An illness-death multistate model to implement delta adjustment and reference-based imputation with time-to-event endpoints.

With a treatment policy strategy, therapies are evaluated regardless of the disturbance caused by intercurrent events (ICEs). Implementing this estimand is challenging if subjects are not followed up after the ICE. This circumstance can be dealt with using delta adjustment (DA) or reference-based (RB) imputation. In the survival field, DA and RB imputation have been researched so far using multiple imputation (MI). Here, we present a fully analytical solution. We use the illness-death multistate model with the following transitions: (a) from the initial state to the event of interest, (b) from the initial state to the ICE, and (c) from the ICE to the event. We estimate the intensity function of transitions (a) and (b) using flexible parametric survival models. Transition (c) is assumed unobserved but identifiable using DA or RB imputation assumptions. Various rules have been considered: no ICE effect, DA under proportional hazards (PH) or additive hazards (AH), jump to reference (J2R), and (either PH or AH) copy increment from reference. We obtain the marginal survival curve of interest by calculating, via numerical integration, the probability of transitioning from the initial state to the event of interest regardless of having passed or not by the ICE state. We use the delta method to obtain standard errors (SEs). Finally, we quantify the performance of the proposed estimator through simulations and compare it against MI. Our analytical solution is more efficient than MI and avoids SE misestimation-a known phenomenon associated with Rubin's variance equation.

Population pharmacokinetics and pharmacodynamics of a novel vascular adhesion protein-1 inhibitor using a multiple-target mediated drug disposition model.

ASP8232 is a novel inhibitor of vascular adhesion protein-1 that was under evaluation for reducing residual albuminuria in patients with diabetic kidney disease. To characterize the pharmacokinetics (PK) of ASP8232 and its effect on vascular adhesion protein 1 (VAP-1) plasma activity and VAP-1 concentrations (pharmacodynamics, PD) in an integrated and quantitative manner, a target mediated drug disposition model was developed based on pooled data from four completed clinical trials with ASP8232 in healthy volunteers, and in patients with diabetic kidney disease and diabetic macular edema, respectively. In this model, the binding of ASP8232 to its soluble and membrane-bound target in the central and peripheral compartments were included. The model was able to adequately describe the non-linear PK and PD of ASP8232. The observed difference in PK between healthy volunteers and renally impaired patients could be explained by an effect of baseline estimated glomerular filtration rate on ASP8232 clearance and relative bioavailability. The relationship between ASP8232 concentration and VAP-1 inhibition was successfully established and can be applied to simulate drug exposure and degree of VAP-1 inhibition for any given dose of ASP8232 across the spectrum of renal function.

Mechanism-based modeling of the effect of a novel inhibitor of vascular adhesion protein-1 on albuminuria and renal function markers in patients with diabetic kidney disease.

The vascular adhesion protein-1 (VAP-1) inhibitor ASP8232 reduces albuminuria in patients with type 2 diabetes and chronic kidney disease. A mechanism-based model was developed to quantify the effects of ASP8232 on renal markers from a placebo-controlled Phase 2 study in diabetic kidney disease with 12 weeks of ASP8232 treatment. The model incorporated the available pharmacokinetic, pharmacodynamic (plasma VAP-1 concentration and activity), serum and urine creatinine, serum cystatin C, albumin excretion rate, urinary albumin-to-creatinine ratio, and urine volume information in an integrated manner. Drug-independent time-varying changes and different drug effects could be quantified for these markers using the model. Through simulations, this model provided the opportunity to dissect the relationship and longitudinal association between the estimated glomerular filtration rate and albuminuria and to quantify the pharmacological effects of ASP8232. The developed drug-independent model may be useful as a starting point for other compounds affecting the same biomarkers in a similar time scale.

Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): study protocol.

BACKGROUND: Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). METHODS: iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. DISCUSSION: iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03716401 ).

MMRM vs joint modeling of longitudinal responses and time to study drug discontinuation in clinical trials using a "de jure" estimand.

