Safety and Performance of DKL Crosslinked Sodium Hyaluronate 23 Dermal Filler for Improvement of NLF Appearance

Study Overview
=================
Brief Summary
-----------------
This is a pivotal, prospective active-controlled, randomized, double blinded (blinded evaluator and subject), intra-individual split-face comparison, non-inferiority study of DKL crosslinked sodium hyaluronate 23 versus Juvederm Volift™ after injection into the mid to deep dermis for correction of moderate to deep nasolabial folds (NLFs).

Detailed Description
-----------------
This is a pivotal, prospective active-controlled, randomized, double blinded (blinded evaluator and subject), intra-individual split-face comparison, non- inferiority study of DKL crosslinked sodium hyaluronate 23 versus Juvederm Volift™ after injection into the mid to deep dermis for correction of moderate to deep nasolabial folds (NLFs). Approximately 40 subjects will be randomized and treated. Subjects will come to the research clinic for up to 6 visits, including a screening/baseline visit and up to 5 follow-up visits. At Screening eligible subjects (males and females aged 18 to 65 years) will be randomized as to which NLF will be treated with the investigational device and which NLF will be treated with the comparator device. The subjects will undergo baseline assessments of NLF Wrinkle Severity Rating Scale (WSRS) by the evaluating investigator and have baseline two-dimensional (2D) photos taken, prior to treatment with the investigational device and comparator. Treatment will be performed by an unblinded treating investigator. Following treatment, the subjects will complete a subject eDiary in which they will assess pre-defined treatment related events experienced during the first 14 days after the injection. Additional visits will take place 1, 3, 6 and 9 months after the treatment. During these visits the subjects will undergo evaluations by an evaluating investigator blinded to the treatment allocation. Assessments will include photography, NLF WSRS and Global Aesthetic Improvement Scale (GAIS). The subjects will also evaluate treatment outcome using the GAIS and complete a patient satisfaction questionnaire. The investigator will record any adverse events (AEs) that have occurred and will note their severity and relationship to the injected product. An optional touch-up treatment will be performed one month after the initial treatment at the discretion of the treating investigator. Subjects requiring touch-up will receive touch-up according to the original randomization scheme, i.e. the investigational device and comparator product will be injected to the same NLF according to the randomization scheme. Following touch-up, these subjects will be asked to complete a subject eDiary for assessment of pre-defined treatment related events experienced during the first 14 days after the injection. Subjects receiving touch-up will attend and additional evaluation visit one month after touch-up (in addition to other visits). The treating investigators will complete a usability questionnaire.

Official Title
-----------------
A Clinical Study to Evaluate the Safety and Performance of DKL Crosslinked Sodium Hyaluronate 23 Dermal Filler for Improvement of Nasolabial Fold Appearance

