Saypha® VOLUME Lidocaine for Midface Augmentation

Study Overview
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Brief Summary
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The clinical investigation is a randomized, subject- and evaluator-blinded, active treatment controlled, multicenter, clinical investigation, to demonstrate the non inferiority of saypha® VOLUME Lidocaine to one of the devices approved for the same indication (Juvéderm® Voluma™ XC).

Detailed Description
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This will be a multi-center, randomized, double-blind, comparator-controlled study. The study will take place in the EU and US with approximately 17 sites. The purpose of the current clinical investigation is to evaluate the effectiveness, safety and long-term safety of saypha® VOLUME Lidocaine for the correction of age-related moderate to severe volume deficit in the midface (augmentation of midface volume deficit), and to demonstrate its non-inferiority to one of the devices approved for the same indication (Juvéderm® Voluma™ XC). In addition, the duration of the aesthetic effect after implantation will be studied. Approximately 486 subjects in total will be randomized and treated resulting in 437 evaluable subjects for the primary endpoint. Randomization will be in a 2:1 ratio (test device: 324, comparator device: 162). Each subject will take part in the investigation for up to 92 weeks. The total anticipated duration of the investigation, from the first-subject-first visit to the last-subject-last-visit, is around 114 weeks, based on expected recruitment period of about 22 weeks.

Official Title
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A Randomized, Subject- and Evaluator-blinded, Controlled, Non-inferiority Multicenter, Parallel Group Comparison Study to Evaluate Effectiveness and Safety of Saypha® VOLUME Lidocaine for Midface Augmentation to Correct Volume Deficit

Conditions
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Moderate to Severe Midface Volume Deficit

Intervention / Treatment
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* Combination Product: saypha® VOLUME Lidocaine
* Combination Product: Juvéderm® Voluma™ XC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (baseline treatment) Male or female subjects aged 22 - 75 years (inclusive) of age at Screening. Subjects with bilateral, approximately symmetric moderate to severe midface volume deficit (severity scores of 2 or 3 on the 5-point Midface Volume Deficit Severity Scale), as assessed by the blinded investigator at the site. Females of childbearing potential must have a negative urine pregnancy test and must agree to use a highly effective method of birth control throughout the entire study. Males subjects with female partners of child-bearing potential must agree to use contraception throughout the entire study (surgical sterilization or a physical barrier such as a condom). Healthy skin in the midface area and free of diseases that could interfere in cutaneous aging evaluation. Willingness to abstain from any aesthetic or surgical procedures in the treatment area for the duration of entire investigation, including botulinum toxin injection (except glabella or forehead botulinum toxin treatment). Subjects who understand the purpose and conduct of the study and having given written informed consent and are willing and able to attend the study visits as judged by the investigator. Exclusion Criteria: (baseline treatment) Females, who are pregnant and/or, lactating or planning to become pregnant during the clinical investigation History of severe allergies manifested by a history of anaphylaxis or history or presence of multiple severe allergies History of hypersensitivity to hyaluronic acid preparations, lidocaine or any amide-based anesthetic Tendency to keloid formation and/or hypertrophic scars and/ or have pigment disorders Known human immune deficiency virus-positive individuals Presence of infectious, inflammatory or proliferative cancerous or pre-cancerous lesions in the treatment area Re-current (three times a year over the last year) herpes simplex in the treatment area History or presence of any autoimmune or connective tissue disease, or current treatment with immuno-modulating therapy Uncontrolled (or unstable) Diabetes mellitus or systemic diseases as per investigator discretion Previous facial plastic surgery, tissue augmentation with silicone, fat or another non-absorbable substance (permanent fillers) and semi-permanent / long-lasting fillers (e.g., poly-L-lactic acid (PLLA), Polymethylmethacrylate (PMMA) filler) in the area of device application and during the entire investigation Implantation of dermal fillers in the treatment area within the preceding 24 months prior to Visit 1 (Screening) and during the entire investigation Subject has received any of the following aesthetic treatments in the midface area: e.g., laser therapy, absorbable and non-absorbable sutures (threads), dermabrasion, mesotherapy, micro-needling and/or botulinum toxin (including treatment of crow´s feet in the outer eye region) within the last 12 months prior to Visit 1, chemical peeling within the last three months prior to Visit 1 or is planning to undergo such procedures during entire investigation. Facial lipolysis, including submental fat treatments, within the previous 12 months prior to Visit 1 (Screening) and