Disease Modification in Alzheimer's Disease: Current Thinking.

Alzheimer's disease (AD) has increasingly been recognized as a huge unmet medical need. Currently, there is no approved drug to cure, prevent, or even slow down the disease. It is imperative to develop disease-modifying treatments for AD to alter the underlying disease progression. This paper reviews the most up-to-date regulatory guidance on how to demonstrate disease modification and provides an overview of available methodologies and applications to clinical trials. The intent is to assist the field with future clinical trials designed to demonstrate disease-modifying effect in AD. The methodologies may be generalizable to broader neurodegenerative diseases.

A mixture model using likelihood-based and Bayesian approaches for identifying responders and non-responders in longitudinal clinical trials.

A longitudinal mixture model for classifying patients into responders and non-responders is established using both likelihood-based and Bayesian approaches. The model takes into consideration responders in the control group. Therefore, it is especially useful in situations where the placebo response is strong, or in equivalence trials where the drug in development is compared with a standard treatment. Under our model, a treatment shows evidence of being effective if it increases the proportion of responders or increases the response rate among responders in the treated group compared with the control group. Therefore, the model has flexibility to accommodate different situations. The proposed method is illustrated using simulation and a depression clinical trial dataset for the likelihood-based approach, and the same depression clinical trial dataset for the Bayesian approach. The likelihood-based and Bayesian approaches generated consistent results for the depression trial data. In both the placebo group and the treated group, patients are classified into two components with distinct response rate. The proportion of responders is shown to be significantly higher in the treated group compared with the control group, suggesting the treatment paroxetine is effective.

Missing data mechanisms in a dose-finding adaptive trial.

Although adaptive trials have become popular, little research has been done to investigate the effect of missing data in adaptive trials. We consider three different types of missing data mechanisms-missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR)-and introduce the "mixture missing mechanism" (MMM) to an adaptive three-period crossover study that uses the "maximizing procedure." These results are compared to a traditional nonadaptive equal allocation crossover study. Simulations suggest that certain missing data mechanisms can result in biased estimates. For equal allocation, the bias is uniform between treatments so treatment comparisons are unbiased. However, for the maximizing procedure, the bias is not uniform between treatments, so treatment comparisons are biased. For the MNAR and MMM mechanisms, unusually large bias occurs in the placebo group, leading to a substantial loss of power.

Placebo-controlled inpatient comparison of venlafaxine and fluoxetine for the treatment of major depression with melancholic features.

The objective of this study was to compare venlafaxine and fluoxetine with placebo in treating major depressive disorder with melancholic features. Adult inpatients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition major depressive disorder with melancholia and 21-item Hamilton Depression Rating Scale (HAM-D21) scores > or =24 (n=289) were randomized to receive (double-blind) venlafaxine 225-375 mg/day, fluoxetine 60-80 mg/day, or placebo for 6 weeks. The primary outcome measures were HAM-D21 total score, HAM-D depressed mood item, Montgomery Asberg Depression Rating Scale total score and the Clinical Global Impressions-Severity (CGI-S) and Improvement (CGI-I) scores. Last observation carried forward (LOCF) was the primary analysis method. In the LOCF analysis, venlafaxine was statistically superior to placebo on the CGI-S (venlafaxine -1.7, placebo -1.1; P=0.003) and the HAM-D depressed mood item (venlafaxine -1.6, placebo -1.1; P=0.010); and to fluoxetine on the CGI-S (-1.2; P=0.012). No significant differences were observed on the other 12 LOCF primary efficacy comparisons. Increases in pulse and blood pressure, dry mouth, constipation, and lightheadedness were significantly more common with venlafaxine than fluoxetine. Venlafaxine was statistically superior to placebo on two of five primary and two of five secondary outcome measures and to fluoxetine on one primary and one secondary outcome measure (LOCF). Venlafaxine was not superior to fluoxetine or placebo in providing remission.

Comprehensive analysis of remission (COMPARE) with venlafaxine versus SSRIs.

BACKGROUND: To compare venlafaxine and selective serotonin reuptake inhibitors (SSRIs; fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram) in the treatment of depression. METHODS AND MATERIALS: Meta-analysis of 34 randomized, double-blind studies identified by a worldwide search of all research sponsored by Wyeth Pharmaceuticals through January 2007. Patients were treated with venlafaxine (n = 4191; mean dose 151 mg/day) or SSRIs (n = 3621); nine studies also included a placebo control group (n = 932). The primary outcome measure was intent-to-treat (ITT) remission rates (Hamilton Rating Scale for Depression

A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in adult outpatients with major depressive disorder.

