The role of sub-retinal fluid in determining treatment outcomes in patients with neovascular age-related macular degeneration--a phase IV randomised clinical trial with ranibizumab: the FLUID study.

BACKGROUND: With increasing experience using anti-VEGF therapy for the treatment of neovascular age-related macular degeneration (nAMD), ophthalmologists have shifted away from a "one size fits all" to an "individualised" approach based on disease activity with the aim of achieving a fluid-free retina. The FLUID study investigates the non-inferiority of a Treat and Extend (T&E) protocol of 0.5 mg ranibizumab, which allows treatment extension in the presence of incomplete resolution of sub-retinal fluid (SRF) ≤200 µm at the foveal centre relative to a T&E protocol that requires complete resolution of all retinal fluid (i.e., both SRF and intra-retinal fluid [IRF]) in patients with nAMD. METHODS/DESIGN: This 24 month, randomised, phase IV trial has completed recruitment of treatment-naïve patients randomised 1:1 to ranibizumab "intensive" treatment (complete resolution of IRF and SRF) or ranibizumab "relaxed" treatment (resolution of IRF or >200 µm SRF only at foveal centre). Patients in both arms follow a T&E regimen where extension decisions are based upon assessment of lesion activity: loss of ≥5 letters of visual acuity, new haemorrhage, presence of IRF and SRF on an optical coherence tomography (OCT) scan. The determination of SRF is conducted at a reading centre while the assessment of IRF is physician-determined. The primary endpoint is the mean change in best-corrected visual acuity (BCVA) from baseline to 24 months. Secondary endpoints include the mean change in central retinal thickness (CRT) from baseline to 12 and 24 months, the number of ranibizumab injections administered at 12 and 24 months, and the pharmacogenomic assessment of AMD Gene Consortium-identified single-nucleotide polymorphisms (SNPs) and their association with treatment response. Three hundred and forty seven (347) patients have been recruited by 16 Australian sites within approximately 16 months. A protocol to adjudicate on SRF has been established by the central reading centre and is demonstrating good concordance with investigator assessment. DISCUSSION: This study will provide important insights into retreatment criteria for managing nAMD using a T&E regimen. The current paper describes the clinical rationale for using a less intensive treatment approach using ranibizumab and details of the treatment protocol. TRIAL REGISTRATION NUMBER: NCT01972789. Date of registration: 24th October 2013.

Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial.

BACKGROUND: The optimal use of various therapeutic combinations for moderate/severe chronic obstructive pulmonary disease (COPD) is unclear. The GLISTEN trial compared the efficacy of two long-acting anti-muscarinic antagonists (LAMA), when combined with an inhaled corticosteroid (ICS) and a long-acting ß2 agonist (LABA). METHODS: This randomised, blinded, placebo-controlled trial in moderate/severe COPD patients compared once-daily glycopyrronium (GLY) 50 µg, once-daily tiotropium (TIO) 18 µg or placebo (PLA), when combined with salmeterol/fluticasone propionate (SAL/FP) 50/500 µg twice daily. The primary objective was to determine the non-inferiority of GLY+SAL/FP versus TIO+SAL/FP on trough FEV1 after 12 weeks. An important secondary objective was whether addition of GLY to SAL/FP was better than SAL/FP alone. RESULTS: 773 patients (mean FEV1 57.2% predicted) were randomised; 84.9% completed the trial. At week 12, GLY+SAL/FP demonstrated non-inferiority to TIO+SAL/FP for trough FEV1: least square mean treatment difference (LSMdiff) -7 mL (SE 17.4) with a lower limit for non-inferiority of -60 mL. There was significant increase in week 12 trough FEV1 with GLY+SAL/FP versus PLA+SAL/FP (LSMdiff 101 mL, p<0.001). At 12 weeks, GLY+SAL/FP produced significant improvement in St George's Respiratory Questionnaire total score versus PLA+SAL/FP (LSMdiff -2.154, p=0.02). GLY+SAL/FP demonstrated significant rescue medication reduction versus PLA+SAL/FP (LSMdiff -0.72 puffs/day, p<0.001). Serious adverse events were similar for GLY+SAL/FP, TIO+SAL/FP and PLA+SAL/FP with an incidence of 5.8%, 8.5% and 5.8%, respectively. CONCLUSIONS: GLY+SAL/FP showed comparable improvements in lung function, health status and rescue medication to TIO+SAL/FP. Importantly, addition of GLY to SAL/FP demonstrated significant improvements in lung function, health status and rescue medication compared to SAL/FP. TRIAL REGISTRATION NUMBER: NCT01513460.

