The Effect of Corticosteroids on Prostate Cancer Outcome Following Treatment with Enzalutamide: A Multivariate Analysis of the Phase III AFFIRM Trial.

PURPOSE: The clinical impact of concurrent corticosteroid use (CCU) on enzalutamide-treated patients with metastatic castration-resistant prostate cancer (mCRPC) is unknown. We investigated the association of CCU with overall survival (OS), radiographic progression-free survival (rPFS), and time to prostate-specific antigen progression (TTPP) in post-chemotherapy, enzalutamide-treated patients with mCRPC. PATIENTS AND METHODS: Post hoc analysis of AFFIRM (NCT00974311) with patients (n = 1,199) randomized 2:1 to enzalutamide 160 mg/day or placebo. Treatment group, CCU, and known prognostic factors were evaluated for impact on OS, rPFS, and TTPP using a multivariate Cox proportional hazards model. CCU was defined as "baseline" (use started at baseline) or "on-study" (baseline plus use that was started during the trial). RESULTS: Enzalutamide significantly improved OS, rPFS, and TTPP independent of baseline CCU but was associated with inferior clinical outcomes when compared with no baseline CCU, including a shorter OS [10.8 months vs. not reached (NR); HR for use vs. no use, 2.13; 95% confidence interval (CI), 1.79-2.54], rPFS (5.2 months vs. 8.0 months; HR, 1.49; 95% CI, 1.29-1.72], and TTPP (4.6 months vs. 5.7 months; HR, 1.50; 95% CI, 1.25-1.81). These findings held in a multivariate analysis adjusting for baseline prognostic factors wherein baseline CCU was independently associated with decreased OS (HR, 1.71; 95% CI, 1.43-2.04; P < 0.0001) and rPFS (HR, 1.28; 95% CI, 1.11-1.48; P = 0.0007). CONCLUSIONS: Patients with mCRPC benefited from enzalutamide treatment independent of CCU, but CCU was associated with worse baseline prognostic factors and outcomes.

Pulmonary and cardiovascular safety of inhaled insulin in routine practice: The Exubera Large Simple Trial (VOLUME).

OBJECTIVE: VOLUME is a randomized, open-label, post-approval pragmatic trial aiming to evaluate long-term pulmonary and cardiovascular safety of Exubera® (EXU; insulin human [rDNA origin] Inhalation Powder) in routine clinical practice. The primary study objective is to compare risk of persistent decline in forced expiratory volume in 1 second (FEV1) among patients treated with and without EXU. RESEARCH DESIGN AND METHODS: Patients eligible to take EXU per approved local label were randomized to EXU or routine care and followed per usual care, with scheduled FEV1 tests at baseline, 6 months, and yearly.Randomization halted in October 2007 after Pfizer announced it would stop marketing EXU due to low sales. EXU patients were subsequently transitioned to usual care and all patients were followed for 6 additional months. RESULTS: Although there was insufficient power to evaluate the primary endpoint (37% of the planned 5,300 were randomized), the study provided important descriptive information.Per the primary endpoint definition, more EXU group patients (n = 8) experienced a persistent decline in FEV1 (n = 0 in usual care). Using a broader, clinically relevant pre-specified supplementary definition of persistent decline, similar numbers were observed in the EXU (n = 27) and usual care (n = 24) groups. Slightly more pulmonary and allergic serious adverse event composite endpoints were seen in the EXU group. There were no consistent treatment group differences in the cardiovascular composite endpoint, all-cause mortality, or glycemic control. CONCLUSIONS: Clinically important declines in lung function that persisted more than 60 days were uncommon and of similar frequency in Exubera and usual care. CLINICALTRIALSGOV: NCT00359801.

Efficacy and Safety of Inhaled Human Insulin (Exu hera®) Compared to Subcutaneous Insulin in Children Ages 6 to 11 Years with Type 1 Diabetes Mellitus: Results of a 3-Month, Randomized, Parallel Trial.

AIM: To compare the efficacy and safety of Exubera® (EXU) with subcutaneous (SC) insulin in children, ages 6-11 years, with type 1 diabetes mellitus. DESIGN AND METHODS: 121 children were randomized to receive EXU or SC insulin, plus intermediate/ long-acting insulin for 12 weeks. Change in HbA1c was the primary efficacy endpoint. RESULTS: Decreases from baseline HbA1c were comparable between treatment groups ( difference between adjusted mean decrease from baseline [EXU - SC insulin], -0.23 [95% CI, -0.49, 0.03]). Differences between groups on pulmonary function tests were small and not significant. Mild to moderate cough occurred in 24.6% of EXU versus 6.8% of SC insulin patients. The risk for hypoglycemia was comparable between EXU and SC insulin (relative risk 0.88 [95% CI, 0.71, 1.11]). Increased insulin antibodies with EXU were not associated with clinical findings. CONCLUSION: The efficacy and safety profiles shown in this study are the foundation for further investigation of EXU in this population.

