dL for triglycerides; 1.7 and 2.4mg/dL for glucose; and 1.4 and 0.3mg/dL forinsulin. No grade 3 or 4 lipid or glucose laboratory abnormalities were reported. Treatment-emergent hyperbilirubinaemia was reported for all volunteers (including five grade 4 cases) duringatazanavir/RTV treatment.ConclusionsCo-administration of darunavir or atazanavir with low-dose RTV resulted in minor and similarchanges in lipid and glucose parameters in HIV-negative healthy volunteers.Keywords: atazanavir, darunavir, HIV, lipids, metabolic, protease inhibitors, TMC114Accepted 20 November 2008

Objective: The objective of this study was to examine the potential of once-daily dosing with darunavir/ritonavir 800/100 mg in a HIV-infected, treatment-experienced patient population with no baseline darunavir resistance-associated mutations (RAMs). Methods: Patients in the randomized controlled POWER 1 and 2 trials were treatment experienced, with ≥1 International AIDS Society-USA primary protease inhibitor (PI) mutation. The virological and immunological responses in patients with no baseline darunavir RAMs receiving darunavir/r 800/100 mg once daily (n = 23), darunavir/r 600/100 mg twice daily (n = 29), or currently available PI(s) (n = 28) plus an optimized background regimen were compared. Results: The proportion of patients achieving HIV RNA

Longitudinal studies are permeating clinical trials in psychiatry. Additionally, in the same field, rating scales are frequently used to evaluate the status of the patients and the efficacy of new therapeutic procedures. There- fore, it is of utmost importance to study the psychometric properties of these instruments within a longitudinal framework. In the area of depression, the Hamilton Depression Rating Scale (HAMD) is regularly used for antidepres- sant treatment evaluation. However, the use of HAMD has not been exempted from criticism what has lead to the development of new scales that are ex- pected to be more sensitive for change, such as the Montgomery-°Asberg De- pression Rating Scale (MADRS). In general, the reliability of these scales has been extensively studied by using classical methods for reliability estimation, developed for specifically designed reliability studies. Unfortunately, the set- tings customarily considered in these reliability studies are usually far from the practical conditions in which these scales are applied in clinical trials and practice. In the present paper we assess the reliability of these instruments in a more realistic scenario thereby using longitudinal data coming from clinical studies. Nowadays, newly developed methodology based on an extended con- cept of reliability, allow us to use longitudinal data for reliability estimation..... Funding Agency: Belgian IUAP/PAI network "Statistical Techniques and Modeling for Complex Substantive Questions with Complex Data"

This work investigates how generalizability, an extension of reliability, can be defined and estimated based on longitudinal data sequences resulting from, for example, clinical studies. Useful and intuitive approximate expressions are derived based on generalized linear mixed models. Data from four double-blind, randomized clinical trials into schizophrenia motivate the research and are used to estimate generalizability for a binary response parameter. The authors are thankful to J&J PRD for their kind permission to use their data. Financial support from the IAP research network #P6/03 of the Belgian Government (Belgian Science Policy) is gratefully acknowledged.

Background An open-label, randomized, crossover study was performed to investigate the effect of multiple doses of darunavir co-administered with low-dose ritonavir (DRV/r) on the steady-state pharmacokinetics of the oral contraceptives ethinyl estradiol (EE) and norethindrone (NE) (commercial name of the combined drug Ortho-Novum 1/35) in 19 HIV-negative healthy women. Methods In session 1, participants received 35 μg EE and 1.0 mg NE from days 1 to 21. In session 2, participants received the same oral contraceptive treatment as in session 1 on days 1 to 21 plus DRV/r (600 mg/100 mg twice daily) on days 1 to 14. Pharmacokinetic assessments were performed on day 14 for each session. Results Steady-state systemic exposure to EE and NE decreased when DRV/r was co-administered, based on the ratio of least square means of the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), and the area under the curve (AUC24h) of EE (which decreased by 62%, 32% and 44%, respectively) and NE (which decreased by 30%, 10% and 14%, respectively) compared with administration of EE and NE alone. Five participants discontinued the study due to grade 2 cutaneous events, as required per protocol, during treatment with EE and NE in combination with DRV/r. There were no clinically relevant findings for laboratory and cardiovascular parameters. Conclusions The pharmacokinetic interaction observed here is considered to be clinically relevant as EE concentrations are considerably reduced when DRV/r is co-administered with EE and NE. Alternative or additional contraceptive measures should be used when oestrogen-based contraceptives are co-administered with DRV/r.

The resistance profile of darunavir (TMC114) in treatment-experienced patients was explored using pooled week 24 data from POWER 1, 2, and 3 at the recommended dose of darunavir with low-dose ritonavir (darunavir/r, 600/100 mg bid, N = 458). Baseline darunavir fold change in EC(50) was a strong predictor of virological response at week 24. Preliminary phenotypic clinical cut-offs of 10 and 40 were established. Virological response to darunavir/r was maintained in the presence at baseline of a high number of IAS-USA PI resistance-associated mutations (IAS-USA PI RAMS); a diminished response occurred with >or=14. Eleven protease mutations associated with diminished darunavir/r virological response were identified (V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V). These darunavir resistance-associated mutations (DRV RAMS) occurred in the presence of a high number of IAS-USA PI RAMS. Virological response was diminished with three or more DRV RAMS in the background of a high number of IAS-USA PI RAMS. Incremental numbers of DRV RAMS were more predictive of outcome than were IAS-USA PI RAMS. Mutations developing during darunavir/r virological failure (V32I, L33F, I47V, I54L, and L89V) were also featured in the DRV RAMS list. Site-directed mutants carrying these five mutations, or any one of these mutations either alone or together with one or two IAS-USA PI RAMS, showed no reduced darunavir susceptibility, suggesting that a high number of additional background mutations is required for darunavir resistance. In this population of treatment-experienced patients, darunavir/r demonstrated significantly greater efficacy than investigator-selected control PIs of trials POWER 1 and 2, regardless of baseline viral genotype or phenotype, while exhibiting a high genetic barrier to the development of resistance.

