saypha® ChiQ
Device Facts
| Record ID | P250021 |
|---|---|
| Device Name | saypha® ChiQ |
| Applicant | Croma-Pharma GmbH |
| Product Code | LMH |
| Decision Date | Jun 12, 2026 |
| Decision | APPR |
| Device Class | Class 3 |
| Attributes | Therapeutic |
Indications for Use
saypha® ChIQ™ is indicated for use in cheek augmentation and restoring midface volume deficits in patients over the age of 21. The device is indicated to be administered by subcutaneous and/or supraperiosteal injection.
Device Story
Sterile, biodegradable, viscoelastic, clear, colorless, homogeneous gel; hyaluronic acid (HA) cross-linked with BDDE; formulated at 23 mg/mL HA with 3 mg/mL lidocaine hydrochloride in phosphate buffered saline. Supplied in prefilled glass syringe; steam sterilized. Used for cheek augmentation and midface volume deficit correction; administered by subcutaneous or supraperiosteal injection by physician. Acts as soft tissue filler to restore volume. Healthcare provider assesses midface volume deficit severity (MVDSS) to determine injection volume; output is physical volume restoration. Benefits patient by correcting midface volume deficits and improving aesthetic appearance.
Clinical Evidence
Pivotal randomized, subject/evaluator-blinded, controlled, non-inferiority multicenter study (IDE G210347) with 483 patients. Primary endpoint: MVDSS responder rate (≥1 point improvement) at Week 24. Results: saypha® ChIQ™ (87.9%) vs. Control (83.9%); non-inferiority demonstrated (p<0.0001). Safety profile comparable to control; common adverse events included tenderness, swelling, firmness, lumps/bumps, bruising, and pain. No clinically relevant safety differences observed.
Technological Characteristics
Materials: Hyaluronic acid (HA) from Streptococcus species, cross-linked with BDDE (1,4-butanediol diglycidyl ether). Concentration: 23 mg/mL HA, 3 mg/mL lidocaine hydrochloride. Form factor: Prefilled glass syringe. Sterilization: Moist heat (autoclave) per ISO 17665-1. Biocompatibility: ISO 10993-1 compliant. Shelf life: 36 months at 5°C to 25°C.
Indications for Use
Indicated for cheek augmentation and midface volume deficit restoration in adults aged 21+. Contraindicated in patients with severe allergies/anaphylaxis history, allergies to gram-positive bacterial proteins or lidocaine, and bleeding disorders.
Submission Summary (Full Text)
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# **SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)**
# **I. GENERAL INFORMATION**
Device Generic Name: Injectable Dermal Filler
Device Trade Name: saypha® ChIQ™
Device Procode: LMH (Implant, Dermal, For Aesthetic Use)
Applicant's Name and Address: CROMA-PHARMA GmbH
Industriezeile 6
2100 Leobendorf
Austria
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P250021
Date of FDA Notice of Approval: 6/12/2026
# **II. INDICATIONS FOR USE**
saypha® ChIQ™ is indicated for use in cheek augmentation and restoring midface volume deficits in patients over the age of 21. The device is indicated to be administered by subcutaneous and/or supraperiosteal injection.
# **III. CONTRAINDICATIONS**
- saypha® ChIQ™ is contraindicated for patients with severe allergies manifested by a history of anaphylaxis or history or presence of multiple severe allergies.
- saypha® ChIQ™ contains trace amounts of gram-positive bacterial proteins and is contraindicated for patients with a history of allergies to such material.
- saypha® ChIQ™ contains lidocaine and is contraindicated for patients with a history of allergies to such material.
- saypha® ChIQ™ is contraindicated for patients with bleeding disorders.
# **IV. WARNINGS AND PRECAUTIONS**
The warnings and precautions can be found in the saypha® ChIQ™ labeling.
# **V. DEVICE DESCRIPTION**
saypha® ChIQ™ is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, colorless, and homogeneous gel used as soft tissue filler. It consists of hyaluronic acid (HA), produced by *Streptococcus* species of bacteria, which is cross-linked with BDDE (1,4-butanediol diglycidyl ether). It is formulated to a concentration of 23 mg/mL in a phosphate buffered saline at physiological pH and contains 3 mg/mL lidocaine hydrochloride to reduce pain and discomfort upon injection. The gel is supplied in a prefilled glass syringe, and the contents of the syringe are steam sterilized.
# **VI. ALTERNATIVE PRACTICES AND PROCEDURES**
There are several other alternatives for cheek augmentation and correction of midface volume deficits including other hyaluronic acid dermal filler products, autologous fat injection or transposition, surgery, and acellular dermal graft treatment. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.
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## **VII. MARKETING HISTORY**
saypha® ChIQ™ received the CE Mark in March 2016 for creating volume in order to correct wrinkles, folds, and moderate to severe nasolabial folds. Currently, saypha® ChIQ™ is marketed under different trade names in more than 70 countries. In addition to being marketed throughout the European Union, it is available in the following regions: North America, Latin America, South America, Eastern Europe, Middle-East, Africa, Asia-Pacific and Australia/New Zealand.
saypha® ChIQ™ has not been withdrawn from marketing in any country for reasons related to safety or effectiveness.
## **VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH**
Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device.
Common treatment responses which can occur with the use of saypha® ChIQ™ include tenderness, swelling, firmness (induration), lumps/bumps (mass), bruising, pain, redness, discoloration, and itching.
In addition to the common treatment responses noted above, the following adverse events reported in the pivotal clinical study include headache, palpatory finding abnormal, injection site pain, injection site bruising, injection site swelling, injection site mass and mastication disorder, jaw disorder, nodule and skin laxity.
Additionally, the following rare but serious adverse events that are associated with intravascular injection of other dermal filler material in the face have been reported in the literature: vision impairment (acute or permanent), blindness, cerebral ischemia or cerebral hemorrhage leading to stroke, skin necrosis, and damage to underlying facial structures.
The following additional adverse events were observed with similar viscoelastic dermal filler implants and are considered as potential risks for this device: abscess, angioedema, bacterial infection, device dislocation, dizziness, fever, fibrosis, granuloma, hematoma, hemorrhage/bleeding, herpes simplex reactivation, hypersensitivity/allergic reaction, hypoesthesia, itching sensation, malaise, medical device site induration, nausea, necrosis, numbness, obstruction/occlusion, paresthesia, peeling, phlebitis, physical asymmetry, presyncope, rash, scleroderma, sebaceous hyperplasia, skin burning sensation, skin disorders, skin inflammation/irritation, syncope/fainting, tactile disorder.
For the specific adverse events that occurred in the clinical study, please see Section X below.
## **IX. SUMMARY OF NONCLINICAL STUDIES**
### **A. Laboratory Studies**
saypha® ChIQ™ has been extensively tested and characterized through physical and chemical analyses (Table 1). Degradation assays were also performed to ensure that saypha® ChIQ™ naturally degrades in the body during its clinical lifespan.
