Conditions: Herpes Labialis
Keywords: HSV, pritelivir, herpes, herpes labialis, topical,
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 362
Healthy volunteers: no

Brief summary:
Randomized, double-blind, multi-center, three arm parallel group, comparative trial to assess pritelivir ointment safety and efficacy, ie, proportion of subjects with non-ulcerative lesions, in adult subjects with recurrent herpes labialis (RHL) in comparison with placebo or Zovirax® Cream. The start of treatment with trial medication will be initiated by the subject within one hour of noticing the first sign or symptom (eg, prodrome) of a recurrence of herpes labialis. Trial medication will be applied to the affected area 5 times daily for 4 days.

After self-initiation of treatment with trial medication subjects will be assessed daily by the Investigator until complete healing for a maximum of 13 days.

Subjects will document application of trial medication and the status of their lesion in a diary. There will also be blood sampling, ECG measurement and physical examination performed at the investigational site.

Detailed description:

Arms:
arm 1: Topical treatment (20 applications), 5 times daily for 4 days arm 2: Topical treatment (20 applications), 5 times daily for 4 days arm 3: Topical treatment (20 applications), 5 times daily for 4 days

Interventions: intervention 1: Pritelivir 5% w/w ointment intervention 2: Pritelivir ointment matching placebo intervention 3: Zovirax® cream
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
 
Summary of the Clinical Trial 
Protocol and Statistical Plan 
AIC316-02-II-01 
31Jan2017 
 
 
 
 
 
 
Summary of the Clinical Trial Protocol and Statistical Plan 
Name of Sponsor/Company: 
AiCuris Anti-infective Cures GmbH 
Title of the trial: A randomized, double-blind, multi-center, three arm (pritelivir, placebo and 
Zovirax®) parallel group, comparative trial to assess the efficacy and safety of pritelivir 5% w/w 
ointment for the treatment of recurrent herpes labialis in adults – LipP 1 
Trial center(s): 10 to 14 investigational sites in the US 
Planned study period (years): 
First Subject First Visit: 4th quarter 2016 
Last Subject Last Visit: 3rd quarter 2017  
Phase of development: 2 
 
Objectives: To assess the efficacy, tolerability and safety of pritelivir 5% w/w ointment applied 5 
times daily for 4 days for the treatment of recurrent herpes labialis (rHL) in adults 
Trial design: This is a randomized, double-blind, multi-center, three arm parallel group, comparative 
trial to assess the safety and efficacy, ie, proportion of subjects with non-ulcerative lesions, in adult 
subjects with rHL treated with pritelivir 5% w/w ointment. The statistical superiority will be tested 
against placebo and a descriptive comparison with Zovirax® Cream will be made. The start of 
treatment with trial medication will be initiated by the subject within one hour of noticing the first sign 
or symptom (eg, prodrome) of a recurrence of herpes labialis (HL). Trial medication will be applied to 
the affected area 5 times daily for 4 days. 
Number of subjects (planned): approx. 360 subjects should be enrolled resulting in at least 71 
subjects dosed in each treatment arm.  
Diagnosis and main criteria for inclusion:  
1. Healthy men and women of any ethnic group aged ≥18 years ; 
2. Subjects should have experienced ≥4 recurrences of HL in the previous 12-month period; 
3. Subjects should have experienced prodromal symptoms in at least 50% of rHL episodes and should 
have developed ulcerative lesions that have progressed through vesicle, ulcer, and crust stages in at 
least 50% of the episodes; 
4. Willingness not to use any topical application (such as cosmetics, lip balm, sunscreens etc.) other 
than the trial medication in the area of lesion development from start of prodromal symptoms to 
healing;  
5. Willingness not to use any systemic and topical anti-HSV agent during the trial participation 
including prescription and over-the-counter products, 
6. Willingness not to use any systemic, anti-inflammatory or analgesic agents from start of prodromal 
symptoms to healing; 
7. Willingness to refrain from mechanical disruption (ie, scrubbing, lancing, shaving) of the 
prodromal area or lesion after start of treatment with trial medication until end of the trial 
participation; 
8. Women of child bearing potential and males must use adequate contraception; 
9. Subject must give written informed consent. 
10. Subjects with current lesion may be enrolled, but must not to treat the lesion present at 
randomization with the trial medication; they should be instructed to wait for the next subsequent 
lesion. 