In pre-marketing stages of drug development, trialists focus on drug efficacy rather than effectiveness, and observations collected after study drug discontinuation are excluded from the analysis, following the so-called "de jure" estimand. In this setting, mixed models for repeated measures (MMRM) are becoming the benchmark to analyze normally distributed longitudinal responses. We have compared the performance of MMRM against shared parameter models (SPM) that jointly fit the longitudinal response and time to study drug discontinuation. Our simulations have first confirmed that MMRM lead to biased treatment effect estimates when longitudinal and event processes are associated via latent shared parameters, especially if the relationship is heterogeneous across treatment groups. SPM produced unbiased estimates with SPM data but faced two important obstacles: (a) SPM led to considerable bias when treatment discontinuation and response were associated with models of the time-varying covariates (TVC) family, and (b) SPM were rather sensitive to the choice of the parameterization to model the relationship between longitudinal and time-to-event processes. When we simulated SPM data but used an incorrect equation to relate the random effects and time-to-event response, SPM led to a bigger bias than that seen with MMRM. We have finally evaluated a methodology to choose between MMRM and SPM consisting of expanding the MMRM density into the likelihood of both longitudinal and time-to-event data by plugging in the likelihood of a parametric TVC model. This approach allowed us to accurately select the optimal tool (MMRM or SPM) with sample sizes typical of phases 2b and 3.

Quality-of-life-adjusted hazard of death: a formulation of the quality-adjusted life-years model of use in benefit-risk assessment.

BACKGROUND: Although the quality-adjusted life-years (QALY) model is standard in health technology assessment, quantitative methods are less frequent but increasingly used for benefit-risk assessment (BRA) at earlier stages of drug development. A frequent challenge when implementing metrics for BRA is to weigh the importance of effects on a chronic condition against the risk of severe events during the trial. The lifetime component of the QALY model has a counterpart in the BRA context, namely, the risk of dying during the study. METHODS: A new concept is presented, the hazard of death function that a subject is willing to accept instead of the baseline hazard to improve his or her chronic health status, which we have called the quality-of-life-adjusted hazard of death. RESULTS: It has been proven that if assumptions of the linear QALY model hold, the excess mortality rate tolerated by a subject for a chronic health improvement is inversely proportional to the mean residual life. CONCLUSIONS: This result leads to a new representation of the linear QALY model in terms of hazard rate functions and allows utilities obtained by using standard methods involving trade-offs of life duration to be translated into thresholds of tolerated mortality risk during a short period of time, thereby avoiding direct trade-offs using small probabilities of events during the study, which is known to lead to bias and variability.

Darexaban (YM150), an oral direct factor Xa inhibitor, has no effect on the pharmacokinetics of digoxin.

To investigate the impact of the direct Factor Xa inhibitor darexaban administered in a modified-release formulation (darexaban-MR) on the pharmacokinetic (PK) profile of digoxin. In this Phase I, randomized, double-blind, two-period crossover study (8 days for each treatment, 10 days washout), 24 healthy subjects received darexaban-MR 120 mg once/day (qd) + digoxin 0.25 mg qd in one treatment period, and placebo + digoxin 0.25 mg qd in the other treatment period. Blood for PK assessment of digoxin and darexaban was obtained in serial profile on day 8, as well as pre-dose on day 6-7; urinary PK samples were obtained up to 24 h after the last dose on day 8. A lack of interaction was determined if 90 % confidence intervals (CIs) for the geometric mean ratios (GMR) of digoxin C max,ss and AUC0-24h,ss with and without darexaban-MR co-administration were within 0.80-1.25 limits. Pharmacodynamic activity was assessed by international normalized ratio and activated partial thromboplastin time. Twenty-three subjects completed the study. The GMR (90 % CI) for C max,ss and AUC0-24h,ss of digoxin plus darexaban versus digoxin plus placebo was 1.03 (90 % CI: 0.94-1.12) and 1.11 (90 % CI: 1.05-1.17), respectively. The 90 % CI for the GMRs fell within the limits of 0.80-1.25, indicating a lack of drug-drug interaction. Co-administration of digoxin with darexaban-MR was well tolerated, with no unexpected treatment-emergent adverse events or safety concerns. Co-administration of darexaban-MR did not impact the steady-state PK profile of digoxin.

