Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efficacy and safety (phase Iiib ALLOW study).

OBJECTIVES: To assess the effect of a temporary interruption in subcutaneous (SC) abatacept on immunogenicity, safety and efficacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial. METHODS: Following a 12-week open-label introduction (period I; intravenous abatacept loading dose and weekly fixed-dose SC abatacept 125 mg), patients were randomised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks (period II). At the end of period II, patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept (12-week open-label period III). The co-primary end points were ELISA-detected immunogenicity rate and safety at the end of period II. Efficacy was also monitored. RESULTS: Of 167 patients entering period I, 72% qualified for period II; during periods II and III, three patients discontinued treatment. Mean (SD) disease duration was 6.6 (6.5) years and Disease Activity Score 28 was 4.8 (0.8). The primary end point was met, with a non-significant increase in immunogenicity upon withdrawal (7/73 placebo vs 0/38 abatacept in period II; p=0.119) which was reversed upon reintroduction of SC abatacept (2/73 vs 1/38, end period III). Safety was comparable regardless of withdrawal, with no unexpected events upon reintroduction. Two patients experienced reactions at the SC injection site. On withdrawal, patients experienced slight worsening in efficacy which improved following reintroduction. CONCLUSIONS: Overall immunogenicity to SC abatacept is low, consistent with intravenous abatacept, and is not significantly affected by a 3-month interruption and reintroduction. This stop-start schedule was well tolerated, with little impact on safety and efficacy. These are important considerations for the clinical use of SC abatacept. CLINICALTRIALS: gov Identifier NCT00533897.

The effect of antipsychotic medication on sexual function and serum prolactin levels in community-treated schizophrenic patients: results from the Schizophrenia Trial of Aripiprazole (STAR) study (NCT00237913).

BACKGROUND: The aim of this paper is to evaluate the effect of antipsychotics for the treatment of schizophrenia in a community based study on sexual function and prolactin levels comparing the use of aripiprazole and standard of care (SOC), which was a limited choice of three widely used and available antipsychotics (olanzapine, quetiapine or risperidone) (The Schizophrenia Trial of Aripiprazole [STAR] study [NCT00237913]). METHOD: This open-label, 26-week, multi-centre, randomised study compared aripiprazole to SOC (olanzapine, quetiapine or risperidone) in patients with schizophrenia (DSM-IV-TR criteria). The primary effectiveness variable was the mean total score of the Investigator Assessment Questionnaire (IAQ) at Week 26. The outcome research variables included the Arizona Sexual Experience scale (ASEX). This along with the data collected on serum prolactin levels at week 4, 8, 12, 18 and 26 will be the focus of this paper. RESULTS: A total of 555 patients were randomised to receive aripiprazole (n = 284) or SOC (n = 271). Both treatment groups experienced improvements in sexual function from baseline ASEX assessments. However at 8 weeks the aripiprazole treatment group reported significantly greater improvement compared with the SOC group (p = 0.007; OC). Although baseline mean serum prolactin levels were similar in the two treatment groups (43.4 mg/dL in the aripiprazole group and 42.3 mg/dL in the SOC group, p = NS) at Week 26 OC, mean decreases in serum prolactin were 34.2 mg/dL in the aripiprazole group, compared with 13.3 mg/dL in the SOC group (p < 0.001). CONCLUSION: The study findings suggest that aripiprazole has the potential to reduce sexual dysfunction, which in turn might improve patient compliance.

Preference of medicine and patient-reported quality of life in community-treated schizophrenic patients receiving aripiprazole vs standard of care: results from the STAR study.

