Trial Outcomes & Findings for RHA® 4 NLF Cannula (NCT NCT04754646)

NCT ID: NCT04754646

Last Updated: 2023-03-09

Results Overview

Non-inferiority of RHA®4 injected with a cannula to the change from Baseline for subjects treated with RHA®4 injected with a needle at 12 weeks after last treatment (initial or touch-up; up to 16 weeks post-baseline)) as assessed by the BLE using the NLF-WSRS. NLF-WSRS (Nasolabial Folds - Wrinkle Severity Rating Scale) is a proprietary validated 5-grade scale with 1 being "Absent" and 5 being "Extreme". An NLF-WSRS change of \>1 grade will be considered clinically significant.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 50 participants
• Primary outcome timeframe: Week 12 after last treatment
• Results posted on: 2023-03-09

Participant Flow

Participant milestones

Measure	Bilateral Treatment of RHA® 4 With a Cannula Vs RHA® 4 With a Needle Split-face injection of RHA® 4 with a cannula into the NLF on one side of the face and RHA® 4 with a needle into the NLF on the opposide side of the face. RHA®4 injected with cannula was administered in a random sequence (first or second injection) and side of the face (left or right NLF) and RHA®4 injected with a sharp needle was administered to the other side. The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.
Overall Study STARTED	50
Overall Study COMPLETED	50
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

RHA® 4 NLF Cannula

Baseline characteristics by cohort

Measure	Bilateral Treatment of RHA® 4 With a Cannula Vs RHA® 4 With a Needle n=50 Participants Split-face injection of RHA® 4 with a cannula into the NLF on one side of the face and RHA® 4 with a needle into the NLF on the opposide side of the face. RHA®4 injected with cannula was administered in a random sequence (first or second injection) and side of the face (left or right NLF) and RHA®4 injected with a sharp needle was administered to the other side. The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.
Age, Continuous	55.8 years STANDARD_DEVIATION 8.18 • n=5 Participants
Sex: Female, Male Female	49 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	45 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants
Race (NIH/OMB) White	39 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Fitzpatrick Skin Type Fitzpatrick Skin Type I-III	38 Participants n=5 Participants
Fitzpatrick Skin Type Fitzpatrick Skin Type IV-VI	12 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 12 after last treatment

Population: Per Protocol population (Of the 50 subjects randomized, 4 subjects experienced at least one major protocol deviation that resulted in their exclusion from the PP population)

Non-inferiority of RHA®4 injected with a cannula to the change from Baseline for subjects treated with RHA®4 injected with a needle at 12 weeks after last treatment (initial or touch-up; up to 16 weeks post-baseline)) as assessed by the BLE using the NLF-WSRS.

NLF-WSRS (Nasolabial Folds - Wrinkle Severity Rating Scale) is a proprietary validated 5-grade scale with 1 being "Absent" and 5 being "Extreme".

An NLF-WSRS change of >1 grade will be considered clinically significant.

Outcome measures

Measure	RHA®4 - Cannula n=46 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=46 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Change in NLF-WSRS Score Between Baseline and Week 12 After Last Treatment as Assessed by the BLE	-1.61 score on a scale Standard Deviation 0.21	-1.65 score on a scale Standard Deviation 0.21

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12 after last treatment

NLF-WSRS (Nasolabial Folds - Wrinkle Severity Rating Scale) is a proprietary validated 5-grade scale with 1 being "Absent" and 5 being "Extreme".