The pharmacokinetics of darexaban are not affected to a clinically relevant degree by rifampicin, a strong inducer of P-glycoprotein and CYP3A4.

AIMS: We investigated the effects of rifampicin on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite, darexaban glucuronide (YM-222714), which almost entirely determines the antithrombotic effect. METHODS: In this open-label, single-sequence study, 26 healthy men received one dose of darexaban 60 mg on day 1 and oral rifampicin 600 mg once daily on days 4-14. On day 11, a second dose of darexaban 60 mg was given with rifampicin. Blood and urine were collected after study drug administration on days 1-14. The maximal plasma drug concentration (C(max)) and exposure [area under the plasma concentration-time curve from time zero to time of quantifiable measurable concentration; (AUC(last)) or AUC(last) extrapolated to infinity (AUC(∞))] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and C(max) ratios were predefined as 80-125%. RESULTS: Darexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUC(last) with/without rifampicin was 1.08 (1.00, 1.16). The C(max) of darexaban glucuronide increased by 54% after rifampicin [ratio 1.54 (1.37, 1.73)]. The plasma concentrations of darexaban were very low (<1% of darexaban glucuronide concentrations) with and without rifampicin. Darexaban alone or in combination with rifampicin was generally safe and well tolerated. CONCLUSIONS: Overall, rifampicin did not affect the PK profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug-drug interactions between darexaban and CYP3A4 or P-glycoprotein-inducing agents is low.

Clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban, an oral direct factor Xa inhibitor, in healthy Caucasian and Japanese subjects.

BACKGROUND: Darexaban (YM150) is a potent direct factor Xa (FXa) inhibitor developed for the prophylaxis of venous and arterial thromboembolic disease. This drug is rapidly and extensively metabolized to darexaban glucuronide (YM-222714), which is a pharmacologically active metabolite. The objective of the present study was to evaluate the clinical pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of ascending multiple oral doses of darexaban in healthy non-elderly Caucasian and Japanese subjects. METHODS: A randomized, double-blind, placebo-controlled, single and multiple dose-escalating study of healthy Caucasian and Japanese male and female subjects was performed. The tested doses were 20, 60, 120 and 240 mg of darexaban. RESULTS: Plasma concentrations of darexaban glucuronide increased with dose, and Cmax and AUC increased dose-dependently after both single and repeated doses in both Caucasians and Japanese. Cmax was about 17%-19% lower in Caucasians than in Japanese, although AUC appeared to be similar. The time-profiles of prothrombin time reported as the international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) and FXa activity closely followed the time-concentration profile of darexaban glucuronide, and no clear differences were observed in ethnicity. Overall, 38 of the 82 enrolled subjects reported a total of 57 treatment-emergent adverse events (TEAEs). Fifty-five TEAEs were of mild intensity and two were of moderate intensity. CONCLUSION: It is concluded that single and multiple doses of darexaban are safe and well tolerated up to 240 mg with predictable PK and PD profiles in both Caucasians and Japanese, and that ethnicity does not affect its PK, PD or tolerability.

Clinical factors for predicting cardiovascular risk, need for renal replacement therapy, and mortality in patients with non-dialysis-dependent stage 3-5 chronic kidney disease from the Salford Kidney Study.