OBJECTIVE: To evaluate quality of life and patient preference for schizophrenia treatment in a community based study comparing the use of aripiprazole to the standard of care (SOC). METHOD: This open-label, 26-week, multi-centre, randomised study compared aripiprazole with SOC (olanzapine, quetiapine or risperidone) in patients with schizophrenia (DSM-IV-TR criteria). The primary effectiveness variable was the mean total score of the Investigator Assessment Questionnaire (IAQ) at Week 26. The outcome research variables included the Preference of Medicine (POM) questionnaire, the Quality of Life Scale (QLS), and the EuroQoL-5D (EQ-5D). The results from these outcome research variables are the focus of this paper addressing quality of life and patient preference. RESULTS: A total of 555 patients were randomised to receive aripiprazole (n=284) or SOC (n=271). The OC data at Week 26, reported that more respondents rated the study medication as 'much better' compared with their previous medication in the aripiprazole group versus SOC for patients (59% vs 35%, P<0.001) and caregivers (58% vs 30%, P=0.014). The improvement in QLS total score was also significantly greater in the aripiprazole group compared with SOC--mean change from baseline in QLS total score of 16.21 vs 10.01 (P<0.001) at Week 26 (OC data set). A greater proportion of patients (93% vs 85%; P=0.005) in the aripiprazole group had a satisfactory response on the EQ-5D Self Care Scale; all other EQ-5D scores were similar. CONCLUSION: The study findings suggest that quality of life and patient medication preference measures were better for aripiprazole than for SOC.

A multicentre, randomized, naturalistic, open-label study between aripiprazole and standard of care in the management of community-treated schizophrenic patients Schizophrenia Trial of Aripiprazole: (STAR) study.

BACKGROUND: Naturalistic effectiveness trials of atypical antipsychotics are needed to provide broader information on efficacy, safety, and tolerability in patients with schizophrenia treated in a community practice setting. METHOD: In this 26-week, open-label, multicentre study, patients with schizophrenia requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled were randomized to receive aripiprazole or an atypical antipsychotic standard of care (SOC) treatment (i.e., olanzapine, quetiapine, or risperidone based on the investigator's judgment of the optimal treatment for the individual patient and the patient's prior response to antipsychotic medication). The primary objective was to compare the effectiveness of a 26-week treatment of aripiprazole versus SOC, as measured by the Investigator Assessment Questionnaire (IAQ) total score at Week 26 last observation carried forward (LOCF) (primary endpoint), a validated measure that monitors relief or worsening of 10 key symptoms associated with the psychopathology of schizophrenia and side effects of antipsychotic treatment. Secondary objectives were to further assess effectiveness using the Clinical Global Impression - Global Improvement (CGI-I) and Clinical Global Impression - Severity of Illness scale, to assess time to treatment discontinuation, patient preference of medication, quality of life, and the tolerability of aripiprazole compared with SOC. RESULTS: Aripiprazole treatment (n=268) resulted in significantly better effectiveness than SOC treatment (n=254; P<0.001; Week 26 LOCF) as evidenced by the IAQ total score beginning at Week 4 (the first assessment point) and sustained through Week 26. A similar relationship was demonstrated among patients who completed the study (observed cases analysis); aripiprazole was associated with significantly better effectiveness at all time points with a greater differential effect from SOC over time. Patients treated with aripiprazole also demonstrated significantly greater improvements on the CGI-I scale (responder rate, P=0.009 at Week 26 LOCF), as well as on quality of life (Quality of Life scale total score; P<0.001 at Week 26). Furthermore, a significantly higher proportion of patients receiving aripiprazole rated their study medication as "much better" on the Preference of Medication Questionnaire (POM) scale than their pre-study medication compared with SOC patients (P<0.001; Week 26). Time to treatment discontinuation and rates of discontinuation due to adverse events were similar in both treatment groups. The incidence of patients with one or more extrapyramidal symptom (e.g., akathisia, dystonia, parkinsonian events, and residual events) was higher in patients receiving aripiprazole compared with patients treated with SOC (13.5% vs. 5.6%); however, a higher proportion of patients in the SOC-treated group had clinically significant weight gain (21.2% vs. 7.3% for aripiprazole) and potentially clinically relevant elevated fasting levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and serum prolactin compared with patients receiving aripiprazole. CONCLUSIONS: Aripiprazole is an effective atypical antipsychotic for the treatment of schizophrenia, demonstrating better effectiveness than SOC agents used in this study in patients for whom a switch in antipsychotic medication was warranted.