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Change in Score From Baseline in the Nasolabial Folds Severity Rated by the Treating Investigator (TI) at Weeks 4, 8 and 12 After Last Treatment Using the NLF-WSRS. Week 4 after last treatment	-1.2 score on a scale Standard Deviation 0.56	-1.3 score on a scale Standard Deviation 0.59
Change in Score From Baseline in the Nasolabial Folds Severity Rated by the Treating Investigator (TI) at Weeks 4, 8 and 12 After Last Treatment Using the NLF-WSRS. Week 8 after last treatment	-1.5 score on a scale Standard Deviation 0.65	-1.6 score on a scale Standard Deviation 0.70
Change in Score From Baseline in the Nasolabial Folds Severity Rated by the Treating Investigator (TI) at Weeks 4, 8 and 12 After Last Treatment Using the NLF-WSRS. Week 12 after last treatment	-1.5 score on a scale Standard Deviation 0.58	-1.6 score on a scale Standard Deviation 0.67

SECONDARY outcome

Timeframe: Week 12 after last treatment

Population: ITT population

NLF-WSRS (Nasolabial Folds- Wrinkle Severity Rating Scale) is a proprietary validated 5-grade scale with 1 being "Absent" and 5 being "Extreme".

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Number of Responders (Change of ≥1-grade From Baseline in the Naso-labial Folds Severity) as Assessed by the Blinded Live Evaluator (BLE) at Week 12 After Last Treatment Using the NLF-WSRS.	47 Participants	47 Participants

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12 after last treatment

NLF-WSRS (Nasolabial Folds- Wrinkle Severity Rating Scale) is a validated 5-grade scale with 1 being "Absent" and 5 being "Extreme"

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Number of Responders (Change of ≥1-grade From Baseline in the Naso-labial Folds Severity) as Assessed by the Treating Investigator (TI) at Weeks 4, 8 and 12 After Last Treatment Using the NLF-WSRS. Week 4 after last treatment	47 Participants	48 Participants
Number of Responders (Change of ≥1-grade From Baseline in the Naso-labial Folds Severity) as Assessed by the Treating Investigator (TI) at Weeks 4, 8 and 12 After Last Treatment Using the NLF-WSRS. Week 8 after last treatment	48 Participants	48 Participants
Number of Responders (Change of ≥1-grade From Baseline in the Naso-labial Folds Severity) as Assessed by the Treating Investigator (TI) at Weeks 4, 8 and 12 After Last Treatment Using the NLF-WSRS. Week 12 after last treatment	49 Participants	49 Participants

SECONDARY outcome

Timeframe: Week 12 after last treatment

The Global Aesthetic Improvement (GAI) is a subjective, balanced, 5-point dynamic scale assessing cosmetic improvement. Possible scores range from "much improved", "improved", "no change", "worse", to "much worse". The GAI will be assessed using the pre-injection baseline photograph. Each side of the face will be assessed independently.

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Number of Subjects Scored Either "Much Improved" or "Improved" on Global Aesthetic Improvement (GAI) Scale by the Blinded Live Evaluator (BLE) at 12 Weeks Following Last Treatment.	50 Participants	50 Participants

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12 after last treatment

The Global Aesthetic Improvement (GAI) is a subjective, balanced, 5-point dynamic scale assessing cosmetic improvement. Possible scores range from "much improved", "improved", "no change", "worse", to "much worse". The GAI will be assessed using the pre-injection baseline photograph. Each side of the face will be assessed independently.

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Number of Subjects Scored Either "Much Improved" or "Improved" on Global Aesthetic Improvement (GAI) Scale by the Treating Investigator (TI) at 4, 8 and 12 Weeks Following Last Treatment. Week 4 after last treatment	46 Participants	47 Participants
Number of Subjects Scored Either "Much Improved" or "Improved" on Global Aesthetic Improvement (GAI) Scale by the Treating Investigator (TI) at 4, 8 and 12 Weeks Following Last Treatment. Week 8 after last treatment	50 Participants	50 Participants
Number of Subjects Scored Either "Much Improved" or "Improved" on Global Aesthetic Improvement (GAI) Scale by the Treating Investigator (TI) at 4, 8 and 12 Weeks Following Last Treatment. Week 12 after last treatment	49 Participants	47 Participants

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12 after last treatment

Population: ITT Population: 50 subjects 1 missing data at week 4

The Global Aesthetic Improvement (GAI) is a subjective, balanced, 5-point dynamic scale assessing cosmetic improvement. Possible scores range from "much improved", "improved", "no change", "worse", to "much worse". The GAI will be assessed using the pre-injection baseline photograph. Each side of the face was assessed independently.