This was an open-label, crossover study to investigate the pharmacokinetic interaction between darunavir (TMC114), coadministered with low-dose ritonavir (darunavir/ritonavir), and the protease inhibitor saquinavir in HIV-negative healthy volunteers. Thirty-two volunteers were randomized into two cohorts (panel 1 and panel 2). In two separate sessions, panel 1 received 400/100 mg darunavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day; panel 2 received 1000/100 mg saquinavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day. All treatments were administered orally under fed conditions for 13 days with an additional single morning dose on day 14. Treatment sessions were separated by a washout period of at least 14 days. Twenty-six volunteers completed the study (n=14, panel 1; n=12, panel 2), whereas six discontinued as a result of adverse events. Coadministration of saquinavir with darunavir/ritonavir resulted in decreases of darunavir area under the curve and maximum and minimum plasma concentrations of 26%, 17%, and 42%, respectively, compared with administration of darunavir/ritonavir alone. Relative to treatment with saquinavir/ritonavir alone, saquinavir exposure was not significantly different with the addition of darunavir. Ritonavir area under the curve12h increased by 34% when saquinavir was added to treatment with darunavir/ritonavir. The coadministration of darunavir/saquinavir/ritonavir was generally well tolerated. Similar findings are expected with the approved 600/100 mg darunavir/ritonavir twice-a-day dose. The combination of saquinavir and darunavir/ritonavir is currently not recommended.

It is shown how hierarchical biomedical data, such as coming from longitudinal clinical trials, meta-analyses, or a combination of both, can be used to provide evidence for quantitative strength of reliability, agreement, generalizability, and related measures that derive from association concepts. When responses are of a continuous, Gaussian type, the linear mixed model is shown to be a versatile framework. At the same time, the framework is embedded in the generalized linear mixed models, such that non-Gaussian, e.g., binary, outcomes can be studied as well. Similarities and, above all, important differences are studied. All developments are exemplified using clinical studies in schizophrenia, with focus on the endpoints Clinician's Global Impression (CGI) or Positive and Negative Syndrome Scale (PANSS).

BACKGROUND The ongoing phase IIb POWER 1 (TMC114-C213) trial is designed to assess efficacy and safety of the protease inhibitor (PI) TMC114 (darunavir) in treatment-experienced HIV-1-infected patients. DESIGN This randomized, partially blinded, 24-week dose-finding study compared efficacy and safety of four doses of TMC114 plus low-dose ritonavir (TMC114/r) with investigator-selected control PI(s) (CPI[s]). METHODS Patients with one or more primary PI mutation and HIV RNA > 1000 copies/ml received optimized background therapy, plus TMC114/r 400/100 mg once daily, 800/100 mg once daily, 400/100 mg twice daily or 600/100 mg twice daily, or CPI(s). The primary endpoint (intent-to-treat) compared proportions of patients achieving viral load reduction >or= 1.0 log10 copies/ml from baseline. RESULTS In total, 318 patients were treated. Baseline mean viral load was 4.48 log10 copies/ml; median CD4 cell count was 179 cells/microl. In the CPI arm 62% of patients discontinued (virological failure: 54%); 10% of TMC114/r patients discontinued. More TMC114/r (69-77%) than CPI patients (25%) reached the primary endpoint (P < 0.001); 43-53% of TMC114/r patients and 18% of the CPI arm achieved viral load < 50 copies/ml (P < 0.001). TMC114/r demonstrated greater mean CD4 cell count increases versus CPI(s) (68-124 versus 20 cells/microl; P < 0.05). TMC114/r 600/100 mg twice daily demonstrated the highest virological and immunological responses. Adverse event incidence was similar between treatments; headache and diarrhoea were more common with CPI(s). CONCLUSIONS TMC114/r demonstrated statistically higher 24-week virological response rates and CD4 cell count increases than CPI(s). TMC114/r 600/100 mg twice daily has received regulatory approval in treatment-experienced patients.