Conditions
-----------------
Aging, Premature

Intervention / Treatment
-----------------
* Device: DKL crosslinked sodium hyaluronate 23
* Device: Juvéderm Volift™ with lidocaine (Allergan, Inc)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Review and sign the Independent Ethics Committee (IEC)-approved Informed Consent Form (ICF) prior to any study-related procedures being performed. In addition, the subject will be asked to provide a separate release for use of their photographs in publications and the clinical investigation report (CIR). The subject has a right to refuse the photo release without jeopardizing their eligibility to participate in the study. Male and female subjects aged 18 to 65 years (inclusive) at the time of screening. Subject desires correction of NLFs. Moderate to severe bilateral aging defects in the nasolabial area, with wrinkles classified as grade 3 or 4 according to the NLF WSRS on each side as assessed by the blinded evaluator. NLFs should be of the same grade on the left and right side of the face (i.e. approximate bilateral symmetry). Subject, that in the opinion of the blinded evaluator, can improve at least 1 step on the investigator-rated NLF WSRS with a maximum volume of 2.0 mL/NLF for initial treatment and 1.0 mL/NLF for touch-up. Female of child-bearing potential (sexually active and not sterile nor postmenopausal for at least 1 year) should have a urine pregnancy test evaluated as negative on the day of enrolment, and agree to use a reliable method of contraception for the duration of the study (effective birth control measures include sexual abstinence, combined [estrogen and progestogen containing] hormonal contraception associated with inhibition of ovulation [oral, intravaginal, transdermal], progestogen-only hormonal contraception associated with inhibition of ovulation [oral, injectable, implantable], intrauterine device [IUD] or intrauterine hormone-releasing system [IUS] and/or condom with spermicide). Subject agrees to abstain from any facial cosmetic or surgical procedures during the study period. Subject agrees to refrain from excessive weight gain or loss (±10%) during the investigation period. Subject has adequate understanding of the local language to understand verbal and written subject information and is willing to comply with the study requirements. Exclusion Criteria: History of any clinically significant disease or disorder, including porphyria or systemic disorders affecting wound healing, which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of investigational device and comparator. History of anaphylaxis, multiple severe allergies, atopy, or allergy to sodium hyaluronate products or to streptococcal proteins or have plans to undergo desensitization therapy during the term of the study. History of immune system disorders (e.g., autoimmune disease, human immunodeficiency virus [HIV]-positive status, history of immune system degradation, or recurrent herpes simplex). History of streptococcal disease (e.g. recurrent sore throat) and subjects with rheumatic fever, as judged by the investigator. Dermatological problems (e.g. cutaneous lesions, inflammatory skin conditions, hypertrophic scars or a tendency for keloid formation) at the discretion of the investigator. Noticeable scarring (including acne scarring), prior surgery, an active inflammation, infection, cancerous or pre-cancerous lesion, history of prior significant trauma to the midface, such as dog bite or laceration, resulting in formation of a scar, or unhealed wound or have undergone radiation treatment in the area to be treated. Cheek tattoos, piercings, facial hair, or scars that would interfere with visualization of the cheek area for the effectiveness assessments. Very thin skin in the mid-facial region, tendency to accumulate fluid in the lower eyelids, or large infraorbital fat pads, i.e., significant convexity or projection from the infraorbital fat pads. Mid-face volume deficit due to congenital defect, trauma, abnormalities in adipose tissue related to immune-mediated diseases such as generalized lipodystrophy (e.g., juvenile dermatomyositis), partial lipodystrophy (e.g., Barraquer-Simons syndrome), inherited disease or HIV-related disease. Moderate or severe abnormal midface or cheek asymmetry. Ongoing or history of use of immunosuppressive therapy. Use of anti-coagulation, anti-platelet, or thrombolytic medications, anti-inflammatory drugs, or other substances known to increase coagulation time (as detailed in Section 9.6.2) within 10 days prior to treatment with the investigational device and comparator. Use of any new (i.e. that the subject has not used before) facial over-the-counter or prescription, oral or topical, anti-wrinkle products within 90 days prior to enrolment or planning to begin use of such products at any time during the study. NOTE: Continued therapy with some cosmeceuticals (e.g., alpha hydroxyl acids, glycolic acids, retinol, or retinoic acids) is allowed if the regimen was established ≥ 90 days prior to enrolment. The use of sunscreens is also allowed. Known sensitivity to any investigational device or comparator components (see Section 10.1). Previous cosmetic or aesthetic procedures as follows: i) All types of previous surgical surgery below the lower orbital rim ii) All types of permanent fillers below the lower orbital rim iii) Previous semi-permanent fillers below the orbital less than 2 years before treatment iv) Previous treatment with HA-based fillers less the 18 months prior to enrolment v) Treatment with photochemotherapy or lasers less than 