BACKGROUND: Established cardiovascular risk assessment tools lack chronic kidney disease-specific clinical factors and may underestimate cardiovascular risk in non-dialysis-dependent chronic kidney disease (CKD) patients. METHODS: A retrospective analysis of a cohort of patients with stage 3-5 non-dialysis-dependent chronic kidney disease in the Salford Kidney Study (UK, 2002-2016) was performed. Multivariable Cox regression models with backward selection and repeated measures joint models were used to evaluate clinical risk factors associated with cardiovascular events (individual and composite cardiovascular major adverse cardiovascular events), mortality (all-cause and cardiovascular-specific), and need for renal replacement therapy. Models were established using 70% of the cohort and validated on the remaining 30%. Hazard ratios ([95% CIs]) were reported. RESULTS: Among 2192 patients, mean follow-up was 5.6 years. Cardiovascular major adverse cardiovascular events occurred in 422 (19.3%) patients; predictors included prior history of diabetes (1.39 [1.13-1.71]; P = 0.002) and serum albumin reduction of 5 g/L (1.20 [1.05-1.36]; P = 0.006). All-cause mortality occurred in 740 (33.4%) patients, median time to death was 3.8 years; predictors included reduction of estimated glomerular filtration of 5 mL/min/1.73 m2 (1.05 [1.01-1.08]; P = 0.011) and increase of phosphate of 0.1 mmol/L (1.04 [1.01-1.08]; P = 0.021), whereas a 10 g/L hemoglobin increase was protective (0.90 [0.85-0.95]; P < 0.001). In 394 (18.0%) patients who received renal replacement therapy, median time to event was 2.3 years; predictors included halving of estimated glomerular filtration rate (3.40 [2.65-4.35]; P < 0.001) and antihypertensive use (1.23 [1.12-1.34]; P < 0.001). Increasing age, albumin reduction, and prior history of diabetes or cardiovascular disease were risk factors for all outcomes except renal replacement therapy. CONCLUSIONS: Several chronic kidney disease-specific cardiovascular risk factors were associated with increased mortality and cardiovascular event risk in patients with non-dialysis-dependent chronic kidney disease.

RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome.

AIMS: To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS). METHODS: In a 26-week, multi-centre, double-blind, randomized, parallel-group study, 1279 patients with recent high-risk non-ST-segment or ST-segment elevation ACS received one of six darexaban regimens: 5 mg b.i.d., 10 mg o.d., 15 mg b.i.d., 30 mg o.d., 30 mg b.i.d., or 60 mg o.d. or placebo, on top of dual antiplatelet treatment. Primary outcome was incidence of major or clinically relevant non-major bleeding events. The main efficacy outcome was a composite of death, stroke, myocardial infarction, systemic thromboembolism, and severe recurrent ischaemia. RESULTS: Bleeding rates were numerically higher in all darexaban arms vs. placebo (pooled HR: 2.275; 95% CI: 1.13-4.60, P = 0.022). Using placebo as reference (bleeding rate 3.1%), there was a dose-response relationship (P = 0.009) for increased bleeding with increasing darexaban dose (6.2, 6.5, and 9.3% for 10, 30, and 60 mg daily, respectively), which was statistically significant for 30 mg b.i.d. (P = 0.002). There was no decrease (indeed a numerical increase in the 30 and 60 mg dose arms) in efficacy event rates with darexaban, but the study was underpowered for efficacy. Darexaban showed good tolerability without signs of liver toxicity. CONCLUSIONS: Darexaban when added to dual antiplatelet therapy after ACS produces an expected dose-related two- to four-fold increase in bleeding, with no other safety concerns but no signal of efficacy. Establishing the potential of low-dose darexaban in preventing major cardiac events after ACS requires a large phase III trial. ClinicalTrials.gov Identifier: NCT00994292.

Single portal arthroscopic temporomandibular joint discopexy: Technique and results.

The aim of the present study is to assess the outcomes of monoportal arthroscopic disc repositioning (discopexy) for disc displacement of the temporomandibular joint. A retrospective, single-institutional clinical study included patients with temporomandibular joint internal derangements diagnosed and treated by monoportal discopexy. Each patient was diagnosed as having anterior disk displacement with or without reduction. The arthroscopy treatment consists of one portal approach fixing the disc with a 3/0 nylon to the tragus cartilage without anterior liberation. Arthroscopy surgery was carried out with a 1.9-mm 0° arthroscope and only one simple cannula. We use a needle to pierce of the disc through the skin and retrieve the suture inside the joint using a blind method through the arthroscopic cannula. The evaluated variables included the maximum interincisal opening, the presence of clicking and pain score. A total of 19 patients, 21 joints, were included in the present study. Of the 21 joints, 16 were classified as disc displacement with reduction and 5 without. Visual analogue scale (VAS) values (0-10) decreased from 5.5 to 1.26 (p < 0.0001) 1 year after surgery. At the first review, all patients had a VAS of at least 4 points less than before the surgery, four patients showed a VAS of 0, and nine patients near to 1. Mouth opening increased from 36.6 (±8.09) mm to 39.37 (±4.35) mm, and no significant limitations in the mouth opening range were seen (p < 0.12) 1 year after surgery. Clicking disappeared in all patients and remained stable after 12 months of follow-up. Postoperative magnetic resonance imaging demonstrated a correct or improved position of the disc in all but one patient. A minimally invasive single portal arthroscopic discopexy is an effective technique to improve function and pain reduction in patients with anterior disk displacement with or without reduction.

Primary outcomes of the VIDI study: phase 2, double-masked, randomized, active-controlled study of ASP8232 for diabetic macular edema.

BACKGROUND: ASP8232 is a potent and specific small molecule vascular adhesion protein-1 (VAP-1) inhibitor. This study evaluated the effect of ASP8232 on excess retinal thickness when given alone or in combination with ranibizumab in patients with center-involved diabetic macular edema (CI-DME). METHODS: This was a phase 2a, placebo and sham-injection controlled, double-masked, randomized, parallel-group clinical trial. Participants were patients with CI-DME and central subfield thickness (CST) ≥ 375 µm in the study eye as assessed by spectral domain optical coherence tomography. Eligible patients were randomized to (1) daily oral ASP8232 40 mg monotherapy; (2) combination therapy of daily oral ASP8232 40 mg and monthly intravitreal ranibizumab 0.3 mg; or (3) monthly intravitreal ranibizumab 0.3 mg monotherapy. The treatment period was 12 weeks. CST and best corrected visual acuity (BCVA) were assessed at baseline and at Weeks 2, 4, 8, 12, 16 and 24. The primary outcome was the mean percent change from baseline in excess CST at Week 12. Secondary outcomes were BCVA, safety and tolerability, and pharmacokinetic and pharmacodynamic characteristics of ASP8232. RESULTS: After 12 weeks, the mean (95% confidence interval) percent change in excess CST was 11.4% (- 15.0%, 37.8%) in the ASP8232 group, - 61.7% (- 86.1%, - 37.2%) in the ASP8232/ranibizumab group, and - 75.3% (- 94.8%, - 55.8%) in the ranibizumab group. The change from baseline in the two ranibizumab arms was statistically significant (P < 0.001) as was the difference between the ranibizumab groups and the ASP8232 group (P < 0.001). Mean (SD) increase in BCVA score from baseline was 3.1 (7.3) in the ASP8232 group, 5.2 (7.1) in the ASP8232/ranibizumab group, and 8.2 (9.5) in the ranibizumab group. The increase from baseline in BCVA score was statistically and clinically significant in the ranibizumab group compared with the ASP8232 group (P = 0.015). ASP8232 resulted in near complete inhibition of plasma VAP-1 activity whilst ranibizumab had no effect. CONCLUSIONS: Near complete inhibition of plasma VAP-1 activity with ASP8232 had no effect on CST in patients with CI-DME. Furthermore, combination therapy did not provide additional benefit to treatment with ranibizumab alone, which significantly reduced CST and improved BCVA.Trial registration clinicaltrials.gov; NCT02302079. Registered on November 26, 2014.