Background and objective: To investigate the potential for pharmacokinetic interactions between the protease inhibitors darunavir (DRV, TMC114) coadministered with low-dose ritonavir (darunavir/r), and atazanavir in HIVnegative, healthy volunteers. Methods: This was an open-label, randomised, three-period, crossover study. Darunavir/r (400/100mg twice daily), atazanavir/r (300/100mg once daily) or darunavir/r (400/100mg twice daily) plus atazanavir (300mg once daily) were administered in three separate sessions, with a washout period of at least 7 days between regimens. The follow-up lasted 30 days. Twenty-three healthy volunteers participated. Pharmacokinetic assessments were performed at steady-state on day 7. Plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were compared between treatments. The safety and tolerability of the study medications were monitored throughout. Results: Darunavir pharmacokinetics were unaffected by atazanavir. No change in overall exposure to atazanavir was observed during coadministration with darunavir/r. However, there was a 52% increase in minimum atazanavir plasma concentration (least squares mean ratio [90% CI 0.99, 2.34]). Mean systemic exposure to ritonavir was increased by 65% and 106%, respectively, with the combination treatment compared with darunavir/r alone or atazanavir/r alone. There were no apparent differences in mean changes in lipids between the darunavir/r, atazanavir/r or darunavir/r plus atazanavir regimens. Hyperbilirubinaemia and ocular icterus were reported with atazanavir-containing regimens. Conclusion: Atazanavir at a dose of 300mg once daily can be coadministered with a darunavir/r twice-daily regimen without any dose adjustment if there is a clinical need to combine darunavir/r and atazanavir in HIV-1-infected patients.

Part of the recent literature on the evaluation of biomarkers as surrogate endpoints starts from a multitrial context, which leads to a definition of validity in terms of the quality of both trial-level and individual-level association between the surrogate and true endpoints (Buyse et al., 2000, Biostatistics1, 49-67). These authors concentrated on cross-sectional continuous responses. However, in many randomized clinical studies, repeated measurements are encountered on either or both endpoints. A challenge in this setting is the formulation of a simple and meaningful concept of "surrogacy."Alonso et al. (2003, Biometrical Journal45, 931-945) proposed the variance reduction factor (VRF) to evaluate surrogacy at the individual level. They also showed how and when this concept should be extended to study surrogacy at the trial level. Here, we approach the problem from the natural canonical correlation perspective. We define a class of canonical correlation functions that can be used to study surrogacy at the trial and individual level. We show that the VRF and the R2 measure defined by Buyse et al. (2000) follow as special cases. Simulations are conducted to evaluate the performance of different members of this family. The methodology is illustrated on data from a meta-analysis of five clinical trials comparing antipsychotic agents for the treatment of chronic schizophrenia.

Repeated measures are exploited to study reliability in the context of psychiatric health sciences. It is shown how test-retest reliability can be derived using linear mixed models when the scale is continuous or quasi-continuous. The advantage of this approach is that the full modeling power of mixed models can be used. Repeated measures with a different mean structure can be used to usefully study reliability, correction for covariate effects is possible, and a complicated variance-covariance structure between measurements is allowed. In case the variance structure reduces to a random intercept (compound symmetry), classical methods are recovered. With more complex variance structures (e.g., including random slopes of time and/or serial correlation), time-dependent reliability functions are obtained. The methodology is motivated by and applied to data from five double-blind randomized clinical trials comparing the effects of risperidone to conventional antipsychotic agents for the treatment of chronic schizophrenia. Model assumptions are investigated through residual plots and by investigating the effect of influential observations.

Longitudinally observed quality of life data with large amounts of drop-out are analysed. First we used the selection modelling framework, frequently used with incomplete studies. An alternative method consists of using pattern-mixture models. These are also straightforward to implement, but result in a different set of parameters for the measurement and drop-out mechanisms. Since selection models and pattern-mixture models are based upon different factorizations of the joint distribution of measurement and drop-out mechanisms, comparing both models concerning, for example, treatment effect, is a useful form of a sensitivity analysis.

In the TORO, RESIST and POWER trials, the HIV-RNA < 50 copy endpoint showed the strongest durability over time, whereas HIV-RNA reductions of more than 1 log 10 or below 400 copies/ml were less sustained during 48 weeks of treatment. Clinical trials of new antiretroviral drugs in highly experienced patients also show high rates of HIV-RNA suppression below 50 copies/ml. HIV-RNA suppression below 50 copies/ml should now become the standard efficacy endpoint across trials of both naive and experienced patients.

Objectives. To compare the efficacy of oral liarozole, the first retinoic acid metabolism-blocking agent (RAMBA) to be developed as differentiation therapy for human solid tumors, with that of cyproterone acetate (CPA), an antiandrogen for the treatment of metastatic prostate cancer. Liarozole promotes differentiation of cancer cells by increasing the intratumoral levels of retinoic acid. Methods. A total of 321 patients with metastatic prostate cancer in relapse after first-line endocrine therapy entered a Phase III international multicenter study (recruitment from February 1992 to August 1994) comparing liarozole (300 mg two times daily) with CPA (100 mg two times daily). Results. Accounting for differences in baseline prognostic factors, the adjusted hazard ratio for survival was 0.74 in favor of liarozole (P = 0.039), indicating a 26% lower risk of death than in patients treated with CPA. Median crude (unadjusted) survival time was the same in the liarozole group as in the CPA group (10.3 months). More patients showed a PSA response (at least 50% reduction in PSA from baseline) when treated with liarozole (20%) than with CPA (4%) (P < 0.001). Prostate-specific antigen (PSA) responders had a median survival benefit of 10 months over nonresponders, irrespective of treatment (hazard ratio 0.43; P = 0.0018). PSA response was apparent within 3 months in approximately 90% of patients who responded. Pain improved more in the liarozole group than in the CPA group (P = 0.03). PSA responders had lower median pain scores than nonresponders (1.7 versus 2.5) and better quality of life (median Functional Living Index-Cancer score 108 versus 98) at end point, ie, treatment discontinuation, as well as throughout the treatment period. Among the most frequently occurring adverse events in the liarozole group were dry skin (51% of patients), pruritus (25%), rash (16%), nail disorders (16%), and hair loss (15%). These adverse events were generally mild to moderate in severity and did not affect the overall quality of life score. There were no detectable effects of either treatment on vital signs such as blood pressure, heart rate, electrocardiogram, and body weight. Conclusions. Liarozole is superior to CPA in terms of PSA response, PSA progression, and survival, and is capable of maintaining patients’ quality of life. The observed adverse events were mild to moderate in nature. These results show that liarozole is a possible treatment option after first-line endocrine therapy has failed.