6 months before enrolment vi) Mechanical, chemical or medical peeling less than 6 months prior to enrolment vii) Treatment with botulinum toxins less than 12 months prior to enrollment viii) Major dental procedures less than 6 months prior to enrolment The presence of abnormal midface function, with inability to effectively puff cheeks, smile broadly, or chew. Pregnant, lactating, or planning to become pregnant at any time during the study. Positive screen for drugs of abuse or alcohol at screening or on admission to the unit prior to administration of the investigational device and comparator. History of alcohol or drug abuse or excessive intake of alcohol, as judged by the investigator. Has received any investigational device within 30 days prior to study enrolment or is planning to participate in another investigation during the course of this study. No access to an electronic device (e.g. smartphone, tablet or personal computer) on which to complete eDiaries. Is an employee (or a relative of an employee) of the contract research organization (CRO) responsible for conducting the study, sponsor, or a sponsor representative. The Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Pivotal, prospective, active-controlled, randomized, double blinded (blinded evaluator and subject), intra-individual split-face comparison
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational device<br>DKL crosslinked sodium hyaluronate 23 | Device: DKL crosslinked sodium hyaluronate 23<br>* is injected into the NLF on Day 1. The volume of injection will not exceed 2 mL per side. If applicable, a touch-up of DKL crosslinked sodium hyaluronate 23 will be injected on Day 30; the volume of injection will not exceed 1 mL per side.<br>|
| Active Comparator: Comparator product<br>Juvéderm Volift™ with lidocaine (Allergan, Inc) | Device: Juvéderm Volift™ with lidocaine (Allergan, Inc)<br>* is injected into the NLF on Day 1. The volume of injection will not exceed 2 mL per side. If applicable, a touch-up of Juvéderm Volift™ will be injected on Day 30; the volume of injection will not exceed 1 mL per side.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the rate of responders determined by the aesthetic improvement of the NLFs according to live on-site evaluator-rated NLF WSRS at 6 months post-treatment between the investigational device and comparator product. | The NLF WSRS is a 5-point scale ranging from 1 (No visible fold; continuous skin line) to 5 (Extremely deep and long folds; detrimental to facial appearance; 2- to 4-mm visible V-shaped fold when stretched). Response is defined as ≥ 1-point improvement on the NLF WSRS for each NLF compared to baseline. Each NLF is to be assessed separately. | Baseline (pre-treatment) to 6 months post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the rate of responders determined by the aesthetic improvement of the NLFs according to live on-site evaluator-rated NLF WSRS at 1, 3 and 9 months post-treatment between the investigational device and comparator product. | The NLF WSRS is a 5-point scale ranging from 1 (No visible fold; continuous skin line) to 5 (Extremely deep and long folds; detrimental to facial appearance; 2- to 4-mm visible V-shaped fold when stretched). Response is defined as ≥ 1-point improvement on the NLF WSRS for each NLF compared to baseline. Each NLF is to be assessed separately. | Baseline (pre-treatment) to 1, 3 and 9 months post-treatment | 
| Comparison of the mean change in evaluator-rated NLF WSRS from baseline (pre-treatment) to at 1, 3, 6 and 9 months post-treatment between the investigational device and comparator product. | The NLF WSRS is a 5-point scale ranging from 1 (No visible fold; continuous skin line) to 5 (Extremely deep and long folds; detrimental to facial appearance; 2- to 4-mm visible V-shaped fold when stretched). | Baseline (pre-treatment) to 1, 3, 6 and 9 months post-treatment | 
| Subject-rated aesthetic improvement in appearance according to GAIS at 1, 3, 6 and 9 months post-treatment. Each NLF is to be assessed separately. | The 5-grade GAIS assesses the appearance of the NLF compared to pre-treatment on a scale ranging from very much improved to worse. | Baseline (pre-treatment) to 1, 3, 6 and 9 months post-treatment | 
| Evaluating Investigator-rated aesthetic improvement in appearance according to the GAIS at 1, 3, 6 and 9 months post-treatment. Each NLF is to be assessed separately. | The 5-grade GAIS assesses the appearance of the NLF compared to pre-treatment on a scale ranging from very much improved to worse. | Baseline (pre-treatment) to 1, 3, 6 and 9 months post-treatment | 
| Usability of the device | Investigator-reported usability of the device. A device usability questionnaire will be completed once by each treating investigator after treatment of his/her last subject. | Baseline - treatment | 
| Subject-reported satisfaction with treatment as assessed by a subject satisfaction questionnaire at 1, 3, 6 and 9 months post-treatment. | Satisfaction will be assessed on a 5-point scale ranging from very satisfied (1) to very dissatisfied (5). | 1, 3, 6 and 9 months post-treatment | 
| Post-treatment events | Incidence, intensity, and duration of pre-defined expected post-treatment events collected using a subject electronic diary (eDiary) for 14 days post treatment. | Up to 14 days post-treatment | 
| Adverse Events | Frequency, intensity and seriousness of adverse events (AEs). | Up to 9 months post-treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Premature skin aging, Correction of facial structural defects, Wrinkles