A prospective, multicenter, randomized, parallel-group, open-label study of aripiprazole in the management of patients with schizophrenia or schizoaffective disorder in general psychiatric practice: Broad Effectiveness Trial With Aripiprazole (BETA).

OBJECTIVE: BETA was designed to evaluate the overall effectiveness of aripiprazole in patients with schizophrenia or schizoaffective disorder treated in a general psychiatry outpatient practice setting. METHODS: In this 8-week, multicenter, open-label study, 1,599 outpatients with schizophrenia or schizoaffective disorder were randomly assigned to receive either aripiprazole (n=1,295) or another antipsychotic medication (safety control [SC] group; n=304). Aripiprazole was initiated at 15 mg/d with the option to adjust between 10-30 mg/d. The SC medication was specifically selected for each patient by the clinician and dosed according to prescribing guidelines for that medication. The primary effectiveness measure was the Clinical Global Impression-Improvement (CGI-I) score of the aripiprazole group at study end point. Secondary measures included response rates and preference of medicine (POM) ratings by patients and caregivers. RESULTS: Sixty-five percent of aripiprazole patients completed the study. The mean aripiprazole dose at end point was 19.9 mg/d, with approximately 39% of patients starting and remaining at 15 mg/d. At end point, the mean CGI-I score of 2.77 demonstrated that aripiprazole was minimally to moderately effective; the mean CGI-I score for the SC group was 3.59 indicating minimally effective to no change. Fifty-three percent of aripiprazole patients responded to treatment (CGI-I score of 1 or 2; last-observation-carried-forward [LOCF]), and approximately 71% of patients and caregivers rated aripiprazole as better than the prestudy medication on the POM (LOCF). Incidence and severity of adverse events (AEs) were similar to those reported in double-blind, randomized, placebo-controlled aripiprazole clinical trials. The most frequent AE in the aripiprazole group was insomnia (24%). CONCLUSIONS: Aripiprazole was effective for the treatment of schizophrenia and schizoaffective disorder in a general psychiatry outpatient practice setting. Overall, aripiprazole was found to be effective by the treating clinician and well accepted by patients and caregivers over the 8-week treatment course.

Glycemic control in patients with type 2 diabetes mellitus switched from twice-daily immediate-release metformin to a once-daily extended-release formulation.

BACKGROUND: The extended-release formulation of metformin (MXR) prolongs drug absorption in the upper gastrointestinal tract and permits once-daily dosing in patients with type 2 diabetes mellitus. This newer formulation may enhance patient compliance with oral therapy and improve long-term control of diabetes compared with the conventional immediate-release formulation of metformin (MIR). OBJECTIVE: The goal of this study was to determine the effects on glycemic control of a switch to MXR therapy in patients with type 2 diabetes currently treated with MIR. METHODS: This was a multicenter, randomized, double-blind, parallel-group study in patients with established type 2 diabetes. Eligible patients were to have a glycated hemoglobin (HbA1c) value < or = 8.5% and mean fasting plasma glucose (FPG) concentrations < or = 200 mg/dL while receiving MIR 500 mg BID for at least 8 weeks. After a 2-week, single-blind lead-in period, patients were randomly assigned to receive MXR 1000 or 1500 mg QD for 24 weeks or to continue MIR 500 mg BID for 24 weeks. The primary efficacy variable was change in HbA1c from baseline to week 12. Other variables included change in FPG levels; change in HbA1c; distribution of HbA1c values; mean daily blood glucose concentrations (self-monitored); levels of fructosamine, serum insulin, and lipids; and body weight. RESULTS: Two hundred seventeen patients were randomized to treatment. The mean change from baseline in HbA1c values at weeks 12 and 24 were small and similar in the 3 treatment groups. At week 12, the mean change from baseline in HbA1c was 0.15% for MIR, 0.23% for MXR 1000 mg, and 0.04% for MXR 1500 mg. The corresponding mean changes at week 24 were 0.06%, 0.25%, and 0.14%. CONCLUSIONS: In this study, patients with type 2 diabetes who had been receiving twice-daily MIR achieved comparable glycemic control when therapy was switched to once-daily MXR at the same or a greater total daily dose.

