Clinical trial NCT03310294: Immune Evidence to the Consumption of Lactobacillus GG and FOS Consumption in Patients With Herpes Labialis
Official title: A Randomized, Double Blind, Placebo-controlled Multicenter Clinical Study to Evaluate the Effect of a Combination of Probiotics and Prebiotics in Subjects With Recurrent Herpes Labialis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Herpes Labialis
Keywords: Lactobacillus
Herpes Labial
Immune repsonse
Lead sponsor: Sprim Advanced Life Sciences
Sponsor class: OTHER
First posted: 2017-10-16
Enrollment: 157
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a phase IV, parallel, placebo-controlled, double-blind, multicenter, randomized study to evaluate the effect of a combination of probiotics and prebiotics in subjects with recurrent Herpes labialis.

This specific design has been chosen as the most suitable to achieve the objectives of the trial, mainly the demonstration of the clinical efficacy of the combination of probiotics and prebiotics in subjects with recurrent Herpes labialis in terms of reduction of the number of HL recurrences at day 49 vs baseline.
Primary purpose: TREATMENT

Brief summary: Herpes labialis (HL) is the result of the presence of a virus called HSV-1 and is a common disease. Because of its visibility due to cold sores it has a serious impact on social life. Until now there is no effective treatment to prevent virus outbreaks. However, prebiotics and probiotics have both been shown to have a favorable and supportive effect on the immune system in different health conditions such as influenza, atopic dermatitis and diarrhea, so it is possible that they are able to have a favourable effect also on HL.

A recently completed pilot clinical trial (Protocol Number 08-SBUS-2-GRA-01, EVIM-1) was completed using a fermented milk (minidrink) containing a combination of L. rhamnosus and FOS; it showed promising results in the reduction of HL recurrences in a population of 78 subjects with HSV-1. The study investigated the effect of pre- or probiotics or a combination of the two on the recurrence of HL lesions as well as on the immune system in general, showing that the consumption of a minidrink containing the probiotic L. rhamnosus or a minidrink containing a combination of L. rhamnosus and FOS reduced the occurrence and the incidence of recurrent HL lesions.

Aim of this study: corroborate whether the consumption of a minidrink containing a combination of L. rhamnosus and FOS results in less recurrence and a better progression of HL lesion, in a larger population. In addition, the response of the consumption of the minidrink on the QoL and the response on immunity specific biomarkers were evaluated.

Design: 152 patients were eligible to participate in the study and after a run-in period of two weeks consuming a placebo minidrink were randomized to one of the two experimental study groups: placebo minidrink (n=79) and a minidrink containing a combination of a pre- and probiotic (n=78). These minidrinks were consumed until the end of the study (day 140). At day 33 of the study the lip most prone to the development of a lesion was stimulated with UVB to provoke a lesion. During the entire study period subjects were checked for any clinical signs of a lesion, completed a self-assessment regarding the lesion and a QoL questionnaire at baseline (day 14), at day 49 and the end of the study (day 140). In addition, a blood sample was collected at baseline, at day 49 and at the end of the study to be analyzed for HSV-specific antibody concentrations , to check immune system specific functions.

Detailed description: Background: Herpes labialis is the result of the presence of HSV-1 and is a common disease. Because of its visibility it has a serious impact on social life. Until now there is no effective treatment to prevent virus outbreaks. However, prebiotics and probiotics have both been shown to have a favorable and supportive effect on the immune system in different health conditions such as influenza, atopic dermatitis and diarrhea.

A recently completed pilot clinical trial (Protocol Number 08-SBUS-2-GRA-01, EVIM-1) parallel groups, placebo controlled, triple blind, single center, randomized study, with a fermented milk (minidrink) containing a combination of L. rhamnosus and FOS showed promising results in the reduction of HL recurrences in a population of 78 subjects with HSV-1; the study investigated the effect of pre- or probiotics or a combination of the two on the recurrence of HL lesions as well as on the immune system in general, showing that the consumption of a minidrink containing the probiotic L. rhamnosus or a minidrink containing a combination of L. rhamnosus and FOS reduced the occurrence and the incidence of recurrent HL lesions.

Aim of the study: corroborate whether the consumption of a minidrink containing a combination of L. rhamnosus and FOS results in less recurrence and a better progression of HL lesion, in a larger population. In addition, the response of the consumption of the minidrink on the QoL and the response on immunity specific biomarkers were evaluated.

