Therapeutic Effect of 1,5-Pentanediol for Herpes Simplex Labialis: a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

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1 Adv Ther (2009) 26(7): DOI /s y ORIGINAL RESEARCH Therapeutic Effect of 1,5-Pentanediol for Herpes Simplex Labialis: a Randomized, Double-Blind, Placebo-Controlled Clinical Trial Regina Busch Hans-Joachim Graubaum Joerg Gruenwald Jan Faergemann Received: May 20, 2009 / Published online: July 27, 2009 / Printed: July 29, 2009 Springer Healthcare Communications 2009 ABSTRACT Introduction: Most episodes of recurrent herpes labialis are self-limited and mild, but can be troublesome when they occur frequently with painful and unsightly lesions. Therefore, there has been much interest in developing agents that can suppress outbreaks in addition to being therapeutically effective. The objective of the present study was to examine the prophylactic and therapeutic efficacy of 1,5-pentanediol (PD) gel in patients with recurrent episodes of herpes labialis. Methods: In this placebo-controlled, randomized, double-blind clinical trial, a total of 105 patients with frequent episodes of recurrening, swelling, and pain in the PD group. herpes were randomized to either PD The global evaluation of efficacy by the inves- placebo. During the 26-week prophylactic phase of the study, the patients applied significant superiority for PD as opposed to tigators and patients showed a statistically placebo (P<0.001). Conclusion: Under the conditions used in the present study, PD did not Regina Busch Hans-Joachim Graubaum show any prophylactic effect against recurrence of herpes episodes. A significantly better Joerg Gruenwald Analyze & Realize AG, Waldseeweg 6, DE Berlin, Germany therapeutic effect of PD over placebo could be Jan Faergemann ( ) Sahlgrenska University Hospital, Clinic of Dermatology, SE Gothenburg, Sweden. jan.faergemann@derm.gu.se PD gel or placebo gel twice daily to both lips. Upon recurrence of an episode, a 5-day therapy phase started during which the gel was to be applied eight times daily. After the therapy phase, the patient resumed prophylactic treatment twice daily until the next herpes episode. The main outcome measures were number of herpes episodes during the prophylactic phase of 26 weeks, and successful therapy of occurring herpes episodes with a 5-day treatment. Results: There was no significant difference in recurrence rate between the two groups (P>0.05). During recurrence there was a statistically significant improvement regarding the therapeutic effect of the symptoms blister- demonstrated on the symptoms blistering, swelling, and pain. PD was very safe as no side effects were observed during the course of the study.

2 720 Adv Ther (2009) 26(7): Keywords: 1,5-pentanediol; double-blind; drug the fusion of the viral envelope with the plasma therapy; herpes labialis; placebo-controlled; membrane and the subsequent blocking of viral prophylaxis; topical replicative events Another agent of potential interest for the INTRODUCTION Herpes of the lips, also called herpes simplex labialis, is a common viral disease caused enhancing effect of the antimycotic, and antibacterial activity. 15,16 The molecule on the waterbinding capacity of the skin may be another by herpes simplex virus type 1, more seldom type 2. 1,2 Initially, small blisters appear important factor for the symptomatic relief on the lips. These areas are sensitive, painful, and itchy. The blisters fill with fluid, break open, and then heal after they have dried up and formed scabs. In the healing phase, painful cracks can appear due to the drying of the affected area. This delays the healing process. Recurrent disease is common and occurs in 20%-40% of the population in Western countries. 3-6 When an appropriate trigger occurs, such as illness, sunlight, trauma, emotional stress, or menses, the virus reactivates, leading to new episodes of blistering and mouth ulcers. 1 Most episodes of recurrent herpes labialis are self-limited and mild. However, it can be more than a nuisance when it occurs several times a year with painful and unsightly lesions. Therefore, there has been much interest in developing agents that not only effectively treat outbreaks, but also in agents that potentially can suppress outbreaks altogether. accordance with the guidelines for good clinical practice CPMP/ICH/135/95. Topical antivirals, such as acyclovir and penciclovir, have been shown to reduce the dura- interested in participating in the study received All patients tion of lesions, especially if applied frequently written information as well as a consent dec- from the prodromal phase. 1,2,4,7-10 Prophylactic treatment with oral acyclovir has been found to treatment of herpes is 1,5-pentanediol (PD). This simple low-toxicity molecule has an antiviral, of herpes infections. PD has been tested in an open, uncontrolled phase 2 trial. 16 In that study the healing time appeared shorter than that of a normal course of herpes episode. The present investigation was conducted in order to examine the clinical usefulness of PD, formulated in a cosmetically acceptable gel for topical application, in a placebo-controlled, double-blind clinical trial, for its prophylactic and therapeutic efficacy. MATERIALS AND METHODS Ethics Committee and Patient Information The study was approved by the Ethics Committee, Charité-University Medicine Berlin, Berlin, Germany. The study design, conduct of the trial, and the data handling were in laration form to be read at their convenience. Subsequently, there was a presentation of the study by the investigators, in which the be effective in one study. 11 However, other similarly conducted trials showed no significant difference between drug and placebo. 4 Aside from answered. If the patient was then prepared to risks were explained and possible questions antivirals, topical docosanol has been found to participate in the clinical trial, he or she confirmed this by signing the consent declaration reduce the healing time of herpes episodes. 4,12 The mode of action of docosanol is not yet clear, form. The clinical trial was conducted at four but may be a consequence of an inhibition of study centers in Berlin, Germany.