Multicenter, randomized, double-masked, parallel-group assessment of simultaneous glipizide/metformin as second-line pharmacologic treatment for patients with type 2 diabetes mellitus that is inadequately controlled by a sulfonylurea.

BACKGROUND: Many patients with type 2 diabetes mellitus (DM) with inadequate long-term blood glucose control with sulfonylurea or metformin monotherapy require additional treatment. The synergistic effects of combining glipizide with metformin on glucose control may be realized by treating the primary effects of type 2 DM, impaired insulin secretion, and insulin resistance. OBJECTIVE: This study assessed therapy with glipizide/metformin combination tablets in patients with type 2 DM that is uncontrolled by at least half the maximum labeled daily dose of a sulfonylurea. METHODS: In this multicenter, double-masked, parallel-group, active-controlled study, patients were randomized to receive glipizide 30-mg, metformin 500-mg, or glipizide/metformin 5/500 mg tablets for 18 weeks (metformin and glipizide/metformin doses were titrated to achieve blood glucose control). Maximum total daily doses were glipizide 30 mg, metformin 2000 mg, and glipizide/ metformin 20/2000 mg. RESULTS: A total of 247 patients were included in the study. The mean (SD) age was 56.2 (10.1) years; 61.5% of patients were male; 70.0% were white, 15.8% were Hispanic/Latino, 13.0% were black, and 1.2% were Asian/Pacific Islanders. Patients were, on average, obese (mean [SD] body mass index, 31.3 [4.7] kg/m2), had moderate to severe hyperglycemia (mean [SD] glycated hemoglobin [HbA1c], 8.7% [1.1]), and had a mean (SD) DM duration of 6.5 (4.9) years. Glipizide/ metformin tablets controlled the HbA1c level more effectively than did either glipizide or metformin monotherapies (mean treatment differences, in favor of glipizide/ metformin, of -1.06% and -0.98%, respectively, P < 0.001). At study end, an HbA1c level < 7.0% was achieved in approximately 4-fold more patients who were treated with glipizide/metformin (36.3%) compared with glipizide (8.9%) or metformin (9.9%) monotherapies. Glipizide/metformin tablets also reduced the fasting plasma glucose (FPG) level and the 3-hour postprandial glucose area under the concentration-time curve more effectively than did either monotherapy, without increasing the fasting insulin level. The greater blood glucose control with glipizide/ metformin tablets was achieved at a mean daily dose of glipizide/metformin 17.5/1747 mg, compared with mean doses of glipizide 30.0 mg or metformin 1927 mg. Treatments were well tolerated, with a low incidence of symptoms of hypoglycemia evidenced by a fingerstick blood glucose measurement < or = 50 mg/dL in the combination group (12.6%); 1 patient discontinued the study treatment for this reason. No patient required medical assistance for hypoglycemia. CONCLUSIONS: Glipizide/metformin tablets were more effective than either glipizide or metformin monotherapy in controlling HbA1c and in reducing FPG compared with baseline in patients with blood glucose that was uncontrolled with previous sulfonylurea treatment. In addition, patients receiving glipizide/ metformin were more likely to achieve an HbA1c level < 7.0%. These results were consistent with the synergistic effects on insulin resistance and beta cell dysfunction. Glipizide/metformin was well tolerated, with a low incidence of hypoglycemia.

A randomized comparative 96-week trial of boosted atazanavir versus continued boosted protease inhibitor in HIV-1 patients with abdominal adiposity.