A randomized, controlled trial of everolimus-based dual immunosuppression versus standard of care in de novo kidney transplant recipients.

Kidney transplant recipients receiving calcineurin inhibitor-based immunosuppression incur increased long-term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36-month, prospective, multinational, open-label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI-WD); everolimus with mycophenolate and steroid withdrawal (steroid-WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/min/1.73 m2 vs. 67.1 ml/min/1.73 m2 by ITT, which met predefined noninferiority criteria (P=0.026). The CNI-WD group experienced a higher rate of BPAR(31% vs. control 13%, P=0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients.

Conversion to enteric-coated mycophenolate sodium from mycophenolate mofetil in stable renal transplant patients: results of an Asia-Pacific study.

AIM: Mycophenolate mofetil has proven efficacy in the prophylaxis of acute rejection in solid organ transplantation; however, gastrointestinal intolerance can risk this efficacy because of associated dose adjustments and discontinued treatment. Enteric-coated mycophenolate sodium has demonstrated improved gastrointestinal tolerability, but the data in Asian subjects are scarce. METHODS: This was a Phase-IIIb, open-label, single-arm, multicentre, prospective 6-month study which investigated safety and graft function in stable maintenance renal transplant recipients of Asian origin, after switching from mycophenolate mofetil to enteric-coated mycophenolate sodium at least 3 months after transplantation. Primary end-points included renal allograft function and safety parameters. RESULTS: The study recruited patients from 16 centres in Asian countries. The intention-to-treat and safety populations both included 122 patients. Graft function remained stable over the course of the study as measured by creatinine clearance and glomerular filtration rate. At 6 months the incidence of any gastrointestinal adverse events was 20.5% (n = 25), none of which required dose adjustments. There were only three cases of biopsy proven acute rejection with no reports of graft loss or death. CONCLUSION: This study demonstrated that enteric-coated mycophenolate sodium is a safe and effective alternative to mycophenolate mofetil in Asian kidney transplant recipients.

Enteric-coated mycophenolate sodium in combination with full dose or reduced dose cyclosporine, basiliximab and corticosteroids in Australian de novo kidney transplant patients.

AIM: Cyclosporine (CsA), dosed to achieve C2 targets, has been shown to provide safe and efficacious immunosuppression when used with a mycophenolate and steroids for de novo kidney transplant recipients. This study examined whether use of enteric-coated mycophenolate sodium (EC-MPS) together with basiliximab and steroids would enable use of CsA dosed to reduced C2 targets in order to achieve improved graft function. METHODS: Twelve-month, prospective, randomized, open-label trial in de novo kidney transplant recipients in Australia. Seventy-five patients were randomized to receive either usual exposure (n = 33) or reduced exposure (n = 42) CsA, EC-MPS 720 mg twice daily, basiliximab and corticosteroids. RESULTS: There was no significant difference in mean Cockcroft-Gault CrCl (creatinine clearance) (60.2 ± 17.6 mL/min per 1.73 m(2) vs 63.2 ± 24.3, P = 0.64 for usual versus reduced exposure respectively) at 6 months. There was no significant difference between treatment groups in the incidence of treatment failure defined as biopsy proven acute rejection, graft loss or death (secondary endpoint: 30.3% full exposure vs 35.7% reduced exposure). At 12 months the incidence of overall adverse events was the same in both groups. CONCLUSION: This exploratory study suggests de novo renal transplant patients can safely receive a treatment regimen of either full or reduced exposure CsA in combination with EC-MPS, corticosteroids and basiliximab, with no apparent difference in efficacy or graft function during the first year after transplant.

Impact of nurse-mediated management on achieving blood pressure goal levels in primary care: Insights from the Valsartan Intensified Primary carE Reduction of Blood Pressure Study.

BACKGROUND: Blood pressure targets in individuals treated for hypertension in primary care remain difficult to attain. AIMS: To assess the role of practice nurses in facilitating intensive and structured management to achieve ideal BP levels. METHODS: We analysed outcome data from the Valsartan Intensified Primary carE Reduction of Blood Pressure Study. Patients were randomly allocated (2:1) to the study intervention or usual care. Within both groups, a practice nurse mediated the management of blood pressure for 439 patients with endpoint blood pressure data (n=1492). Patient management was categorised as: standard usual care (n=348, 23.3%); practice nurse-mediated usual care (n=156, 10.5%); standard intervention (n=705, 47.3%) and practice nurse-mediated intervention (n=283, 19.0%). Blood pressure goal attainment at 26-week follow-up was then compared. RESULTS: Mean age was 59.3±12.0 years and 62% were men. Baseline blood pressure was similar in practice nurse-mediated (usual care or intervention) and standard care management patients (150 ± 16/88 ± 11 vs. 150 ± 17/89 ± 11 mmHg, respectively). Practice nurse-mediated patients had a stricter blood pressure goal of ⩽125/75 mmHg (33.7% vs. 27.3%, p=0.026). Practice nurse-mediated intervention patients achieved the greatest blood pressure falls and the highest level of blood pressure goal attainment (39.2%) compared with standard intervention (35.0%), practice nurse-mediated usual care (32.1%) and standard usual care (25.3%; p<0.001). Practice nurse-mediated intervention patients were almost two-fold more likely to achieve their blood pressure goal compared with standard usual care patients (adjusted odds ratio 1.92, 95% confidence interval 1.32 to 2.78; p=0.001). CONCLUSION: There is greater potential to achieve blood pressure targets in primary care with practice nurse-mediated hypertension management.