3 Adv Ther (2009) 26(7): Study Objectives after weeks) were performed. During the prophylactic phase the patients applied PD The objective of the study was to examine the or placebo gel twice daily to both lips. Upon prophylactic and therapeutic efficacy of PD gel occurrence of a herpes episode the patient given to patients with recurrent episodes of herpes labialis during a 6-month period, as compared and presented herself/himself promptly to the started immediately with the therapy phase with the efficacy of placebo gel. The primary study participating investigator for confirmation of objective was to determine if prophylactic treatment could reduce the number of herpes episodes during 6 months as compared with the number of herpes episodes occurring in the placebo group. The secondary study objective was to determine if therapeutic treatment with PD initiated at the patients should have had at least six episodes of recurrent herpes during the preceding 12-month period. The randomization for this clinical trial was undertaken with the help of randomization plan NP/RL/060407/132. The randomization code remained with the study sponsor until the final closure of the database. the herpes symptoms. During the 5-day therapy phase the gel was applied eight times daily. On day 6 after the start of the therapy the patient visited the investigator again for examination and evaluation of the healing process, and started prophylactic treatment twice start of a herpes episode could reduce the healing time for the episode as compared with the patients documented the intensity and charac- daily again until the next herpes episode. The healing time in the placebo group. In addition, ter of the following four symptoms in a patient there were overall patient and doctor evaluations diary each day during the episodes: blistering, of the efficacy and safety of PD as compared with swelling, pain, and open wounds/scab. A threegraded scale was used to describe the severity placebo in the treatment of herpes episodes. of each symptom: 0 = no symptoms, 1 = moderate symptoms, 2 = severe symptoms. At the Patients end of the 5-day treatment period, the patient A total of 105 patients meeting the inclusion criteria were recruited to the trial between efficacy and safety of the applied gel on a four- made her/his own subjective evaluation of the July 2006 and March 2007 by advertisements in graded scale: very good, good, moderate, or the local press and by informing general practitioners and dermatologists of the planned were reported by the patients in their diaries poor. Adverse events during the clinical trial trial. The patients were randomized to either and by the investigator at each patient visit. PD (53 patients) or to placebo (52 patients). The Study Medication The PD and the placebo gel were packed in 4 g tubes and labeled for the clinical trial. The gels were not distinguishable by color or smell. The concentration of PD in the gel was 25%. The amount of gel to be applied to both lips was 0.04 g/day in the prophylactic phase and Study Procedure 0.16 g/day in the therapeutic phase. By weighing the returned tubes from each patient it The clinical trial consisted of a prophylactic period of 26 weeks, during which at least than 50% of the recommended dose of the became obvious that all patients had used more two examinations (at the start of the trial and study medication.

