Received 5 December 2003; accepted 21 January 2004

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1 Journal of Antimicrobial Chemotherapy (2004) 53, DOI: /jac/dkh154 Advance Access publication 24 March 2004 Clinical significance of antiviral therapy for episodic treatment of herpes labialis: exploratory analyses of the combined data from two valaciclovir trials Spotswood L. Spruance 1 * and Joanne Hill 2 1 Division of Infectious Diseases, RM 4B319, University of Utah School of Medicine, 50 North Medical Drive, Salt Lake City, UT 84132, USA; 2 Department of Statistics, GlaxoSmithKline, Greenford, Middlesex, UK Received 5 December 2003; accepted 21 January 2004 Valaciclovir (Valtrex) 2 g twice daily for 1 day was recently approved in the United States for treatment of cold sores. In order to apply more clinically relevant assumptions to the analysis, we examined the effect of different missing data and endpoint assumptions on apparent valaciclovir efficacy. Results of each analysis demonstrate statistically significant increases in the proportion of subjects whose cold sores were aborted with valaciclovir compared with placebo, and significant decreases in healing times for subjects with cold sore lesions who were treated with valaciclovir compared with placebo. These exploratory analyses provide evidence of the robustness of the results to differing missing data assumptions and show that use of more clinically relevant endpoint assumptions increases the magnitude of some therapeutic responses. We also introduce a new measure that combines the two observed drug effects (reduced lesion duration, increased aborted lesions) into a single endpoint that captures the global benefit of the drug to the patient. Keywords: cold sores, HSV-1, valaciclovir Introduction Recurrent cold sores caused by herpes simplex virus type 1 (HSV-1) occur in 15 40% of adults worldwide 1 but finding an effective and convenient episodic treatment has been elusive. Valaciclovir, the L-valine ester prodrug of the acyclic guanosine analogue aciclovir, was developed to improve aciclovir bioavailability and was recently approved in the United States for the 1 day treatment of cold sores. The indication was based on the results of two randomized, placebocontrolled, multi-centre clinical trials of early, high-dose valaciclovir regimens in subjects ( 12 years of age) with histories of cold sores. 2 Subjects initiated treatment upon the first symptoms of a cold sore with either 2 g of valaciclovir twice daily for 1 day, 2 g of valaciclovir twice daily for 1 day and then 1 g of valaciclovir twice daily for 1 day, or matching placebo. In the 1 day treatment group, the median duration of the episode and time to lesion healing were reduced by approximately 1 day (P < 0.001) and the proportion of subjects in whom cold sore lesion development was aborted was increased by approximately 7% compared to placebo but did not reach statistical significance. Results were similar in the 1 and 2 day treatment groups and between studies. These studies provided evidence supporting a simple, safe and effective 1 day valaciclovir treatment regimen for cold sores. In order to apply more clinically relevant assumptions to the analysis, we combined the data set from the two studies and examined the effect of different missing data and endpoint assumptions on apparent drug efficacy. The missing data and endpoint assumptions for the primary and exploratory analyses are summarized in Figure 1. Exploratory analyses on the combined data set The primary analysis of the aborted lesion data in these studies 2 assumed that all of the subjects for whom information was unknown were treatment failures, i.e. that vesicular lesions occurred. This is a conservative assumption regarding the likely outcome for these subjects and almost certainly overestimated the percentage of subjects with vesicular lesions. Additional analyses were carried out that may be more clinically relevant whereby patients with missing information on lesion prevention were: (i) excluded, (ii) assumed to be treatment successes, i.e. assumed that vesicle formation was prevented or (iii) imputed at the placebo rate. In the previously published assessment of duration of episode and time to lesion healing, subjects with missing data were assigned either the maximum observed value plus 1 day, or assigned a value of 15 days, whichever was shorter. 2 Additional analyses were carried... *Corresponding author. Tel: ; Fax: ; woody.spruance@hsc.utah.edu JAC vol.53 no.5 The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.

