Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial.

BACKGROUND: Biological agents offer good control of rheumatoid arthritis, but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear. The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining (or not) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy. METHODS: This trial was done at 161 sites worldwide. Patients with early (<1 year duration) rheumatoid arthritis naive to methotrexate were randomly allocated (by interactive voice response system, in a 1:1 ratio, block size four) to adalimumab (40 mg every other week) plus methotrexate (initiated at 7·5 mg/week, increased by 2·5 mg every 1-2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks (period 1). Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target (28-joint disease activity score with C-reactive protein [DAS28]<3·2 at weeks 22 and 26) were randomised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks (period 2). Patients achieving the target with initial methotrexate continued methotrexate-monotherapy. Inadequate responders were offered adalimumab plus methotrexate. All patients and investigators were masked to treatment allocation in period 1. During period 2, treatment reallocation of patients who achieved the target was masked to patients and investigators; patients who did not achieve the target remained masked to original randomisation, but were aware of the subsequent assignment. The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78, compared between adalimumab-continuation and methotrexate-monotherapy. Adverse events were monitored throughout period 2. This trial is registered with ClinicalTrials.gov, number NCT00420927. FINDINGS: The study was done between Dec 28, 2006, and Aug 3, 2010. 1636 patients were assessed and 1032 were randomised in period 1 (515 to adalimumab plus methotrexate; 517 to placebo plus methotrexate). 466 patients in the adalimumab plus methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% [95% CI 2-28%], p=0·0225). Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups. INTERPRETATION: Treatment to a stable low disease activity target resulted in improved clinical, functional, and structural outcomes, with both adalimumab-continuation and methotrexate-monotherapy. However, a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone. Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate. FUNDING: AbbVie.

Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study.

OBJECTIVE: To assess the efficacy and safety of adalimumab plus methotrexate (ADA+MTX) compared with methotrexate monotherapy in achieving stable low disease activity (LDA; disease activity score (DAS28(CRP)) <3.2 at weeks 22 and 26) and clinical, radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis (RA). METHODS: 1032 patients with active RA were randomly assigned 1:1 to ADA+MTX or placebo plus methotrexate (PBO+MTX) for 26 weeks. Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP) <3.2 at weeks 22 and 26. Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission. RESULTS: Among patients completing 6 months, 44% (207/466) ADA+MTX versus 24% (112/460) PBO+MTX patients achieved stable LDA at weeks 22 and 26 (p<0.001). Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses, more clinical remissions, greater mean reductions in DAS28(CRP), no radiographic progression, and normal functional status at week 26 (p<0.001 for all). The only factor predicting stable LDA was disease activity at week 12. Patients achieving ACR/EULAR remission, particularly in the PBO+MTX group, had some advantage in radiographic outcomes compared with patients who only achieved LDA (but not remission). The overall frequency of adverse events was comparable between groups. There were more serious infections and deaths in the ADA+MTX group, with a possible age effect. CONCLUSIONS: Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical, radiographic and functional outcomes in patients with early active RA. Before initiating treatment with adalimumab, individual patient evaluation of the benefit/risk ratio should be carefully considered.

A double-blind, randomized, placebo-controlled study of the dopamine D3 receptor antagonist ABT-925 in patients with acute schizophrenia.

There is substantial preclinical and clinical evidence to suggest a potential role for the dopamine D3 receptor in the treatment of schizophrenia. ABT-925 is a selective dopamine D3 receptor antagonist with an approximately 100-fold higher in vitro affinity for dopamine D3 versus D2 receptors. This double-blind, randomized, placebo-controlled, escalating-dose, parallel-group study assessed the efficacy and safety of ABT-925 in the treatment of patients with acute exacerbation of schizophrenia. One hundred fifty-five patients were assessed over a 6-week double-blind treatment period (placebo: n = 48; ABT-925 50 mg once daily [QD]: n = 53; ABT-925 150 mg QD: n = 54). The primary efficacy measure was mean change from baseline to final evaluation on the Positive and Negative Syndrome Scale total score. Secondary measures of efficacy and pharmacokinetic parameters were also assessed. Safety assessments included adverse event monitoring, laboratory tests, vital signs, movement rating scales, and electrocardiogram measures. No statistically significant treatment effect was observed with ABT-925 50 mg QD or 150 mg QD compared with placebo on primary or secondary efficacy end points. Pharmacokinetic parameter estimates increased with dose in a linear fashion. ABT-925 50 mg QD and 150 mg QD were generally well tolerated, with adverse event profiles similar to that of placebo. Findings from a concurrent positron emission tomography study among healthy volunteers suggest that the ABT-925 doses used in this study may not have been sufficient to adequately occupy D3 receptors, thereby underscoring the importance of pharmacodynamic markers, such as PET, in determining appropriate compound doses before embarking on studies in a target population.