Transcultural adaptation and validation of the Spanish language version of the questionnaire OQLQ for the assessment of quality of life in orthognathic patients.

BACKGROUND: Orthognathic surgery is the cornerstone of the treatment of dentofacial deformities, which have a great psychological and social impact on the life of the patient. Patient satisfaction and the impact on quality of life have recently become clinical parameters of growing importance. The aim of this study was to undertake a transcultural adaptation, translation to Spanish and validation of this version of the questionnaire OQLQ, used to measure quality of life in the context of Spanish culture. MATERIAL AND METHODS: Validation of the OQLQ questionnaire to the Spanish language was carried out through the methodology of translation and back translation, conceptual equivalence and piloting. The Spanish version was applied through a cross-sectional study to a total of 50 patients undergoing orthognathic surgery. RESULTS: The adapted and validated version showed adequate metric properties of reliability, change sensitivity and validity. In this study, a positive impact of orthognathic surgery on the specific quality of life was evident in 96% of patients, with an average improvement of 58% with respect to the initial score. CONCLUSIONS: Dentofacial deformities have a marked negative impact on the lives of patients, with orthognathic surgery being a therapeutic tool of great value in improving the quality of life in social, functional and aesthetic terms. The pilot test of this Spanish language version of the OQLQ proved valid for the assessment of quality of life in Spanish-speaking orthognathic patients or those with a Spanish culture. Key words:Orthognathic surgery, quality of life, validation studies, dentofacial deformities, patient satisfaction, treatment outcome.

Efficacy of a novel inhibitor of vascular adhesion protein-1 in reducing albuminuria in patients with diabetic kidney disease (ALBUM): a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Many patients with diabetic kidney disease have residual albuminuria and are at risk of disease progression. The ALBUM trial investigated the efficacy of a novel, orally active inhibitor of vascular adhesion protein-1, ASP8232, compared with placebo for reducing albuminuria in individuals with type 2 diabetes and chronic kidney disease. METHODS: In this randomised, double-blind, placebo-controlled phase 2 trial, we randomly assigned individuals (aged 18-85 years) from 64 clinical sites in nine European countries to receive ASP8232 40 mg or placebo orally once daily for 12 weeks using a web-based randomisation schedule (block size 4), stratified by country. Eligible patients had a urinary albumin-to-creatinine ratio (UACR) of 200-3000 mg/g, an estimated glomerular filtration rate of at least 25 mL/min per 1·73 m2 but lower than 75 mL/min per 1·73 m2, HbA1c less than 11·0% (97 mmol/mol), and stable treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antidiabetic medication for 3 months or more. The primary endpoint was mean change from baseline to week 12 in log-transformed first morning void UACR, which was assessed in all patients who received at least one dose of study drug and had at least one post-baseline UACR measurement (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. Participants and investigators were masked to treatment allocation. This trial is registered with ClinicalTrials.gov, number NCT02358096. FINDINGS: 125 participants were randomly assigned to receive ASP8232 (n=64) or placebo (n=61), of whom 120 (60 in each group) were included in the full analysis set; all participants were assessed for safety endpoints. At 12 weeks, UACR decreased by 17·7% (95% CI 5·0 to 28·6) in the ASP8232 group and increased by 2·3% (-11·4 to 18·1) in the placebo group; the placebo-adjusted difference between groups was -19·5% (95% CI -34·0 to -1·8; p=0·033). 39 (61%) patients in the ASP8232 group and 34 (56%) patients in the placebo group had a treatment-emergent adverse event, of which 16 in the ASP8232 group and four in the placebo group were drug-related. The most frequently reported adverse events that were possibly drug-related in the ASP8232 group were renal impairment (five patients) and decreased eGFR (three patients); in the placebo group, no single drug-related treatment-emergent adverse event was reported by more than one participant. INTERPRETATION: ASP8232 is effective in reducing albuminuria in patients with diabetic kidney disease and is safe and well tolerated. These findings warrant further research to ascertain the effect of ASP8232 on delaying progression of diabetic kidney disease. FUNDING: Astellas.