Subjects will be instructed: "Use a mirror to compare your face to the photograph provided to you and rate the degree of aesthetic improvement by using the following scale".

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Number of Subjects Who Scored Themselves Either "Much Improved" or "Improved" on Global Aesthetic Improvement (GAI) Scale at 4, 8 and 12 Weeks Following Last Treatment. Week 4 after last treatment	46 Participants	47 Participants
Number of Subjects Who Scored Themselves Either "Much Improved" or "Improved" on Global Aesthetic Improvement (GAI) Scale at 4, 8 and 12 Weeks Following Last Treatment. Week 8 after last treatment	48 Participants	47 Participants
Number of Subjects Who Scored Themselves Either "Much Improved" or "Improved" on Global Aesthetic Improvement (GAI) Scale at 4, 8 and 12 Weeks Following Last Treatment. Week 12 after last treatment	47 Participants	48 Participants

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12 after last treatment

Population: ITT Population: 50 subjects 1 missing data at week 4

The Subject Satisfaction Scale is a subjective, balanced, 5-point scale assessing subject satisfaction with study treatment. Possible scores range from with 1 (very satisfied) to 5 (very dissatisfied).

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Number of Subjects "Satisfied" or "Very Satisfied" With Study Treatment Using the Subject Satisfaction Scale at 4, 8 and 12 Weeks Following Last Treatment. Week 12 after last treatment	45 Participants	48 Participants
Number of Subjects "Satisfied" or "Very Satisfied" With Study Treatment Using the Subject Satisfaction Scale at 4, 8 and 12 Weeks Following Last Treatment. Week 4 after last treatment	46 Participants	45 Participants
Number of Subjects "Satisfied" or "Very Satisfied" With Study Treatment Using the Subject Satisfaction Scale at 4, 8 and 12 Weeks Following Last Treatment. Week 8 after last treatment	48 Participants	48 Participants

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12 after last treatment

Population: ITT Population: 50 subjects 1 missing data at week 4

The FACE-Q | Aesthetics© questionnaire is composed of 5 questions with a score linked to answers (1 being 'Not at all' and 4 being 'Extremely').

The subject will be instructed as follows: "These questions ask about how you look right now. For each question, circle only one answer. With your nasolabial folds in mind (the deep lines that run downward from the sides of your nose), in the past week, how much have you been bothered by:", and will provide response.

To calculate the FACE-Q, outcomes from all 5 questions were pooled, data were transformed so that higher scores reflected a superior (positive) outcome, and adapted to a scale of 100 units (i.e. worst/lowest score = 0, best/highest score = 100).

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Subject's Perception of Treatment Effectiveness as Per the FACE-Q | Aesthetics© (Nasolabial Folds Domain) Questionnaire. The FACE-Q Measures the Experience and Outcomes of Aesthetic Facial Procedures From the Patient's Perspective. Week 4 after last treatment	35.8 score on a scale Standard Deviation 28.17	37.8 score on a scale Standard Deviation 26.71
Subject's Perception of Treatment Effectiveness as Per the FACE-Q | Aesthetics© (Nasolabial Folds Domain) Questionnaire. The FACE-Q Measures the Experience and Outcomes of Aesthetic Facial Procedures From the Patient's Perspective. Week 8 after last treatment	40.0 score on a scale Standard Deviation 27.52	42.0 score on a scale Standard Deviation 27.29
Subject's Perception of Treatment Effectiveness as Per the FACE-Q | Aesthetics© (Nasolabial Folds Domain) Questionnaire. The FACE-Q Measures the Experience and Outcomes of Aesthetic Facial Procedures From the Patient's Perspective. Week 12 after last treatment	40.7 score on a scale Standard Deviation 25.61	42.3 score on a scale Standard Deviation 27.93