This 2-part, phase 1, open-label, randomized, crossover study (NCT00752310) assessed ritonavir-boosted darunavir bioavailability (oral suspension vs. tablets), and steady-state darunavir pharmacokinetics (suspension). Part 1: 20 healthy adults randomly received 3 treatments with a ≥7-day washout between treatments; twice-daily ritonavir (100 mg, days 1-5) with darunavir (600 mg, day 3) as 2 × 300-mg tablets (fed, reference), or 6 mL of a 100-mg/mL suspension (fed or fasted, test). Part 2: 18 healthy volunteers received twice-daily darunavir (suspension, 600 mg days 1-6, one dose day 7) with twice-daily ritonavir (100 mg, days 1-9). Darunavir pharmacokinetics were evaluated (part 1 day 3; part 2 day 7). Safety/tolerability were assessed. In part 1, 90% confidence intervals for darunavir Cmax and AUC were all within 80-125% for suspension (fed or fasted) versus tablets (fed). Steady-state darunavir (suspension) pharmacokinetics in part 2 were similar to historic controls (tablets). No clinically relevant differences in adverse events or laboratory abnormalities occurred between treatments. Darunavir administered as an oral suspension or tablets (both with low-dose ritonavir) showed comparable bioavailability in healthy adults after a single dose. Steady-state darunavir pharmacokinetics (suspension, 600/100 mg twice daily) were consistent with historic controls; this formulation is considered suitable for pediatric use and for adults who cannot swallow tablets.

Background: Once-daily (qd) darunavir/ritonavir (DRV/r) 800/100mg was evaluated in two randomised and controlled Phase III trials, showing high response rates in treatment-naive (ARTEMIS; TMC114-C211) and treatment-experienced patients with no DRV resistance-associated mutations (ODIN; TMC114-C229). Treatment interruptions, medical co-morbidities, drug-drug interactions, and challenges to adherence can decrease exposures and result in suboptimal DRV coverage. Consequences of suboptimal dosing could be detrimental to patients, namely the selection of drug-resistant HIV strains. No relevant relationship between DRV area under the plasma concentration-time curve over 24 hours (AUC 24h ) or plasma trough concentrations (C 0h ) and efficacy or safety were observed in ARTEMIS or ODIN [1,2]. The PK/PD analysis for efficacy has been extended using a generalized additive model (GAM). Methods: A univariate GAM analysis was undertaken for each trial, exploring the relationship between DRV C 0h and virological response at Week 48. A quadratic spline (2 degrees of freedom) was selected, based on the Akaike information criterion value. Additionally, a linear logistic regression model was applied to model virologic response as a function of DRV C 0h . Results: In ARTEMIS, there was no relationship between DRV C 0h and the observed virological response or virological response predicated in the GAM analysis, with no indication that lower values within the observed DRV C 0h range are associated with lower predicted virological response (Figure A). The mean predicted virological response was 92.8% in the total population (N=304). A 50% reduction in DRV C 0h would result in a similar predicted mean virological response (93.9%). In ODIN, for values of DRV C 0h up to 3000ng/mL, there was no clear relationship between DRV C 0h and observed virological response. The GAM analysis showed a counter-intuitive inverse relationship between DRV C 0h and predicted virological response (Figure B). The mean predicted virological response was 80.6% in the total population (N=252). For each trial, similar results to GAM were obtained when a linear logistic regression model was applied. Conclusion: In patients who received 800/100mg qd DRV/r in the ARTEMIS and ODIN trials, a reduction in DRV C 0h of up to 50% is not associated with a reduced virologic response at Week 48, as predicted by both the GAM and logistic regression model. DRV/r doses below 800/100mg qd should not be administered. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Kakuda T et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18338 http://www.jiasociety.org/index.php/jias/article/view/18338 | http://dx.doi.org/10.7448/IAS.15.6.18338

This work aims at investigating marginal correlation within and between longitudinal data sequences. Useful and intuitive approximate expressions are derived based on generalized linear mixed models. Data from four double-blind randomized clinical trials are used to estimate the intra-class coefficient of reliability for a binary response. Additionally, the correlation between such a binary response and a continuous response is derived to evaluate the criterion validity of the binary response variable and the established continuous response variable. Financial support from the IAP research network #P6/03 of the Belgian Government (Belgian Science Policy) is gratefully acknowledged.

P>The reliability of multi-item scales has received a lot of attention in the psychometric literature, where a myriad of measures like the Cronbach's alpha or the Spearman-Brown formula have been proposed. Most of these measures, however, are based on very restrictive models that apply only to unidimensional instruments. In this article, we introduce two measures to quantify the reliability of multi-item scales based on a more general model. We show that they capture two different aspects of the reliability problem and satisfy a minimum set of intuitive properties. The relevance and complementary value of the measures is studied and earlier approaches are placed in a broader theoretical framework. Finally, we apply them to investigate the reliability of the Positive and Negative Syndrome Scale, a rating scale for the assessment of the severity of schizophrenia. We are grateful to J&J PRD for the data. We gratefully acknowledge support from Belgian IUAP/PAI network "Statistical Techniques and Modeling for Complex Substantive Questions with Complex Data."