**Table 1. Summary of Key Bench Testing on saypha® ChIQ™**
| Test | Purpose | Results |
| --- | --- | --- |
| pH | Ensures pH meets specification | Passed |
| Osmolality | Ensures osmolality meets specification | Passed |
| Rheology | Ensures rheology meets specification | Passed |
| Extractable Volume | Ensures extractable volume meets specification | Passed |
| Injection Force | Ensures injection force meets specification | Passed |
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| Test | Purpose | Results |
| --- | --- | --- |
| Content Sodium Hyaluronate | Ensures content sodium hyaluronate meets specification | Passed |
| Residual Crosslinker | Ensures residual crosslinker meets specification | Passed |
| Endotoxin | Ensures endotoxin meets specification | Passed |
| Sterility | Ensures sterility meets specification | Passed |
| Content Lidocaine | Ensures content lidocaine meets specification | Passed |
| Purity Lidocaine | Ensures purity lidocaine meets specification | Passed |
### B. Biocompatibility Testing
A biological evaluation was performed on saypha® ChIQ™ according to ISO 10993-1, Biological Evaluation of medical devices – Part 1: Evaluation and testing within a risk management process (Table 2). According to ISO 10993-1, saypha® ChIQ™ is categorized as implant device in contact with tissue where the contact duration is more than 30 days. All tests were performed according to Good Laboratory Practices (GLP), which are consistent with the requirements of the Federal Good Laboratory Practices Regulation (21 CFR § 58). The requirements of all tests were met demonstrating that saypha® ChIQ™ is biocompatible.
Table 2. Summary of Biocompatibility Testing on saypha® ChIQ™
| Test | Method | ISO Standard | Results |
| --- | --- | --- | --- |
| Chemical Characterization and Toxicological Risk Assessment | HS GC-MS GC-MS, HPLC-MS, ICP-MS | ISO 10993-18 ISO 10993-17 | Passed |
| Cytotoxicity | Agarose overlay, XTT staining | ISO 10993-5 | Non cytotoxic |
| Irritation | Intracutaneous reactivity in rabbits | ISO 10993-10 | Non irritant |
| Skin sensitization | Maximization test in guinea pigs | ISO 10993-10 | Non sensitizer |
| Implantation | Intradermal implantation in rabbits | ISO 10993-6 | Locally safe |
| Acute systemic toxicity | Intraperitoneal injection in mice | ISO 10993-11 | Not systemically toxic |
| Subacute systemic toxicity (4-week) | Subcutaneous implantation in rats | ISO 10993-11 | Not systemically toxic |
| Subchronic systemic toxicity (13-week) | Subcutaneous implantation in rats | ISO 10993-11 | Not systemically toxic |
| Chronic systemic toxicity (26-week) | Subcutaneous implantation in rats | ISO 10993-11 | Not systemically toxic |
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| Test | Method | ISO Standard | Results |
| --- | --- | --- | --- |
| Pyrogenicity | Rabbit pyrogen study | USP <151> | Non pyrogenic |
| Genotoxicity | Bacterial reverse mutation, chromosomal aberration, micronucleus | ISO 10993-3 | Non genotoxic, non clastogenic |
Carcinogenicity risks: the biological evaluation concluded that the cancer risks from lifetime exposure to residual BDDE (limited to 2 ppm) in saypha® ChIQ™ are minimal and in the same range of acceptable cancer risks as other previously approved dermal filler products.
### C. Additional Studies
Filled syringes were sterilized using a validated moist heat process in a pressurized autoclave. The sterilization cycle was validated according to ISO 17665-1 sterilization standard. The validated sterilization cycle provided a minimum Sterility Assurance Level (SAL) of 10⁻⁶.
Stability data have been collected through 36 months at 25°C / 60% relative humidity, at 30°C / 65% relative humidity, at 2-8°C / 60% relative humidity, and through 13 months at 40°C / 20% relative humidity. Conformance with all specifications was confirmed to support a shelf life of 36 months at storage conditions of 5°C to 25°C.
### X. SUMMARY OF PRIMARY CLINICAL STUDY
The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of saypha® ChIQ™ for midface augmentation in order to correct volume deficit in the US under IDE G210347. Data from this clinical study were the basis for the PMA approval decision.
A summary of the clinical study is presented below.
### A. Study Design
Patients were treated between September 16, 2022 and June 17, 2024. The database for this PMA reflected data collected through February 11, 2025 and included 483 patients. There were 16 investigational sites.
The study was a randomized, subject- and evaluator-blinded, controlled, non-inferiority multicenter, parallel group comparison study to evaluate effectiveness and safety of saypha® ChIQ™ for midface augmentation in order to correct volume deficit.
The control group was a legally marketed alternative with similar indications for use.
The primary endpoint was non-inferiority in the effectiveness of saypha® ChIQ™ for midface augmentation to correct moderate to severe volume deficit versus Control, based on the blinded evaluator's live assessment at Week 24 after last injection of initial treatment phase and compared to baseline assessments.
Secondary objectives were to assess the effectiveness of saypha® ChIQ™ versus Control for correction of moderate to severe midface volume deficit, based on the blinded evaluator's live assessment (except Week 24 after last injection of initial treatment phase for responder rate), and on the independent blinded photographic reviewers assessment (initial treatment phase only). Further secondary objectives were to assess the mean change in midface volume deficit as measured by volumetric change measurement by using 3D digital photographic images (initial treatment phase only), and to assess the effect of midface treatment with saypha® ChIQ™ on the nasolabial folds (NLFs) based on the blinded evaluator's live assessment.
Other secondary objectives included the evaluation of global aesthetic improvement based on subject's assessments (initial treatment phase only) and based on the blinded evaluator's assessments (initial treatment
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phase only), the subject's satisfaction with outcome and appearance appraisal, and the subject's pain assessment and injection volume.
Eligible subjects were randomized in a 2:1 ratio (test device:comparator device) to receive bilateral midface augmentation treatment with either saypha® ChIQ™ or Control. The dosage (volume) of filler administered depended on the severity of the midface volume deficit to be corrected and was decided in each case by the treating investigator, but the maximum volume (left and right side of the midface together) was not allowed to exceed 10 mL in total per treatment phase (initial and repeat-treatment, respectively, including touch-up treatments) or 20 mL per 60 kg (130 lbs) body mass per year. The treating investigator administered the treatment unblinded. Subjects were blinded to the treatments they received until finalization of Visit 9 (SV1). The blinded evaluator at the site performing live assessments of treatment effectiveness during the initial treatment phase, as well as the central independent blinded photographic reviewers were blinded to the treatment administered.
Clinical data sources included investigator assessments (Midface Volume Deficit Severity Scale (MVDSS), Nasolabial Folds Severity Rating Scale (NLF-SRS) and modified Global Aesthetic Improvement Scale (GAIS)) central independent blinded photographic reviewer assessments (MVDSS), subject-reported outcome measures (FACE-Q™ questionnaires and modified GAIS), volumetric change measurements based on standardized 3D photography, subject diaries, clinical examinations, and adverse event reporting.
The primary effectiveness endpoint was analyzed in both the Per-Protocol Set (PPS) and Full Analysis Set (FAS). A hierarchical testing procedure was applied, with initial testing performed in the PPS and subsequent testing in the FAS. Non-inferiority was considered demonstrated only if results were consistent across both analysis populations. Safety analyses were performed using the Safety Analysis Set (SAF).
# 1. Clinical Inclusion and Exclusion Criteria
Enrollment in the clinical study was limited to patients who met the following inclusion criteria:
- 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 MVDSS), as assessed by the blinded evaluator at the site
- Females of childbearing potential must have a negative urine pregnancy test and must agree to use an effective method of birth control throughout the entire study
- Male 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 the 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
Patients were not permitted to enroll in the clinical study if they met any of the following exclusion criteria:
- 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
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- • 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 immunomodulating 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, 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 weight loss for a minimum of 10% 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
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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.
## 2. Follow-up Schedule
All patients were scheduled to return for follow up examinations at 4, 8, 16, 24, 36 and 48 weeks after last treatment.
