Herpes Labialis
Conditions
Brief summary
To demonstrate the efficacy of a single dose of acyclovir Lauriad® 50mg muco-adhesive buccal tablet versus a single dose of matching placebo on the primary vesicular lesion of cold sore.
Interventions
DRUGAcyclovir Lauriad
50 mg muco-adhesive buccal tablets, single application on the gum
DRUGPlacebo
50 mg muco-adhesive buccal tablets, single application on the gum
Sponsors
Valerio Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* History of recurrent herpes labialis lesions where: * At least 50% of previous episodes produced classical lesions to the vesicular stage (i.e. episodes that progressed through macula, papule, vesicle, crust and healed); * Prodromal symptoms (itching, tingling, pain etc.) should precede herpes labialis lesions in at least 50% of the previous herpes episodes * Good general health (ECOG \< 2), immunocompetent * Signed and dated written informed consent * Women of childbearing potential must have effective contraception method
Exclusion criteria
* More than 50% of recurrences that aborted spontaneously in the past 12 months * Primary herpes lesion outside the lips (e.g. nose, chin, etc.) * Abnormal peri-oral skin condition that might affect the normal course of cold sores (e.g. eczema, psoriasis…) * Oral diseases whose prodromal symptoms may mimick those of herpes labialis, including recurrent oral aphthous disease * Oral diseases that might interfere with the evaluation of the efficacy or safety of the treatments, including gingivitis, parondotis, mucositis, oropharyngeal candidiasis… * History of infection known to be resistant to acyclovir family agents * Previous vaccination against herpes * Concomitant treatment likely to interfere with acyclovir * Allergy to any acyclovir containing agents * Immunocompromised condition, including HIV+ * Unability to properly understand protocol requirements, to follow the study procedures, to complete the patient diary or to start the self-initiation of the treatment * Upper full or partial dentures with acrylic border in the canine fossa * Milk allergy or known history of hypersensitivity to one of the components of the products * Rare hereditary problems of galactose intolerance. * Lactase enzyme deficiency or glucose galactose malabsorption * Clinically significant abnormal level of serum creatinine * Patients whose occupations make them unlikely to return to the clinic within 24h of treatment initiation * Pregnancy or breast-feeding * Investigational drug or immunomodulator treatment in the 30 days prior randomisation * Prior enrollment in this study * Participation in another therapeutic trial evaluating new drugs or which could interfere with the evolution of herpes labialis or the evaluation of the drug in the study within preceding 30 day.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Healing (TTH) of Vesicular Primary Lesion | Assessed from time of treatment initiation through Day 14 | Healing was defined as the loss of crust (erythema may be present) as assessed by the investigator. TTH was the time from treatment initiation to healing as defined above and was assessed from the time of treatment initiation through Day 14. The primary vesicular lesion was the first developed lesion located on the lip and was not to have extended more than 1 cm outside the lip. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Abortion of Primary Lesions | Assessed from the time of treatment initiation through Day 14 | Aborted lesions were defined as herpetic lesions preceded by prodromal symptoms that did not progress beyond the papule stage. |
| TTH of Non-primary Lesions (Aborted Lesions Excluded) | Assessed from the time of treatment initiation through Day 14 | TTH of non-primary lesions was defined as the time from treatment initiation to healing of all non-primary vesicular lesions. Non-primary lesions were those that developed in addition to and/or in 1 or more days after the primary vesicular lesion and that were located at least 1 cm from the primary lesion. Aborted lesions were not included in this parameter. TTH was to be assessed by the investigator. |
| Duration of Episode (DOE) | Assessed from initiation of treatment to Day 14 | For patients who experienced a vesicular lesion, DOE was defined as the time from treatment initiation to healing of primary and secondary vesicular lesions (loss of crust). For subjects whose primary and secondary lesions were not vesicular in nature, DOE was defied as the time from treatment initiation to return to normal skin or to cessation of symptoms, whichever came last. |
| Time to Cessation of Symptoms | Assessed from time of treatment initiation through Day 14 | Time to cessation of symptoms was defined as the time from treatment initiation to cessation of all symptoms: pain, burning, itching, tingling, tenderness and discomfort. It was to be assessed by the investigator. |
| Patient Assessment of Efficacy of the Treatment | Assessed on Day 14 (or within 24 hours of healing) | At the end of study (Day 14 \[ or within 24 hours of healing\]), patients were asked to rate efficacy of treatment using a 4-point scale (inactive, mildly active, moderately active, or very active). |
| Time to Recurrence of Non-aborted Lesions During 9-month Follow-up | From time of initial healing through the 9-month follow-up | Time to recurrence was the time from the healing of all lesions of the initial episode to the occurrence of new lesions. |
| Patient Incidence of Recurrence of Non-aborted Lesions During 9-month Follow-up | From time of initial healing through the 9-month follow-up | Recurrence was the occurrence of new lesions and was evaluated in a subgroup of patients who agreed to record recurrences during the 9-month follow-up period. |
| Symptom Intensity (Visual Analogue Scale [VAS]) | Assessed on Days 1, 3, 5, 7 and 14 (or within 24 hours of healing) | Patients were asked to place a tick mark on a 10 centimeter VAS indicating their symptom intensity. Scale ratings ranged from a minimum of 0 (none at all) to a maximum of 10 (worst possible). The location of the tick mark from 0 was measured in millimeters (0 - 100) and recorded. |
| Patient Satisfaction With Treatment | Assessed on Day 14 (or within 24 hours of healing) | At the end of study (Day 14 \[or within 24 hours of healing\]), patients were asked whether they were satisfied with treatment (yes/no). |
| TTH of Aborted Primary Lesions | Assessed from time of treatment initiation through Day 14 | TTH of aborted primary lesions was defined as the time from treatment initiation to healing of the primary lesion (erythema or papule) or cessation of symptoms, whichever came last. It was to be assessed by the investigator. |
Countries
Australia, Czechia, France, Germany, Poland, United Kingdom, United States
Participant flow
Recruitment details
Patients were screened beginning March 2007 and the last patient was treated in October 2008. The study was conducted at 47 sites in Australia, the Czech Republic, France, Germany, Poland, the United Kingdom and the United States.
Pre-assignment details
Per protocol, a total of 1950 patients were to be randomized. Following randomization, patients were not to start treatment until a new labial herpes episode occurred. Thus, of those randomized, only 780 patients were planned to be treated (390 patients per treatment group) and 1170 patients were to be randomized, but not treated.
Participants by arm
| Arm | Count |
|---|---|
| Acyclovir Lauriad Group Acyclovir Lauriad 50mg muco-adhesive tablet/Intent-to-Treat population | 376 |
| Placebo Group muco-adhesive buccal tablet with placebo/Intent-to-Treat population | 395 |
| Total | 771 |
Baseline characteristics
| Characteristic | Acyclovir Lauriad Group | Placebo Group | Total |
|---|---|---|---|
| Age Continuous | 40 years STANDARD_DEVIATION 12.97 | 41.9 years STANDARD_DEVIATION 13.33 | 41.0 years STANDARD_DEVIATION 13.18 |
| Region of Enrollment Australia | 53 participants | 68 participants | 121 participants |
| Region of Enrollment Czech Republic | 47 participants | 50 participants | 97 participants |
| Region of Enrollment France | 41 participants | 49 participants | 90 participants |
| Region of Enrollment Germany | 79 participants | 77 participants | 156 participants |
| Region of Enrollment Poland | 74 participants | 70 participants | 144 participants |
| Region of Enrollment United Kingdom | 11 participants | 9 participants | 20 participants |
| Region of Enrollment United States | 71 participants | 72 participants | 143 participants |
| Sex: Female, Male Female | 258 Participants | 271 Participants | 529 Participants |
| Sex: Female, Male Male | 118 Participants | 124 Participants | 242 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 378 | 22 / 397 |
| serious Total, serious adverse events | 0 / 378 | 1 / 397 |
Outcome results
Primary
Time to Healing (TTH) of Vesicular Primary Lesion
Healing was defined as the loss of crust (erythema may be present) as assessed by the investigator. TTH was the time from treatment initiation to healing as defined above and was assessed from the time of treatment initiation through Day 14. The primary vesicular lesion was the first developed lesion located on the lip and was not to have extended more than 1 cm outside the lip.
Time frame: Assessed from time of treatment initiation through Day 14
Population: The modified Intent-to-Treat (mITT) population was the population used for analysis of this endpoint. The mITT population included all randomized patients who received at least one dose of study medication and who reached the vesicular stage (ie, episodes that progressed through macula, papule, vesicle, crust and healing).
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Acyclovir Lauriad Group | Time to Healing (TTH) of Vesicular Primary Lesion | 7.00 Days | 95% Confidence Interval 0.18 |
| Placebo Group | Time to Healing (TTH) of Vesicular Primary Lesion | 7.32 Days | 95% Confidence Interval 0.18 |
p-value: 0.015Log Rank
Secondary
Abortion of Primary Lesions
Aborted lesions were defined as herpetic lesions preceded by prodromal symptoms that did not progress beyond the papule stage.
Time frame: Assessed from the time of treatment initiation through Day 14
Population: This endpoint was analyzed using the Intent-to-Treat (ITT) population, which consisted of all randomized patients who received at least one dose of study medication and who had complete information recorded for the application time.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acyclovir Lauriad Group | Abortion of Primary Lesions | Aborted Lesions = Yes | 130 participants |
| Acyclovir Lauriad Group | Abortion of Primary Lesions | Aborted Lesions = No | 242 participants |
| Acyclovir Lauriad Group | Abortion of Primary Lesions | Aborted Lesions = Missing | 4 participants |
| Placebo Group | Abortion of Primary Lesions | Aborted Lesions = Yes | 109 participants |
| Placebo Group | Abortion of Primary Lesions | Aborted Lesions = No | 279 participants |
| Placebo Group | Abortion of Primary Lesions | Aborted Lesions = Missing | 7 participants |
p-value: 0.041995% CI: [0.0025, 0.1339]Chi-squared
Secondary
Duration of Episode (DOE)
For patients who experienced a vesicular lesion, DOE was defined as the time from treatment initiation to healing of primary and secondary vesicular lesions (loss of crust). For subjects whose primary and secondary lesions were not vesicular in nature, DOE was defied as the time from treatment initiation to return to normal skin or to cessation of symptoms, whichever came last.
Time frame: Assessed from initiation of treatment to Day 14
Population: This endpoint was analyzed using the ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir Lauriad Group | Duration of Episode (DOE) | 5.57 Days |
| Placebo Group | Duration of Episode (DOE) | 6.38 Days |
p-value: 0.0033Log Rank
Secondary
Patient Assessment of Efficacy of the Treatment
At the end of study (Day 14 \[ or within 24 hours of healing\]), patients were asked to rate efficacy of treatment using a 4-point scale (inactive, mildly active, moderately active, or very active).
Time frame: Assessed on Day 14 (or within 24 hours of healing)
Population: This endpoint was analyzed using the ITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acyclovir Lauriad Group | Patient Assessment of Efficacy of the Treatment | Moderately active | 100 participants |
| Acyclovir Lauriad Group | Patient Assessment of Efficacy of the Treatment | Very active | 154 participants |
| Acyclovir Lauriad Group | Patient Assessment of Efficacy of the Treatment | Midly active | 49 participants |
| Acyclovir Lauriad Group | Patient Assessment of Efficacy of the Treatment | Missing | 23 participants |
| Acyclovir Lauriad Group | Patient Assessment of Efficacy of the Treatment | Inactive | 50 participants |
| Placebo Group | Patient Assessment of Efficacy of the Treatment | Missing | 22 participants |
| Placebo Group | Patient Assessment of Efficacy of the Treatment | Inactive | 79 participants |
| Placebo Group | Patient Assessment of Efficacy of the Treatment | Midly active | 44 participants |
| Placebo Group | Patient Assessment of Efficacy of the Treatment | Very active | 146 participants |
| Placebo Group | Patient Assessment of Efficacy of the Treatment | Moderately active | 104 participants |
Secondary
Patient Incidence of Recurrence of Non-aborted Lesions During 9-month Follow-up
Recurrence was the occurrence of new lesions and was evaluated in a subgroup of patients who agreed to record recurrences during the 9-month follow-up period.
Time frame: From time of initial healing through the 9-month follow-up
Population: This endpoint was analyzed using the follow-up population, a subgroup of the ITT population who continued to the 9 month follow-up and had at least 1 diary assessment during that period. The follow-up population was defined as patients whose lesions were healed at the end of Day 14 and had no recurrence within 15 days of healing of all lesions.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acyclovir Lauriad Group | Patient Incidence of Recurrence of Non-aborted Lesions During 9-month Follow-up | Recurrence during 9-month follow-up = yes | 149 participants |
| Acyclovir Lauriad Group | Patient Incidence of Recurrence of Non-aborted Lesions During 9-month Follow-up | Recurrence during 9-month follow-up = no | 83 participants |
| Acyclovir Lauriad Group | Patient Incidence of Recurrence of Non-aborted Lesions During 9-month Follow-up | Recurrence during 9-month follow-up = missing | 35 participants |
| Placebo Group | Patient Incidence of Recurrence of Non-aborted Lesions During 9-month Follow-up | Recurrence during 9-month follow-up = yes | 181 participants |
| Placebo Group | Patient Incidence of Recurrence of Non-aborted Lesions During 9-month Follow-up | Recurrence during 9-month follow-up = no | 65 participants |
| Placebo Group | Patient Incidence of Recurrence of Non-aborted Lesions During 9-month Follow-up | Recurrence during 9-month follow-up = missing | 24 participants |
p-value: 0.0271Chi-squared
Secondary
Patient Satisfaction With Treatment
At the end of study (Day 14 \[or within 24 hours of healing\]), patients were asked whether they were satisfied with treatment (yes/no).
Time frame: Assessed on Day 14 (or within 24 hours of healing)
Population: This endpoint was analyzed using the ITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acyclovir Lauriad Group | Patient Satisfaction With Treatment | Satisfied with treatment = yes | 297 participants |
| Acyclovir Lauriad Group | Patient Satisfaction With Treatment | Satisfied with treatment = no | 66 participants |
| Acyclovir Lauriad Group | Patient Satisfaction With Treatment | Missing | 13 participants |
| Placebo Group | Patient Satisfaction With Treatment | Satisfied with treatment = yes | 275 participants |
| Placebo Group | Patient Satisfaction With Treatment | Satisfied with treatment = no | 105 participants |
| Placebo Group | Patient Satisfaction With Treatment | Missing | 15 participants |
p-value: 0.0022Chi-squared
Secondary
Symptom Intensity (Visual Analogue Scale [VAS])
Patients were asked to place a tick mark on a 10 centimeter VAS indicating their symptom intensity. Scale ratings ranged from a minimum of 0 (none at all) to a maximum of 10 (worst possible). The location of the tick mark from 0 was measured in millimeters (0 - 100) and recorded.
Time frame: Assessed on Days 1, 3, 5, 7 and 14 (or within 24 hours of healing)
Population: This endpoint was analyzed using the safety population, which consisted of all randomized patients who took at least 1 dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acyclovir Lauriad Group | Symptom Intensity (Visual Analogue Scale [VAS]) | Day 3 | 21.2 units on a scale (0 - 100) | Standard Deviation 22.88 |
| Acyclovir Lauriad Group | Symptom Intensity (Visual Analogue Scale [VAS]) | Day 7 | 8.2 units on a scale (0 - 100) | Standard Deviation 13.63 |
| Acyclovir Lauriad Group | Symptom Intensity (Visual Analogue Scale [VAS]) | Day 5 | 12.7 units on a scale (0 - 100) | Standard Deviation 17.6 |
| Acyclovir Lauriad Group | Symptom Intensity (Visual Analogue Scale [VAS]) | Day 14 (or within 24 hours of healing) | 1.0 units on a scale (0 - 100) | Standard Deviation 5.14 |
| Acyclovir Lauriad Group | Symptom Intensity (Visual Analogue Scale [VAS]) | Day 1 | 30.5 units on a scale (0 - 100) | Standard Deviation 22.37 |
| Placebo Group | Symptom Intensity (Visual Analogue Scale [VAS]) | Day 14 (or within 24 hours of healing) | 0.9 units on a scale (0 - 100) | Standard Deviation 3.61 |
| Placebo Group | Symptom Intensity (Visual Analogue Scale [VAS]) | Day 1 | 31.1 units on a scale (0 - 100) | Standard Deviation 22.07 |