 
Summary of the Clinical Trial 
Protocol and Statistical Plan 
AIC316-02-II-01 
31Jan2017 
 
 
 
 
 
 
Diagnosis and main criteria for exclusion:  
1. Known intolerance to pritelivir or any of the ointment ingredients (ie, butylated hydroxytoluene 
(BHT), PEG-400, PEG-4000, propylene glycol); 
2. Known intolerance to Zovirax® Cream or any of the ingredients (ie, acyclovir, cetostearyl alcohol, 
mineral oil, poloxamer 407, propylene glycol, sodium lauryl sulfate, and white petrolatum) or 
valacyclovir; 
3. Any skin conditions that could interfere with the assessment of HL recurrences (eg, eczema, 
psoriasis, acne);  
4. Any other condition which in the opinion of the Investigator would interfere with successful 
completion of this clinical trial; 
5. Pregnant and/or breastfeeding women; 
6. Participation in any investigational drug trial within the last 30 days before randomization for this 
clinical trial; 
7. Previous treatment with pritelivir tablets; 
8. Previous participation in a HSV vaccination trial (unless having received placebo); 
9. Clinically relevant ECG abnormalities (eg, QTc according to Fridericia: QTcF > 450ms for males 
and QTcF > 470ms for females; PR > 220 ms) at screening; 
10. Clinically relevant abnormalities in laboratory indices at screening which in the opinion of the 
investigator might have an impact on the safety and evaluability of the subject; 
11. Known chronic infections which in the opinion of the investigator might have an impact on the 
safety and evaluability of the subject;  
12. Evidence of active malignancy or immunodeficiency disease, or require chronic use of 
immunosuppressive drugs (eg, systemic steroids) or topical steroids, or chronically use antiviral 
medication with activity against HSV; 
13. HIV positive based on screening labs. 
 
Test product, dose and mode of administration 
Pritelivir 5% w/w ointment, 5 times daily, topical application. 
Duration of Treatment: 
Four days (20 applications). 
Reference therapy, dose and mode of administration 
Pritelivir placebo ointment, 5 times daily, topical application  
Zovirax® Cream, 5 times daily, topical application.  
Criteria for evaluation: 
Efficacy:  
Primary endpoint: 
• 
The percentage of subjects with non-ulcerative lesions in each treatment group. 
Secondary endpoints: 
• 
Duration of lesion episode (DOE), defined as time from treatment initiation to the healing of the 
primary lesion (loss of crust) for subjects who experienced a vesicular lesion. For subjects whose 
primary lesions were not vesicular in nature, DOE is the time from the treatment initiation to the 
return to normal skin or to the cessation of symptoms, whichever occurs last; 
• 
Pain rate, defined as number of days with pain at lesion site relative to the total number of days 
with analyzable pain through daily subject self-assessment; 


 
Summary of the Clinical Trial 
Protocol and Statistical Plan 
AIC316-02-II-01 
31Jan2017 
 
 
 
 
 
 
• 
Subject-assessed duration of lesion pain, defined as the time from first dose of trial medication 
until pain is no longer reported by the subject (date and time); 
• 
Subject-assessed severity of lesion pain defined as the average daily NUMERICAL RATING 
SCALE (NRS) pain score using a single-dimensional scale assessing pain intensity at lesion site, 
11 intensities [no pain (0) to worst pain imaginable (10)]; 
 
 
 
• 
Maximum lesion area (length x width) for ulcerative lesions during the vesicular, ulcerative and 
hard crust stages; 
• 
Cumulative lesion area (sum of daily maximum lesion areas); 
• 
Duration of lesion tenderness (unpleasantness upon touching the affected area). 
Safety:  
• 
An overall summary of adverse events (AEs) will be provided including the number and 
percentage of subjects with any AE, treatment emergent AE (TEAE), related TEAE, serious AE, 
severe AE, and TEAE leading to early termination; 
• 
TEAEs by system organ class (SOC), preferred term (PT), and treatment group. Summarization by 
maximum severity will also be presented; 
• 
Safety laboratory parameters; 
• 
Safety signals such as hematological changes, lymphadenopathy, CRP increase, cutaneous adverse 
events and changes in (a)PTT;  
• 
Vital signs (systolic and diastolic blood pressure, pulse rate) by visit and treatment group; 
• 
Standard 12-lead electrocardiogram (ECG) by visit and treatment group; 
• 
Physical examination by visit and treatment group. 
Compliance: 
• 
The percentage compliance will be calculated as the number of doses applied documented in the 
diary divided by 20 times 100. 
Pharmacokinetics: 
• 
Cmax, Tmax, AUC, if feasible 
 
Methodology:  
Efficacy measurements: 
After self-initiation of treatment with trial medication subjects will be assessed daily for the following 
parameters by the Investigator until healing:  
1. 
Lesion stage: 
- prodrome (symptoms including itching, pain, tingling, but no physical evidence of disease by 
inspection or by palpation in the application area),  
- erythema 
- papule (any elevation of skin without fluid in the application area)/edema,  
- vesicle (blister, fluid filled or collapsed, in the application area),  
- ulcer/soft crust,  
- hard crust, 
- residual abnormalities (residual erythema/scaling), 
- normal appearing skin. 