Subjects who were eligible and willing could receive optional repeat-treatment (with saypha® ChIQ™ only) 48 to 60 weeks after initial treatment (or touch-up treatment). If necessary, an optional touch-up treatment was performed 2 weeks after the repeat-treatment. Follow-up visits were performed at Weeks 4, 12 and 24 after last treatment of the repeat-treatment phase. In case of touch-up treatment during initial and repeat-treatment phase, an additional safety follow-up visit 2 weeks after touch-up injections occurred. Subjects who did not qualify for any retreatment had their end of study visit at Week 48 (Visit 9).
Clinical photography was taken at Screening, and at the follow-up visits for 4, 8, 16, 24, 36, and 48 weeks.
At the end of each treatment session, subjects received a web-based electronic diary to record the injection site reactions (ISRs) and AEs (including those that were potentially associated with unintended intravascular injection) that occurred during the first 4 weeks (28 days) after each treatment (i.e., 4 weeks after baseline and repeat-treatment, respectively, and 6 weeks in case of touch-up treatment).
Preoperatively, pretreatment procedures and evaluations included: Informed Consent, medical/aesthetic procedure history, demographics, Fitzpatrick Skin Type, body weight, visual examinations, urine pregnancy test, MVDSS – blinded evaluator at site, MVDSS – central blinded photographic reviewer, NLF-SRS –blinded evaluator at site, Volumetric Change Measurements, Assessment of eligibility, randomization, clinical photography, FACE-Q™ “Satisfaction with Cheeks” – subject, ”, and prior concomitant treatments.
Postoperatively, the objective parameters measured during the study included body weight, visual examinations, neurological examination, urine pregnancy test, prior concomitant treatments, MVDSS – blinded evaluator at site, MVDSS – central blinded photographic reviewer, NLF-SRS –blinded evaluator at site, Volumetric Change Measurements, Assessment of eligibility, clinical photography, Assessment of eligibility, Modified GAIS – blinded evaluator at site, Modified GAIS – subject, FACE-Q™ “Satisfaction with Outcome” – subject, FACE-Q™ “Satisfaction with Cheeks” – subject, Evaluation of pain – subject (Numeric Pain Rating Scale (NPRS). Adverse events and complications were recorded at all visits.
The key timepoints are shown below in Tables 3, 4 and 5.
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**Table 3.** Schedule of procedures and assessments for the initial treatment phase (Visit 1-to Visit 9 (SV1) (all subjects))
| Visit | Visit 1 Screening^{0} | Visit 2 Baseline^{0} | Follow-up for initial treatment (baseline and touch-up treatment) (initial treatment phase) | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Visit 2a Phone contact | Visit 3 TUP1 | Visit 3a Phone contact^{13} | Visit 3b Safety Follow-up^{13} | Visit 4 | Visit 5 | Visit 6 | Visit 7 | Visit 8 | Visit 9 (SV1)^{21, 24} |
| Day / week | Day-14 to Day 0 | Day 0 | 24 – 48 hours after Day 0 | 2 weeks after BL injection | 24 – 48 hours after Visit 3 | 2 weeks after TUP1 injection | 4 weeks after last injection^{22} | 8 weeks after last injection^{22} | 16 weeks after last injection^{22} | 24 weeks after last injection^{22} | 36 weeks after last injection^{22} | 48 weeks after last injection^{22} |
| Visit window | | | ± 4 hours | ± 3 days | ±4 hours | ±3 days | ±5 days | ±5 days | ±7 days | ±7 days | ±7 days | ±7 days |
| **Procedure** | | | | | | | | | | | | |
| Informed consent | X* | | | | | | | | | | | |
| Medical History^{10} | X | X* | | | | | | | | | | |
| Aesthetic History | X | X* | | | | | | | | | | |
| Prior and concomitant treatments^{1} | X | X* | X | X | X | X | X | X | X | X | X | X |
| Demographics^{2} | X* | | | | | | | | | | | |
| Fitzpatrick skin type | X* | | | | | | | | | | | |
| Body weight | X* | | | | | | X | X | X | X | X | X |
| Urine pregnancy test^{3} | X | X* | | X* | | X | X | X | X | X | X | X |
| Visual examinations^{11} | | X^{11} | | X^{11} | | X | X | X | X | X | X | X |
| Neurological examinations^{17} | | X | | X | | X | X | X | X | X | X | X |
| Clinical photography | X*^{25} | | | | | | X | X | X | X | X | X |
| MVDSS – blinded evaluator at site | X*^{4} | | | X* | | | X | X | X | X | X | X^{4} |
| MVDSS – central blinded photographic reviewer^{8} | X | | | | | | X | X | X | X | X | X |
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| | | | Follow-up for initial treatment (baseline and touch-up treatment) (initial treatment phase) | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Visit | Visit 1 Screening^{0} | Visit 2 Baseline^{0} | Visit 2a Phone contact | Visit 3 TUP1 | Visit 3a Phone contact^{13} | Visit 3b Safety Follow-up^{13} | Visit 4 | Visit 5 | Visit 6 | Visit 7 | Visit 8 | Visit 9 (SV1)^{21, 24} |
| Day / week | Day-14 to Day 0 | Day 0 | 24 – 48 hours after Day 0 | 2 weeks after BL injection | 24 – 48 hours after Visit 3 | 2 weeks after TUP1 injection | 4 weeks after last injection^{22} | 8 weeks after last injection^{22} | 16 weeks after last injection^{22} | 24 weeks after last injection^{22} | 36 weeks after last injection^{22} | 48 weeks after last injection^{22} |
| Visit window | | | ± 4 hours | ± 3 days | ±4 hours | ±3 days | ±5 days | ±5 days | ±7 days | ±7 days | ±7 days | ±7 days |
| Procedure | | | | | | | | | | | | |
| NLF-SRS – blinded evaluator at site^{18} | X* | | | X* | | | X | X | X | X | X | X |
| Volumetric Change Measurements^{12} | X | | | | | | X | X | X | X | X | X |
| Assessment of eligibility | X | X* | | X*^{13} | | | | | | | | X^{15} |
| Randomization | | X* | | | | | | | | | | |
| Treatment | | X | | X^{16} | | | | | | | | |
| Modified GAIS^{6} – blinded evaluator at site | | | | | | | X | X | X | X | X | X |
| Modified GAIS^{6} – subject | | | | | | | X | X | X | X | X | X |
| FACE-Q^{TM} “Satisfaction with Outcome” – subject^{7} | | | | | | | X | X | X | X | X | X |
| FACE-Q^{TM} “Satisfaction with Cheeks” – subject^{8} | | X* | | | | | X | X | X | X | X | X |
| Evaluation of pain – subject (NPRS)^{9} | | X | | X^{13} | | | | | | | | |
| Injection volume^{23} | | X | | X^{13} | | | | | | | | |
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| | | | Follow-up for initial treatment (baseline and touch-up treatment) (initial treatment phase) | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Visit | Visit 1 Screening^{0} | Visit 2 Baseline^{0} | Visit 2a Phone contact | Visit 3 TUP1 | Visit 3a Phone contact^{13} | Visit 3b Safety Follow-up^{13} | Visit 4 | Visit 5 | Visit 6 | Visit 7 | Visit 8 | Visit 9 (SV1)^{21, 24} |
| Day / week | Day-14 to Day 0 | Day 0 | 24 – 48 hours after Day 0 | 2 weeks after BL injection | 24 – 48 hours after Visit 3 | 2 weeks after TUP1 injection | 4 weeks after last injection^{22} | 8 weeks after last injection^{22} | 16 weeks after last injection^{22} | 24 weeks after last injection^{22} | 36 weeks after last injection^{22} | 48 weeks after last injection^{22} |
| Visit window | | | ± 4 hours | ± 3 days | ±4 hours | ±3 days | ±5 days | ±5 days | ±7 days | ±7 days | ±7 days | ±7 days |
| Procedure | | | | | | | | | | | | |
| Initiate / Explain subject diary^{19} | | X | | X^{13} | | | | | | | | |
| Review subject diary^{20} | | | | X | | X | X | | | | | |
| Adverse events^{14} | X | X | X | X | X | X | X | X | X | X | X | X |
| Device deficiencies | | X | | X^{13} | | | | | | | | |
* Prior to injection (i.e., either at baseline or touch-up treatment (TUP1))
0 Screening and Baseline visits may be performed as one visit
1 Includes information on prior treatments, defined as all medications and non-drug therapies taken/received within the previous ten days prior to Screening up to end of study
2 Includes date of birth, sex, race and ethnicity
3 In women of childbearing potential only, including those who are postmenopausal for less than 12 months
4 Evaluation and grading of midface volume deficit by the blinded evaluator at the site (live assessment) using the 5-point MVDSS. The score does not have to be the same on both sides but must be 2 or 3.