More rigorous protocol adherence to intensive structured management improves blood pressure control in primary care: results from the Valsartan Intensified Primary carE Reduction of Blood Pressure study.

OBJECTIVE: To examine protocol adherence to structured intensive management in the Valsartan Intensified Primary carE Reduction of Blood Pressure (VIPER-BP) study involving 119 primary care clinics and 1562 randomized participants. METHODS: Prospective criteria for assessing adherence to treatment prescription, uptitration, and visit attendance at 6, 10, 14, and 18 weeks postrandomization were applied to 1038 intervention participants. Protocol adherence scores of 1-5 (least to most adherent) were compared to blood pressure (BP) control during 26 weeks of follow-up. RESULTS: Mean age was 59.3 ±â€Š12.0 years, 963 (62%) were men, and 1045 (67%) had longstanding hypertension. Clinic attendance dropped from 91 (week 6) to 83% (week 26) and pharmacological instructions were followed for 93% (baseline) to 61% at week 14 (uptitration failures commonly representing protocol deviations). Overall, 26-week BP levels and BP target attainment ranged from 132 ±â€Š14/79 ±â€Š9 and 51% to 141 ±â€Š15/83 ±â€Š11  mmHg and 19% in those participants subject to the highest (n = 270, 26%) versus least (n = 148, 14%) per protocol adherence, respectively; adjusted relative risk (RR) 1.22 per unit protocol adherence score, 95% confidence interval (CI) 1.15-1.31; for achieving BP target (P < 0.001). Participants with a per protocol score of 4 or 5 (512/1038, 49.3%) were 1.54-fold (95% CI 1.31-1.81; P < 0.001) more likely to achieve their individual BP target compared with usual care. Clinics equipped with a practice nurse significantly influenced protocol adherence (adjusted RR 1.20, 95% CI 1.06-1.37; P = 0.004) and individual BP control (RR 1.21, 95% CI 1.04-1.41; P = 0.015). CONCLUSION: There is considerable potential for structured care management to improve BP control in primary care, especially when optimally applied.

Determinants of achieving early blood pressure control with monotherapy in a primary care setting.

This study sought to identify the determinants of early blood pressure (BP) control associated with monotherapy in hypertensive individuals being managed in the primary care setting. The Valsartan Intensified Primary Care Reduction of Blood Pressure (VIPER-BP) study, was a multicenter, randomized controlled trial of an intensive approach to BP management. During a standardized run-in, 2185 participants commenced monotherapy (valsartan 80 mg/d) for 14 to 28 days. A total of 1978 participants aged 59±12 years (60% men) completed the run-in phase. Of these, 15.1%, 43.5%, and 41.4% participants had an initial BP target of ≤125/75, 130/80, and 140/90 mm Hg, respectively. A total of 416 of 2185 participants (19.0%) subsequently achieved their individual BP target during run-in with a mean BP change of -22.6±12.1/-12.9±8.2 mm Hg vs -4.2±16.2/-3.0±9.6 mm Hg for the rest (P<.001). These early responders were more likely to be women (adjusted odds ratio, 1.41; 95% confidence interval, 1.10-1.80), had lower BP at baseline, were less likely to have been treated previously (or for less time), and had a less stringent BP target. An initial period of monotherapy achieved BP control in a high proportion of hypertensive individuals with key groups (including women and de novo cases) more likely to show an early BP response.

Effect of intensive structured care on individual blood pressure targets in primary care: multicentre randomised controlled trial.

OBJECTIVE: To determine the effectiveness of intensive structured care to optimise blood pressure control based on individual absolute risk targets in primary care. DESIGN: Pragmatic multicentre randomised controlled trial. SETTING: General practices throughout Australia, except Northern Territory, 2009-11. PARTICIPANTS: Of 2185 patients from 119 general practices who were eligible for drug treatment for hypertension according to national guidelines 416 (19.0%) achieved their individual blood pressure target during a 28 day run-in period of monotherapy. After exclusions, 1562 participants not at target blood pressure (systolic 150 (SD 17) mm Hg, diastolic 88 (SD 11) mm Hg) were randomised (1:2 ratio) to usual care (n=524) or the intervention (n=1038). INTERVENTION: Computer assisted clinical profiling and risk target setting (all participants) with intensified follow-up and stepwise drug titration (initial angiotensin receptor blocker monotherapy or two forms of combination therapy using angiotensin receptor blockers) for those randomised to the intervention. The control group received usual care. MAIN OUTCOME MEASURES: The primary outcome was individual blood pressure target achieved at 26 weeks. Secondary outcomes were change in mean sitting systolic and diastolic blood pressure, absolute risk for cardiovascular disease within five years based on the Framingham risk score, and proportion and rate of adverse events. RESULTS: On an intention to treat basis, there was an 8.8% absolute difference in individual blood pressure target achieved at 26 weeks in favour of the intervention group compared with usual care group (358/988 (36.2%) v 138/504 (27.4%)): adjusted relative risk 1.28 (95% confidence interval 1.10 to 1.49, P=0.0013). There was also a 9.5% absolute difference in favour of the intervention group for achieving the classic blood pressure target of ≤ 140/90 mm Hg (627/988 (63.5%) v 272/504 (54.0%)): adjusted relative risk 1.18 (1.07 to 1.29, P<0.001). The intervention group achieved a mean adjusted reduction in systolic blood pressure of 13.2 mm Hg (95% confidence interval -12.3 to -14.2 mm Hg) and diastolic blood pressure of 7.7 mm Hg (-7.1 to -8.3 mm Hg) v 10.1 mm Hg (-8.8 to 11.3 mm Hg) and 5.5 mm Hg (-4.7 to -6.2 mm Hg) in the usual care group (P<0.001). Among 1141 participants in whom five year absolute cardiovascular risk scores were calculated from baseline to the 26 week follow-up, the reduction in risk scores was greater in the intervention group than usual care group (14.7% (SD 9.3%) to 10.9% (SD 8.0%); difference -3.7% (SD 4.5%) and 15.0% (SD 10.1%) to 12.4% (SD 9.4%); -2.6% (SD 4.5%): adjusted mean difference -1.13% (95% confidence interval -0.69% to -1.63%; P<0.001). Owing to adverse events 82 (7.9%) participants in the intervention group and 10 (1.9%) in the usual care group had their drug treatment modified. CONCLUSIONS: In a primary care setting intensive structured care resulted in higher levels of blood pressure control, with clinically lower blood pressure and absolute risk of future cardiovascular events overall and with more people achieving their target blood pressure. An important gap in treatment remains though and applying intensive management and achieving currently advocated risk based blood pressure targets is challenging.

Optimising management of hypertension in primary care: the Valsartan Intensified Primary Care Reduction of Blood Pressure (Viper-Bp) study.

BACKGROUND: The Valstartan Intensified Primary CarE Reduction of Blood Pressure Study (VIPER-BP) Study is an open-label, randomised controlled trial comparing usual primary care management with an intensive BP management strategy using three forms of valsartan-based therapy (mono-therapy, thiazide diuretic or calcium channel blocker combinations) to achieve individualised BP control. METHODS: To identify the features of General Practitioner (GP) management of hypertension in Australia, we analyse the response to a case scenario-based survey of 500 GPs. We subsequently recruited a national cohort of GP Investigators to enrol up to 2500 patients into the VIPER-BP Study. RESULTS: GP responses clearly demonstrated that, compared to the VIPER-BP intervention, a heterogeneous approach to the primary care management of hypertension persists in Australia. By November 2010, 2157 hypertensive patients from 272 actively recruiting GP Investigators were enrolled into the study. Of these, 1965 (91%) patients were entered into a standardised "run-in" phase of 28 days of valsartan 80 mg/day. Subsequently, 1285 patients were randomised to usual care (n=435) or the VIPER-BP intervention (n=850). There was a predominance of males (62%), whilst 55% had pre-existing diabetes or cardiovascular disease and 63% had been previously treated for hypertension. Mean systolic and diastolic BP on randomisation for men and women, respectively, was 148 ± 15/88 ± 11 and 148 ± 18/87 ± 10 mm Hg. CONCLUSIONS: In contrast to typical primary care management of hypertension, VIPER-BP combines more intensive and aggressive therapies with structured management to more rapidly attain and sustain individualised BP targets in hypertensive patients.