Do patients with alcohol dependence respond to placebo? Results from the COMBINE Study.

OBJECTIVE: The purpose of this study was to examine the nature of the effect of placebo medication plus accompanying medical management in the treatment of alcohol dependence. METHOD: The National Institute on Alcohol Abuse and Alcoholism COMBINE (Combining Medications and Behavioral Interventions) study, a randomized controlled double-blind trial of 1,383 alcohol-dependent patients, compared combinations of medications (acamprosate [Campral] and naltrexone [ReVia]) and behavioral therapy (medical management and specialist-delivered behavioral therapy) for alcohol dependence. This report focuses on a subset of that study population (n = 466) receiving (1) specialized behavioral therapy alone (without pills), (2) specialized behavioral therapy + placebo medication + medical management, or (3) placebo + medical management. RESULTS: During 16 weeks of treatment, participants receiving behavioral therapy alone had a lower percentage of days abstinent (66.6%) than did the participants receiving placebo and medical management (73.1%) or those receiving specialized behavioral therapy + placebo + medical management (79.4%). The group receiving behavioral therapy alone relapsed to heavy drinking more often (79.0%) than those receiving behavioral therapy + placebo + medical management (71.2%). This report focuses on potential explanations for this finding. The two groups of participants receiving placebo + medical management were more likely to attend Alcoholics Anonymous meetings during treatment (32.7% and 32.0% vs 20.4%) and were less likely to withdraw from treatment (14.1% and 22.9% vs 29.3%). CONCLUSIONS: There appeared to be a significant "placebo effect" in the COMBINE Study, consisting of pill taking and seeing a health care professional. Contributing factors to the placebo response may have included pill taking itself, the benefits of meeting with a medical professional, repeated advice to attend Alcoholics Anonymous, and optimism about a medication effect.

Combined pharmacotherapies and behavioral interventions for alcohol dependence (The COMBINE Study): examination of posttreatment drinking outcomes.

OBJECTIVE: The aim of this study was to examine the efficacy of pharmacological and behavioral interventions across 1 year posttreatment in the COMBINE (Combining Medications and Behavioral Interventions) Study. METHOD: Alcohol-dependent individuals (N = 1,383; 428 women) recruited at 11 outpatient academic alcoholism-treatment clinics across the United States participated in a randomized, double-blind, placebo-controlled trial. They received 16 weeks of naltrexone (Revia) or acamprosate (Campral) or both medications and/or placebos in combination with medical management (MM), with or without combined behavioral intervention (CBI); one group received CBI without pills or MM. Drinking behavior and clinical status were assessed at the end of treatment (Week 16) and at Weeks 26, 52, and 68. RESULTS: Prior treatment with active naltrexone, without active acamprosate or CBI or with active acamprosate plus CBI, and CBI with double placebo resulted in a significantly higher percentage of days abstinent than double placebos with no CBI (p < .05). Having received CBI was associated with positive clinical response posttreatment, compared with not having received CBI. Prior treatment with naltrexone increased the time to the first heavy-drinking day posttreatment (p = .03). No differences were found between patients who had received CBI without MM or pills and those having received MM and double placebo with or without CBI. No significant main effects for acamprosate were found on any of the outcome measures. CONCLUSIONS: Previous treatment with MM and either CBI or naltrexone, or both, but not acamprosate, was associated with sustained efficacy beyond discontinuation. Reasons for the maintained treatment gains with naltrexone and/or CBI and potential methods to extend them are discussed.

Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial.

CONTEXT: Alcohol dependence treatment may include medications, behavioral therapies, or both. It is unknown how combining these treatments may impact their effectiveness, especially in the context of primary care and other nonspecialty settings. OBJECTIVES: To evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence. INTERVENTIONS: Eight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral intervention (CBI). A ninth group received CBI only (no pills). Patients were also evaluated for up to 1 year after treatment. MAIN OUTCOME MEASURES: Percent days abstinent from alcohol and time to first heavy drinking day. RESULTS: All groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone x behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P<.001). One year after treatment, these between-group effects were similar but no longer significant. CONCLUSIONS: Patients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00006206.

Factorial designs in clinical trials: options for combination treatment studies.