5 Evaluation and grading of midface volume deficit severity by the central independent blinded photographic reviewer using the 5-point MVDSS and based on photographs
6 Evaluation of global aesthetic improvement using the modified GAIS against subject's photographs obtained at the Visit 1
7 Subject satisfaction will be determined using the FACE-Q™ questionnaire "Satisfaction with Outcome"
8 Evaluation of subject appearance appraisal using the FACE-Q™ questionnaire "Satisfaction with Cheeks"
9 NPRS starting immediately and every 15 min after last injection for 60 min post-treatment. Separate pain assessments will be performed for the right and left midface area treated.
10 Relevant medical history includes prior and ongoing concomitant diseases and possibly recurring conditions
11 Visual exams (including Snellen visual acuity, confrontational visual fields and ocular motility). The subject should wear the same corrective eyewear (i.e., glasses/contact lenses) at each assessment, if appropriate. At treatment visits: Examination will be performed both before and 30 min after the injection. For subjects not receiving TUP, exams will only be performed once.
12 Volumetric change measurement on photographs will be done centrally by the photography provider once the photography images are received at the photography provider after all subjects have finalized Visit 9 (SV1). The left and right midface will be evaluated separately.
13 Concerning only subjects who receive touch-up treatment
14 All subjects must be asked if they are experiencing or have experienced any signs/symptoms of vision changes or stroke since the injection or other events indicating an embolic event.
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| 15 | Repeat-treatment is optional and possible for all subjects who fulfill the eligibility criteria, irrespective of the treatment (either test device or comparator device) they received in the initial treatment (baseline plus touch-up). The subject does NOT have to return to his/her baseline severity to be permitted to receive a repeat-treatment, but the present condition of midface volume deficit has to meet the initial inclusion level of severity scores of 2 or 3 on the 5-point MVDSS. The score does not have to be the same on both sides but must be 2 or 3. In case the subject is eligible in MVDSS score at Visit 9 (SV1), a full eligibility assessment for repeat-treatment will be performed. |
| --- | --- |
| 16 | Touch-up treatment for optimal correction if deemed necessary in the discretion of **treating investigator** |
| 17 | A basic neurological examination (F.A.S.T) will be performed for all subjects who show signs of ophthalmic complications due to filler injection in visual exams |
| 18 | Evaluation and grading of nasolabial folds severity by the **blinded evaluator at the site** (live assessment) using the 5-point NLF-SRS |
| 19 | Explain diary use incl. documentation of injection site reactions / symptoms of interest to the subject. |
| 20 | Review subject diary regarding injection site reactions / symptoms of interest; confirm review. **Note:** Subjects will record injection site reactions, and symptoms of interest (i.e., changes in vision or symptoms of stroke) over the first four weeks (28 days) after each treatment (i.e., 4 weeks after baseline treatment, and 6 weeks in case of touch-up treatment). |
| 21 | In case of Early Termination attempts should be made to perform the assessments described for Visit 9 (SV1). |
| 22 | Last injection always either refers to initial treatment (BL) or touch-up treatment (TUP1) |
| 23 | Injection volume will be documented by site of the midface (left/right) and for each of the 3 anatomical areas of midface treatment (anteromedial cheek, submalar, and zygomaticomalar) |
| 24 | Visit 9 (SV1) will be the end of study visit, in case an inclusion criterion is not met / an exclusion criterion is met for optional repeat-treatment and further follow up in screening is not useful because the subject will apparently not qualify for repeat-treatment. |
| 25 | In addition to clinical photography (3D photos), another baseline photo (2D) should be taken on-site at Visit 1. |
| **Abbreviations:** MVDSS: Midface Volume Deficit Severity Scale; NLF-SRS: Nasolabial Folds Severity Rating Scale; GAIS: Global Aesthetic Improvement Scale; NPRS: Numerical Pain Rating Scale; SV: Screening Visit; TUP1: Touch-up treatment after baseline treatment | |
Table 4. Schedule of procedures and assessments for screening phase for repeat-treatment (Visit SV2 to SV4)
| | Screening phase for repeat-treatment | | |
| --- | --- | --- | --- |
| Visit | Visit SV2^{3} (optional)* | Visit SV3^{3} (optional)* | Visit SV4^{3} (optional)* |
| Day / week | 4 weeks after Visit 9 (SV1) | 8 weeks after Visit 9 (SV1) | 12 weeks after Visit 9 (SV1) |
| Visit window | ±7 days | ±7 days | ±7 days |
| MVDSS^{1} – blinded evaluator at site^{2} | X | X | X |
| Concomitant treatments^{4} | X | X | X |
| Adverse events^{5} | X | X | X |
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| * Visits SV2 to SV4 are optional. As soon as the subject is eligible in MVDSS score, a full eligibility assessment for optional repeat-treatment will be done and Visit RT1 will be performed. | |
| --- | --- |
| 1 | Subjects do not have to return to their baseline severity of midface volume deficit to be eligible and receive a repeat-treatment, but the present condition of midface volume deficit has to meet the initial inclusion level of severity scores of 2 or 3 on the 5-point MVDSS. The score does not have to be the same on both sides but must be 2 or 3. |
| 2 | Midface volume deficit severity is determined by the blinded evaluator. Note: The blinded evaluator at the site is not blinded for treatment allocation during the repeat-treatment phase. However, he/she will be still blinded for the treatment a subject received during the initial treatment phase |
| 3 | Visit SV4 will be the end of study visit for subjects who do not qualify for repeat-treatment. In case an inclusion criterion is not met / an exclusion criterion is met during the screening phase for repeat-treatment and further follow up in screening is not useful because the subject will apparently not qualify for repeat-treatment, SV 2 or SV 3 will be the end of study visit for the respective subject. |
| 4 | All medications taken and non-pharmacological procedures applied by a subject during the course of a clinical study. |
| 5 | All subjects must be asked if they are experiencing or have experienced any signs/symptoms of vision changes or stroke since the injection or other events indicating an embolic event. |
| Abbreviations: MVDSS: Midface Volume Deficit Severity Scale; SV: Screening Visit; RT: Repeat Treatment | |
Table 5. Schedule of procedures and assessments for repeat-treatment phase (Visits RT1 to RT5)
| | Repeat-treatment and Follow-up for repeat-treatment (repeat-treatment phase) | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Visit | Visit RT1^{9} | Visit RT1a Phone contact | Visit RT2 TUP2 | Visit RT2a^{13} Phone contact | Visit RT2b^{13} Safety Follow-up | Visit RT3 | Visit RT4 | Visit RT5 (EOS)^{21} |
| Day / week | Up to 14 days after Screening Visit † | 24 – 48 hours after RT1 | 2 weeks after RT1 injection | 24 – 48 hours after RT2 | 2 weeks after TUP2 injection | 4 weeks after last injection^{22} | 12 weeks after last injection^{22} | 24 weeks after last injection^{22} |
| Visit window | | ± 4 hours | ± 3 days | ± 4 hours | ±3 days | ± 5 days | ± 7 days | ± 7 days |
| Procedure | | | | | | | | |
| Assessment of eligibility | X* | | X*^{13} | | | | | |
| Concomitant treatments^{1} | X* | X | X | X | X | X | X | X |
| Body weight | X* | | X | | | X | X | X |
| Urine pregnancy test^{2} | X* | | X* | | X | X | X | X |
| Visual examinations^{8} | X | | X | | X | X | X | X |
| Neurological examinations^{17} | X | | X | | X | X | X | X |
| MVDSS – blinded evaluator at site^{3} | X* | | X* | | | X | X | X |
| NLF-SRS – blinded evaluator at site^{4} | X* | | X* | | | X | X | X |
| Treatment | X | | X^{16} | | | | | |
| FACE-Q^{TM} “Satisfaction with Outcome” – subject^{6} | X* | | X* | | | X | X | X |
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| | Repeat-treatment and Follow-up for repeat-treatment (repeat-treatment phase) | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Visit | Visit RT1^{0} | Visit RT1a Phone contact | Visit RT2 TUP2 | Visit RT2a^{13} Phone contact | Visit RT2b^{13} Safety Follow-up | Visit RT3 | Visit RT4 | Visit RT5 (EOS)^{21} |
| Day / week | Up to 14 days after Screening Visit † | 24 – 48 hours after RT1 | 2 weeks after RT1 injection | 24 – 48 hours after RT2 | 2 weeks after TUP2 injection | 4 weeks after last injection^{22} | 12 weeks after last injection^{22} | 24 weeks after last injection^{22} |
| Visit window | | ± 4 hours | ± 3 days | ± 4 hours | ±3 days | ± 5 days | ± 7 days | ± 7 days |
| Procedure | | | | | | | | |
| FACE-Q^{TM} “Satisfaction with Cheeks” – subject^{7} | X* | | X* | | | X | X | X |
| Evaluation of pain – subject (NPRS)^{9} | X | | X^{13} | | | | | |
| Injection volume^{23} | X | | X^{13} | | | | | |
| Initiate / Explain subject diary^{19} | X | | X^{13} | | | | | |
| Review subject diary^{20} | | | X | | X | X | | |
| Adverse events^{10} | X | X | X | X | X | X | X | X |
| Device deficiencies | X | | X^{13} | | | | | |
* Prior to injection (i.e., either at repeat-treatment or touch-up treatment (TUP2))
† Visit RT1 may be performed up to 14 days after Screening Visit case the subject qualifies for repeat-treatment at one of these Visits. Screening Visit are Visit 9 (SV1) to SV4.
0 Screening Visits (i.e., Visit 9 (SV1) to SV4) and Visit RT1 may be performed as one visit in case the subject qualifies for repeat-treatment at one of these visits. In case of only one visit, the following assessments do not need to be done twice
- Visit 9 (SV1) = RT1: * pre-treatment assessments at Visit RT1
- Visits SV2 to SV4 = RT1: MVDSS by blinded evaluator, concomitant treatments, adverse events
1 Defined as all medications and non-drug therapies taken/received within the previous ten days prior to initial Screening up to end of study
2 In women of childbearing potential only, including those who are postmenopausal for less than 12 months
3 Evaluation and grading of midface volume deficit by the blinded evaluator at the site (live assessment) using the 5-point MVDSS. Note: The blinded evaluator at the site is not blinded for treatment allocation during the repeat-treatment phase. However, he/she will be still blinded for the treatment a subject received during the initial treatment phase.
4 Evaluation and grading of nasolabial folds severity by the blinded evaluator at the site (live assessment) using the 5-point NLF-SRS.
5 Subject satisfaction will be determined using the FACE-Q™ questionnaire “Satisfaction with Outcome”
6 Evaluation of subject appearance appraisal using the FACE-Q™ questionnaire “Satisfaction with Cheeks”
7 Visual exams (including Snellen visual acuity, confrontational visual fields and ocular motility). The subject should wear the same corrective eyewear (i.e., glasses/contact lenses) at each assessment, if appropriate. At treatment visits: Examination will be performed both before and 30 min after the injection. For subjects not receiving TUP, exams will only be performed once.
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| 9 | NPRS starting immediately and every 15 min after last injection for 60 min post-treatment |
| --- | --- |
| 10 | All subjects must be asked if they are experiencing or have experienced any signs/symptoms of vision changes or stroke since the injection or other events indicating an embolic event. |
| 13 | Concerning only subjects who receive touch-up treatment. |
| 16 | Touch-up treatment for optimal correction if deemed necessary in the discretion of **treating investigator** |
| 17 | A basic neurological examination (F.A.S.T) will be performed for all subjects who show signs of ophthalmic complications due to filler injection in visual exams |
| 19 | Explain diary use incl. documentation of injection site reactions / symptoms of interest to the subject. |
| 20 | Review subject diary regarding injection site reactions / symptoms of interest; confirm review. **Note:** Subjects will record injection site reactions, and symptoms of interest (i.e., changes in vision or symptoms of stroke) over the first four weeks (28 days) after each treatment (i.e., 4 weeks after repeat-treatment, and 6 weeks in case of touch-up treatment. |
| 21 | In case of Early Termination attempts should be made to perform the assessments described for Visit RT5. |
| 22 | Last injection in repeat treatment phase always either refers to repeat-treatment (RT1) or touch-up treatment (TUP2) |
| 23 | Injection volume will be documented by site of the midface (left/right) and for each of the 3 anatomical areas of midface treatment (anteromedial cheek, submalar, and zygomaticomalar) |
| **Abbreviations:** MVDSS: Midface Volume Deficit Severity Scale; NLF-SRS: Nasolabial Folds Severity Rating Scale; GAIS: Global Aesthetic Improvement Scale, NPRS: Numerical Pain Rating Scale; SV: Screening Visit; RT: Repeat Treatment; TUP2: Touch-up treatment after repeat-treatment | |
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### 3. Clinical Endpoints
With regards to safety, applied measures included the frequency, severity, seriousness, and causal relationship of adverse events (AEs), adverse device effects (ADEs), serious adverse events (SAEs), and serious adverse device effects (SADEs) during the clinical study. This included events reported by subjects in diaries during the 4 weeks after each treatment (i.e., 4 weeks after baseline and repeat-treatment, respectively, and 6 weeks in case of touch-up treatment).
With regards to effectiveness, the saypha® ChIQ™ was assessed for correction of midface volume deficit, evaluated live by the blinded evaluator at the site using the validated 5-point MVDSS during follow-up visits of the initial and repeat-treatment phase. MVDSS scores were ranked as follows:
0 (none/minimal): Zygomaticomalar region, anteromedial cheek, and/or submalar region show convexity; appearance of a full round face with no volume deficit in the midface; no to minimal loss of fullness
1 (mild): Zygomaticomalar region, anteromedial cheek, and/or submalar region are somewhat flattened; fairly full face appearance; mild loss of fullness
2 (moderate): Zygomaticomalar region, anteromedial cheek, and/or submalar region have slightly concave shape; moderate loss of fullness in the midface area
3 (severe): Zygomaticomalar region, anteromedial cheek, and/or submalar region are more concave; underlying bone structure may start to show; severe loss of fullness
4 (very severe): Zygomaticomalar region and/or anteromedial cheek showing deep concavity; bone structure is prominent, sagging features and visible hollowing below malar prominence; very severe loss of fullness
A central independent blinded photographic reviewer assessed the MVDSS at the same time points of the initial treatment phase based on photographs taken during the subject's visits. In addition, volume changes were measured using 3D photographs.