SECONDARY outcome

Timeframe: Baseline (Week 0, Visit 1) and Touch-up (Week 4, Visit 2)

Number of subjects receiving treatment (initial and touch up)

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Number of Participants Receiving Initial and Touch-Up Treatment Sessions to Obtain an Optimal Cosmetic Results as Judged by the Treating Investigator Baseline (initial treatment)	50 Participants	50 Participants
Number of Participants Receiving Initial and Touch-Up Treatment Sessions to Obtain an Optimal Cosmetic Results as Judged by the Treating Investigator Touch up (week 4)	20 Participants	17 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) and Touch-up (Week 4)

Population: ITT: 50 subjects 20 subjects received a touch-up injection with cannula 17 subjects recieved a touch-up injection with needle

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Total Volume Per NLF to Obtain an Optimal Cosmetic Results as Judged by the Treating Investigator. Baseline (Week 0)	1.37 mL Standard Deviation 0.48	1.40 mL Standard Deviation 0.45
Total Volume Per NLF to Obtain an Optimal Cosmetic Results as Judged by the Treating Investigator. Touch Up (Week 4)	0.85 mL Standard Deviation 0.38	0.78 mL Standard Deviation 0.41
Total Volume Per NLF to Obtain an Optimal Cosmetic Results as Judged by the Treating Investigator. Total	1.71 mL Standard Deviation 0.64	1.67 mL Standard Deviation 0.63

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 12 after last treatment

NLF symmetry will be assessed for right and left NLF by answering the question "Are the NLFs symmetric or asymmetric?" (answer = symmetric or asymmetric answer). If asymmetric, the asymmetry will be further assessed as mild, moderate or severe.

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
NLF Symmetry as Assessed by the Blinded-live Evaluator at Baseline and 12 Weeks Following Last Treatment. Symmetric at Baseline (post treatment)	50 Participants	—
NLF Symmetry as Assessed by the Blinded-live Evaluator at Baseline and 12 Weeks Following Last Treatment. Symmetric at Week 12 after last treatment	47 Participants	—

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12 after last treatment

Population: ITT population: 50 subjects 1 missing value at week 4

NLF symmetry will be assessed by the TI for right and left NLF by answering the question "Are the NLFs symmetric or asymmetric?" (answer = symmetric or asymmetric answer). If asymmetric, the asymmetry will be further assessed as mild, moderate or severe.

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
NLF Symmetry as Assessed by the Treating Investigator at Baseline 4, 8 and 12 Weeks Following Last Treatment. Symmetric at baseline (post treatment)	50 Participants	—
NLF Symmetry as Assessed by the Treating Investigator at Baseline 4, 8 and 12 Weeks Following Last Treatment. Symmetric at Week 4 after last treatment	33 Participants	—
NLF Symmetry as Assessed by the Treating Investigator at Baseline 4, 8 and 12 Weeks Following Last Treatment. Symmetric at Week 8 after last treatment	40 Participants	—
NLF Symmetry as Assessed by the Treating Investigator at Baseline 4, 8 and 12 Weeks Following Last Treatment. Symmetric at Week 12 after last treatment	38 Participants	—

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12 after last treatment

Population: ITT popualtion : 50 subjects 1 missing value at week 4

NLF symmetry will be assessed for right and left NLF by answering the question "Are the NLFs symmetric or asymmetric?" (answer = symmetric or asymmetric answer). If asymmetric, the asymmetry will be further assessed as mild, moderate or severe.

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
NLF Symmetry as Assessed by the Subject at Baseline, 4, 8 and 12 Weeks Following Last Treatment. Symmetric at Baseline (post treatment)	41 Participants	—
NLF Symmetry as Assessed by the Subject at Baseline, 4, 8 and 12 Weeks Following Last Treatment. Symmetric at Week 4 after last treatment	25 Participants	—
NLF Symmetry as Assessed by the Subject at Baseline, 4, 8 and 12 Weeks Following Last Treatment. Symmetric at Week 8 after last treatment	32 Participants	—
NLF Symmetry as Assessed by the Subject at Baseline, 4, 8 and 12 Weeks Following Last Treatment. Symmetric at Week 12 after last treatment	31 Participants	—

SECONDARY outcome

Timeframe: Baseline through Week 12 after last treatment

The Treating Investigator will assess adverse events and record details of seriousness, severity, duration, and action taken with the study device, and relationship to the study device. AEs will be reported from the time of consent until week 12 of the last treatment.