| Placebo Group | Symptom Intensity (Visual Analogue Scale [VAS]) | Day 3 | 22.9 units on a scale (0 - 100) | Standard Deviation 22.6 |
| Placebo Group | Symptom Intensity (Visual Analogue Scale [VAS]) | Day 5 | 17.3 units on a scale (0 - 100) | Standard Deviation 20.7 |
| Placebo Group | Symptom Intensity (Visual Analogue Scale [VAS]) | Day 7 | 10.7 units on a scale (0 - 100) | Standard Deviation 18.48 |
Comparison: Analysis conducted between treatment groups at Day 1 timepoint.p-value: 0.5695Wilcoxon (Mann-Whitney)
Comparison: Analysis conducted between treatment groups at Day 3 timepointp-value: 0.1824Wilcoxon (Mann-Whitney)
Comparison: Analysis conducted between treatment groups at the Day 5 timepointp-value: 0.0078Wilcoxon (Mann-Whitney)
Comparison: Analysis conducted between treatment groups at the Day 7 timepointp-value: 0.3303Wilcoxon (Mann-Whitney)
Comparison: Analysis conducted between treatment groups at the Day 14 timepointp-value: 0.6045Wilcoxon (Mann-Whitney)
Secondary
Time to Cessation of Symptoms
Time to cessation of symptoms was defined as the time from treatment initiation to cessation of all symptoms: pain, burning, itching, tingling, tenderness and discomfort. It was to be assessed by the investigator.
Time frame: Assessed from time of treatment initiation through Day 14
Population: This endpoint was analyzed using the ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir Lauriad Group | Time to Cessation of Symptoms | 3.57 Days |
| Placebo Group | Time to Cessation of Symptoms | 4.16 Days |
p-value: 0.0098Log Rank
Secondary
Time to Recurrence of Non-aborted Lesions During 9-month Follow-up
Time to recurrence was the time from the healing of all lesions of the initial episode to the occurrence of new lesions.
Time frame: From time of initial healing through the 9-month follow-up
Population: This endpoint was analyzed using the follow-up population, a subgroup of the ITT population who continued to the 9 month follow-up and had at least 1 diary assessment during that period. The follow-up population was defined as patients whose lesions were healed at the end of Day 14 and had no recurrence within 15 days of healing of all lesions.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Acyclovir Lauriad Group | Time to Recurrence of Non-aborted Lesions During 9-month Follow-up | 205.0 Days | 95% Confidence Interval 19.4 |
| Placebo Group | Time to Recurrence of Non-aborted Lesions During 9-month Follow-up | 165.0 Days | 95% Confidence Interval 9.3 |
p-value: 0.0412Log Rank
Secondary
TTH of Aborted Primary Lesions
TTH of aborted primary lesions was defined as the time from treatment initiation to healing of the primary lesion (erythema or papule) or cessation of symptoms, whichever came last. It was to be assessed by the investigator.
Time frame: Assessed from time of treatment initiation through Day 14
Population: This endpoint was analyzed using the subgroup of patients within the ITT population with aborted lesions.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir Lauriad Group | TTH of Aborted Primary Lesions | 2.57 Days |
| Placebo Group | TTH of Aborted Primary Lesions | 2.67 Days |
p-value: 0.8005Log Rank
Secondary
TTH of Non-primary Lesions (Aborted Lesions Excluded)
TTH of non-primary lesions was defined as the time from treatment initiation to healing of all non-primary vesicular lesions. Non-primary lesions were those that developed in addition to and/or in 1 or more days after the primary vesicular lesion and that were located at least 1 cm from the primary lesion. Aborted lesions were not included in this parameter. TTH was to be assessed by the investigator.
Time frame: Assessed from the time of treatment initiation through Day 14
Population: This endpoint was analyzed using a subgroup of patients in the ITT population with non-primary lesions.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir Lauriad Group | TTH of Non-primary Lesions (Aborted Lesions Excluded) | 7.00 Days |
| Placebo Group | TTH of Non-primary Lesions (Aborted Lesions Excluded) | 9.08 Days |
p-value: 0.0683Log Rank