OBJECTIVE: This study evaluated the efficacy and tolerability of desvenlafaxine succinate (desvenlafaxine) in the treatment of major depressive disorder (MDD). METHOD: In this 8-week, multicenter, randomized, double-blind, placebo-controlled trial, adult outpatients (aged 18-75 years) with a primary diagnosis of MDD (DSM-IV criteria) were randomly assigned to treatment with desvenlafaxine (100-200 mg/day) or placebo. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression (HAM-D(17)) score at final on-therapy evaluation. The Clinical Global Impressions-Improvement scale (CGI-I) was the key secondary measure. Other secondary measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Severity of Illness scale, Visual Analog Scale-Pain Intensity (VAS-PI) overall and subcomponent scores, and HAM-D(17) response and remission rates. The study was conducted from June 2003 to May 2004. RESULTS: Of the 247 patients randomly assigned to treatment, 234 comprised the intent-to-treat population. Following titration, mean daily desvenlafaxine doses ranged from 179 to 195 mg/day. At endpoint, there were no significant differences in scores between the desvenlafaxine (N = 120) and placebo (N = 114) groups on the HAM-D(17) or CGI-I. However, the desvenlafaxine group had significantly greater improvement in MADRS scores (p = .047) and in VAS-PI overall pain (p = .008), back pain (p = .006), and arm, leg, or joint pain (p < .001) scores than the placebo group. The most common treatment-emergent adverse events (at least 10% and twice the rate of placebo) were nausea, dry mouth, constipation, anorexia, somnolence, and nervousness. CONCLUSION: Desvenlafaxine was generally safe and well tolerated. In this study, it did not show significantly greater efficacy than placebo on the primary or key secondary efficacy endpoints, but it did demonstrate efficacy on an alternate depression scale and pain measure associated with MDD. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00063206.

A randomized controlled trial of venlafaxine ER and paroxetine in the treatment of outpatients with panic disorder.

RATIONALE: Few randomized, placebo-controlled trials have evaluated the comparative efficacy and tolerability of more than one pharmacological agent for panic disorder. OBJECTIVES: The primary objective of this study was to compare the efficacy and tolerability of venlafaxine extended release (ER) with placebo in treating panic disorder. Secondary objectives included comparing paroxetine with venlafaxine ER and placebo. METHODS: Outpatients aged > or =18 years (placebo, n = 157; venlafaxine ER 75 mg, n = 156; venlafaxine ER 225 mg, n = 160; paroxetine, n = 151), with a primary diagnosis of panic disorder (+/-agoraphobia) based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for > or =3 months were randomly assigned to receive venlafaxine ER (titrated to 75 mg/day or 225 mg/day), paroxetine (titrated to 40 mg/day), or placebo for 12 weeks. The primary efficacy measure was the percentage of patients free of full-symptom panic attacks (> or = four symptoms) at endpoint. Key secondary outcomes included the Panic Disorder Severity Scale (PDSS) mean score change and response. RESULTS: At endpoint, all active treatment groups showed a significantly (P < 0.01) greater proportion of patients free of full-symptom panic attacks, compared with placebo, and were superior (P < 0.05) on most secondary measures. The venlafaxine ER 225 mg group had significantly (P < 0.05) greater mean PDSS score improvement than the paroxetine group (-12.58 vs -11.87) and a significantly higher proportion of patients free of full symptom panic attacks (70.0 vs 58.3%). Both drugs were generally well tolerated. CONCLUSION: Venlafaxine ER 75 mg/days and 225 mg/days and paroxetine 40 mg/day were both well tolerated and effective for short-term treatment of panic disorder.

A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder.