OBJECTIVE: This study reviews the use of factorial designs in clinical trials investigating combinations of therapies. METHOD: Factorial designs may be used when (1) the factors are regarded as being independent or (2) the factors are thought to be complementary and a specific aim is to investigate these interactions. We describe what is meant by a factorial design and the issues that need to be addressed when using such a design. We discuss these issues in general and describe how they have been addressed in various prevention trials and in the COMBINE Study, which is a treatment trial of combinations of therapies for alcohol dependence. RESULTS: Trials of type (1) can provide substantial cost savings in conducting multiple unrelated prevention studies in the same group of participants. Such a factorial trial poses few design challenges beyond those of a standard parallel group trial. Trials of type (2) require consideration of aspects that are intrinsic to the factorial design. CONCLUSIONS: A factorial design is a useful way to examine the effects of combinations of therapies, but it poses challenges that need to be addressed in determining the appropriate sample size and in conducting interim and final statistical analyses.

Design and analysis of trials of combination therapies.

OBJECTIVE: Combination therapies can have significant advantages over monotherapies. Combinations of therapies can provide additive (or even synergistic) effects on efficacy. They may permit use of lower doses of each component to achieve a given level of efficacy, improving tolerability and reducing adverse effects. A multicomponent treatment may facilitate tailoring of therapy to the needs of individual patients (e.g., treatment augmentation in nonresponders). These characteristics seem highly attractive in developing treatment strategies for alcohol abuse and dependence, because existing monotherapies have shown modest efficacy, at best. METHOD: However, trials of combination therapies present challenges in design, execution and interpretation, including: (1) choice of the treatment combinations to be compared; (2) definition of primary and secondary hypotheses; (3) differences between interventions in the duration of treatment, the time lag from the start of treatment to an observable effect on outcomes and interval for assessment of efficacy; (4) study power/sample size; (5) logistics of treatment delivery, masking and outcome assessment; and (6) attribution of adverse events. RESULTS: Most of these issues arose in the COMBINE project, a sequence of trials intended to explore the use of combinations of behavioral and pharmacological approaches in the treatment of alcohol dependence. The resolution and impact of the challenges above for the COMBINE trial will be described. CONCLUSIONS: Trials of combination therapies address many important clinical questions; however, their level of complexity requires considerable forethought, pilot investigations and organization.

Use of a "psychotherapy with no pills" treatment condition as part of a combined pharmacotherapy-psychotherapy research study of alcohol dependence.

OBJECTIVE: The purpose of this article is to review issues related to the use of placebo medication in a study examining combined pharmacotherapy and psychotherapy for alcohol dependence. METHOD: Little is known about the strength of the placebo effect in alcohol-dependent patients. One way to study this is to compare placebo to no pharmacological treatment. The multisite National Institute on Alcohol Abuse and Alcoholism COMBINE Study is examining optimal combinations of two medications (acamprosate and naltrexone) and two behavioral treatments (a moderate-intensity treatment called Combined Behavioral Intervention [CBI] and a low-intensity treatment called Medical Management [MM]) for alcohol-dependent patients. The study initially included a 2 x 2 x 2 eight-cell design. This article relates our experience adding a ninth treatment condition (Cell 9), consisting of CBI alone, with no pills or MM. By comparing patients receiving CBI alone to patients receiving two placebos, MM and CBI, we can examine the strength of the placebo effect for these two medications in alcohol-dependent patients. Moreover, we can study CBI in the context in which it is frequently delivered clinically, that is, in the absence of pharmacotherapy and certainly in the absence of placebo medication. RESULTS: This article explains the background and rationale behind the decision to include Cell 9 in COMBINE. Recruitment challenges faced as a result of adding this condition are reviewed, as is the experience implementing this condition in a pilot feasibility study. CONCLUSIONS: The use of a "psychotherapy with no pills" treatment condition as part of a combined pharmacotherapy-psychotherapy study of alcohol dependence is feasible and can help enrich the results of this research.

How pilot studies improve large-scale clinical trials: lessons learned from the COMBINE Study.

OBJECTIVE: The design of a clinical trial to evaluate a potential therapy requires decisions about issues that include safety, efficacy, measurement, feasibility and training. Experience from the COMBINE Study, which tests the combination of medications and behavioral therapies for alcohol dependence, is presented as an example of how pilot studies improve large-scale clinical trials. METHOD: The COMBINE Pilot 1 inpatient study was designed to inform the main trial about the safety and tolerability of the doses of acamprosate (3 g/day) and naltrexone (100 mg/day) selected for study, alone and in combination. Pilot 2 was conducted as a feasibility study for the main trial, with the goals of (1) assessing the length of and compliance with research assessments, (2) developing methods for subject recruitment and staff training and (3) assessing the safety of the medications under less controlled outpatient conditions. RESULTS: Results from Pilot 1 provided safety information to support testing the medications in an outpatient study and contributed to the decision to incorporate dose reductions into the main trial protocol to manage adverse events. The results of Pilot 2 formed a basis for (1) reducing the length of the assessment battery, (2) having staff fully trained and recruitment procedures established for the main trial and (3) extending the drug safety results of Pilot 1 to outpatient conditions similar to those of the main trial. CONCLUSIONS: The COMBINE Study provides several examples of the successful application of pilot studies to inform the design of a clinical trial.