An AE is any untoward medical occurrence in a subject administered the study device and which may, but does not necessarily, have a causal relationship with the device. An AE can therefore be any unfavorable or unintended sign (for example an abnormal laboratory finding), symptom or disease temporally associated with the use the study device, whether or not considered related to that device.

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Number of Participants With Adverse Events (AEs) for the Safety Evaluation of RHA® 4 Any Treatment Emergent Adverse Event	27 Participants	33 Participants
Number of Participants With Adverse Events (AEs) for the Safety Evaluation of RHA® 4 Any Treatment Related Adverse Event	23 Participants	29 Participants
Number of Participants With Adverse Events (AEs) for the Safety Evaluation of RHA® 4 Any Serious Adverse Event	0 Participants	0 Participants
Number of Participants With Adverse Events (AEs) for the Safety Evaluation of RHA® 4 Any Treatment Related Serious Adverse Event	0 Participants	0 Participants
Number of Participants With Adverse Events (AEs) for the Safety Evaluation of RHA® 4 Any Unexpected Adverse Device Effects	0 Participants	0 Participants
Number of Participants With Adverse Events (AEs) for the Safety Evaluation of RHA® 4 Any Adverse Effects of Special Interest	3 Participants	3 Participants

SECONDARY outcome

Timeframe: During 28 days after initial treatment and touch-up, so a total of 42 days post-baseline if the subject received a touch-up

The subjects will receive a diary booklet and instructions for recording his/her observations of the Common Treatment Responses of the study treatments for the first 28 days after treatment. The diary will be discussed during telephone follow-up visit. Subjects should complete the diary at approximately the same time each day (i.e., am or pm).

The subject diary captures the following Common Treatment Responses (CTR) that occur following the injection of a dermal filler; specifically, redness, pain, tenderness, firmness, swelling, lumps/bumps, bruising, itching, discoloration, and "other".

The 28-day patient CTR diary includes a detailed glossary describing all signs/symptoms listed in the diary; an option was provided to rate "other" if the subject experienced a sign/symptom that is not listed.

The table presents the number of subjects experiencing at least 1 Common Treatment Response (CTR).

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Number of Post-Injection Treatment Responses (From Common Treatment Responses (CTR) Diary) for the Safety Evaluation of RHA® 4. Bruising	10 Participants	27 Participants
Number of Post-Injection Treatment Responses (From Common Treatment Responses (CTR) Diary) for the Safety Evaluation of RHA® 4. Discoloration	9 Participants	16 Participants
Number of Post-Injection Treatment Responses (From Common Treatment Responses (CTR) Diary) for the Safety Evaluation of RHA® 4. Firmness	40 Participants	43 Participants
Number of Post-Injection Treatment Responses (From Common Treatment Responses (CTR) Diary) for the Safety Evaluation of RHA® 4. Itching	10 Participants	17 Participants
Number of Post-Injection Treatment Responses (From Common Treatment Responses (CTR) Diary) for the Safety Evaluation of RHA® 4. Lumps/Bumps	33 Participants	45 Participants
Number of Post-Injection Treatment Responses (From Common Treatment Responses (CTR) Diary) for the Safety Evaluation of RHA® 4. Pain	21 Participants	30 Participants
Number of Post-Injection Treatment Responses (From Common Treatment Responses (CTR) Diary) for the Safety Evaluation of RHA® 4. Redness	21 Participants	33 Participants
Number of Post-Injection Treatment Responses (From Common Treatment Responses (CTR) Diary) for the Safety Evaluation of RHA® 4. Swelling	36 Participants	41 Participants
Number of Post-Injection Treatment Responses (From Common Treatment Responses (CTR) Diary) for the Safety Evaluation of RHA® 4. Tenderness	38 Participants	44 Participants

SECONDARY outcome

Timeframe: Immediately after treatment, and at 5, 30, and 60 minutes post-treatment

The Injection Site Pain (during injection and post-injection) will be self-assessed by the subject using a 100 mm Visual Analog Scale (VAS). VAS is a 100 mm Visual Analog Scale with 0 meaning no pain and 100 meaning intolerable pain.

Outcome measures

Measure	RHA®4 - Cannula n=50 Participants Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 Participants Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
Assessment at Each Injection Visit (Initial Inejction and Touch-up) of Injection Site Pain Felt by the Patient for the Safety Evaluation of RHA® 4 Immediately After Treatment, and at 5, 30, and 60 Minutes Post-treatment Immediately after treatment	34.7 score on a scale Standard Deviation 25.9	41.3 score on a scale Standard Deviation 25.8
Assessment at Each Injection Visit (Initial Inejction and Touch-up) of Injection Site Pain Felt by the Patient for the Safety Evaluation of RHA® 4 Immediately After Treatment, and at 5, 30, and 60 Minutes Post-treatment 5 minutes post-treatment	3.5 score on a scale Standard Deviation 9.3	3.5 score on a scale Standard Deviation 8.9
Assessment at Each Injection Visit (Initial Inejction and Touch-up) of Injection Site Pain Felt by the Patient for the Safety Evaluation of RHA® 4 Immediately After Treatment, and at 5, 30, and 60 Minutes Post-treatment 30 minutes post-treatment	1.3 score on a scale Standard Deviation 5.3	0.2 score on a scale Standard Deviation 1.4
Assessment at Each Injection Visit (Initial Inejction and Touch-up) of Injection Site Pain Felt by the Patient for the Safety Evaluation of RHA® 4 Immediately After Treatment, and at 5, 30, and 60 Minutes Post-treatment 60 minutes post-treatment	0.4 score on a scale Standard Deviation 2.2	0.0 score on a scale Standard Deviation 0.0

Adverse Events

RHA®4 - Cannula

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

RHA®4 - Needle

Serious events: 0 serious events

Other events: 29 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	RHA®4 - Cannula n=50 participants at risk Split-face injection of RHA® 4 with a cannula into a single NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF). The brand of cannula used for injection is up to the discretion of the Treating Investigator (TI), providing the cannula is registered for use by the US FDA.	RHA®4 - Needle n=50 participants at risk Split-face injection of RHA® 4 with a needle (TSK 27G x ½") into the contralateral NLF.: RHA® 4 is a sterile, biodegradable, biocompatible, viscoelastic, clear, colorless, homogenized gel implant. It consists of cross-linked hyaluronic acid produced by fermentation of Streptococcus equi bacteria, formulated to a concentration of 23 mg/mL and 0.3% w/w lidocaine in a physiologic buffer. Up to 3.0 mL injected per NLF (mid-dermis to deep-dermis). Touch-up treatment provided at 2 weeks (up to 3.0 mL per NLF).
General disorders Injection site induration	26.0% 13/50 • Number of events 13 • across the duration of the study, approximately 12 weeks after last treatment (initial and touch up), up to 16 weeks	28.0% 14/50 • Number of events 14 • across the duration of the study, approximately 12 weeks after last treatment (initial and touch up), up to 16 weeks
General disorders Injection site mass	20.0% 10/50 • Number of events 13 • across the duration of the study, approximately 12 weeks after last treatment (initial and touch up), up to 16 weeks	30.0% 15/50 • Number of events 16 • across the duration of the study, approximately 12 weeks after last treatment (initial and touch up), up to 16 weeks

Additional Information

Clinical Project Manager

TEOXANE SA

Phone: +41(0) 22 344 96 36

Email: clinical@teoxane.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: GT60