BACKGROUND: Abdominal adiposity in HIV-1 patients initiating antiretroviral therapy may be part of a restoration-to-health phenomenon. Lipoatrophy is associated with long-term thymidine analogue therapy. Individual protease inhibitors (PIs) differ in their effects on lipids and insulin resistance. METHODS: A randomized open-label multicentre 96-week trial compared changes in fat distribution in patients with suppressed HIV-1 RNA and abdominal adiposity, who either continued on their current twice-daily ritonavir-boosted PI (PI/r) or switched to once-daily boosted atazanavir (ATV/r). Treatment with two nucleoside reverse transcriptase inhibitors was unchanged. Body composition was assessed by dual-energy x-ray absorptiometry (DEXA) and abdominal computerized tomography (CT) scanning. RESULTS: In total, 201 patients were randomized; 131 switched to ATV/r. Viral suppression (<50 copies/ml) was similarly maintained (93% ATV/r versus 89% PI/r). Mean changes from baseline in trunk-to-limb fat ratio were similar; difference estimates 0.03 (95% CI -0.06, 0.12; P=0.48 at week 48) and 0.02 (95% CI -0.10, 0.14; P=0.73 at week 96). More patients in the PI/r arm had a decrease of ≥20% in limb fat from baseline at week 96. Significantly greater reductions in proatherogenic lipids occurred following switch to ATV/r. Both treatment regimens were generally well-tolerated; the incidence of grade 3-4 treatment-related clinical adverse events was 34% among ATV/r recipients versus 4% of PI/r-treated patients. CONCLUSIONS: Switching to ATV/r had no demonstrable benefit on abdominal adiposity. Maintenance of efficacy, less limb fat loss and marked reduction in proatherogenic lipids was observed with ATV/r compared with continuing a PI/r regimen.

A prospective, multicentre, open-label study of aripiprazole in the management of patients with schizophrenia in psychiatric practice in Europe: Broad Effectiveness Trial with Aripiprazole in Europe (EU-BETA).

OBJECTIVE: To examine the effectiveness of aripiprazole in schizophrenia in a naturalistic setting in 14 European countries. METHODS: This multicentre, open-label study of aripiprazole evaluated outpatients with schizophrenia for whom a medication switch was clinically reasonable or antipsychotic initiation was required. Patients (n = 833) were randomized in a 4:1 ratio to aripiprazole (recommended starting dose 15 mg/day, permitted adjustment 10-30 mg/day) (n = 680) or another antipsychotic (safety control [SC] group) (n = 153) for 8 weeks. The control group received an antipsychotic different to their recent pre-study medication. The primary effectiveness measure was the Clinical Global Impression - Improvement (CGI - I) score of aripiprazole-treated patients at Week 8 (last observation carried forward [LOCF]). Patients' and caregivers' medication preference was assessed using the Preference of Medication (POM) questionnaire. The Investigator Assessment Questionnaire (IAQ) was used to record investigators' assessments of their patients' responses to the study antipsychotic. Adverse events (AEs) were recorded. RESULTS: At endpoint (Week 8, LOCF), the mean CGI - I score of 3.16 (95% confidence interval, [CI]: 3.04, 3.28) demonstrated the effectiveness of aripiprazole. At endpoint, 43% of aripiprazole-treated patients showed a response (CGI - I score = 1/2). Aripiprazole was rated as slightly or much better than previous antipsychotic at endpoint by 68% of patients and 65% of caregivers. The mean CGI - I score (Week 8, LOCF) for the SC group was 3.37 (95% CI: 3.14, 3.60). No major differences in the occurrence of AEs were noted between aripiprazole- and SC-treated patients. LIMITATIONS: As this is an open-label design, there may have been a bias. Secondly, the study was not powered to show differences between treatment groups and no statistical comparisons were planned. Thirdly, 8 weeks is too short to evaluate long-term effectiveness. CONCLUSIONS: Aripiprazole was effective, well tolerated and well accepted by patients and caregivers in this naturalistic study.