Pharmacokinetic Evaluation of the Interactions of Amenamevir (ASP2151) with Ketoconazole, Rifampicin, Midazolam, and Warfarin in Healthy Adults.

INTRODUCTION: Amenamevir is a nonnucleoside antiherpes virus compound available for treating herpes zoster infections. Four studies aimed to determine any potential interactions between amenamevir and ketoconazole, rifampicin, midazolam, or warfarin in healthy male participants. METHODS: Two studies were open-label studies that evaluated the effects of multiple doses of ketoconazole (400 mg) and rifampicin (600 mg) on the pharmacokinetics of a single oral dose of amenamevir. The other two studies were randomized, double-blind, parallel-group studies that evaluated the effects of multiple doses of amenamevir on the pharmacokinetics of a single dose of midazolam (7.5 mg) and warfarin (25 mg). A drug interaction was considered to occur if the 90% confidence interval (CI) of the least squares geometric mean ratio (GMR) of amenamevir to the comparator was outside the prespecified interval of 0.80-1.25. RESULTS: Interactions were observed between amenamevir and ketoconazole, rifampicin, and midazolam, but not between amenamevir and warfarin. After a single 400-mg dose of amenamevir, the GMRs of amenamevir plus ketoconazole or rifampicin versus amenamevir alone for C max and the area under the plasma concentration-time curve from time zero to infinity (AUCinf) were 1.30 (90% CI 1.17-1.45) and 2.58 (90% CI 2.32-2.87), respectively, for ketoconazole and 0.42 (90% CI 0.37-0.49) and 0.17 (90% CI 0.15-0.19), respectively, for rifampicin. Following multiple doses of amenamevir (400 mg), the GMRs of midazolam plus amenamevir versus midazolam alone for AUCinf and C max were 0.53 (90% CI 0.47-0.61) and 0.63 (90% CI 0.50-0.80), respectively. After a single dose of warfarin, the (S)-warfarin and (R)-warfarin mean C max increased and mean AUCinf decreased in the presence of amenamevir; however, the 90% CIs of the GMRs for these parameters remained within the predefined limits. CONCLUSION: These findings confirm that amenamevir (as a cytochrome P450 3A4 substrate) can interact with ketoconazole or rifampicin, and (as a cytochrome P450 3A4 inducer) can interact with midazolam; however, no interaction between amenamevir and (S)-warfarin was observed, indicating that amenamevir is not an inducer of cytochrome P450 2C9. FUNDING: Astellas Pharma. TRIAL REGISTRATION: EudraCT2007-002227-33 (study 15L-CL-008), EudraCT2007-002228-14 (study 15L-CL-009), EudraCT2007-002761-13 (study 15L-CL-010), and EudraCT2007-002779-14 (study 15L-CL-018).

Is increasing urinary albumin a better marker for microvascular than for macrovascular complication of type 2 diabetes mellitus?