Design: 152 patients were eligible to participate in the study and after a run-in period of two weeks consuming a placebo minidrink were randomized to one of the two experimental study groups: placebo minidrink (n=79) and a minidrink containing a combination of a pre- and probiotic (n=78). These minidrinks were consumed until the end of the study (day 140). At day 33 of the study the lip most prone to the development of a lesion was stimulated with UVB to provoke a lesion. During the entire study period subjects were checked for any clinical signs of a lesion, completed a self-assessment regarding the lesion and a QoL questionnaire at baseline (day 14), at day 49 and the end of the study (day 140). In addition, a blood sample was collected at baseline, at day 49 and at the end of the study to be analyzed for HSV-specific antibody concentrations (circulating concentrations of IgG1 and IgG3 (Th1) and IgG4 (Th2), NK activity, CXCL10 analyzed by ELISA at days 14, 49 and 140).

as regards the primary endpoint results have shown that there was a significant decrease (54.3%) in the recurrences of Herpes labialis lesions, post UV stimulation, at day 49 (V4) compared to placebo in the PP population with consumption of the study product minidrink with fermented low fat milk added with Lactobacillus rhamnosus and FOS. Considering the secondary endpoints in the PP population, considering the number of subjects who presented lesions between V0 and V5, the number of lesions is reduced significantly (both statistically and clinically) in the treatment group compared to the placebo group. There was a decrease in the lesion size in the treatment group when compared to placebo although the statistical significance is marginal. As regards 'Subjective assessment of pain', evaluated by means of a VAS scale, significant pain reduction was found in the treatment group compared to the placebo group. As regards immunological parameters was shown an increase in CXCL10 at V4 in the study group compared to the placebo group. As regards IgG1, IgG3 and IgG4 (V0, V4 and V5) although substantial increases were registered for some of these parameters, these were not sufficient to describe a definite trend. The natural killer (NK) cell activity did not show significant difference in their functional activity in the treatment group as compared to the placebo group.

It has been verified through quality of life questionnaire (SF-36 questionnaire) that treatment improved Mental Health in the treatment group (Nervous, Peaceful, Happy, Down in Dumps, Sad) compared to the placebo group and clinical significance was found at V4 and V5. General Health and Vitality has been improved at V4 and V5.

For each trial participant the adverse events/serious adverse events occurrences and a brief clinical examination were assessed. No special or unusual features of the safety evaluations were found.

Eligibility criteria: Inclusion Criteria:

* Healthy free-living men and women aged 18 to 65 years-old.
* History of recurrent HL (2 - 4 episodes) after exposure to sunlight in the previous 12 months.
* Fitzpatrick skin type 1 to 4 (appendix 1 of the study protocol).
* No presence of HL lesions at time of recruitment, including baseline.
* Agreement to adhere to the prescribed list of dietary recommendations provided at the start of the study (appendix 3 of the study protocol).
* Women of child-bearing potential are required to use adequate birth protection during the study.
* Sign and date the ICF to and to comply with study procedures

Exclusion Criteria:

* Presence of acute/terminal disease.
* Intolerance for milk protein or lactose.
* Treatment with acyclovir or other medication believed to interfere with immune responses at the time of the study.
* Participation in any herpes UV reactivation study within the previous three months.
* Pregnancy or lactation.
* Any condition (e.g. schizophrenia, psychosis, major depression or mental deficiency) or major co-morbidity that the study investigator thinks might compromise the person's ability to comply with the requirements of the study.

Primary outcomes:
measure: reduction of HL recurrence.
timeFrame: Day 49
Secondary outcomes:
measure: reduction of HL recurrence.
timeFrame: day 14
measure: reduction of HL recurrence.
timeFrame: day 140
measure: change IGS markers concentration
timeFrame: day 14
measure: change IGS markers concentration
timeFrame: day 49
measure: change IGS markers concentration
timeFrame: day 140
measure: time to healing
timeFrame: Day 14
measure: time to healing
timeFrame: Day 49
measure: time to healing
timeFrame: Day 140
measure: lesion size
timeFrame: Day 14
measure: lesion size
timeFrame: Day 49
measure: lesion size
timeFrame: Day 140
measure: SF-36
timeFrame: Day 14
measure: SF-36
timeFrame: Day 49
measure: SF-36
timeFrame: Day 140
Other outcomes:
Locations:
Study officials:
affiliation: Dipartimento di Medicina Interna, dell'Invecchiamento e Malattie Nefrologiche Università degli Studi di Bologna
name: Michelangelo La Placa, master
role: PRINCIPAL_INVESTIGATOR
References: