665
Randomized, Double-Blind, Placebo-Controlled, Clinic-Initiated, Canadian Multicenter Trial of Topical Edoxudine 3.0% Cream in the Treatment of Recurrent Genital Herpes Stephen L. Sacks, Lorne D. Tyrrell, David Lawee, Walter Schlech III, M. John Gill, Fred Y. Aoki, Alain Y. Martel, Jeroham Singer, and the Canadian Cooperative Study Group
Faculty of Medicine and Herpes Clinic, University of British Columbia, Vancouver; University of Toronto. Toronto General Hospital, and Ortho Pharmaceutical (Canada) Ltd., Don Mills. Ontario; University of Alberta. Edmonton. and University of Calgary, Alberta; Victoria General Hospital, Halifax, Nova Scotia; Health Sciences Center. Cadham Provincial Laboratory, and University ofManitoba, Winnipeg; Le Centre Hospitalier de L 'Universite Laval, Ste-Foy, Quebec
Genital herpes simplex virus (HSV) infection continues to be a major public health concern [1-3]. Although primary infections are more severe, recurrences are far more frequent and may remain troublesome and uncomfortable for the patient. Recurrent episodes generally follow a predictable lesion stage progression [4], often heralded by prodromal symptoms [5]. Oral acyclovir is the only product licensed for use in active symptomatic recurrent infection in nonimmunocompromised hosts, yet in most clinical trials, even when used in the early prodromal phases of infection, oral acyclovir has not generally reduced the symptoms of active recurrent genital infection in the normal host. Licensed, topical antivirals effective for treatment ofactive recurrent disease in the normal host are not yet available [4]. However, in a recent topical study of interferon-a in the treatment of recurrent genital herpes, antiviral and clinical benefits were observed [6] using a patient-initiated study design. Edoxudine (5-ethyl 2'-deoxyuridine) is a deoxythymidine
Received 18 December 1989; revised 24 May 1991. Presented in part: 27th Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, October 1987. Written informed consent was obtained from all participants before study in accordance with guidelines established by each center's independent review board and by Health and Welfare, Canada. Grant support: grant-in-aid, Ortho Pharmaceutical (Canada) Ltd. Reprints or correspondence: Dr. Stephen L. Sacks, Division of Infectious Diseases. Department of Medicine, University Hospital-UBC Site, 2211 Wesbrook Mall, Vancouver. BC V6T lZ3, Canada. The Journal of Infectious Diseases 1991;164:665-72 © 1991 by The University of Chicago. All rights reserved. 0022-1899/91/6404-0005$01.00
analogue that demonstrates significant in vitro and in vivo antiherpesviral activity, on the basis of selective phosphorylation by viral thymidine kinase [7-10]. To further explore the topical route for administration of antiviral therapy for genital herpes infection and to evaluate the efficacy and safety of topical 3% edoxudine cream, we conducted a Canadian, multicenter, randomized, double-blind, clinic-initiated trial comparing active treatment with its placebo cream. The results of that study are reported herein.
Patients and Methods Patients. Otherwise healthy patients, 16-60 years old, with a previous clinical diagnosis of genital herpes proven by viral culture were instructed to report for treatment within 6 h of the onset of a clinically evident recurrent lesion. Patients were considered eligible for efficacy analyses if they successfully reported for treatment within 9 h of lesion onset. Excluded from study were pregnant women, nursing mothers, women planning a pregnancy within the study period, patients who had received antiviral chemotherapy, topical corticosteroids, or any nonspecific therapy for genital HSV infection in the previous 7 days or immunotherapy or any investigational drug in the previous 30 days, subjects with an underlying immune deficiency, chronic alcoholism, or drug abuse or clinical suspicion of secondary bacterial infection of the affected area and women of childbearing potential who were not practicing adequate contraception. Study design. At or before the enrollment visit, subjects who fit the eligibility criteria were confirmed to be in good health by medical history and physical examination. Pregnancy was excluded by urine and serum tests. Volunteers were then ran-
Downloaded from http://jid.oxfordjournals.org/ at Yale University on July 6, 2015
Treatment for recurrent genital herpes using edoxudine 3% cream for 5 days was evaluated in 200 patients in a randomized, multicenter, double-blind, placebo-controlled, clinic-initiated trial. Lesion tenderness was predictive of and more sensitive and longer-lasting than the symptom of pain, Among patients receiving placebo, times to crusting (P = .043), cessation of investigator-observed signs (P = .005), lesion-associated signs (P = .02), and groin signs (P = .05) were longer in women. Edoxudine reduced viral shedding in men (mean 2.7 vs. 3.4 days, P = .009) and women (2.0 days vs. 3.5 days, P = .0001). Loss of investigator-observed signs (4.4 vs. 6.2 days, P = .002), investigator-observed lesion tenderness (P = .01), lesion signs (P = .02), groin adenopathy (P = .01), and tenderness (P = .01) occurred earlier in women taking edoxudine. Edoxudine was well-tolerated and reduced several signs of herpes in women. Its clinical role in recurrent genital herpes remains to be fully determined.
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Sacks et al.
for one-tailed tests were considered significant between treatments, while two-tailed tests were applied to all demographic, gender, and natural history comparisons. Times to end points were calculated from the time of application of medication to the point of cessation of the particular outcome measure. Cessation times were recorded for individual outcome measures (e.g., cessation oflesion tenderness) or for a group of outcome measures taken collectively (cessation of symptoms or signs) as noted. Negative outcomes followed by subsequent positives were considered positive if they occurred within the 5-day treatment period or negative thereafter. Patients whose first positive outcome occurred after the treatment period were censored from that particular outcome analysis.
Results Patients. A total of 210 subjects were entered into the study at seven study centers. Of these, 200 were available for efficacy analyses, including 103 edoxudine recipients, and 97 placebo recipients. The remaining 10 were excluded because of significant protocol violations (6) or voluntary withdrawal (4); these were 4 women (2 edoxudine, 2 placebo) and 6 men (2 edoxudine, 4 placebo). Of the efficacy-evaluatable subjects, 49, 18, and 15 edoxudine recipients and 47, 19, and 14 placebo recipients were studied in Vancouver, Toronto, and Edmonton, respectively. Four remaining centers enrolled the additional subjects. Efficacy-evaluatable women ranged in age from 17 to 59 years; men were 19-58 years old. Most of the study population (97% women, 93% men) were Caucasian. No statistically significant differences were found among treatment groups with regard to sex, race, or age. Characteristics at presentation. The characteristics ofgenitallesions before therapy are shown in table 1. For comparing treatment groups, each gender was analyzed separately. Only patients who applied the study medication within 9 h of lesion onset were included in efficacy analyses. The lesion sign "tenderness" was observed in 63 (61.1 %) of 103 men and 83 (85.6%) of 97 women. Of these patients, 38 men (60.3%) concomitantly denied the symptom "pain" compared with only 21 (25.3%) women (P = .001). Conversely, only 6 (15%) of 40 men (P = .009) and 5 (35.7%) of 14 women (P = .009) complained of pain while denying tenderness. By contrast, lesion tenderness did not correlate with all patient lesion symptoms taken as a whole (pain + itching + tingling) for men or women. For women versus men, respectively, lesion tenderness (85.6% vs. 61.1 %, P = .001), symptom pain (69.1% vs. 30.1%, P = .001), and all symptoms (96.9% vs. 79.6%, P = .00 1), but not lesion edema (38.1 % vs. 26.2%, P = .095) were observed significantly more frequently. The mean time from appearance of lesion to application of the study drug was
Randomized, Double-Blind, Placebo-Controlled, Clinic-Initiated, Canadian Multicenter Trial of Topical Edoxudine 3.0% Cream in the Treatment of Recurrent Genital Herpes Stephen L. Sacks, Lorne D. Tyrrell, David Lawee, Walter Schlech III, M. John Gill, Fred Y. Aoki, Alain Y. Martel, Jeroham Singer, and the Canadian Cooperative Study Group
Faculty of Medicine and Herpes Clinic, University of British Columbia, Vancouver; University of Toronto. Toronto General Hospital, and Ortho Pharmaceutical (Canada) Ltd., Don Mills. Ontario; University of Alberta. Edmonton. and University of Calgary, Alberta; Victoria General Hospital, Halifax, Nova Scotia; Health Sciences Center. Cadham Provincial Laboratory, and University ofManitoba, Winnipeg; Le Centre Hospitalier de L 'Universite Laval, Ste-Foy, Quebec
Genital herpes simplex virus (HSV) infection continues to be a major public health concern [1-3]. Although primary infections are more severe, recurrences are far more frequent and may remain troublesome and uncomfortable for the patient. Recurrent episodes generally follow a predictable lesion stage progression [4], often heralded by prodromal symptoms [5]. Oral acyclovir is the only product licensed for use in active symptomatic recurrent infection in nonimmunocompromised hosts, yet in most clinical trials, even when used in the early prodromal phases of infection, oral acyclovir has not generally reduced the symptoms of active recurrent genital infection in the normal host. Licensed, topical antivirals effective for treatment ofactive recurrent disease in the normal host are not yet available [4]. However, in a recent topical study of interferon-a in the treatment of recurrent genital herpes, antiviral and clinical benefits were observed [6] using a patient-initiated study design. Edoxudine (5-ethyl 2'-deoxyuridine) is a deoxythymidine
Received 18 December 1989; revised 24 May 1991. Presented in part: 27th Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, October 1987. Written informed consent was obtained from all participants before study in accordance with guidelines established by each center's independent review board and by Health and Welfare, Canada. Grant support: grant-in-aid, Ortho Pharmaceutical (Canada) Ltd. Reprints or correspondence: Dr. Stephen L. Sacks, Division of Infectious Diseases. Department of Medicine, University Hospital-UBC Site, 2211 Wesbrook Mall, Vancouver. BC V6T lZ3, Canada. The Journal of Infectious Diseases 1991;164:665-72 © 1991 by The University of Chicago. All rights reserved. 0022-1899/91/6404-0005$01.00
analogue that demonstrates significant in vitro and in vivo antiherpesviral activity, on the basis of selective phosphorylation by viral thymidine kinase [7-10]. To further explore the topical route for administration of antiviral therapy for genital herpes infection and to evaluate the efficacy and safety of topical 3% edoxudine cream, we conducted a Canadian, multicenter, randomized, double-blind, clinic-initiated trial comparing active treatment with its placebo cream. The results of that study are reported herein.
Patients and Methods Patients. Otherwise healthy patients, 16-60 years old, with a previous clinical diagnosis of genital herpes proven by viral culture were instructed to report for treatment within 6 h of the onset of a clinically evident recurrent lesion. Patients were considered eligible for efficacy analyses if they successfully reported for treatment within 9 h of lesion onset. Excluded from study were pregnant women, nursing mothers, women planning a pregnancy within the study period, patients who had received antiviral chemotherapy, topical corticosteroids, or any nonspecific therapy for genital HSV infection in the previous 7 days or immunotherapy or any investigational drug in the previous 30 days, subjects with an underlying immune deficiency, chronic alcoholism, or drug abuse or clinical suspicion of secondary bacterial infection of the affected area and women of childbearing potential who were not practicing adequate contraception. Study design. At or before the enrollment visit, subjects who fit the eligibility criteria were confirmed to be in good health by medical history and physical examination. Pregnancy was excluded by urine and serum tests. Volunteers were then ran-
Downloaded from http://jid.oxfordjournals.org/ at Yale University on July 6, 2015
Treatment for recurrent genital herpes using edoxudine 3% cream for 5 days was evaluated in 200 patients in a randomized, multicenter, double-blind, placebo-controlled, clinic-initiated trial. Lesion tenderness was predictive of and more sensitive and longer-lasting than the symptom of pain, Among patients receiving placebo, times to crusting (P = .043), cessation of investigator-observed signs (P = .005), lesion-associated signs (P = .02), and groin signs (P = .05) were longer in women. Edoxudine reduced viral shedding in men (mean 2.7 vs. 3.4 days, P = .009) and women (2.0 days vs. 3.5 days, P = .0001). Loss of investigator-observed signs (4.4 vs. 6.2 days, P = .002), investigator-observed lesion tenderness (P = .01), lesion signs (P = .02), groin adenopathy (P = .01), and tenderness (P = .01) occurred earlier in women taking edoxudine. Edoxudine was well-tolerated and reduced several signs of herpes in women. Its clinical role in recurrent genital herpes remains to be fully determined.
666
Sacks et al.
for one-tailed tests were considered significant between treatments, while two-tailed tests were applied to all demographic, gender, and natural history comparisons. Times to end points were calculated from the time of application of medication to the point of cessation of the particular outcome measure. Cessation times were recorded for individual outcome measures (e.g., cessation oflesion tenderness) or for a group of outcome measures taken collectively (cessation of symptoms or signs) as noted. Negative outcomes followed by subsequent positives were considered positive if they occurred within the 5-day treatment period or negative thereafter. Patients whose first positive outcome occurred after the treatment period were censored from that particular outcome analysis.
Results Patients. A total of 210 subjects were entered into the study at seven study centers. Of these, 200 were available for efficacy analyses, including 103 edoxudine recipients, and 97 placebo recipients. The remaining 10 were excluded because of significant protocol violations (6) or voluntary withdrawal (4); these were 4 women (2 edoxudine, 2 placebo) and 6 men (2 edoxudine, 4 placebo). Of the efficacy-evaluatable subjects, 49, 18, and 15 edoxudine recipients and 47, 19, and 14 placebo recipients were studied in Vancouver, Toronto, and Edmonton, respectively. Four remaining centers enrolled the additional subjects. Efficacy-evaluatable women ranged in age from 17 to 59 years; men were 19-58 years old. Most of the study population (97% women, 93% men) were Caucasian. No statistically significant differences were found among treatment groups with regard to sex, race, or age. Characteristics at presentation. The characteristics ofgenitallesions before therapy are shown in table 1. For comparing treatment groups, each gender was analyzed separately. Only patients who applied the study medication within 9 h of lesion onset were included in efficacy analyses. The lesion sign "tenderness" was observed in 63 (61.1 %) of 103 men and 83 (85.6%) of 97 women. Of these patients, 38 men (60.3%) concomitantly denied the symptom "pain" compared with only 21 (25.3%) women (P = .001). Conversely, only 6 (15%) of 40 men (P = .009) and 5 (35.7%) of 14 women (P = .009) complained of pain while denying tenderness. By contrast, lesion tenderness did not correlate with all patient lesion symptoms taken as a whole (pain + itching + tingling) for men or women. For women versus men, respectively, lesion tenderness (85.6% vs. 61.1 %, P = .001), symptom pain (69.1% vs. 30.1%, P = .001), and all symptoms (96.9% vs. 79.6%, P = .00 1), but not lesion edema (38.1 % vs. 26.2%, P = .095) were observed significantly more frequently. The mean time from appearance of lesion to application of the study drug was