2 Results of the exploratory analyses Figure 1. Missing data and endpoint assumptions in the primary and exploratory analyses. out where patients with missing data were: (i) excluded, (ii) assigned a value of zero days or (iii) assigned the overall median value. The initial analysis of time to lesion healing included data only for patients with classical lesions (i.e. vesicle, ulcer and/or crusts developed). 2 In order to assess the overall effect of valaciclovir on herpes labialis lesion healing, we present a post hoc analysis that includes cases where lesion formation was aborted. In this latter analysis, aborted lesions are included in the lesion healing time analysis by assigning them a classical lesion healing time of zero. Since results for the valaciclovir 1 day and 2 day treatment arms are comparable, we focus only on the 1 day arm here. Therefore, for this combined retrospective analysis, the intent-to-treat (ITT) population comprised1218 subjects: 609 in the placebo group and 609 in the 2 g valaciclovir twice daily for 1 day group. The population was predominantly female (74%) and white (93%) and the median age was 37.0 years. The median number of years with recurrent cold sore episodes was 20.0 and the median number of episodes of cold sores in the last 12 months was The primary reason for the missing data in these studies was premature discontinuation as a result of loss to follow-up. Prevention (abortion) of lesions The proportion of subjects in whom cold sore lesion development was aborted was 37% (223/609) of subjects in the placebo group and 44% (267/609) of subjects in the 1 day group when subjects with missing data were assumed treatment failures (primary analysis) (Table1). Cold sore lesion progression data were missing for 23 (4%) placebo-treated patients and 17 (3%) valaciclovir-treated patients. Exploratory analyses were carried out with missing data excluded, missing data assumed as successes (i.e. lesions aborted) or missing data imputed at the placebo rate and results are summarized in Table 1. Results of each analysis demonstrate a statistically significant increase in the proportion of subjects whose cold sores were aborted with valaciclovir compared with placebo, and provide evidence of the robustness of the results to differing missing data assumptions. Episode duration In the primary analysis (missing values imputed as 15 days), the duration of cold sore episodes (time to loss of crust for vesicular lesions, and return to normal skin for non-vesicular lesions) was significantly decreased (P < 0.001) by approximately 1 day for subjects in the valaciclovir treatment group compared to placebo (6.2 versus 5.2 days in the placebo and 1 day groups, respectively). Data were missing for 26 (4%) placebo-treated patients and 20 (3%) valaciclovir-treated patients. All missing data assumptions (values excluded, values imputed as zero days, or values imputed with the overall median) show statistically and clinically significant differences for the valaciclovir regimen over placebo and provide consistent estimates for the treatment differences and percent reduction in episode duration (Table 2 and Figure 2). Episode duration is an endpoint of interest to regulatory authorities and determines the amount of time between the onset of therapy and loss of crust (for subjects with vesicular lesions) or the time between the onset of therapy and the return of skin to a completely normal state no redness, no residual swelling (for subjects with aborted lesions). It has the drawback of being difficult to gauge, since the time point when redness disappears is subjective. Furthermore, persistence of redness is of little clinical significance to patients, who are more concerned with the duration of blisters, ulcers and eschars, which are captured by determination of lesion healing time. Lesion healing The mean time to cold sore lesion healing (time to loss of crust for patients with vesicular lesions) was 6.3 and 4.9 days for the placebo and 1 day treatment groups, respectively, in the primary analysis (Table 3). This analysis included only subjects with vesicular lesions. When all subjects were included in the analysis by assigning aborted lesions a healing time of zero days, mean healing time was reduced to 4.3 and 3.1 days for the placebo and 1 day treatment groups, and the effect of 1 day valaciclovir therapy increased from a 21% to 29% reduction in lesion healing time relative to the primary analysis (Figure 2). Data were missing for 27 (4%) placebo-treated patients and 21 (3%) valaciclovir-treated patients. Excluding missing values or assigning values of zero or the median healing time, rather than 15 days, resulted in a further decrease in healing times and an additional enhancement of the apparent valaciclovir effect. Significant treatment differences were observed for all of the sensitivity analyses (Table 3). The percent decrease in healing times for valaciclovir- 704