Severity of nasolabial folds (NLFs) was assessed live using the validated 5-point NLF-SRS during initial and repeat-treatment phase at each onsite visit by the blinded evaluator at the site. NLF-SRS scores were ranked as 0 (none/minimal), 1 (mild), 2 (moderate), 3 (severe), and 4 (extreme).
The global aesthetic improvement after correction of midface volume deficit was independently evaluated by the blinded evaluator at the site and the subject using the modified Global Aesthetic Improvement Scale (modified GAIS). mGAIS scores ranged from 1 (much improved), to 2 (improved), 3 (no change), 4 (worse), and 5 (much worse).
Subject satisfaction was evaluated using FACE-Q™ questionnaires on 'Satisfaction with Outcome' and 'Satisfaction with Cheeks'. The FACE-Q™ Subject Satisfaction with Outcome Questionnaire consisted of 6 questions with answers of 1 (definitely disagree), 2 (somewhat disagree), 3 (somewhat agree), or 4 (definitely agree). The FACE-Q™ Subject Appearance Appraisal 'Satisfaction with Cheeks' Questionnaire consisted of 5 questions with answers of 1 (very dissatisfied), 2 (somewhat dissatisfied), 3 (somewhat satisfied), or 4 (very satisfied). The raw sum scores were each converted into equivalent Rasch transformed scores which ranged from 0 (worst) to 100 (best).
Pain assessment using the NPRS ranging from 0 (no pain) to 10 (the worst pain imaginable) was done after initial and repeat-treatment in 15-minute increments, starting 15 minutes after the last injection until 60 minutes post-treatment.
With regards to success/failure criteria, the primary endpoint was the percentage of responders on the 5-point MVDSS, 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. Subjects were defined as responders on the MVDSS if they had a clinically meaningful improvement (≥1 point) relative to baseline.
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The hypothesis for the primary effectiveness endpoint was that saypha® ChIQ™ was non-inferior to Control, which was evaluated by means of a one-sided two-group Farrington-Manning test for the difference between proportions with the following hypotheses:
H0: pA – pB ≤ – 10%
H1: pA – pB > – 10%
At this, pA is the percent response rate for saypha® ChIQ™ based on the blinded evaluator’s live assessment at Week 24 after last injection of initial treatment phase, while pB was the corresponding response rate for Control. Thus, a negative value of the difference meant that the response rate of saypha® ChIQ™ was lower than the response rate for Control. The non-inferiority margin was -10%.
### B. Accountability of PMA Cohort
At the time of database lock, of 486 patients enrolled in the PMA study, 423 (87.0%; 423/486) patients were available for analysis at the completion of the initial treatment phase, the 48-week post-treatment visit (Visit 9), which was the final visit for the primary effectiveness evaluation.
In addition, 192 patients (39.5%; 192/486) were eligible for the repeat-treatment phase, and of these, 178 (36.6%; 178/486) patients completed the study through the Week 24 follow-up visit after repeat treatment (Visit RT5), which represented the final study visit.
A total of 486 subjects passed screening and were randomized. Of these, 324 subjects were randomized to the saypha® ChIQ™ group, and 162 subjects were randomized to the Control group. Of the 486 subjects randomized, 483 subjects were treated (322 subjects with saypha® ChIQ™ and 161 subjects with the Control).
At Week 2, 218 subjects received a touch-up treatment with saypha® ChIQ™ and 111 subjects received a touch-up treatment with Control. The median injection volume (both sides combined) of saypha® ChIQ™ required to achieve optimal correction was 4.0 mL at initial treatment and 1.0 mL at touch-up treatment.
Subjects who were eligible and willing could receive optional repeat-treatment (with saypha® ChIQ™ only) 48 to 60 weeks after initial treatment (or touch-up treatment). A total of 192 subjects (118 subjects in the saypha® ChIQ™ group and 74 subjects in the Control group) received a repeat-treatment. The repeat-treatment was performed with saypha® ChIQ™ on both patient groups and the median injection volume required to achieve optimal correction was 2.0 mL at repeat- treatment and 1.0 mL at touch-up treatment.
Of the 486 subjects randomized, 483 (99.4%; 483/486) subjects overall were valid for the Full Analysis Set (FAS) and for the Safety Analysis Set (SAF): 322 (99.4%; 322/324) subjects in the saypha® ChIQ™ group and 161 (99.4%; 161/162) subjects in the Control group.
A total of 451 (92.8%; 451/486) subjects overall were included in the Per-Protocol Set (PPS): 303 (93.5%; 303/324) subjects in the saypha® ChIQ™ group and 148 (91.4%; 148/162) subjects in the Control group. Overall, 35 (7.2%; 35/486) subjects were excluded from PPS. Thereof, 32 (91.4%; 32/35) subjects overall were excluded due to a major PD, and 3 (8.6%; 3/35) subjects overall were not treated.
Overall, 423 (87.0%; 423/486) subjects completed the study (or completed Visit 9). The most common reasons for discontinuation from the study were ‘withdrawal of consent’ (30 [47.6%; 30/63] subjects) and ‘lost to follow-up’ (26 [41.3%; 26/63] subjects).
A flowchart of the disposition of subjects per treatment phase is shown in Figure 1.
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Figure 1. Disposition of Subjects per Treatment Phase
### C. Study Population Demographics and Baseline Parameters
Subject Demographic and Baseline Characteristics for initial treatment phase are provided in Table 6. Subject Demographic Characteristics for repeat-treatment phase are summarized in Table 7. Baseline MVDSS scores were comparable between the 2 treatment groups with individual MVDSS grades of 2 (288 [59.6%; 288/483] subjects overall) and 3 (195 [40.4%; 195/483] subjects overall).
Demographics and baseline characteristics in the PPS were comparable to those in the FAS.