Lung Cancer-Related Mortality With Inhaled Insulin or a Comparator: Follow-Up Study of patients previously enrolled in Exubera Controlled Clinical Trials (FUSE) Final Results.

OBJECTIVE: The Follow-Up Study of patients previously enrolled in Exubera controlled clinical trials (FUSE) was designed to evaluate whether patients previously treated with Exubera (EXU; insulin human [rDNA origin], inhaled powder) in controlled clinical trials died because of incident primary lung cancer at a substantially higher rate than patients treated with a comparator. RESEARCH DESIGN AND METHODS: FUSE is a hybrid, randomized, controlled trial/cohort study including participants of 17 prior EXU clinical trials. Pooled patient data from these trials were used, and the subset of patients enrolled in the follow-up cohort study was followed prospectively for 2 years in order to evaluate the incidence of fatal and nonfatal primary lung cancers and all-cause mortality. RESULTS: There were 24,409 person-years (PY) of observation among 7,439 trial patients, with 4,017 PY (16.5%) from the period after the trials but before the prospective follow-up and 5,299 PY (21.7%) from the prospective follow-up. Just over half of the 2,631 patients (51.6%) in the prospective follow-up were randomized to EXU in the original trial. The incidence density ratio was 2.8 (95% CI 0.5, 28.5) for lung cancer-related mortality and 3.7 (95% CI 1.0, 20.7) for incident primary lung cancer. The hazard ratio for all-cause mortality was 0.81 (95% CI 0.60, 1.10). CONCLUSIONS: These data cannot exclude an increased risk of lung cancer-related mortality associated with EXU use. If real, the absolute increased risk of lung cancer-related mortality was small (0.48 cases per 1,000 PY). For all-cause mortality-the most reliably measured end point with the clearest interpretation-EXU users did not experience an excess all-cause death rate (relative or absolute) compared with users of other diabetes treatments over the study period.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy.

INTRODUCTION: Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). METHODS: In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. RESULTS: Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aß1-x and Aß1-40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. CONCLUSIONS: Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Relationship between atorvastatin dose and the harm caused by torcetrapib.

Development of the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, was halted after the ILLUMINATE trial revealed an increase in both all-cause mortality (ACM) and major cardiovascular events (MCVEs) associated with its use. We now report that the harm caused by torcetrapib was confined to those in the 10 mg atorvastatin subgroup for both ACM [hazard ratio (HR) = 2.68, 95% CI (1.58, 4.54), P < 0.0001] and MCVEs [HR = 1.41, 95% CI (1.14, 1.74), P = 0.002], with no evidence of harm when torcetrapib was coadministered with higher doses of atorvastatin. In the atorvastatin 10 mg subgroup, age, prior heart failure and stroke were significantly associated with ACM, independent of torcetrapib treatment, whereas low apoA-I, smoking, hypertension, heart failure, myocardial infarction, and stroke were independently associated with MCVEs. After adjusting for these factors, the HR associated with torcetrapib treatment in the 10 mg atorvastatin subgroup remained elevated for both ACM [HR = 2.67, 95% CI (1.57, 4.54), P < 0.001] and MCVE [HR = 1.36, 95% CI (1.10, 1.69), P = 0.005]. Thus, the harm caused by torcetrapib was confined to individuals taking atorvastatin 10 mg. The harm could not be explained by torcetrapib-induced changes in lipid levels, blood pressure, or electrolytes. It is conceivable that higher doses of atorvastatin protected against the harm caused by torcetrapib.

Safety and efficacy of inhaled human insulin (exubera) during discontinuation and readministration of therapy in adults with type 2 diabetes: a 3-year randomized controlled trial.

OBJECTIVE: This study assessed pulmonary safety following discontinuation and readministration of inhaled human insulin {Exubera [EXU] [Pfizer Inc., New York, NY] (insulin human [recombinant DNA origin]) inhalation powder} in adults with type 2 diabetes (T2DM). METHODS: Patients were randomized to receive EXU (n = 316) or subcutaneous (SC) insulin (n = 311) for 2 years (comparative phase), followed by 6 months of SC insulin (washout phase) and 6 months of original therapy (readministration). Highly standardized lung function tests were performed throughout all phases. RESULTS: Small, nonprogressive treatment group differences were observed to occur early during the comparative phase for parameters such as change from baseline for forced expiratory volume in 1 s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)). These differences resolved during washout and recurred to the same small magnitude during readministration. Both treatment groups maintained similar glycemic control and hypoglycemic event rates. In the EXU group, insulin antibody (IAb) levels reached a plateau at 9 months, declined to near baseline levels during washout, and increased during readministration to levels observed in the comparative phase. CONCLUSIONS: FEV(1) and DL(CO) changes observed during discontinuation and readministration of EXU therapy were consistent with a reversible, nonprogressive, and nonstructural pathologic effect on lung function in adults with T2DM. EXU readministration was not associated with an augmented IAb response.