OBJECTIVE: This study evaluated the efficacy and safety of desvenlafaxine succinate extended-release in major depressive disorder (MDD). METHOD: Adult outpatients with DSM-IV-defined MDD were randomly assigned to desvenlafaxine 100 mg/day (N = 114), 200 mg/day (N = 116), or 400 mg/day (N = 113) or placebo (N = 118) for 8 weeks. Efficacy variables included change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D(17), the primary efficacy measure), Clinical Global Impressions-Improvement scale (CGI-I), Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions-Severity of Illness scale (CGI-S), rates of response (> or = 50% decrease from baseline HAM-D(17) score) and remission (HAM-D(17) score < or =7), and Visual Analog Scale-Pain Intensity overall score. The study was conducted from November 2003 to November 2004. RESULTS: At the final on-therapy evaluation, the mean HAM-D(17) scores for desvenlafaxine 100 mg/day (12.75) and 400 mg/day (12.50) were significantly lower than for placebo (15.31; p = .0038 and p = .0023, respectively); for desvenlafaxine 200 mg/day, the mean score was 13.31 (p = .0764). CGI-I and Montgomery-Asberg Depression Rating Scale results were significant for all groups; CGI-S results were significant with 100 mg/day and 400 mg/day. Response rates were significantly greater for desven-lafaxine 100 mg/day (51%) and 400 mg/day (48%) versus placebo (35%; p = .017 and p = .046, respectively); the response rate for desvenlafaxine 200 mg/day was 45% (p = .142). Remission rates were significantly greater for desvenlafaxine 400 mg/day (32%) versus placebo (19%; p = .035); remission rates were 30% for desvenlafaxine 100 mg/day (p = .093) and 28% for desvenlafaxine 200 mg/day (p = .126). Visual Analog Scale-Pain Intensity results were significant for desvenlafaxine 100 mg/day versus placebo (p = .002), but not for the higher doses. The most commonly reported adverse events were nausea, insomnia, somnolence, dry mouth, dizziness, sweating, nervousness, anorexia, constipation, asthenia, and abnormal ejaculation/orgasm. CONCLUSIONS: Desvenlafaxine is effective and well tolerated in the short-term treatment of MDD.

Relapse prevention of panic disorder in adult outpatient responders to treatment with venlafaxine extended release.

OBJECTIVE: To compare the long-term efficacy of venlafaxine extended release (ER) with placebo in preventing panic disorder relapse in out-patient treatment responders. METHOD: Outpatients aged > or = 18 years who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for panic disorder with or without agoraphobia for at least the previous 3 months, with > or = 6 full symptom panic attacks in the 2 weeks prior to screening and > or = 3 in the 2 weeks before baseline and a Clinical Global Impressions-Severity of Illness rating > or = 4 at screen were eligible to participate. Outpatients received flexible-dose (75-225 mg/day) venla-faxine ER for 12 weeks. Treatment responders were randomly assigned to venlafaxine ER or placebo for 26 weeks. Criteria for response were < or = 1 panic attack per week during the last 2 weeks of open-label treatment and a Clinical Global Impressions-Improvement score of 1 or 2. The primary endpoint, time to relapse during double-blind treatment, defined as > or = 2 full symptom panic attacks per week for 2 consecutive weeks or discontinuation due to loss of effectiveness, was evaluated using Kaplan-Meier survival analysis. The study was conducted between December 2001 and August 2003. RESULTS: The intent-to-treat population had 291 patients in the open-label phase and 169 in the double-blind phase (placebo, N = 80; venlafaxine ER, N = 89; mean daily dose 165-171 mg). Time to relapse was significantly longer with venlafaxine ER than placebo (p < .001). All secondary measures of panic attack treatment efficacy, quality of life, and disability were significantly better with venlafaxine ER than placebo (p < or = .005). CONCLUSION: Venlafaxine ER was safe, well tolerated, and effective in preventing relapse in outpatients with panic disorder.

Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions.

OBJECTIVE: To investigate whether differences in antidepressant efficacy are moderated by an interaction of age and gender. METHODS: A pooled dataset from eight randomized, controlled trials of patients with major depressive disorder (MDD) was reanalyzed to compare remission rates following therapy with venlafaxine (n = 851), one of several selective serotonin reuptake inhibitors (SSRIs) (n = 748), or placebo (n = 446). Remission was defined as a final Hamilton Rating Scale for Depression (HAM-D) score < or =7. Pairwise comparisons were conducted using stepwise multiple logistic regression models with main effect and interaction terms for treatment, sex, and age (younger: <50; older: > or =50). Among older women, the impact of hormone replacement therapy (HRT) on remission rates also was examined. RESULTS: Remission rates on venlafaxine therapy were not affected by age, sex, or HRT use. Among women, but not men, there was a significant interaction reflecting poorer SSRI response in the older age group (Wald chi-square = 4.21, df = 1, p = 0.04); HRT appeared to eliminate this difference. Whereas the advantage in remission rates favoring venlafaxine was modest for men and younger women (6%-9%), the difference among older women not taking HRT was 23%. CONCLUSIONS: These findings provide further evidence that age, gender, and HRT moderate response to antidepressant medications.

Venlafaxine XR demonstrates higher rates of sustained remission compared to fluoxetine, paroxetine or placebo.

The combined serotonin-norepinephrine reuptake inhibitor, venlafaxine XR, has demonstrated significant response and remission in patients diagnosed with depression when measured with the Hamilton Depression Rating Scale (HAM-D). This pooled analysis of data from five studies compared the sustained remission of depressive symptoms in patients treated with venlafaxine XR, the selective serotonin reuptake inhibitors (SSRIs) fluoxetine or paroxetine, or placebo. Data from 1391 subjects enrolled in five active and placebo-controlled studies who met the DSM-III-R or DSM-IV criteria for major depressive disorder were analysed. Three treatment groups were compared: venlafaxine XR (n = 560), fluoxetine/paroxetine (n = 298) and placebo (n = 496). Mean treatment duration was 8 weeks. Responders were defined as those patients whose HAM-D-21 score decreased by > or = 50% from baseline. Remission was defined as a HAM-D-17 score < or = 7. Sustained remission was defined as maintenance of remission through week 8 or the end of treatment (if before week 8) and for > or = 2 weeks. Between-group rate comparisons in outcome measures were carried out using Fisher's exact and log-rank tests. Venlafaxine XR produced significantly higher rates of sustained remission in depressed patients compared to fluoxetine/paroxetine or placebo over this 8-week treatment period. As early as week 2, a significantly greater proportion of patients treated with venlafaxine achieved improved depression scores (remission and response). A significantly greater rate of remission and sustained remission occurred with venlafaxine compared to placebo. Remission was achieved earlier with venlafaxine and lasted throughout the remainder of the study. These results demonstrate that venlafaxine XR is more effective than fluoxetine/paroxetine for sustaining remission of depressive symptoms.

Venlafaxine versus placebo in the preventive treatment of recurrent major depression.

BACKGROUND: Major depression is often chronic and recurrent, yet most long-term therapeutic trials are not adequately designed to assess antidepressant efficacy in recurrence prevention. Long-term efficacy and safety of prophylactic venlafaxine treatment were evaluated in outpatients with recurrent major depression. METHOD: Patients with a history of recurrent DSM-III-R major depression received open-label treatment with venlafaxine, 100 to 200 mg/day, for 6 months. Those who responded to treatment (Hamilton Rating Scale for Depression [HAM-D(21)] score < or = 12, day 56) and remained relapse-free (no more than 2 HAM-D(21) scores > 10 and no Clinical Global Impressions-Severity of Illness [CGI-S] score > or = 4, months 2-6) either continued taking venlafaxine, 100 to 200 mg/day, or were switched in a double-blind fashion to placebo for 12 months. The primary efficacy outcome was the number of patients experiencing a recurrence of major depression (CGI-S score > or = 4). The cumulative probability of recurrence was calculated using the Kaplan-Meier method of survival analysis. Data were collected from November 1992 through December 1995. RESULTS: Of the 235 patients who enrolled in the recurrence-prevention period, 225 (N = 109, venlafaxine; N = 116, placebo) provided efficacy data. Survival analysis determined a 22% cumulative probability of recurrence in venlafaxine-treated patients after 12 months compared with 55% for the placebo group (p <.001). More than twice as many placebo-treated patients (48%) as venlafaxine-treated patients (21%) discontinued treatment because of lack of efficacy (p <.001). CONCLUSION: Twelve-month maintenance venlafaxine treatment was significantly more efficacious than placebo in preventing major depression recurrence in patients who had been successfully treated with venlafaxine for 6 months.

Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression.

BACKGROUND: Serotonergic and adrenergic enhancement may be synergistic and more effective than serotonergic enhancement alone in treating depression. The dual serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine is a dual reuptake inhibitor that may therefore offer greater efficacy than selective serotonin reuptake inhibitors (SSRIs). METHODS: Data from eight randomized, double-blind, controlled studies were pooled to compare efficacy in depressed patients receiving venlafaxine/venlafaxine extended release (XR), SSRIs, or placebo for

A critical examination of the sensitivity of unidimensional subscales derived from the Hamilton Depression Rating Scale to antidepressant drug effects.