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**Table 6. Subject Demographic and Baseline Characteristics (FAS)**
| Characteristics | saypha® ChIQ™ (N=322) | Control (N=161) | Overall (N=483) |
| --- | --- | --- | --- |
| **Age (years)** | | | |
| Mean (SD) | 54.6 (10.7) | 56.0 (9.5) | 55.1 (10.3) |
| Median (Q1, Q3) | 55.0 (49.0, 62.0) | 56.0 (50.0, 63.0) | 55.0 (49.0, 62.0) |
| Min, Max | 24, 75 | 30, 75 | 24, 75 |
| **Age Category, (%; n/N)** | | | |
| 22 – 45 years | 17.7%; 57/322 | 14.3%; 23/161 | 16.6%; 80/483 |
| ≥46 – 65 years | 65.5%; 211/322 | 70.2%; 113/161 | 67.1%; 324/483 |
| ≥66 – 75 years | 16.8%; 54/322 | 15.5%; 25/161 | 16.4%; 79/483 |
| **Gender, (%; n/N)** | | | |
| Male | 5.9%; 19/322 | 4.3%; 7/161 | 5.4%; 26/483 |
| Female | 94.1%; 303/322 | 95.7%; 154/161 | 94.6%; 457/483 |
| Childbearing Potential^{1} | 23.4%; 71/303 | 20.1%; 31/154 | 22.3%; 102/457 |
| Not of Childbearing Potential^{1} | 76.6%; 232/303 | 79.9%; 123/154 | 77.7%; 355/457 |
| **Baseline Body Weight (kg)** | | | |
| Mean (SD) | 68.6 (13.0) | 70.3 (16.1) | 69.2 (14.1) |
| Median (Q1, Q3) | 66.5 (59.0, 76.0) | 68.0 (60.0, 77.0) | 67.0 (59.0, 77.0) |
| Min, Max | 44, 116 | 45, 150 | 44, 150 |
| **Race, (%; n/N)** | | | |
| White | 87.9%; 283/322 | 87.0%; 140/161 | 87.6%; 423/483 |
| Asian | 1.6%; 5/322 | 4.3%; 7/161 | 2.5%; 12/483 |
| Black or African American | 6.2%; 20/322 | 4.3%; 7/161 | 5.6%; 27/483 |
| American Indian or Alaska Native | 2.8%; 9/322 | 4.3%; 7/161 | 3.3%; 16/483 |
| Native Hawaiian or Other Pacific Islander | 0.6%; 2/322 | 0%; 0/0 | 0.4%; 2/483 |
| **Other, n (%)** | | | |
| Afghan | 0.3%; 1/322 | 0%; 0/0 | 0.2%; 1/483 |
| Bi-racial | 0.3%; 1/322 | 0%; 0/0 | 0.2%; 1/483 |
| Black/white | 0.3%; 1/322 | 0%; 0/0 | 0.2%; 1/483 |
| **Ethnicity, (%; n/N)** | | | |
| Hispanic or Latino | 21.1%; 68/322 | 17.4%; 28/161 | 19.9%; 96/483 |
| Not Hispanic or Latino | 78.9%; 254/322 | 82.6%; 133/161 | 80.1%; 387/483 |
| **Fitzpatrick skin type^{2}, (%; n/N)** | | | |
| Type I | 1.6%; 5/322 | 3.1%; 5/161 | 2.1%; 10/483 |
| Type II | 31.4%; 101/322 | 27.3%; 44/161 | 30.0%; 145/483 |
| Type III | 34.2%; 110/322 | 38.5%; 62/161 | 35.6%; 172/483 |
| Type IV | 23.9%; 77/322 | 22.4%; 36/161 | 23.4%; 113/483 |
| Type V | 5.3%; 17/322 | 5.0%; 8/161 | 5.2%; 25/483 |
| Type VI | 3.7%; 12/322 | 3.7%; 6/161 | 3.7%; 18/483 |
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| Characteristics | saypha® ChIQ™ (N=322) | Control (N=161) | Overall (N=483) |
| --- | --- | --- | --- |
| **Fitzpatrick skin type categories, (%; n/N)** | | | |
| Type I, II and III | 67.1%; 216/322 | 68.9%; 111/161 | 67.7%; 327/483 |
| Type IV, V and VI | 32.9%; 106/322 | 31.1%; 50/161 | 32.3%; 156/483 |
| Type V and VI | 9.0%; 29/322 | 8.7%; 14/161 | 8.9%; 43/483 |
| **MVDSS at baseline^{3}, (%; n/N)** | | | |
| 2 (moderate) | 58.7%; 189/322 | 61.5%; 99/161 | 59.6%; 288/483 |
| 3 (severe) | 41.3%; 133/322 | 38.5%; 62/161 | 40.4%; 195/483 |
Note: N = Number of subjects in analysis population. n (%) = Number and percentage of subjects among N. SD = Standard deviation. Q1 = First quartile. Q3 = Third quartile. FAS = Full Analysis Set. MVDSS = Midface Volume Deficit Severity Scale.
$^{1}$ Percentage denominator is the number of females
$^{2}$ FST were defined as I (always burns easily, never tans), II (always burns easily, tans minimally), III (burns moderately, tans gradually (light brown)), IV (burns minimally, always tans well (moderate brown)), V (barely burns, tans very well (moderate brown)), VI (never burns, deeply pigmented).
$^{3}$ By blinded evaluator at site. Baseline was defined as the last assessment prior to initial administration of the medical devices.
**Table 7. Repeat-Treatment Phase: Demographic Characteristics (mFAS)**
| Characteristics | saypha® ChIQ™ (N=118) | Control (N=74) | Overall (N=192) |
| --- | --- | --- | --- |
| **Age (years)** | | | |
| Mean (SD) | 54.1 (11.5) | 56.3 (9.5) | 55.0 (10.8) |
| Median (Q1, Q3) | 55.0 (48.0, 63.0) | 56.5 (52.0, 63.0) | 56.0 (49.0, 63.0) |
| Min, Max | 26, 75 | 33, 75 | 26, 75 |
| **Age Category, (%; n/N)** | | | |
| 22 – 45 years | 19.5%; 23/118 | 13.5%; 10/74 | 17.2%; 33/192 |
| ≥46 – 65 years | 61.9%; 73/118 | 71.6%; 53/74 | 65.6%; 126/192 |
| ≥66 – 75 years | 18.6%; 22/118 | 14.9%; 11/74 | 17.2%; 33/192 |
| **Gender, (%; n/N)** | | | |
| Male | 6.8%; 8/118 | 2.7%; 2/74 | 5.2%; 10/192 |
| Female | 93.2%; 110/118 | 97.3%; 72/74 | 94.8%; 182/192 |
| Childbearing Potential^{1} | 26.4%; 29/110 | 22.2%; 16/72 | 24.7%; 45/182 |
| Not of Childbearing Potential^{1} | 73.6%; 81/110 | 77.8%; 56/72 | 75.3%; 137/182 |
| **Baseline Body Weight (kg)** | | | |
| Mean (SD) | 68.5 (13.4) | 70.3 (17.8) | 69.2 (15.2) |
| Median (Q1, Q3) | 66.5 (58.0, 75.0) | 67.0 (59.0, 75.0) | 67.0 (59.0, 75.0) |
| Min, Max | 45, 117 | 45, 151 | 45, 151 |
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| Characteristics | saypha® ChIQ™ (N=118) | Control (N=74) | Overall (N=192) |
| --- | --- | --- | --- |
| **Race, (%; n/N)** | | | |
| White | 87.3%; 103/118 | 87.8%; 65/74 | 87.5%; 168/192 |
| Asian | 2.5%; 3/118 | 8.1%; 6/74 | 4.7%; 9/192 |
| Black or African American | 6.8%; 8/118 | 4.1%; 3/74 | 5.7%; 11/192 |
| American Indian or Alaska Native | 1.7%; 2/118 | 0%; 0/0 | 1.0%; 2/192 |
| Native Hawaiian or Other Pacific Islander | 0.8%; 1/118 | 0%; 0/0 | 0.5%; 1/192 |
| Other | 0.8%; 1/118 | 0%; 0/0 | 0.5%; 1/192 |
| Black/white | 0.8%; 1/118 | 0%; 0/0 | 0.5%; 1/192 |
| **Ethnicity, (%; n/N)** | | | |
| Hispanic or Latino | 22.0%; 26/118 | 16.2%; 12/74 | 19.8%; 38/192 |
| Not Hispanic or Latino | 78.0%; 92/118 | 83.8%; 62/74 | 80.2%; 154/192 |
| **Fitzpatrick skin type^{2}, (%; n/N)** | | | |
| Type I | 2.5%; 3/118 | 4.1%; 3/74 | 3.1%; 6/192 |
| Type II | 29.7%; 35/118 | 21.6%; 16/74 | 26.6%; 51/192 |
| Type III | 30.5%; 36/118 | 44.6%; 33/74 | 35.9%; 69/192 |
| Type IV | 25.4%; 30/118 | 16.2%; 12/74 | 21.9%; 42/192 |
| Type V | 8.5%; 10/118 | 10.8%; 8/74 | 9.4%; 18/192 |
| Type VI | 3.4%; 4/118 | 2.7%; 2/74 | 3.1%; 6/192 |
| **Fitzpatrick skin type categories, (%; n/N)** | | | |
| Type I, II and III | 62.7%; 74/118 | 70.3%; 52/74 | 65.6%; 126/192 |
| Type IV, V and VI | 37.3%; 44/118 | 29.7%; 22/74 | 34.4%; 66/192 |
| Type V and VI | 11.9%; 14/118 | 13.5%; 10/74 | 12.5%; 24/192 |
| **MVDSS at baseline^{3}, (%; n/N)** | | | |
| 2 (moderate) | 97.5%; 115/118 | 91.9%; 68/74 | 95.3%; 183/192 |
| 3 (severe) | 2.5%; 3/118 | 8.1%; 6/74 | 4.7%; 9/192 |
Note: N = Number of subjects in analysis population. n (%) = Number and percentage of subjects among N. SD = Standard deviation. Q1 = First quartile. Q3 = Third quartile. mFAS = Modified Full Analysis Set. MVDSS = Midface Volume Deficit Severity Scale.