Aspects of social support associated with depression at hospitalization and follow-up assessment among cardiac patients.

PURPOSE: High levels of depressive symptoms have been shown to affect the morbidity, mortality, and functioning of patients with myocardial infarction (MI). Findings have shown that social support is associated with depression in both patient and community samples. This study examined various aspects of social support as they relate to depressive symptoms in patients with MI, both in the hospital and 2 weeks later. METHODS: As part of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) pilot study, measures of perceived social support, social networks, social support received, and social conflict were administered to 196 patients with MI. These patients also were administered the Beck Depression Inventory and the Hamilton Rating Scale for Depression. Depression was reassessed 2 weeks later. Relations between social support indicators and the depression measures were examined. RESULTS: The prevalence of depression symptoms was high, especially among poorer and younger patients. There was modest improvement across time. Patients with high social support scores, particularly those reflecting perceived support, had lower scores on depression measures at baseline. High levels of perceived support and low social conflict at baseline were associated with less follow-up depression, as measured by the Beck cognitive scale, but not the Beck somatic scale nor the Hamilton scale. There were few associations with measures of social networks and received support. CONCLUSIONS: Social support indicators were differentially related to depression among patients with MI while in the hospital and 2 weeks later. The pattern of associations also depended on the measure of depression. A broad assessment strategy of both social support and depression is needed for a full understanding of their interrelations.

A randomized controlled trial of a public health nurse directed treatment program for rural patients with high blood cholesterol.

BACKGROUND: Many rural residents do not have access to high-quality nutrition counseling for high blood cholesterol. The objective of this study was to assess the effectiveness of an intervention program designed to facilitate dietary counseling for hypercholesterolemia by rural public health nurses. METHODS: Eight health departments (216 participants) were randomized to give the special intervention (SI) and nine (252 participants) to give the minimal intervention (MI). The SI consisted of three individual diet counseling sessions given by a public health nurse, using a structured dietary intervention (Food for Heart Program), referral to a nutritionist if lipid goals were not achieved at 3-month follow-up, and a reinforcement phone call and newsletters. Diet was assessed by the Dietary Risk Assessment (DRA), a validated food frequency questionnaire, at baseline, 3-, and 12-month follow-up; blood lipids and weight were assessed at baseline, 3-, 6-, and 12-month follow-up. RESULTS: Participants were largely female (71%), older (mean age 55), and white (80%). At 3-month follow-up, the average reduction (indicating dietary improvement) in total Dietary Risk Assessment score was 3.7 units greater in the SI group (95% confidence interval [CI] 1.9 to 5.5, P = 0.0006), while both groups experienced a similar reduction in blood cholesterol, 14.1 mg/dL (0.37 mmol/L) for SI and 14.5 mg/dL (0.38 mmol/L) for minimal intervention group (difference -0.4 mg/dL [-0.010 mmol/L], 95% CI -12.5 to 11.7 [-0.32 to 0.30], P = 0.9). At 12-month follow-up, the reduction in total Dietary Risk Assessment score was 2.1 units greater in the SI group (95% CI 0.8 to 3.5, P = 0.005), while the reduction in blood cholesterol was similar in both groups, 18.4 mg/dL (0.48 mmol/L) for SI and 15.6 mg/dL (0.40 mmol/L) for minimal intervention group (difference 2.8 mg/dL [0.07 mmol/L], 95% CI -7.5 to 13.1 [-0.19 to 0.34], P = 0.6). During follow-up, weight loss was greater in the SI group; the difference between groups was statistically significant at 3 (1.9 lb [0.86 kg], 95% CI 0.3 to 3.4 [0.14 to 1.55], P = 0.022) and 6 months (2.1 lb [0.95 kg], 95% CI 0.1 to 4.1 [0.04 to 1.86], P = 0.04). At 12 months, the difference was not significant (1.6 lb [0.73 kg], 95% CI -0.05 to 3.7 [-0.02 to 1.68], P = 0.13). CONCLUSIONS: Improvement in self-reported dietary intake was significantly greater in the SI group, while reduction in blood cholesterol was similar in both groups.