4 722 Adv Ther (2009) 26(7): Blinding unbalanced samples, nonparametric tests were supplemented by exact tests. For metric data the The gel supplied to the patients had a consecutive random number on the label. This number consistency was made by comparing independ- t test was also applied. Testing of the variance was previously assigned to the PD gel and to the ent or paired data by means of Fisher's exact placebo gel externally. Neither the investigator test. The t test was calculated accepting the same nor the patients had any knowledge of what variance. Frequency distribution of interval kind of treatment was given. Data Collection and Processing In accordance with good clinical practice, double data entry with computer-controlled data comparison in dbase IV (dbase; Vestal, NY, USA) was used. For data analysis, the data were exported over a standard filter to SPSS for Windows, v (Chicago, IL, USA). All further procedures such as data processing, modeling, and report compilation were performed in SPSS. Information concerning adverse events, concurrent illness, and concurrent medication was recorded in Microsoft Excel (Redmond, WA, USA) and checked by the second data entry for accuracy. After data cleaning, the databank was declared clean and closed. Thereafter the biometrician received the random code for evaluation of the study data. rated, ordinal, or nominal data were evaluated by means of χ 2 test for a maximum of five categories or with the Mann-Whitney U test. The statistical evaluations were made with SPSS. Evaluation of the primary target criterion was performed according to the intention-to-treat principle. Sample Size The sample size was calculated assuming a drop-out rate of 10% and a difference of one episode per patient between the patients in the PD group and the placebo group during treatment for 6 months. Under these assumptions there should be 60 patients per group recruited to the clinical trial; however, the study was stopped when a total of 105 patients were included, due to the long and slow recruitment time. RESULTS Statistical Methods Patients All the variables determined in the data collection were described by means of their sta- dropped out from the study. These patients had Of the 105 patients recruited, three patients tistical operating figures or their frequency been assigned to treatment with PD. One of the distribution, and statistically analyzed in consideration to their group-specific differences. The entries for P values had a significance level of patients withdrew his signed informed consent 16 days after having entered the clinical trial without giving any reason. The two other 5%. Ordinal and metric data were evaluated by patients did not show up at any of the scheduled doctor's visits. The only data available for means of a U test. Independent sample tests were made by means of Mann-Whitney U test for two these patients are the demographic data collected at the start of the trial. Thus 102 patients, samples or Kruskal-Wallis test for more than two samples. Independent samples were evaluated 50 in the PD group and 52 in the placebo group, by means of Wilcoxon test. For low case rates or were available for the intention-to-treat analyses

5 Adv Ther (2009) 26(7): of efficacy and safety. Demographic data for all the 105 patients enrolled into the clinical trial are presented in Table 1. There were no significant differences between the two groups of patients regarding the recorded parameters. The first patient was enrolled into the study in July 2006 and the last patient finished the study in October The clinical trial was performed according to the clinical trial protocol. A change occurred regarding the sample size: due to slow recruiting, only 105 subjects were included in the clinical trial instead of the planned 120. Efficacy of Prophylactic Treatment The primary objective of the clinical trial was to investigate if PD could reduce the number of herpes episodes in patients with recurrent herpes. The number of herpes episodes in the PD group Table 1. Demographic data and clinical characteristics of the patients included in the study and randomized to treatment with either 1,5-pentanediol (PD) gel or placebo gel. PD Placebo Patients, n Female/male 43/10 38/14 Median age, years Median weight, kg Median BMI, kg/m There were no significant differences between groups for any of the variables. and in the placebo group is shown in Table 2. It is obvious that there was no significant difference in recurrence rate between the two groups (P>0.05). Table 2 also shows the presenting symptoms for all episodes. Efficacy of Therapeutic Treatment The secondary objective of the clinical trial was to investigate if PD initiated at the start of a herpes episode could reduce the healing time for the episode as compared with the healing time in the placebo group. To avoid the complication rendered by the symptom open wounds/scabs, the therapeutic effect was analyzed based only on the symptoms blistering, swelling, and pain. For these symptoms the patients had given a rating of the degree of severity for each day of the treatment. The combined score for the symptoms blistering, swelling, and pain are given in Table 3. There were no significant differences between the absolute score values for PD and placebo during the treatment days. However, the rate of reduction of the symptoms from day 1 of treatment was significantly more rapid in PD patients than in placebo patients, with a more pronounced symptom reduction on the last 2 days of treatment. The statistically significantly better effect of PD was confirmed by multivariate variance analysis for repeated measurements, which gave a P value of < Table 2. Number of herpes episodes and their presenting symptoms in patients treated prophylactically during 26 weeks, with local applications of 1,5-pentanediol (PD) gel or placebo gel. Treatment Patients, n Episodes, n* Blistering, swelling, or pain Presenting symptom Open wounds or scabs PD (79%) 22 (21%) Placebo (76%) 29 (24%) *No significant difference between PD and placebo (P>0.05, U test; P>0.05, χ 2 test). Data from 105 episodes. Patient diaries were incompletely filled out for four episodes. Data from 119 episodes. Patient diaries were incompletely filled out for one episode.

6 724 Adv Ther (2009) 26(7): Table 3. Therapeutic effect of frequent local applications of 1,5-pentanediol (PD) gel or placebo gel on blistering, swelling, and pain in 105* episodes of herpes treated with PD, and 119 episodes treated with placebo, accounted for in patient diaries. Day of treatment Symptom score (median±sd) Change in symptom score from day 1 (median±sd) PD Placebo PD Placebo Day 1 3.0± ±1.6 Day 2 3.1± ± ± ±1.4 Day 3 2.5± ± ± ±1.7 Day 4 1.7± ± ± ±1.8 Day 5 1.0± ± ±1.5# 1.4±1.7# *109 episodes occurred in patients treated with PD. Patient diaries were incompletely filled out for four episodes. 120 episodes occurred in patients treated with placebo. Patient diaries were incompletely filled out for one episode. Significant difference PD vs. placebo: P=0.046 (U test). Significant difference PD vs. placebo: P=0.013 (t test). #Significant difference PD vs. placebo: P=0.038 (U test), P=0.005 (t test). Table 4. Results of the doctor clinical evaluations of the therapeutic efficacy of frequent local applications of 1,5-pentanediol (PD) gel or placebo gel at the end of each episode of herpes labialis occurring during the study. Treatment Episodes, n Very good, n (%) Good, n (%) Moderate, n (%) Poor, n (%) PD* (32) 52 (48) 22 (20) 0 (0) Placebo* (38) 25 (21) 50 (42) 0 (0) *Significant difference PD vs. placebo: P<0.001 (χ 2 test). Table 5. Results of the patient subjective evaluations of the therapeutic efficacy of frequent local applications of 1,5-pentanediol (PD) gel or placebo gel at each episode of herpes labialis occurring during the study. Treatment Episodes, n Very good, n (%) Good, n (%) Moderate, n (%) Poor, n (%) PD* (33) 50 (46) 23 (21) 0 (0) Placebo* (37) 28 (23) 48 (40) 0 (0) *Significant difference PD vs. placebo: P<0.001 (χ 2 test). The overall therapeutic efficacy was also Safety evaluated at the end of the treatment period by the investigators and the patients. Table 4 shows that there was a highly significant difference between PD and placebo regarding therapeutic efficacy as evaluated by the investigators. Similarly, the patients made their own evaluation of the efficacy of treatment. Table 5 shows that the patients also perceived PD to be significantly more efficacious than placebo. There were no serious adverse events reported during the study period for any of the patients, except for one patient who developed severe acute lumbago deemed to be unrelated to the treatment. In total, 20 adverse events were reported; 10 in the PD group and 10 in the placebo group. In no case was the adverse event considered to be caused by the treatment with PD

