Effectiveness and Safety of STYLAGE® M Lidocaïne for Lips' Volume Augmentation and/or Redefinition of the Outline of the Lips (SMILE)

STYLAGE® M Lidocaine is a hyaluronic acid injectable gel CE (conformité européenne)-marketed since 2009 . It is indicated for the outline of the lips and/or for lips augmentation in lips mucosa. It is also indicated to fill skin depressions on the face. Lidocaine is intended to reduce the pain associated with the injection.

The aim of SMILE study is to demonstrate that STYLAGE® M Lidocaine is non-inferior to an active comparator that has shown its effectiveness in lips' volume augmentation and restoration in improving the aesthetic appearance of the lips evaluated by subjects.

In this study, 92 healthy volunteers between 18 and 65 years old, who expressed the wish for augmentation or restoration of the volume of the lips and/or lips' outline redefinition, confirmed by investigators at inclusion, who have given his/her informed consent and who met all the eligibility criteria, will be enrolled.

Subjects will randomly receive STYLAGE® M Lidocaïne or the active comparator (ratio 1:1) injection in the lips at first visit on Day 0. At second visit, one month after Day 0, an optional touch-up injection could be performed according to subject's and investigator's opinions and if the subject is still eligible.

Subjects will have a total of 6 visits over a 12 months follow-up period and a screening visit prior to first injection.

Proportion of subjects having a global aesthetic improvement of their lips (blinded self-evaluation), 3 months after treatment initiation will be assessed and compared between the two groups. This will also be done during the other visits (1, 6, 9 and 12 months after treatment initiation). Global aesthetic improvement according to blinded independent evaluator, subjects' satisfaction, pain during injection and safety parameters will also be assessed during the study period.

This is a prospective, double blinded, randomized, active controlled, multicenter study. Subjects are randomly assigned to receive either STYLAGE® M Lidocaine or the active comparator (ratio 1:1).

Ninety two subjects between 18 and 65 years old who expressed the wish for augmentation or restoration of the volume of the lips and/or lips' outline redefinition, confirmed by investigators at inclusion, who have given his/her informed consent and who met all the eligibility criteria (especially according to the instructions for use of the devices), will be include.

After a screening visit for selection, each subject will be followed for 12 months after 1st injection at Visit 1 (on Day 0). Five follow-up visits are scheduled 1, 3, 6, 9 and 12 months after initial injection (Visits 2 to 6). At 1 month (Visit 2), an optional touch-up injection may be done (if needed).

The primary objective is to demonstrate non-inferiority of STYLAGE® M Lidocaine versus the active comparator in improving the aesthetic appearance of the lips. The comparison of effectiveness between the devices will be done according to proportion of subjects having an improvement on the 5-point Global Aesthetic Improvement Scale (GAIS) evaluated by the blinded subject on the lips (after mirror self-examination), 3 months after treatment initiation (V1). Improvement according to GAIS corresponds to one of these three categories: "Very much improved", "Much improved" or "Improved".

Secondary objectives include subjects' self-evaluation of their lips according to GAIS, at 1, 6, 9 and 12 months after treatment initiation. Global aesthetic improvement of the lips according to blinded independent evaluator, subjects' satisfaction, subjects' self-evaluation of pain during injection will also be measured and collected at each visit during the whole study period. Study products tolerance will be assessed by collection of injection site reactions after each injection session, and adverse events throughout the study.

Eligibility Criteria:
Inclusion Criteria:

* Healthy volunteer.
* Sex: female or male.
* Age: between 18 and 65 years.
* Subject having given freely and expressly his/her informed consent and data privacy consent.
* Subject who expressed the wish for augmentation or restoration of the volume of the lips and/or lips' outline redefinition.
* Lips requiring volume and/or lips' outline requiring redefinition according to the investigator's judgement.
* Subject with attainable expectations for lips' volume augmentation or restoration and/or outline redefinition.
* Subject willing to have photographs of the face taken.
* Subject psychologically able to understand the study related information and to give a written informed consent.
* Subject able and agreeing to follow study procedures, instructions and likely to complete all required visits.
* Subject affiliated to a health social security system.
* Female of childbearing potential should use a medically accepted contraceptive regimen since at least 12 weeks before screening visit and during all the study.
* Subject agreeing to be treated with hyaluronidase product in case of vascular complication at the injection site.