Efficacy and safety of inhaled human insulin (Exubera) compared to subcutaneous insulin in children ages 6 to 11 years with type 1 diabetes mellitus: results of a 3-month, randomized, parallel trial.

AIM: To compare the efficacy and safety of Exubera (EXU) with subcutaneous (SC) insulin in children, ages 6-11 years, with type 1 diabetes mellitus. DESIGN AND METHODS: 121 children were randomized to receive EXU or SC insulin, plus intermediate/long-acting insulin for 12 weeks. Change in HbA1c was the primary efficacy endpoint. RESULTS: Decreases from baseline HbA1c were comparable between treatment groups (difference between adjusted mean decrease from baseline [EXU-SC insulin], -0.23 [95% CI, -0.49, 0.03]). Differences between groups on pulmonary function tests were small and not significant. Mild to moderate cough occurred in 24.6% of EXU versus 6.8% of SC insulin patients. The risk for hypoglycemia was comparable between EXU and SC insulin (relative risk 0.88 [95% CI, 0.71, 1.11]). Increased insulin antibodies with EXU were not associated with clinical findings. CONCLUSION: The efficacy and safety profiles shown in this study are the foundation for further investigation of EXU in this population.

Two-year pulmonary safety and efficacy of inhaled human insulin (Exubera) in adult patients with type 2 diabetes.

OBJECTIVE: The purpose of this study was to evaluate the 2-year pulmonary safety of inhaled human insulin (Exubera [EXU]) in 635 nonsmoking adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients were randomly assigned to receive prandial EXU or subcutaneous insulin (regular or short-acting) plus basal (intermediate- or long-acting) insulin. The primary end points were the annual rate of decline in forced expiratory volume in 1 s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)). RESULTS: Small differences in FEV(1) favoring subcutaneous insulin developed during the first 3 months but did not progress. Adjusted treatment group differences in FEV(1) annual rate of change were -0.007 l/year (90% CI -0.021 to 0.006) between months 0 and 24 and 0.000 l/year (-0.016 to 0.016) during months 3-24. Treatment group differences in DL(CO) annual rate of change were not significant. Both groups sustained similar reductions in A1C by month 24 (last observation carried forward) (EXU 7.7-7.3% vs. subcutaneous insulin 7.8-7.3%). Reductions in fasting plasma glucose (FPG) were greater with EXU than with subcutaneous insulin (adjusted mean treatment difference -12.4 mg/dl [90% CI -19.7 to -5.0]). Incidence of hypoglycemia was comparable in both groups. Weight increased less with EXU than with subcutaneous insulin (-1.3 kg [-1.9 to -0.7]). Adverse events were comparable, except for a higher incidence of mild cough and dyspnea with EXU. CONCLUSIONS: Two-year prandial EXU therapy showed a small nonprogressive difference in FEV(1) and comparable sustained A1C improvement but lower FPG levels and less weight gain than seen in association with subcutaneous insulin in adults with type 2 diabetes.

Intersession variability in single-breath diffusing capacity in diabetics without overt lung disease.

RATIONALE: American Thoracic Society guidelines state that a 10% or greater intersession change in diffusing capacity of the lung (DL(CO)) should be considered clinically significant. However, little is known about the short-term intersession variability in DL(CO) in untrained subjects or how variability is affected by rigorous external quality control. OBJECTIVES: To characterize the intersession variability of DL(CO) and the effect of different quality control methods in untrained individuals without significant lung disease. METHODS: Data were pooled from the comparator arms of 14 preregistration trials of inhaled insulin that included nonsmoking diabetic patients without significant lung disease. A total of 699 participants performed repeated DL(CO) measurements using a highly standardized technique. A total of 948 participants performed repeated measurements using routine clinical testing. MEASUREMENTS AND MAIN RESULTS: The mean intersession absolute change in DL(CO) using the highly standardized method was 1.45 ml/minute/mm Hg (5.64%) compared with 2.49 ml/minute/mm Hg (9.52%) in the routine testing group (P < 0.0001 for both absolute and percent difference). The variability in absolute intersession change in DL(CO) increased with increasing baseline DL(CO) values, whereas the absolute percentage of intersession change was stable across baseline values. Depending on the method, 15.5 to 35.5% of participants had an intersession change of 10% or greater. A 20% or greater threshold would reduce this percentage of patients to 1 to 10%. CONCLUSIONS: Intersession variability in DL(CO) measurement is dependent on the method of testing used and baseline DL(CO). Using a more liberal threshold to define meaningful intersession change may reduce the misclassification of normal variation as abnormal change.

Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.

BACKGROUND: Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia. METHODS: We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4.8) months. This trial is registered with ClinicalTrials.gov, number NCT00134238. FINDINGS: The change in maximum carotid intima-media thickness was 0.025 (SD 0.005) mm per year in patients given torcetrapib with atorvastatin and 0.030 (0.005) mm per year in those given atorvastatin alone (difference -0.005 mm per year, 95% CI -0.018 to 0.008, p=0.46). Patients in the combined-treatment group had a 63.4% relative increase in HDL cholesterol (p<0.0001) and an 17.7% relative decrease in LDL cholesterol (p<0.0001), compared with controls. Systolic blood pressure increased by 6.6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatin-only group (difference 5.4 mm Hg, 95% CI 4.3-6.4, p<0.0001). INTERPRETATION: Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.

Effect of torcetrapib on the progression of coronary atherosclerosis.

BACKGROUND: Levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, increases HDL cholesterol levels, but the functional effects associated with this mechanism remain uncertain. METHODS: A total of 1188 patients with coronary disease underwent intravascular ultrasonography. After treatment with atorvastatin to reduce levels of low-density lipoprotein (LDL) cholesterol to less than 100 mg per deciliter (2.59 mmol per liter), patients were randomly assigned to receive either atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily. After 24 months, disease progression was measured by repeated intravascular ultrasonography in 910 patients (77%). RESULTS: After 24 months, as compared with atorvastatin monotherapy, the effect of torcetrapib-atorvastatin therapy was an approximate 61% relative increase in HDL cholesterol and a 20% relative decrease in LDL cholesterol, reaching a ratio of LDL cholesterol to HDL cholesterol of less than 1.0. Torcetrapib was also associated with an increase in systolic blood pressure of 4.6 mm Hg. The percent atheroma volume (the primary efficacy measure) increased by 0.19% in the atorvastatin-only group and by 0.12% in the torcetrapib-atorvastatin group (P=0.72). A secondary measure, the change in normalized atheroma volume, showed a small favorable effect for torcetrapib (P=0.02), but there was no significant difference in the change in atheroma volume for the most diseased vessel segment. CONCLUSIONS: The CETP inhibitor torcetrapib was associated with a substantial increase in HDL cholesterol and decrease in LDL cholesterol. It was also associated with an increase in blood pressure, and there was no significant decrease in the progression of coronary atherosclerosis. The lack of efficacy may be related to the mechanism of action of this drug class or to molecule-specific adverse effects. (ClinicalTrials.gov number, NCT00134173 [ClinicalTrials.gov].).

Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia.

BACKGROUND: Torcetrapib, an inhibitor of cholesteryl ester transfer protein, may reduce atherosclerotic vascular disease by increasing levels of high-density lipoprotein (HDL) cholesterol. METHODS: A total of 850 patients with heterozygous familial hypercholesterolemia underwent B-mode ultrasonography at baseline and at follow-up to measure changes in carotid intima-media thickness. The patients completed an atorvastatin run-in period and were subsequently randomly assigned to receive either atorvastatin monotherapy or atorvastatin combined with 60 mg of torcetrapib for 2 years. RESULTS: After 24 months, in the atorvastatin-only group, the mean (+/-SD) HDL cholesterol level was 52.4+/-13.5 mg per deciliter and the mean low-density lipoprotein (LDL) cholesterol level was 143.2+/-42.2 mg per deciliter, as compared with 81.5+/-22.6 mg per deciliter and 115.1+/-48.5 mg per deciliter, respectively, in the torcetrapib-atorvastatin group. During the study, average systolic blood pressure increased by 2.8 mm Hg in the torcetrapib-atorvastatin group, as compared with the atorvastatin-only group. The increase in maximum carotid intima-media thickness, the primary measure of efficacy, was 0.0053+/-0.0028 mm per year in the atorvastatin-only group and 0.0047+/-0.0028 mm per year in the torcetrapib-atorvastatin group (P=0.87). The secondary efficacy measure, annualized change in mean carotid intima-media thickness for the common carotid artery, indicated a decrease of 0.0014 mm per year in the atorvastatin-only group, as compared with an increase of 0.0038 mm per year in the torcetrapib-atorvastatin group (P=0.005). CONCLUSIONS: In patients with familial hypercholesterolemia, the use of torcetrapib with atorvastatin, as compared with atorvastatin alone, did not result in further reduction of progression of atherosclerosis, as assessed by a combined measure of carotid arterial-wall thickness, and was associated with progression of disease in the common carotid segment. These effects occurred despite a large increase in HDL cholesterol levels and a substantial decrease in levels of LDL cholesterol and triglycerides. (ClinicalTrials.gov number, NCT00136981 [ClinicalTrials.gov].).