OBJECTIVE: Characterization of resistance development in virologic failure patients on the protease inhibitor darunavir administered with low-dose ritonavir (DRV/r) in the 48-week analysis of TMC114/r In Treatment-experienced pAtients Naive to lopinavir (TITAN). DESIGN: TITAN is a randomized, controlled, open-label, phase III, noninferiority trial comparing the efficacy and safety of DRV/r with that of lopinavir/ritonavir (LPV/r) in HIV-1-infected, treatment-experienced, LPV-naive patients. The primary endpoint was the proportion of patients with HIV-1 RNA less than 400 copies/ml at week 48. METHODS: Patients received DRV/r 600/100 mg twice daily (n = 298) or LPV/r 400/100 mg twice daily (n = 297), and an optimized background regimen. Patients who lost or never achieved HIV-1 RNA less than 400 copies/ml after week 16 were considered virologic failure patients. Genotyping and phenotyping were performed. RESULTS: The virologic failure rate in the DRV/r arm (10%, n = 31) was lower than in the LPV/r arm (22%, n = 65). Furthermore, fewer virologic failure patients in the DRV/r arm than in the LPV/r arm developed primary protease inhibitor mutations (6 vs. 20) or nucleoside reverse transcriptase inhibitor resistance-associated mutations (4 vs. 15). In addition, fewer virologic failure patients on DRV/r than on LPV/r lost susceptibility to the protease inhibitor (3 vs. 13) or nucleoside reverse transcriptase inhibitor(s) (3 vs. 14) used in the treatment regimen or to other protease inhibitors. Most DRV/r-treated virologic failure patients retained susceptibility to all protease inhibitors. CONCLUSION: In treatment-experienced, LPV-naive patients, the overall virologic failure rate in the DRV/r arm was low and was associated with limited resistance development. These findings showed that the use of DRV/r in earlier lines of treatment was less likely to lead to cross-resistance to other protease inhibitors compared with LPV/r.

Objective: To investigate the potential for a pharmacokinetic interaction between darunavir (DRV, TMC114, Prezista®), indinavir (IDV, Crixivan®) and low-dose ritonavir (RTV, Norvir®). Methods: In three 7-day sessions, 17 HIV-negative healthy volunteers received treatment A (DRV/r 400/100 mg b.i.d.), treatment B (IDV/r 800/100 mg b.i.d.) and treatment C (DRV/r 400/100 mg b.i.d. + IDV 800 mg b.i.d.). On day 7, full pharmacokinetic profiles of DRV, IDV and RTV were determined. Safety and tolerability were also assessed. Results: Based on the least-squares means ratios, the steady-state exposure (area under the curve, AUC12h) and plasma concentrations (Cmin and Cmax) of IDV were increased by 23, 125 and 8%, respectively, when DRV was co-administered. The co-administration of IDV with DRV/r resulted in increases of 24, 44 and 11% for, respectively, DRV AUC12h, Cmin and Cmax, compared with administration of DRV/r alone. Eight volunteers discontinued due to an adverse event. Overall, adverse events and laboratory abnormalities were more commonly reported during treatments including IDV. Conclusions: When used in combination with DRV/r, dose adjustment of IDV from 800 mg b.i.d. to 600 mg b.i.d. may be warranted in cases of intolerance.

The concept of reliability denotes one of the most important psychometric properties of a measurement scale. Reliability refers to the capacity of the scale to discriminate between subjects in a given population. In classical test theory, it is often estimated by using the intraclass correlation coefficient based on two replicate measurements. However, the modelling framework that is used in this theory is often too narrow when applied in practical situations. Generalizability theory has extended reliability theory to a much broader framework but is confronted with some limitations when applied in a longitudinal setting. We explore how the definition of reliability can be generalized to a setting where subjects are measured repeatedly over time. On the basis of four defining properties for the concept of reliability, we propose a family of reliability measures which circumscribes the area in which reliability measures should be sought. It is shown how different members assess different aspects of the problem and that the reliability of the instrument can depend on the way that it is used. The methodology is motivated by and illustrated on data from a clinical study on schizophrenia. On the basis of this study, we estimate and compare the reliabilities of two different rating scales to evaluate the severity of the disorder. The authors gratefully acknowledge support from the Belgian Interuniversity Attraction Polenetwork ‘Statistical techniques and modelling for complex substantive questions with complexdata’.

BACKGROUND The present primary analysis of AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS) compares the efficacy and safety of once-daily darunavir/ritonavir (DRV/r) with that of lopinavir/ritonavir (LPV/r) in treatment-naive patients. METHODS Patients with HIV-1 RNA at least 5000 copies/ml were stratified by HIV-1 RNA and CD4 cell count in a phase III, open-label trial, and randomized to receive DRV/r 800/100 mg qd or LPV/r 800/200 mg total daily dose (bid or qd) plus fixed-dose tenofovir and emtricitabine for 192 weeks. The primary objective was to demonstrate non-inferiority of DRV/r as compared with LPV/r in HIV-1 RNA less than 50 copies/ml per-protocol time-to-loss of virologic response at 48 weeks. RESULTS Six hundred and eighty-nine patients were randomized and treated; mean baseline HIV-1 RNA: 4.85 log10 copies/ml and median CD4 count: 225 cells/microl. At 48 weeks, 84% of DRV/r and 78% of LPV/r patients achieved HIV-1 RNA less than 50 copies/ml (estimated difference = 5.6 [95% confidence interval -0.1-11]%), demonstrating non-inferiority of DRV/r as compared with LPV/r (P < 0.001; per-protocol time-to-loss of virologic response). Patients with HIV-1 RNA at least 100 000 copies/ml had a significantly higher response rate with DRV/r (79%) versus LPV/r (67%; P < 0.05). Median CD4 cell count increases (non-completer = failure; cells/mul) were 137 for DRV/r and 141 for LPV/r. DRV/r had a lower incidence of possibly treatment-related grade 2-4 gastrointestinal-related adverse events (7 versus 14%) and treatment-related moderate-to-severe diarrhea (4 versus 10%) than LPV/r. Adverse events leading to discontinuation were DRV/r: 3% and LPV/r: 7%. CONCLUSION DRV/r 800/100 mg qd was non-inferior to LPV/r 800/200 mg at 48 weeks, with a more favorable safety profile. Significantly higher response rates were observed with DRV/r in patients with HIV-1 RNA at least 100 000 copies/ml. DRV/r 800/100 mg offers a new effective and well tolerated once-daily, first-line treatment option for treatment-naive patients.

Background and objectives: Darunavir (DRV, TMC114) is a novel protease inhibitor administered in combination with low-dose ritonavir (DRV/r) and is highly active against both wild-type and multidrug-resistant HIV-1 strains. Sildenafil is an oral therapy for erectile dysfunction. Concomitant administration of protease inhibitors and sildenafil increases sildenafil plasma concentrations. The potential for a pharmacokinetic drug interaction exists when sildenafil and DRV/r are co-administered, as these drugs are primarily metabolized by cytochrome P450 (CYP) 3A, and darunavir and ritonavir are CYP3A inhibitors. The primary objective of this open-label, crossover, phase I study was to assess the effect of multiple doses of DRV/r on the pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil. The secondary objective was to assess the short-term safety and tolerability of co-administration of sildenafil and DRV/r. Methods: Sixteen HIV-negative healthy male subjects were randomized to one of two sequences. In two sessions each subject received treatments A and B. In treatment A, a single dose of sildenafil 100 mg was administered. In treatment B, the subjects received DRV/r 400/100 mg twice daily for 8 days and on day 7 a single dose of sildenafil 25 mg was co-administered. Full pharmacokinetic profiles of sildenafil, N-desmethyl sildenafil, darunavir and ritonavir were determined. Safety and tolerability were also assessed. Results: Sildenafil exposure (area under the plasma concentration-time curve [AUC]) was comparable between the two treatments despite administration of a lower dose of sildenafil (25 mg) with DRV/r than when sildenafil (100 mg) was administered alone. When sildenafil 25 mg was co-administered with DRV/r, the sildenafil maximum plasma concentration (Cmax) was 38% lower compared with Cmax after administration of sildenafil alone at a dose of 100 mg. N-desmethyl sildenafil Cmax and AUC from the time of administration until the last time point with a measurable concentration after dosing (calculated by linear trapezoidal summation [AUClast]) values decreased by approximately 95% when sildenafil 25 mg was co-administered with DRV/r compared with sildenafil 100 mg alone. Combined treatment with DRV/r and sildenafil was generally safe and well tolerated. Conclusion: Sildenafil exposure is increased in the presence of DRV/r. In this setting, a dose adjustment for sildenafil is warranted; no more than 25 mg of sildenafil is recommended over a 48-hour period when co-administered with DRV/r.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system. • Co-administration of ketoconazole and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs, which could increase or prolong both therapeutic and adverse effects. • Therefore, unless otherwise specified, appropriate dosage adjustments may be necessary. WHAT THIS PAPER ADDS • The current study was conducted to determine the extent of interaction between the potent CYP3A inhibitor, ketoconazole, and the CYP 3A substrate, darunavir (given alone and with low-dose ritonavir). • This information provides data on the pharmacokinetic boosting ability of ketoconazole and serves as important guidance to HIV-infected patients and their treating physicians with regard to appropriate (co-)administration of darunavir/ritonavir and ketoconazole. Aims To investigate the interaction between ketoconazole and darunavir (alone and in combination with low-dose ritonavir), in HIV–healthy volunteers. Methods Volunteers received darunavir 400 mg bid and darunavir 400 mg bid plus ketoconazole 200 mg bid, in two sessions (Panel 1), or darunavir/ritonavir 400/100 mg bid, ketoconazole 200 mg bid and darunavir/ritonavir 400/100 mg bid plus ketoconazole 200 mg bid, over three sessions (Panel 2). Treatments were administered with food for 6 days. Steady-state pharmacokinetics following the morning dose on day 7 were compared between treatments. Short-term safety and tolerability were assessed. Results Based on least square means ratios (90% confidence intervals), during darunavir and ketoconazole co-administration, darunavir area under the curve (AUC12h), maximum plasma concentration (Cmax) and minimum plasma concentration (Cmin) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC12h, Cmax and Cmin increased by 42% (23, 65), 21% (4, 40) and 73% (39, 114), respectively, during darunavir/ritonavir and ketoconazole co-administration, relative to darunavir/ritonavir treatment. Ketoconazole pharmacokinetics was unchanged by co-administration with darunavir alone. Ketoconazole AUC12h, Cmax and Cmin increased by 212% (165, 268), 111% (81, 144) and 868% (544, 1355), respectively, during co-administration with darunavir/ritonavir compared with ketoconazole alone. Conclusions The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day−1 is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.