during the entire investigation Bariatric surgery within 12 months prior to Visit 1 (Screening) and during the entire investigation History of bleeding disorder and/or use of anticoagulant, antiplatelet, thrombolytic medication, or anti-inflammatory drugs (oral/injectable corticosteroids or non steroidal anti-inflammatory drugs, e.g., Motrin® or Advil®) or other substances known to increase coagulation time (vitamins or herbal supplements, e.g., St. John's Wort, high doses of vitamin E supplements) from ten days pre- to seven days post injection (baseline treatment and touch-up treatment) Planned dental/oral surgery or modification (bridge-work, implants) within four weeks prior to each injection and to a minimum of four weeks post injection baseline treatment and touch-up treatment Beard longer than three-day beard, or excessive facial hair that could interfere in evaluation of treatment as judged by the investigator Subjects who have one of the following assessments during the visual examinations at Visit 2 (Baseline): Snellen visual acuity test worse than 20/40 (with corrective eyewear, if applicable), abnormal confrontational visual field test, or abnormal ocular motility test. Subjects with active COVID-19 infection and subjects with symptoms consistent with COVID-19 infection including any other respiratory symptoms/illnesses within the past 14 days unless tested negative prior to Visit 1 (Screening) Any medical condition prohibiting the inclusion in the study according to the judgment of the treating investigator Previous enrollment in this clinical investigation Current participation in another clinical trial, or treatment with any investigational drug/medical device within 30 days prior to Visit 1 (Screening) or within five half-lives of an investigational drug, whichever is longer and during the entire investigation Midface volume deficit due to a congenital defect, trauma, or abnormalities in facial adipose tissue distribution such as those associated with HIV related lipodystrophy Subjects who experienced fat loss for a minimum of 10% of body weight over the last 12 months (e.g., post bariatric patients), or subjects who have the intention to change eating habits that result in a weight gain or loss >10% during the entire investigation Any individual whose willingness to volunteer in this clinical investigation could be unduly influenced by the expectation, whether justified or not, of benefits associated with participation or of retaliatory response from senior members of a hierarchy in case of refusal to participate (e.g., persons with a legal custodian appointed due to mental disability, prisoners, soldiers and other members of the armed forces, civil servants). Close affiliation with the investigator (e.g., a close relative, financially dependent on the study site) or subject who is an employee of the sponsor's company or group companies of the sponsor. Inclusion criteria: (touch-up treatment) 1. Females of childbearing potential must have a negative urine pregnancy test Exclusion criteria: (touch-up treatment) Occurrence of a serious adverse event or Adverse Event of Special Interest (i.e., changes in vision [loss of vision, blurriness, double vision, pain in or around the eye, blindness, blind spots, problems moving the eyes], skin changing color around the eyelids or around the site of injection, other embolic phenomenon, e.g., stroke) during or after the previous injection Subjects who experienced visual changes considered abnormal clinically significant or other serious medical conditions during or after the previous injections Subjects who have one of the following assessments during the visual examinations: Snellen acuity test worse than 20/40 (with corrective eyewear, if applicable), abnormal confrontational visual field test, or abnormal ocular motility test. Inclusion criteria: (repeat-treatment) Subjects with bilateral, approximately symmetric moderate to severe midface volume deficit (severity scores of 2 or 3 on the 5-point MVDSS), as assessed by the blinded evaluator at the site. The subject does not have to return to his baseline severity to be permitted to receive a repeat-treatment. Subject has completed initial treatment phase up to Visit 9 (SV1) Females of childbearing potential must have a negative urine pregnancy test Healthy skin in the midface area and free of diseases that could interfere in cutaneous aging evaluation Exclusion criteria: (repeat-treatment) Occurrence of a related Serious Adverse Event or Adverse Event of Special Interest (i.e., changes in vision [loss of vision, blurriness, double vision, pain in or around the eye, blindness, blind spots, problems moving the eyes], skin changing color around the eyelids or around the site of injection, other embolic phenomenon, e.g., stroke) during or after the baseline injection and/or touch-up injections Occurrence of a related Adverse Event that occurred during the initial treatment phase, and is ongoing at the time of the repeat treatment (i.e., relationship is classified as possible, probable or causal relationship; outcome is not recovered / resolved, recovering / resolving, recovered / resolved with sequelae or unknown) Subjects who experienced visual changes considered abnormal clinically significant or other serious medical conditions during or after the baseline or touch-up injections, respectively Subjects who have one of the following assessments during the visual examinations: Snellen acuity test worse than 20/40 (with corrective eyewear, if applicable), abnormal confrontational visual field test, or abnormal ocular motility test Subjects who became pregnant since start of the study or planning to become pregnant during the clinical investigation Known human immune deficiency virus-positive individuals Presence of infectious, inflammatory or proliferative cancerous or pre-cancerous lesions in the treatment area Development of re-current (three times a year over the last year) herpes simplex in the treatment area since study start Development of any autoimmune or connective tissue disease since study start, or current treatment with immuno-modulating therapy Development of uncontrolled (or unstable) diabetes mellitus or systemic diseases since study start as per investigator discretion Facial plastic surgery, tissue augmentation with silicone, fat or another non-absorbable substance (permanent fillers) and semi-permanent fillers (e.g., poly-L-lactic acid) in the area of device application and during the initial treatment phase of the investigation Implantation of dermal fillers (other than the test and comparator device used in the investigation) in the treatment area during the initial treatment phase of the investigation Subject has received any of the following aesthetic treatments in the midface area: e.g., laser therapy, absorbable and non-absorbable sutures (threads), dermabrasion, mesotherapy, micro-needling and/or botulinum toxin (including treatment of crow´s feet in the outer eye region), or chemical peeling during the initial treatment phase of the investigation or is planning to undergo such procedures during the repeat-treatment phase of the investigation Facial lipolysis, including submental fat treatments during the initial treatment phase of the investigation Bariatric surgery during the initial treatment phase of the investigation Development of bleeding disorder and/or use of anticoagulant, antiplatelet, thrombolytic medication, or anti-inflammatory drugs (oral/injectable corticosteroids or non steroidal anti-inflammatory drugs, e.g., Motrin® or Advil®) or other substances known to increase coagulation time (vitamins or herbal supplements, e.g., St. John's Wort, high doses of vitamin E supplements) from ten days pre- to seven days post injection (repeat-treatment and touch-up treatment) Planned dental/oral surgery or modification (bridge work, implants) within four weeks prior to the injection and to a minimum of four weeks post injection Any medical condition prohibiting the inclusion for repeat-treatment according to the judgement of the treating investigator Beard longer than three-day beard, or excessive facial hair that could interfere in evaluation of treatment as judged by the investigator Previous enrollment in initial treatment phase of this clinical investigation and early termination, or significant incompliance with the protocol requirements Current or previous treatment with another investigational drug and/or medical device or participation in another clinical study Midface volume deficit due to a trauma, or abnormalities in facial adipose tissue distribution such as those associated with HIV related lipodystrophy Subjects who experienced fat loss for a minimum of 10% of body weight since study start or subjects who have the intention to change eating habits that result in a weight gain or loss >10% during the entire investigation Subjects with active COVID-19 infection and subjects with symptoms consistent with COVID-19 infection including any other respiratory symptoms/illnesses within the past 14 days unless tested negative prior to Visit RT1

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: saypha® VOLUME Lidocaine<br>For injection, either a needle (27G ½'') or cannula (25G 1½) may be used. Randomization will be stratified by injection equipment in a 1:1 ratio. The volume administered is at the discretion of the treating investigator and depends on the severity of the midface volume deficit to be corrected. However, the maximum volume (left and right side of the midface together) must not exceed 10 mL in total per treatment (initial and repeat-treatment) or 20 mL per 60 kg (130 lbs) body mass per year. | Combination Product: saypha® VOLUME Lidocaine<br>* Crosslinked hyaluronic acid (HA) 23 mg/mL + 0.3% lidocaine hydrochloride.<br>|
| Active Comparator: Juvéderm® Voluma™ XC<br>For injection, either a needle (27G ½'') or cannula (25G 1½) may be used. Randomization will be stratified by injection equipment in a 1:1 ratio. The volume administered is at the discretion of the treating investigator and depends on the severity of the midface volume deficit to be corrected. However, the maximum volume (left and right side of the midface together) must not exceed 10 mL in total per treatment (initial and repeat-treatment) or 20 mL per 60 kg (130 lbs) body mass per year. | Combination Product: Juvéderm® Voluma™ XC<br>* Crosslinked HA 20 mg/mL + 0.3% lidocaine hydrochloride<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of responders on the 5-point MVDSS at Week 24 | The percentage of responders on the 5-point MVDSS (Mid-Face Volume Deficit Severity Scale where 0 means no deficit and 4 means Extreme Deficit) based on the blinded evaluator´s live assessment at Week 24 after last injection of initial treatment phase compared to the pre-treatment score at Baseline visit | Week 24 relative to baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of responders on the 5-point MVDSS at Weeks 4, 8, 16, 36, and 48 as rated by the blinded evaluator | The percentage of responders on the 5-point MVDSS (Mid-Face Volume Deficit Severity Scale where 0 means no deficit and 4 means Extreme Deficit) , based on the blinded evaluator´s live assessment at W4 to 48 after last injection of initial treatment compared to the score at Baseline | Study Weeks 4, 8, 16, 24, 36, and 48 | 
| The percentage of responders on the 5-point MVDSS at Weeks 4, 8, 16, 36, and 48 as rated by the independent blinded photographic reviewer | •The percentage of responders on the 5-point MVDSS (Mid-Face Volume Deficit Severity Scale where 0 means no deficit and 4 means Extreme Deficit), based on the independent blinded photographic reviewer´s assessment by using Baseline photographs at W4 to 48 after last injection of initial treatment compared to the score at Baseline | Study Weeks 4, 8, 16, 24, 36, and 48 | 
| Mean change in midface volume deficit | Mean change in midface volume deficit measured on the 5-point MVDSS(Mid-Face Volume Deficit Severity Scale where 0 means no deficit and 4 means Extreme Deficit), and based on the blinded evaluator´s live assessment at Week 4 to Week 48 after last injection of initial treatment compared to the score at Baseline | Study Weeks 4, 8, 16, 24, 36, and 48 | 
| Mean change in midface volume deficit as measured by volumetric change measurement | Mean change in midface volume deficit as measured by volumetric change measurement by using 3D digital photographic images at Week 4 to Week 48 after last injection of initial treatment compared to Baseline | Study Weeks 4, 8, 16, 24, 36, and 48 | 
| Change in Nasolabial Folds Measurements | Shift from baseline in nasolabial folds measured by the 5-point validated NLF_SRS (Nasolabial Folds Severity Rating Scale, where 0 means no NLF and 4 means Extreme Nasolabial fold) based on the blinded evaluator´s live assessment at Week 4 to Week 48 after last injection of initial treatment | Study Weeks 4, 8, 16, 24, 36, and 48 | 
| Global aesthetic improvement based on modified GAIS as rated by blinded evaluator | The percentage of subjects with a global aesthetic improvement over baseline (at Baseline visit) (subjects who have been rated as much improved or improved), based on the blinded evaluator's assessment at Week 4, 8, 16, 24, 36, and 48, after last injection of initial treatment phase using the 5-point modified GAIS (Global Aesthetic Improvement Scale, where Investigators and subjects separately assess aethetic improvement via photographs comparing baseline photos against the respective study visit week photo with the following possible 5 outcomes: much worse; worse; unchanged; improved; much improved). | Study Weeks 4, 8, 16, 24, 36, and 48 | 
| Global aesthetic improvement based on modified GAIS as rated by Subject | The percentage of subjects with a global aesthetic improvement over baseline (at Baseline visit) (subjects who have been rated as much improved or improved), based on subject´s assessment at Week 4, 8, 16, 24, 36, and 48, after last injection of initial treatment phase using the 5-point modified GAIS (Global Aesthetic Improvement Scale, where Investigators and subjects separately assess aethetic improvement via photographs comparing baseline photos against the respective study visit week photo with the following possible 5 outcomes: much worse; worse; unchanged; improved; much improved). | Study Weeks 4, 8, 16, 24, 36, and 48 | 
| Subject's assessment of satisfaction with outcome appraisal based on FACE-Q(TM) | •The extent of subject´s satisfaction with overall treatment outcome at Week 4, 8, 16, 24, 36, and 48 after last injection of initial treatment phase as assessed by the subject using the Face-Q(TM) Questionnaire Satisfaction with Outcome. This validated patient reported outcome is based on subject's answers to pre-specified questions with answers ranging for fully agree to fully disagree. The answers are mathematically transferred to a numerical result between 100 and 0, where 100 reflects the highest possible satisfaction and 0 means the the lowest possible satisfaction. | Week 4, 8, 16, 24, 36, and 48 | 
| Subject's assessment of satisfaction with appearance based on FACE-Q(TM) | •The extent of subject´s appearance appraisal at Week 4, 8, 16, 24, 36, and 48 after last injection of initial treatment phase as assessed by the FACE-Q(TM) questionnaire Satisfaction with Cheeks compared to Baseline visit. This validated patient reported outcome is based on subject's answers to pre-specified questions with answers ranging for fully agree to fully disagree. The answers are mathematically transferred to a numerical result between 100 and 0, where 100 reflects the highest possible satisfaction and 0 means the the lowest possible satisfaction. | Week 4, 8, 16, 24, 36, and 48 | 
| Subject´s pain assessment | Subject evaluation of pain after each treatment (baseline and touch-up treatment) on an 11-point scale, where 0 is no pain and 10 is the worst pain imaginable | Day 0 and Week 2 (in case a touch-up treatment is performed) | 
| Evaluation of Injection Volume | Injection volume required to achieve optimal aesthetic result at each treatment | Day 0 and Week 2 (in case a touch-up treatment is performed) |