3 Table 1. Comparison of differences a in the percentage of aborted lesions using different missing data assumptions Aborted lesions (%) Analyses Primary: missing values assumed as treatment failures excluded imputed at placebo rate assumed as successes P values determined by Mantel Haenszel test stratified by study. a Differences (valaciclovir minus placebo) in percentage of patients with aborted lesions. Figure 2. Impact of sensitivity analyses on efficacy results for valaciclovir 1 day regimen. Primary analyses = missing values imputed as 15 days; Excluded = missing values excluded; 0 days = missing values imputed as 0 days; All = all subjects included; Median = missing values imputed with the median. Percent reduction in number of days refers to the decrease in mean days needed for lesion healing in valaciclovir-treated subjects compared with placebo. treated subjects for the different sensitivity analyses are summarized in Figure 2. As shown in Table 3 and Figure 2, the effect of treatment on lesion healing was consistently greater than on episode duration. This is because episode duration includes aborted lesions, and valaciclovir did not appear to affect the duration of aborted lesions (data not shown). Using lesion healing as an endpoint has been criticized because it excludes part of the data (aborted lesions). We feel aborted lesions can be included in lesion healing time by assigning them a value of zero. Since aborted lesions by definition do not contribute to time in the painful and disfiguring vesicle, ulcer and eschar stages, they are not lesions in the classic sense of cold sores, and assigning them a healing time of zero is justified. This endpoint redefinition has the further advantage of adding a qualitative element to time, since only the most troublesome periods of time are measured. Secondly, it (1.6, 12.9) (1.3, 12.8) (1.2, 12.6) (0.5, 12.0) has the advantage of capturing the effect of an agent which may increase the rate of aborted lesions, thereby expressing the drug s value to the patient in one global term. Discussion The different sensitivity analyses carried out on the data were based on inclusion of aborted lesion data and various missing data assumptions and are exploratory analyses that present the full range of potential clinical outcomes rather than a single analysis based on the most conservative assumptions. We feel that the assumptions we elected are more likely to reflect clinical reality. Use of more clinically relevant endpoint assumptions increased the magnitude of some therapeutic responses, such as lesion healing (Figure 2). Lesion healing, although a secondary endpoint in our studies, may actually be more important to the patient than episode duration since the lesion stages from vesicle to loss of crust are the most uncomfortable and disfiguring parts of the episode. In the primary analysis, patients with aborted lesions were excluded from the analysis of lesion healing. However, the population of patients with aborted lesions obviously includes some successfully treated patients, and their exclusion from the lesion healing analysis may bias the outcome against the drug. These exploratory analyses included aborted lesions in this measure by assigning them a lesion healing time value of zero reflecting the failure of a classical lesion to form. By doing so, we combined the two observed drug effects (reduced lesion duration, increased aborted lesions) into a single endpoint that captures the global benefit of the drug to the patient. This modified version of the lesion healing endpoint will likely be useful as a prospective primary endpoint in future herpes labialis studies. The magnitude of the treatment difference improves from a 21% reduction in the number of days to healing in the primary analysis to a 31% reduction for the 1 day valaciclovir group when missing values were excluded. This clinically meaningful improvement, in association with the convenience of 1 day therapy, should 705

4 Table 2. Comparison of differences a in duration of episode using different missing data assumptions Mean duration of episode (days) Analyses Primary: missing ( 1.4, 0.6) <0.001 values imputed as 15 days excluded ( 1.3, 0.6) < ( 1.2, 0.5) <0.001 as 0 days with the median (5 days) ( 1.2, 0.6) <0.001 Means are adjusted for study. a Differences in mean days are valaciclovir minus placebo. Table 3. Comparison of differences a in time to lesion healing using different missing data assumptions Only subjects with vesicular lesions: missing values imputed as 15 days Mean time to lesion healing (days) Treatment group: primary analysis placebo (n = 363); missing data 1% daily for 1 day (n = 325); missing data 1% Difference a (95% CI) P value ( 1.7, 0.9) <0.001 Mean time to lesion healing (days) Treatment group: all subjects b ( 1.7, 0.8) <0.001 as 15 days excluded ( 1.5, 0.8) < ( 1.5, 0.7) <0.001 as 0 days with the median (4.8 days) ( 1.5, 0.8) <0.001 Means are adjusted for study. a Differences in mean days are valaciclovir minus placebo. b Patients with aborted lesions were assigned a lesion healing time of zero days. motivate more patients and practitioners to manage cold sores with episodic antiviral therapy. Aborted lesions prevent the painful and disfiguring stages of cold sore episodes and are the most desirable outcomes of cold sore therapy. Combined analysis of data from these trials also show that 1 day high-dose valaciclovir therapy significantly increases the frequency of aborted lesions by 6 7% depending on the data assumptions used in the analysis. Although an increase in aborted lesions was noted in one large trial of valaciclovir for treatment of recurrent genital herpes, 3 this is the first time that an episodic antiviral treatment alone has achieved a clinically and statistically significant effect against naturally occurring cold sore lesions. 706

5 Acknowledgements Results of these studies were described in part in an oral presentation at the 15th International Conference on Antiviral Research, March 19, 2002, Prague, Czech Republic. Funding for this study was provided by GlaxoSmithKline. Transparency declarations Dr Spruance has been an investigator, speaker and consultant for GlaxoSmithKline and a consultant for Novartis and Medivir. Ms Hill is an employee of GlaxoSmithKline and holds stock options. References 1. Embil, J. A., Stephens, R. G. & Manuel, F. R. (1975). Prevalence of recurrent herpes labialis and aphthous ulcers among young adults on six continents. Canadian Medical Association Journal 113, Spruance, S., Jones, T., Blatter, M. et al. (2003). High-dose, shortduration, early valacyclovir therapy for the episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies. Antimicrobial Agents and Chemotherapy 47, Spruance, S. L., Tyring, S. K., DeGregorio, B. et al. (1996). A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group. Archives of Internal Medicine 156,