Longitudinal studies are permeating clinical trials in psychiatry. Additionally, in the same field, rating scales are frequently used to evaluate the status of the patients and the efficacy of new therapeutic procedures. Therefore, it is of utmost importance to study the psychometric properties of these instruments within a longitudinal framework. In the area of depression, the Hamilton depression rating scale (HAMD) is regularly used for antidepressant treatment evaluation. However, the use of HAMD has not been exempted from criticism what has lead to the development of new scales that are expected to be more sensitive for change, such as the Montgomery-Asberg depression rating scale (MADRS). In general, the reliability of these scales has been extensively studied by using classical methods for reliability estimation, developed for specifically designed reliability studies. Unfortunately, the settings customarily considered in these reliability studies are usually far from the practical conditions in which these scales are applied in clinical trials and practice. In the present paper, we assess the reliability of these instruments in a more realistic scenario thereby using longitudinal data coming from clinical studies. Nowadays, newly developed methodology based on an extended concept of reliability, allows us to use longitudinal data for reliability estimation. This new approach not only enables to avoid bias by offering a better control of disturbing factors but it also produces more precise estimates by taking advantage of the large sample taking sizes available in clinical trials. Further, it offers practical guidelines for an optimal use of a rating scale in order to achieve a particular level of reliability. The merits of this new approach are illustrated by applying it on two clinical trials in depression to assess the reliability of the three outcome scales, HAMD, MADRS, and the Hamilton anxiety rating scale (HAMA). (C) 2008 Elsevier Ltd. All rights reserved. IAP Research Network P6/03 of the Belgian Government (Belgian Science Policy

This study investigated the steady-state pharmacokinetic interaction between the HIV protease inhibitor, darunavir (TMC114), administered with low-dose ritonavir (darunavir/ritonavir), and clarithromycin in HIV-negative healthy volunteers. In a 3-way crossover study, 18 individuals received darunavir/ritonavir 400/100 mg bid, clarithromycin 500 mg bid, and darunavir/ritonavir 400/100 mg bid plus clarithromycin 500 mg bid in 3 separate sessions for 7 days, with a washout period of at least 7 days between treatments. Pharmacokinetic assessment was performed on day 7. Safety and tolerability of the study medication were monitored throughout. Coadministration of darunavir/ritonavir with clarithromycin resulted in a reduction in darunavir maximum plasma concentration (Cmax) and area under the curve from administration until 12 hours postdose (AUC12 h) of 17% and 13%, respectively. Ritonavir Cmax and AUC12 h were unchanged. During coadministration with darunavir/ritonavir, clarithromycin Cmax and AUC12 h increased by 26% and 57%, respectively; 14-hydroxy-clarithromycin plasma concentrations were reduced to below the lower limit of quantification (

Objective: In POWER 1 and POWER 2, darunavir (TMC114) with low-dose ritonavir (darunavir/r) demonstrated greater efficacy versus control protease inhibitors (Pis). To examine the efficacy and safety of the selected darunavir/r dose further, additional patients were analyzed. Methods: Treatment-experienced HIV-1-infected patients received darunavir/r at a dose of 600/100 mg twice daily plus an optimized background regimen. The primary intent-to-treat analysis was the proportion of patients with an HIV-1 RNA reduction ≥1 log 10 at week 24. Results: Three hundred twenty-seven patients were treated; the baseline mean HIV-1 RNA was 4.6 log 10 copies/mL, and the median CD4 count was 115 cells/mm 3 (median primary PI mutations = 3, PI resistance-associated mutations = 9). Two hundred forty-six patients reached week 24 by the cutoff date and were included in the efficacy analysis: 65% and 40% achieved HIV-1 RNA reductions of ≥ 1 log 10 and

This open-label, randomized, crossover study investigated the bioavailability, short-term safety, and tolerability of darunavir (TMC114) coadministered with low-dose ritonavir under fasted conditions and after different meal types in HIV-negative healthy volunteers. All volunteers received ritonavir 100 mg twice daily on days 1 to 5, with a single darunavir 400-mg tablet given on day 3 (darunavir/rtv). Pharmacokinetic parameters for darunavir and ritonavir were determined under fasted conditions and following a standard breakfast, a high-fat breakfast, a nutritional protein-rich drink, or a croissant with coffee. Administration of darunavir/rtv in a fasting state resulted in a decrease in darunavir C(max) and AUC(last) of approximately 30% compared with administration after a standard meal. No significant differences in darunavir plasma concentrations were observed between different fed states. Darunavir/rtv should therefore be administered with food, but exposure to darunavir is not affected by the type of meal.