Unidimensional subscales for assessment of major depression may be more sensitive to antidepressant drug effects than the Hamilton Depression Rating Scale (HAM-D). To further examine this possibility, we analyzed pooled data from eight comparable, well-controlled clinical trials of venlafaxine and compared such subscales and the 17-item HAM-D (HAM-D(17)) based on effect size and number of patients required for 80% power. Symptoms of depression were assessed using the HAM-D among intent-to-treat patients (2045) randomly assigned to receive venlafaxine (immediate release, n = 474; extended release, n = 377), one of several selective serotonin reuptake inhibitors (SSRIs) (n = 748), or placebo (n = 446) for up to 8 weeks. With SSRIs or venlafaxine vs. placebo, subscales yielded effect sizes (0.328-0.528) 16 to 76% larger than the HAM-D(17) did (0.237 and 0.396, respectively), and required 31 to 64% fewer patients for 80% power. With venlafaxine vs. SSRIs, the subscales showed no advantage over the HAM-D(17); all devices yielded comparable, positive effect sizes (0.183-0.195). Final subscale scores significantly predicted (all P < 0.05) whether patients met criteria for remission (eg, HAM-D(17) score of < or = 7). These findings suggest that unidimensional subscales are more sensitive to antidepressant drug effects than the HAM-D(17) is, but only in active agent/placebo comparisons. Our data further suggest the subscales can predict the presence of remission. Given these findings, prudent use of these subscales may be appropriate, cost-effective, and informative.

Global benefit-risk assessment of antidepressants: venlafaxine XR and fluoxetine.

BACKGROUND: Quantifying efficacy and safety differences between drugs is difficult because rigorous statistical methods to assess benefit and risk simultaneously are lacking. METHODS: Global benefit-risk (GBR) analysis of clinical trial data was used retrospectively to compare venlafaxine extended release (XR) and fluoxetine. Of 301 outpatients with moderate to severe depression given venlafaxine XR 75-225 mg/day (n=100), fluoxetine 20-60 mg/day (n=103), or placebo (n=98) for up to 8 weeks, 295 qualified for analysis. Primary efficacy variables were Hamilton Rating Scale for Depression (HAM-D) remission (final on-therapy score risk category were 2.1 (1.1-4.0) and 2.2 (1.1-4.3) for venlafaxine XR vs. fluoxetine and placebo, respectively. For CGI response, relative gains of venlafaxine XR were 1.39 (P<0.01) and 1.45 (P<0.01) vs. fluoxetine and placebo; benefit exceeded risk in 66, 53, and 52% of patients given venlafaxine XR, fluoxetine, and placebo (P=0.041 vs. venlafaxine XR), respectively. CONCLUSIONS: GBR analysis can be applied to a wide array of efficacy and safety data to form statistical tests of clinically meaningful treatment comparisons. In this comparison, the GBR assessments on response and remission significantly favored venlafaxine XR.

Global Benefit-risk Evaluation of Antidepressant Action: Comparison of Pooled Data for Venlafaxine, SSRIs, and Placebo.

Do antidepressants have an equivalent risk-benefit ratio? Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is an effective antidepressant for treating major depression. The results of some clinical studies have suggested that venlafaxine may have more potent efficacy in sustaining remission in patients with major depression. Comparative clinical studies, however, lack suitable power to discern treatment differences in safety and also lack a quantitative basis for comparing risk and benefit. A global benefit-risk analysis of pooled data from eight randomized, double-blind, clinical trials of the safety and efficacy of venlafaxine and selective serotonin reuptake inhibitors (SSRIs) was performed. By using the ratio measure of risk-benefit, patients treated with venlafaxine (n=851) for 6-8 weeks experienced a relative gain of 1.57 compared with SSRI-treated patients (n=743) and a relative gain of 2.27 compared with placebo-treated patients (n=439). Subgroup analyses showed a relative gain of 1.35 for venlafaxine-treated patients (n=538) compared with fluoxetine-treated patients (n=549) and a relative gain of 2.53 compared with placebo-treated patients (n=357). A dose-response relationship was apparent between low (<75 mg/day), medium (75-150 mg/day), and high (>150 mg/day) dosages of venlafaxine; r values were 0.758, 0.822, and 1.181, respectively (P=.023, high dosage versus placebo; P=.030, medium dosage versus placebo). Important differences in risk and benefit exist between venlafaxine and SSRIs as a group compared with fluoxetine alone. A significant gain in benefit-risk in the treatment of major depression was observed with an increase in venlafaxine dosage from 75->150 mg/day.