 
Summary of the Clinical Trial 
Protocol and Statistical Plan 
AIC316-02-II-01 
31Jan2017 
 
 
 
 
 
 
2. 
Maximum lesion area (length x width) in mm2 
 
Subject diary documentation: 
Subjects will document the following in their diary: 
1. 
Time of each application of trial treatment, 
2. 
Pain intensity, changes in pain intensity, and cessation of pain at each application of trial 
treatment (at the first and last daily application as a minimum), 
3. 
Pain intensity, changes in pain intensity, and cessation of pain in the morning and evening on 
days after stop of application of trial treatment until  pain disappeared,  
4. 
Lesion stage at each application of trial treatment,  
5. 
Lesion stage in the morning and evening on days after stop of application of trial treatment 
until lesion healing,  
6. 
Lesion tenderness at each application of trial treatment, and, 
7. 
Lesion tenderness in the morning and evening on days after stop of application of trial 
treatment until lesion tenderness disappeared. 
Subject diaries will be reviewed by the investigational site staff at each visit. 
Safety measurements: 
The following safety measures will be performed at screening and at Visit 5 (Day 5/6) and at the End 
of Trial Visit (Day 12±1) after initiation of treatment: 
1. 
Safety laboratory parameters, ie, serum chemistry, hematology, coagulation and urinalysis 
2. 
Vital signs, ie, systolic and diastolic blood pressure, pulse rate 
3. 
Standard 12-lead electrocardiogram (ECG) according to Einthoven, Goldberger and Wilson  
4. 
Physical examination including the assessment of the skin, head, eyes, ears, nose, neck, lymph 
nodes, throat, and extremities, and the following body systems: musculoskeletal, 
cardiovascular, respiratory, gastrointestinal and neurological.  
Any other clinically relevant findings will be recorded. 
Blood sampling for pharmacokinetics: 
Blood sampling for pharmacokinetic analysis (one per day, in total seven samples) will be performed 
at randomization, daily at Visit 1 to Visit 5, and at the End of Trial Visit (Day 12±1). 
The time of PK blood sampling will be documented. 


 
Summary of the Clinical Trial 
Protocol and Statistical Plan 
AIC316-02-II-01 
31Jan2017 
 
 
 
 
 
 
Statistical methods: 
Sample size calculation: 
The primary endpoint will be the percentage of subjects with non-ulcerative lesions in each treatment 
group.  
The percentage of subjects with non-ulcerative lesions if left untreated with HL is estimated as 26%. 
The percentage of subjects with non-ulcerative lesions is assumed to be 50% when applying pritelivir 
5% w/w ointment as compared to placebo. The following table shows the total number of subjects with 
recurrences needed to show superiority of pritelivir compared with placebo with 80% power and 
assuming a type I error rate of 5%.  
Proportion of subjects 
with non-ulcerative 
lesions: 
Total number of evaluable 
recurrences needed 
1:1:1 randomization 
Total 
evaluable 
recurrences 
needed 
Total number 
of subjects 
needed 
(including 
40% who do 
not develop a 
recurrence) 
Placebo 
Pritelivir 
Pritelivir 
Placebo 
Zovirax® 
26% 
50% 
71 
71 
71 
213 
360 
It is assumed that 71 recurrences in each arm are sufficient to allow for a descriptive comparison of 
pritelivir with Zovirax®. 
In order to obtain 213 evaluable HL recurrences, 360 subjects need to be randomized in a 1:1:1 
randomization scheme to cover the rate of approx. 40% of subjects which do not develop a recurrence 
or drop out. 
Primary efficacy analysis: 
The primary efficacy analysis will be performed in the ITT (Intend to Treat Set) and the PPS (Per-
Protocol Set). 
ITT includes the results from all randomized subjects who applied the trial medication at least once 
and had at least one lesion status assessment done/reported after start of treatment. 
PPS is a subset of the ITT excluding subjects with major protocol violations. 
Secondary efficacy analyses 
The secondary efficacy analyses will be performed in the ITT and the PPS. 
Safety 
All safety and tolerability parameters will be listed. All safety analyses will be performed in the Safety 
Set (= all randomized subjects who applied at least one dose of trial medication).