BACKGROUND: The protease inhibitor darunavir has been shown to be efficacious in highly treatment-experienced patients with HIV infection, but needs to be assessed in patients with a broader range of treatment experience. We did a randomised, controlled, phase III trial (TITAN) to compare 48-week efficacy and safety of darunavir-ritonavir with that of lopinavir-ritonavir in treatment-experienced, lopinavir-naive patients. METHODS: Patients received optimised background regimen plus non-blinded treatment with darunavir-ritonavir 600/100 mg twice daily or lopinavir-ritonavir 400/100 mg twice daily. The primary endpoint was non-inferiority (95% CI lower limit for the difference in treatment response -12% or greater) for HIV RNA of less than 400 copies per mL in plasma at week 48 (per-protocol analysis). TITAN (TMC114-C214) is registered with ClinicalTrials.gov, number NCT00110877. FINDINGS: Of 595 patients randomised and treated, 187 (31%) were protease inhibitor naive; 476 of 582 (82%) were susceptible to four or more protease inhibitors. At week 48, significantly more darunavir-ritonavir than lopinavir-ritonavir patients had HIV RNA of less than 400 copies per mL (77% [220 of 286] vs 68% [199 of 293]; estimated difference 9%, 95% CI 2-16). Fewer virological failures treated with darunavir-ritonavir than with lopinavir-ritonavir developed primary protease inhibitor mutations (21% [n=6] vs 36% [n=20]) and nucleoside analogue-associated mutations (14% [n=4] vs 27% [n=15]). Safety data were generally similar between the groups; grade 3 or 4 adverse events occurred in 80 (27%) darunavir-ritonavir and 89 (30%) lopinavir-ritonavir patients. INTERPRETATION: In lopinavir-naive, treatment-experienced patients, darunavir-ritonavir was non-inferior to lopinavir-ritonavir treatment in terms of our virological endpoint, and should therefore be considered as a treatment option for this population. Udgivelsesdato: 2007

This work aims at applying concepts of generalizability theory to data resulting from clinical trials. The focus is to study the sources of variance and their impact on the reliability and generalizability of a psychiatric measurement scale. The goal is to identify, measure, and thereby potentially find strategies to reduce the influence of these sources on the measurement in question for future trials. This approach was originally devised by Cronbach and his associates and is known as generalizability theory. This work shows how full modeling power in mixed models can be used to study generalizability using data from five double-blind randomized clinical trials, comparing the effects of risperidone to conventional antipsychotic agents for the treatment of chronic schizophrenia.

The objective of this paper is to extend the surrogate endpoint validation methodology proposed by Buyse et al. (2000) to the case of a longitudinally measured surrogate marker when the endpoint of interest is time to some key clinical event. A joint model for longitudinal and event time data is required. To this end, the model formulation of Henderson et al. (2000) is adopted. The methodology is applied to a set of two randomized clinical trials in advanced prostate cancer to evaluate the usefulness of prostate-specific antigen (PSA) level as a surrogate for survival. The first and fourth authors gratefully acknowledge support from an LUC Bijzonder Onderzoeksfonds grant. The second author was supported by the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT), Belgium.

This work investigates whether techniques that are generally used for the validation of surrogate markers in clinical trials can be applied in the validation of psychiatric health measurements (often scales) and more generally to investigate relationships between treatment effects on different measurements. However, the categorical nature of some scales makes these techniques inapplicable in the way they were originally defined. In this work, we show a possible extension of this methodology to the setting in which one of the scales is an ordinal categorical variable. When psychiatric health measurements are either developed or used in a new population, reliability and validity must be investigated. Reliability, more specifically internal consistency, test-retest reliability, and inter-rater reliability, is focused on the reproducibility of the measurement. Validity is defined as the degree to which the scale measures what it purports to measure. This can be performed through the analysis of content, construct, and criterion validity. We argue that recent methodology, in particular developed to study surrogate endpoints, can be used to examine criterion validity, concurrent validity, and predictive validity. In concurrent validity, we correlate the measurement with a criterion measure, both of which are given at the same time. In predictive validity, the criterion will not be available to some point in time in the future. The surrogate methods were applied on pooled data from five trials in schizophrenia. The first author acknowledges support from an LUC Bijzonder Onderzoeksfonds grant. The second author was supported by the Institute for the Promotion of Innovation by Science and Technology (IWT) in Flanders, Belgium. The authors are grateful to the Janssen Research Foundation for permission to use their data. The authors are also grateful to the UIAP for their financial support.

Part of the recent literature on the validation of biomarkers as surrogate endpoints proposes to undertake the validation exercise in a multi-trial context which led to a definition of validity in terms of the quality of both trial level and individual level association between the surrogate and the true endpoints (Buyse et al., 2000). These authors concentrated on continuous univariate responses. However, in many randomized clinical studies, repeated measurements are encountered on either or both endpoints. When both the surrogate and true endpoints are measured repeatedly over time, one is confronted with the modelling of bivariate longitudinal data. In this work, we show how such a joint model can be implemented in the context of surrogate marker validation. In addition, another challenge in this setting is the formulation of a simple and meaningful concept of surrogacy. We propose the use of a new measure, the so-called variance reduction factor, to evaluate surrogacy at the trial and individual level. On the other hand, most of the work published in this area assume that only one potential surrogate is going to be evaluated. We also show that this concept will let us evaluate surrogacy when more than one surrogate variable is available for the analysis. The methodology is illustrated on data from a meta-analysis of five clinical trials comparing antipsychotic agents for the treatment of chronic schizophrenia. The first author gratefully acknowledges support from an LUC Bijzonder Onderzoeksfonds grant. The second author was supported as postdoctoral research fel-low from the “Fonds voor wetenschappelijk onderzoek (FWO)-Vlaanderen”, Belgium