Exclusion Criteria:

* Subject who had been deprived of their freedom by administrative or legal decision or who is under guardianship.
* Subject in a social or sanitary establishment.
* For France only: subject having received 4500 euros indemnities for participation in researches involving human beings in France in the 12 previous months, including participation in the present study).
* Subject participating to another research on human beings or who is in an exclusion period of one.
* Pregnant or breastfeeding woman or planning a pregnancy during the study.
* Subject with scar(s), mole(s) or anything on the studied zones, which might interfere with the evaluation (tattoo, permanent make-up...), including lips presenting a marked asymmetry (especially when smiling) and missing front tooth or teeth.
* Subjects with severe perioral wrinkles and seeking for upper cutaneous lip or perioral rejuvenation.
* Subject suffering from a severe or progressive disease or any other pathology that may interfere with the evaluation of the study results and/or subject safety (e.g. on-going active infection).
* Subject suffering from epilepsy, impaired cardiac conduction, severely impaired hepatic function, or severe renal dysfunction.
* Subject with known history of or suffering from autoimmune disease and/or immune deficiency.
* Subject suffering from active disease such as inflammation, infection (including oral or dental localisations), tumours, inflammatory and/or infectious cutaneous disorders (herpes, acne...) on or around the lips. Subject with history of herpes is not eligible even if asymptomatic at time of inclusion.
* Subjects suffering from porphyria.
* Subject having history of allergy or anaphylactic shock including known hypersensitivity to one of the ingredient of tested devices (i.e. hyaluronic acid, lidocaine) or to any other component of the devices used in this study, to gram-positive bacterial proteins, to antiseptic solution or to amide-type local anaesthetics.
* Subject with a history of streptococcal disease, such as acute rheumatic fever, especially with cardiac localisation or recurrent sore throats.
* Subject with a tendency to develop keloids or hypertrophic scars or any other healing disorders.
* Subject with bleeding, haemostatic disorders.
* Subject having received treatment with a laser, a dermabrasion, a surgery, a chemical peeling or any other procedure based on active dermal response on/around the lips within the past 12 months prior to screening visit or who plans to undergo any of these procedures during the study.
* Subject having received a hyaluronic acid implant into the lips within the past 18 months prior to screening visit or who plans to undergo this procedure during the study.
* Subject having received at any time, any product other than hyaluronic acid into and/or around the lips, like collagen or injection with a slowly resorbable filling product (polylactic acid, calcium hydroxyapatite, combinations of hyaluronic acid (HA) and hypromellose, HA and dextran microbeads or HA and TriCalcium Phosphate (TCP), ...) or with a non-resorbable filling product (polyacrylamide, silicone, combination of methacrylic polymers and collagen, polymer particles,...) or who plans to undergo any of these procedures during the study.
* Subject having received at any time a lip threading surgery or who plans to undergo this procedure during the study.
* Subject who received oral surgery (e.g. tooth extraction, orthodontia or implantation) within 6 weeks prior to screening visit or who plans to undergo any of these procedures during the study.
* Subject having started or changed her oral contraceptive or any other hormonal treatment during 12 weeks prior to screening visit.
* Subject using medication such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents, thrombolytics, anticoagulants or vitamin C within one week prior to first injection visit (V1) and agreeing not to take such treatments within 1 week prior to touch-up visit (V2) or being a chronic user.
* Subject using medication that reduce or inhibit hepatic metabolism (i.e. protease inhibitors, azole antifungals, macrolides, amiodarone, diltiazem, verapamil, ciprofloxacin, fluvoxamine).
* Total injection volume of cross-linked hyaluronic acid \>17,5 mL (whole body) within 1 year prior to screening visit.
* Subject undergoing a topical treatment on the test area or a systemic treatment:

  * Anti-histamines during the 2 weeks prior to injection visit (V1) and agreeing not to take such treatment within 2 weeks prior to touch-up visit (V2);
  * Immunosuppressors and/or corticoids during the 4 weeks prior to screening visit;
  * Retinoids during the 6 months prior to screening visit.