7 Adv Ther (2009) 26(7): or placebo. Clinical parameters, heart rate, body be raised that the prophylactic treatment with temperature, and weight were almost unchanged the gel, with and without PD, may have reduced during the clinical trial in both the PD group the recurrences owing to an increased hydration and the placebo group. The global evaluation of of the epidermis of the lips, or through other the safety by the investigators and the patients possible mechanisms. In any case, PD did not was approximately two thirds very good and enhance this possible effect of the gel treatment one third good. No interaction with concomi- on the number of episodes of herpes during the tant medication was observed. This shows that PD gel can be considered to be a safe agent for therapy of recurrent herpes. DISCUSSION ent from that of the placebo gel. It is of interest though that the total number of herpes episodes during this 6-month clinical trial was only 229 study period of 6 months. Another explanation may be the vehicle; topical formulation other than a gel may remain on the lips for a longer time and give longer protection. Principal Findings: Therapeutic Efficacy Principal Findings: Prophylactic Efficacy The therapeutic efficacy of PD was obvious There has been much interest in finding and when analyzing the healing of the three prodromal symptoms: blistering, swelling, and developing agents that not only effectively treat herpes outbreaks, but could also suppress outbreaks altogether. A variety of agents and prepa- rate with PD treatment than after treatment pain. These symptoms subsided at a quicker rations, eg, ascorbic acid, lysine, zinc, and balm with placebo. These findings were also corroborated by the investigator and patient evalua- mint extract have been examined in clinical trials and found to be therapeutically effective. 4 Even tions of the therapeutic efficacy of the given topically applied honey has been found to be treatment, with PD being significantly more therapeutically more effective than acyclovir. 17 effective than placebo. It is surprising that close However, few attempts have been made to demonstrate any prophylactic effect of such agents or scabs as presenting symptoms. Such symp- to a quarter of the patients had open wounds or preparations. So far, no topical agent, including the antivirals, has been shown unequivo- However, more than 75% of the patients toms usually occur late in the healing process. cally to be effective as prophylactic treatment. reported the usual prodromal symptoms of blis- The results of the present clinical trial show that tering, swelling, and pain. The reason for this PD gel, at least under the conditions used here, is unclear. is also ineffective as a prophylactic treatment in herpes labialis, as its efficacy was not differ- Mode of Action The mode of action of PD for accelerating the healing process in recurrent herpes (Table 2). The patients had had at least six herpes is presently unknown. PD is known to have episodes each during the preceding 12-month an antiviral, antibacterial, and antifungal period and thus could be expected to experience at least three episodes during the 6 months membranes. 16 This may be of importance for effect, probably due to an osmotic effect on of the trial. However, they experienced only a the therapeutic efficacy of PD. However, the mean of 2.2 episodes. Thus the question might effect of PD on the water-binding capacity of

8 726 Adv Ther (2009) 26(7): the stratum corneum is also important. 16 The preceding 12-month period. Therefore they increase of hydration of the lip epidermis by could be expected to have around three episodes during the 6-month trial period. With repeated applications of PD may facilitate the healing process and increase the resistance of 105 patients included there should have been the cells to secondary infection. around 315 herpes episodes in total. However, there were 25% fewer. It seems likely that the Safety included patients had exaggerated to some extent the frequency of herpes episodes in The safety of PD appears to be very high order to be included into the study. It cannot because no adverse events related to the treat- be excluded that analyses of the therapeutic ment with PD were observed. If the waterbinding capacity of PD is of importance for the therapeutic effect this should be compared with the local effect of other agents that improve the water-binding capacity of the skin, eg, urea, lactic acid, and hypertonic sodium chloride. Antivirals have a long standing as the preferred treatment of herpes labialis. However, new agents, including PD, have been shown to be effective as well. Comparative trials of these new agents versus acyclovir or penciclovir seem to be warranted to establish the optimal therapy for this painful and disfiguring disease, with the future goal of finding an effective prophylactic treatment. Limitations of the Study Few clinical studies are perfect. In this study, patient recruitment was stopped at 105 patients symptoms of recurrent herpes, and comparative studies of this agent prior to the intended 120 because of slow versus antivirals and recruitment rate at the end of the recruitment docosanol seem to be warranted. period. This has obviously weakened the statistical strength of the study. However, even with 15 further patients included into the study there seems to be little possibility for reaching activity in 300 herpes episodes instead of in 229 would have resulted in a stronger statist- ical significance for the difference between PD and placebo regarding therapeutic activity. CONCLUSION Based on the results of the present clinical trial, PD must be considered to lack any prophylactic activity against recurrences of herpes episodes. However, PD was found to accelerate the healing process of herpes episodes with respect to symptoms of blistering, swelling, and pain; a finding consistent with the evaluation of the therapeutic efficacy of PD by both doctors and patients. In addition, PD appears to be completely devoid of side effects. Thus, the results of the present clinical trial suggest that PD may be a new effective agent in the treatment of the ACKNOWLEDGMENTS We t h a n k N a t u m i n P h a r m a A B, a statistically significant difference regarding Kungsängsvägen 27, S Huskvarna, prophylactic effect between PD and placebo. Sweden, for the financial support to conduct Another limitation of the study turned out this clinical trial. JG has received reimbursement to be the frequency of reported herpes episodes. The included patients were to have received funds for research, and fees for consult- for consulting from Natumin Pharma AB. JF has had at least six herpes episodes during the ing from Natumin Pharma AB.

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