Suicidality and divalproex sodium: analysis of controlled studies in multiple indications.

BACKGROUND: Recent analyses of antiepileptic drugs have indicated an increase in the risk of suicidality. The objective of this report was to provide clinical information and an independent meta-analysis of divalproex sodium and suicidality events by analyzing data from 13 placebo-controlled studies and 1 low-dose controlled study. METHODS: Adverse events considered to be possibly suicide related were identified using the Columbia Classification Algorithm of Suicide Assessment (C-CASA) methodology. Indications included epilepsy, bipolar disorder, migraine prophylaxis, impulsive aggression, and dementia. Narratives were produced for every event, and suicidality event ratings were performed by a third party blinded to treatment assignment. Statistical analyses were conducted using methodology similar to that reported by the US Food and Drug Administration (FDA). RESULTS: Suicidality events were identified in 5 of the 13 placebo-controlled studies. Of the 1,327 (0.83%) subjects taking divalproex sodium, 11 had suicidality events: 2 suicide attempts and 9 suicidal ideation. Of 992 (0.91%) subjects taking placebo, 9 had suicidality events: 1 preparatory act toward suicide, 2 suicide attempts, and 6 suicidal ideation. Across placebo-controlled studies, the overall estimated odds ratio (OR) of suicidal behavior or ideation was 0.72 (95% CI 0.29 to 1.84). The OR for suicidal behavior was 0.37 (95% CI 0.04 to 2.58), and the OR for suicidal ideation was 0.90 (95% CI 0.31 to 2.79). CONCLUSIONS: In this meta-analysis, divalproex sodium does not appear to increase the risk of suicide-related adverse events relative to placebo in the populations studied. Clinicians should nonetheless remain vigilant in assessing suicidality, not only in patients treated for mental disorders with inherently high suicide risk, but also in patients taking antiepileptic medications.

Blockade of [11C](+)-PHNO binding in human subjects by the dopamine D3 receptor antagonist ABT-925.

Dopamine D3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [11C](+)-PHNO is the first preferential D3 receptor radioligand in humans, yet there are no blockade studies with a D3 receptor antagonist in humans. This study characterized the blockade of [11C](+)-PHNO binding by ABT-925, a D3 receptor antagonist, in healthy male subjects. Sixteen subjects underwent 2-3 positron emission tomography (PET) scans, at baseline and following one or two doses of ABT-925 ranging from 50 mg to 600 mg. Receptor occupancies were estimated for globus pallidus, substantia nigra, caudate, putamen, and ventral striatum. At the 600-mg dose (n=9), ABT-925 receptor occupancy (mean+/-s.d.) was higher in substantia nigra (75+/-10%) and globus pallidus (64+/-22%) than in ventral striatum (44+/-17%), caudate (40+/-18%) and putamen (38+/-17%) (ANOVA: F4,140=15.02, p<0.001). The fractions of [11C](+)-PHNO binding attributable to D3 receptors in D3 receptor-rich regions were 100% (substantia nigra) and 90% (globus pallidus), and in D2 receptor-rich regions were 55% (caudate) and 53% (putamen). The ED50 of ABT-925 was 4.37 microg/ml across regions. Our results demonstrate that [11C](+)-PHNO binding can be blocked by a D3 receptor antagonist and confirm preclinical findings that [11C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D3 receptors. Thus, [11C](+)-PHNO seems a suitable PET radiotracer to estimate D3 receptor occupancy in humans.

Dopaminergic activity in depressed smokers: a positron emission tomography study.

Tobacco dependence is highly prevalent in depressed patients. We assessed changes in [(11)C]-raclopride binding potential (BP) using positron emission tomography (PET) before and after the oral administration of d-amphetamine in healthy controls and unmedicated patients with current depression with and without current tobacco dependence. Over a single study day 2 [(11)C]-raclopride positron emission tomography scans were taken in 38 subjects: at baseline and 2 h following oral d-amphetamine 30 mg. Twenty controls (9 smokers, 11 nonsmokers) and 18 subjects with current major depressive episode (8 smokers, 10 non-smokers). Striatal [(11)C]-raclopride binding potential was measured before and after d-amphetamine administration. Depressed smokers had a lower baseline [(11)C]-raclopride binding potential compared with both control non-smokers (P < 0.007) and depressed non-smokers (P < 0.001). There was a main effect of smoking status on amphetamine-induced change in [(11)C]-raclopride binding potential (P < 0.02), but no main effect of depression. This may be due to a floor effect because of the low BP at baseline. Depressed subjects reported significant increase of positive mood after d-amphetamine administration compared with controls (depressed smokers vs. control smokers: P < 0.05; depressed non-smokers vs. controls: P < 0.055). Tobacco dependence appears to decrease d-amphetamine-induced changes in [(11)C]-raclopride binding potential as measured by positron emission tomography. Comorbid major depression and tobacco dependence exacerbates this effect, suggesting an altered dopamine system in comorbid patients.