AIMS: The aims of the study were to evaluate the prevalence of increased urinary albumin excretion (UAE) and associated cardiovascular risk factors and vascular diabetes complications in patients with type 2 diabetes mellitus (DM). METHODS: We studied 975 patients in a cross-sectional design from 1998 to 2000. Frequency of micro- and macroalbuminuria, and their associations with cardiovascular risk factors and vascular DM complications, were examined. RESULTS: Prevalence of increased UAE was 28.5% (18.3% micro- and 10.2% macroalbuminuria). Body mass index (BMI) (only females) and hemoglobin (Hb)A1c significantly correlated with macroalbuminuria (p = 0.034, p = 0.027, respectively), while high blood pressure (diastolic) was associated with microalbuminuria (p = 0.008). Diabetes duration, high systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides were significantly correlated with both micro- and macroalbuminuria. Increased UAE was associated with neuropathy (relative risk (RR) 2.12, confidence interval (CI) 1.07-4.19), retinopathy (RR 2.19, CI 1.76-2.74) and hypertension (RR 2.91, CI 1.77-4.78), but not with cardiovascular disease, high cholesterol and peripheral vascular disease. In the multiple logistic regression analysis, a significant association of albuminuria was found with diabetes duration (odds ratio (OR) 1.59, CI 0.98-2.58; p < 0062), hypertension (OR 3.42, CI 2.22-5.27; p < 0.0001), low HDL cholesterol (OR 1.78, CI 1.31-2.43; p < 0.0003), current smoking status (OR 2.19, CI 1.32-3.64; p < 0.0024), and increased serum creatinine (OR 11.16, CI 5.7-21.7; p < 0.0001). CONCLUSION: Prevalence of increased UAE was similar to that described in other geographically close populations. The stronger association found with microvascular diabetes complications suggests that increased UAE is a better predictor for renal damage than for cardiovascular disease in this type 2 DM population.

A Note on the Validity and Reliability of Multi-Criteria Decision Analysis for the Benefit-Risk Assessment of Medicines.

The comparative evaluation of benefits and risks is one of the most important tasks during the development, market authorization and post-approval pharmacovigilance of medicinal products. Multi-criteria decision analysis (MCDA) has been recommended to support decision making in the benefit-risk assessment (BRA) of medicines. This paper identifies challenges associated with bias or variability that practitioners may encounter in this field and presents solutions to overcome them. The inclusion of overlapping or preference-complementary criteria, which are frequent violations to the assumptions of this model, should be avoided. For each criterion, a value function translates the original outcomes into preference-related scores. Applying non-linear value functions to criteria defined as the risk of suffering a certain event during the study introduces specific risk behaviours in this prescriptive, rather than descriptive, model and is therefore a questionable practice. MCDA uses weights to compare the importance of the model criteria with each other; during their elicitation a frequent situation where (generally favourable) mild effects are directly traded off against low probabilities of suffering (generally unfavourable) severe effects during the study is known to lead to biased and variable weights and ought to be prevented. The way the outcomes are framed during the elicitation process, positively versus negatively for instance, may also lead to differences in the preference weights, warranting an appropriate justification during each implementation. Finally, extending the weighted-sum MCDA model into a fully inferential tool through a probabilistic sensitivity analysis is desirable. However, this task is troublesome and should not ignore that clinical trial endpoints generally are positively correlated.

¿Cuál es su diagnóstico? / What is your diagnosis?

No disponible

The pharmacokinetics of darexaban (YM150), an oral direct factor Xa inhibitor, are not affected by ketoconazole, a strong inhibitor of CYP3A and P-glycoprotein.

We investigated the effects of ketoconazole on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite darexaban glucuronide (YM-222714) which almost entirely determines the antithrombotic effect. In this open-label, randomized, two-period crossover study, 26 healthy male volunteers received in one treatment period a single dose of darexaban 60 mg, and in the other treatment period, ketoconazole 400 mg once daily on Days 1-9 with a single dose of darexaban 60 mg on Day 4. Washout between periods was at least 1 week. The geometric mean ratio (90% confidence interval) of darexaban glucuronide (darexaban plus ketoconazole versus darexaban) for AUCinf was 1.11 (1.00, 1.23), and for Cmax 1.18 (1.03, 1.35). Darexaban concentrations remained very low (AUClast ∼196-fold lower) in relation to darexaban glucuronide concentrations. In conclusion, the PK of darexaban glucuronide was not affected to a clinically relevant degree by co-administration of the strong CYP3A/P-glycoprotein inhibitor, ketoconazole. The PK of the parent compound darexaban were changed, however, concentrations remained quantitatively insignificant in relation to the main active moiety, darexaban glucuronide.