depicts the disposition of COMBINE study participants into the groups used for analyses in this study. Of the 1,383 study participants in the COMBINE study, 54 (4%) did not provide sufficient information to compute the Babor typology, and 191 (14%) had missing values for the age-of-onset variable. Of the participants classified using the Babor typology (N= 1329 or 96% of the original sample), 829 were assigned Type A and 500 Type B. Of the participants we were able to include for the age-of-onset typology (N= 1192 or 86% of the original sample), 439 were classified as early onset and 753 as late onset. No relationships were found between missing intake data and treatment group assignment. provides intake demographic information and measures of alcohol use and consequences for the COMBINE sample divided by typologic classification. The pattern of differences seen between Types A and B was similar to that seen between early and late onset groups, but the differences were generally larger in magnitude in the Type A/B classification. The more severe category in both typologies (Type B, Early Onset), indicated that more impaired alcohol users were younger, less educated, less likely to be married, and more likely to be male. Likewise, both of the more severe subgroups reported more alcohol dependence symptoms and alcohol-related consequences. Interestingly, participants in both of the more severe categories reported drinking more drinks per drinking episode, but fewer drinking days relative to the less severely impaired participants.
Disposition of COMBINE study participants in analyses of typological effects
Intake Characteristics by Typologic Classification of the COMBINE Sample (S.D.)
A chi square test was done to assess the extent of agreement between the two typologies in classifying participants as less (Type A or late onset) or more (Type B or early onset) severely alcohol-impaired. Of the 1,143 participants with complete data, agreement between typologies was achieved with only 56.6% (n = 651) of the participants, χ2 (1) 8.89, p < .003. Both typologies placed 461 participants (40.3%) in the less severe group and 190 subjects in the more severe category (16.6%). Disagreements in classification included a similar number of false positives and negatives. Specifically, 233 (20.4%) participants were classified as Type A and early onset, while 259 (22.7%) were classified as Type B and late onset.
For the planned primary analyses, the sample was reduced to the participants in COMBINE study conditions of placebo + MM and naltrexone + MM (no CBI). Parallel secondary analyses were conducted in the two groups receiving placebo + MM+ CBI and naltrexone + MM + CBI. The reasoning for this was as follows. Results of the COMBINE study showed that the effect of naltrexone was limited to the patients who did not receive CBI (Anton et al., 2006
). Therefore, we expected that naltrexone-by-typology interactions were more likely to be significant in the MM-only condition. Participants receiving acamprosate were excluded from the analyses because the aim of the study was to investigate whether typology moderated the effects of opioid antagonism. Including the subjects who received acamprosate would have introduced the possibility that effects of acamprosate in particular subgroups (i.e., acamprosate-by-typology or acamprosate-by-naltrexone-by-typology interactions) could obscure the effects we were interested in. depicts the disposition of COMBINE participants for the analyses reported here. With these sample sizes, with alpha = .05, statistical power to detect a clinically significant effect size of d = .21 was .80 for the Babor typology and .75 for the age-of-onset typology in the MM-only groups. With alpha set at .025 to account for the two primary contrasts, the corresponding powers were .71 and .65, respectively.
To test whether alcohol typology moderated the effectiveness of naltrexone (relative to placebo) during the 16-week treatment phase of the trial, we used multivariate repeated measures that jointly included four (1-4) monthly values of PHDD as the within-subject factor and two between-subject factors: Typology (2 levels, A vs. B, late vs. early onset) and medication group (2 levels, placebo versus naltrexone). Baseline PHDD was included as a covariate.
reports the results of the two primary and two secondary repeated measure MANCOVAs with PHDD as the dependent variable. Among those receiving MM without CBI, A significant interaction was found between Babor typology and medication (p < .019), with no main effect of typology or medication. In contrast, for the age of onset typology, among the MM-only participants a main effect of medication was found (p < .035), but no effect of typology or typology-by-medication interaction. Among participants receiving CBI, for both typologies there was no significant main effect of medication or typology, and there was no significant interaction between medication and typology.
Moderating Effect of Alcohol Typology on Percentage Heavy Drinking Days During Active Medication Phase
To assess whether there were baseline differences that could account for the observed interactions between A vs. B typology and medication condition in the MM only groups, 2×2 ANOVAs were conducted for each of the continuous baseline variables included in , testing for the significance of the typology-by-medication interaction term. None of these was significant (p > .05). For the categorical variables in , 2 X 2 Chi square analyses were conducted for each level of each variable. Again, none of these was significant. Finally, additional MANCOVAs were performed with the Babor typology in the MM-only groups to assess whether participant characteristics not clearly related to typology could have accounted for the effect of the typology-by-medication interaction on PHDD. Age, gender, readiness for change (from the University of Rhode Island Change Assessment (URICA) (McConnaughy et al., 1983)), and baseline AA attendance (from the Form 90) were added one at a time to the model, along with their interaction with medication. In each case, the typology-by medication interaction remained significant.
depicts the mean monthly values of percentage heavy drinking days for the four groups involved in the observed interaction of Babor typology and medication in the participants receiving MM without CBI. As shown, the most favorable mean response to naltrexone was reported by Type A alcoholics, and simple main effect tests indicated that this group reported significantly fewer heavy drinking episodes relative to the other three groups at the 2-, 3-, and 4-month time points (F (3, 275) = 2.99, p < .032, F (3, 275) = 3.25, p < .02, and F (3, 275) = 3.83, p < .01, respectively). Descriptively, the magnitude of the observed advantage of naltrexone for Type A alcoholics relative to the next best mean outcome was moderate, e.g. d = .48 at 4 months.
Percent Heavy Drinking Days by Typology and Medication Condition
Additional and parallel repeated measure MANCOVAs were done to try to replicate the observed interaction in the MM condition, this time using secondary measures of alcohol use. A moderating effect was found with monthly PDA, again with Type A alcoholics faring better in the naltrexone group, F (1, 191) = 4.87, p < .013. Also similar to primary analyses, Type A alcoholics receiving placebo fared most poorly, with 15% lower mean values in abstinence frequency relative to Type A alcoholics receiving naltrexone. Using a measure of DPD, the moderating effect of typology was not significant, although a weak trend (p < .11) was observed favoring naltrexone in the type A group. Finally, Cox regression was conducted with days to first heavy drinking day (censored at 113 days) as the dependent measure. Main effects of group (placebo vs. naltrexone) and typology (Type A vs. B) were entered in step 1, and in step two the product term representing the group-by-typology interaction was entered. Neither the main effects nor the interaction term approached significance in this analysis.
To provide a more meaningful picture of the clinical significance of typology on response to naltrexone in the COMBINE study, depicts naltrexone vs. placebo end-of-treatment (weeks 13-16) outcomes for Type A and Type B alcoholics on three key drinking variables analyzed above: PHDD, PDA, and DPD. Percent achieving Good Clinical Outcome are also reported for the four groups. Highly significant (p < .002) differences on all four outcomes were found between naltrexone- and placebo-treated participants with Type A alcoholism. For Type B alcoholics, naltrexone- and placebo treated participants were not significantly different on any of these outcomes. The Type A naltrexone group also had significantly (p < .02) better outcomes on all four measures than either of the Type B groups.
End of Treatment Drinking Outcomes by Babor Typology: Naltrexone versus Placebo in the Medication Management Condition (no CBI)a