A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents.

OBJECTIVE: To compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day double-blind study of bipolar disorder in children and adolescents and evaluate the safety of divalproex ER in a 6-month open-label extension study. METHOD: In the double-blind study, 150 patients (manic or mixed episode, aged 10-17 years) with baseline Young Mania Rating Scale (YMRS) score of 20 or higher were randomized to once-daily placebo or divalproex ER, which was titrated to clinical response or serum valproate concentration of 80 to 125 microg/mL. Sixty-six patients enrolled in the extension study. RESULTS: In the double-blind study, a treatment effect was not observed with divalproex ER based on change in mean YMRS score (divalproex ER -8.8 [n = 74]; placebo -7.9 [n = 70]) or secondary measures. Divalproex was similar to placebo based on incidence of adverse events. Four subjects treated with divalproex ER and three treated with placebo discontinued because of adverse events. Mean ammonia levels increased in the divalproex ER group, but only one patient was symptomatic. In the long-term study, YMRS scores decreased modestly (2.2 points from baseline). The most common adverse events were headache and vomiting. CONCLUSIONS: The results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder, mixed or manic state. Further controlled trials are required to confirm or refute the findings from this study.

Divalproex ER combined with olanzapine or risperidone for treatment of acute exacerbations of schizophrenia.

The objective of this study was to evaluate the efficacy and safety of divalproex sodium extended release (divalproex ER) vs placebo in combination with olanzapine or risperidone for the treatment of acute exacerbations of schizophrenia. In this 12-week, randomized, double-blind, parallel-group, multi-center trial, a total of 402 patients were randomized and treated; 103 received olanzapine/placebo, 99 received olanzapine/divalproex ER, 101 received risperidone/placebo, and 99 received risperidone/divalproex ER. Divalproex ER was initiated on day 1 at 20 mg/kg per day q AM and was titrated to clinical effect on days 3, 7, and 10, not to exceed a maximum dosage of 35 mg/kg per day. Olanzapine and risperidone were initiated at 5 and 2 mg/day q PM, respectively, increased to 10 and 4 mg/day on day 3, and increased to fixed target doses of 15 and 6 mg/day on day 6. No significant treatment difference was demonstrated between the combination therapy and antipsychotic monotherapy groups on the primary efficacy variable of the mean change from baseline to day 14 last observation carried forward on the Positive and Negative Syndrome Scale (PANSS) total score, although antipsychotic monotherapy did demonstrate superiority to combination therapy on the PANSS Negative subscale at several time points. Combination therapy also failed to show an advantage over antipsychotic monotherapy at day 84 on the PANSS total score. Most adverse events observed in the study were mild to moderate in severity, and the overall number of adverse events did not differ significantly between the combination therapy groups and their corresponding antipsychotic monotherapy group.

Long-term safety of divalproex sodium extended-release in children and adolescents with bipolar I disorder.

OBJECTIVE: The objective of this open-label study was to assess the safety of divalproex sodium extended-release in the treatment of children and adolescents with acute mania associated with bipolar I disorder. METHODS: This was a 6-month, Phase 3, open-label study in healthy subjects aged 9-17 years with a current Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition, Text Revision (DSM-IV-TR) diagnosis of bipolar I disorder manic or mixed episode. Divalproex sodium extended-release (DVPX-ER) was initiated at 15 mg/kg per day on day 1 (not to exceed 750 mg/day) with increases allowed to a maximum of 35 mg/kg per day. Study visits were conducted on day 1 and at months 1, 2, 3, and 6. Assessments included standard safety evaluations and appropriate rating scales for clinical effect. RESULTS: A total of 226 subjects were enrolled; 109 subjects completed the study. The most common adverse events were weight gain (16%), nausea (9%), and increased appetite (8%). Nonsymptomatic elevations of mean ammonia levels in plasma were observed. The mean Young Mania Rating Scale (YMRS) decreased 12.4 from baseline to final visit; small improvements were seen in behavior and caregiver stress ratings. CONCLUSIONS: DVPX-ER was generally well tolerated in children and adolescents with acute mania, with a side-effect profile similar to that observed in adults.