$^{1}$ Percentage denominator is the number of females
$^{2}$ FST were defined as I (always burns easily, never tans), II (always burns easily, tans minimally), III (burns moderately, tans gradually (light brown)), IV (burns minimally, always tans well (moderate brown)), V (barely burns, tans very well (moderate brown)), VI (never burns, deeply pigmented).
$^{3}$ By blinded evaluator at site. Baseline was defined as the last assessment prior to first repeat-treatment.
## D. Safety and Effectiveness Results
### 1. Safety Results
The analysis of safety was based on the cohort of 483 patients for Treatment-Emergent Adverse Events (TEAE) after initial treatment and of 467 patients for Injection Site Reactions (ISR) after initial treatment as well as of 165 patients for ISRs after repeat-treatment recorded through patient diaries. The key safety outcomes for this study are presented below in Tables 8 to 13. Adverse effects are reported in Tables 10 to 13. The ISRs are presented below in Table 8 and Table 9. An overview of the AEs documented during the initial treatment phase is given in Table 10. The most commonly reported adverse device effects (ADEs) by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Classes (SOC) are presented in Table 12.
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### Injection Site Reactions After Initial and Repeat-Treatments
Overall, ~30% of subjects in each treatment group reported at least one ISR after the baseline injection with less subjects affected in the saypha® ChIQ™ group ([28.5%; 89/312] subjects) compared to Control ([34.2%; 53/155] subjects).
The most common ISRs reported in both treatment groups were tenderness to touch, firmness, lumps/bumps, swelling, pain after injection, bruising, and redness (Table 8).
Subjects documenting severe ISR were comparable between treatment groups with the (4.5% (14/312) for saypha® ChIQ™ vs 5.2% (8/155) for the control.
A lower proportion of subjects (17% subjects overall) reported ISRs after repeat-treatments. Documented ISRs of severe maximum intensity also reduced to 1.8% subjects overall.
**Table 8. Initial Treatment Phase: Injection Site Reactions from Diary by Maximum Intensity (SAF)**
| Type of ISR Intensity | Baseline Treatment^{1} | | Touch-up Treatment | |
| --- | --- | --- | --- | --- |
| | saypha® ChIQ™ (N = 312) (%; n/N) | Control (N = 155) (%; n/N) | saypha® ChIQ™ (N = 214) (%; n/N) | Control (N = 108) (%; n/N) |
| **At least one ISR** | **28.5; 89/312** | **34.2; 53/155** | **19.6; 42/214** | **23.1; 25/108** |
| Mild | 9.3; 29/312 | 14.8; 23/155 | 11.7; 25/214 | 13.0; 14/108 |
| Moderate | 14.7; 46/312 | 14.2; 22/155 | 7.0; 15/214 | 9.3; 10/108 |
| Severe | 4.5; 14/312 | 5.2; 8/155 | 0.9; 2/214 | 0.9; 1/108 |
| **Bruising** | **20.2; 63/312** | **22.6; 35/155** | **11.2; 24/214** | **13.9; 15/108** |
| Mild | 9.9; 31/312 | 11.6; 18/155 | 7.9; 17/214 | 10.2; 11/108 |
| Moderate | 8.3; 26/312 | 7.7; 12/155 | 3.3; 7/214 | 3.7; 4/108 |
| Severe | 1.9; 6/312 | 3.2; 5/155 | 0; 0/214 | 0; 0/108 |
| **Discoloration^{2}** | **9.9; 31/312** | **8.4; 13/155** | **2.8; 6/214** | **5.6; 6/108** |
| Mild | 7.1; 22/312 | 6.5; 10/155 | 2.3; 5/214 | 5.6; 6/108 |
| Moderate | 2.6; 8/312 | 1.9; 3/155 | 0; 0/214 | 0; 0/108 |
| Severe | 0.3; 1/312 | 0; 0/155 | 0.5; 1/214 | 0; 0/108 |
| **Firmness** | **24.7; 77/312** | **27.7; 43/155** | **17.3; 37/214** | **15.7; 17/108** |
| Mild | 11.9; 37/312 | 13.5; 21/155 | 13.6; 29/214 | 10.2; 11/108 |
| Moderate | 11.5; 36/312 | 12.9; 20/155 | 3.7; 8/214 | 5.6; 6/108 |
| Severe | 1.3; 4/312 | 1.3; 2/155 | 0; 0/214 | 0; 0/108 |
| **Itching** | **4.5; 14/312** | **7.1; 11/155** | **3.7; 8/214** | **1.9; 2/108** |
| Mild | 3.2; 10/312 | 7.1; 11/155 | 2.3; 5/214 | 1.9; 2/108 |
| Moderate | 1.3; 4/312 | 0; 0/155 | 1.4; 3/214 | 0; 0/108 |
| Severe | 0; 0/312 | 0; 0/155 | 0; 0/214 | 0; 0/108 |
| **Lumps/Bumps** | **23.7; 74/312** | **27.7; 43/155** | **15.9; 34/214** | **16.7; 18/108** |
| Mild | 13.1; 41/312 | 20.0; 31/155 | 11.7; 25/214 | 14.8; 16/108 |
| Moderate | 8.7; 27/312 | 7.1; 11/155 | 3.7; 8/214 | 1.9; 2/108 |
| Severe | 1.9; 6/312 | 0.6; 1/155 | 0.5; 1/214 | 0; 0/108 |
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| Type of ISR Intensity | Baseline Treatment^{1} | | Touch-up Treatment | |
| --- | --- | --- | --- | --- |
| | saypha® ChIQ™ (N = 312) (%; n/N) | Control (N = 155) (%; n/N) | saypha® ChIQ™ (N = 214) (%; n/N) | Control (N = 108) (%; n/N) |
| **Pain after injection** | **20.2; 63/312** | **26.5; 41/155** | **10.7; 23/214** | **13.0; 14/108** |
| Mild | 12.5; 39/312 | 17.4; 27/155 | 8.9; 19/214 | 9.3; 10/108 |
| Moderate | 6.4; 20/312 | 8.4; 13/155 | 1.9; 4/214 | 3.7; 4/108 |
| Severe | 1.3; 4/312 | 0.6; 1/155 | 0; 0/214 | 0; 0/108 |
| **Redness** | **17.9; 56/312** | **23.2; 36/155** | **7.5; 16/214** | **8.3; 9/108** |
| Mild | 13.1; 41/312 | 18.7; 29/155 | 7.0; 15/214 | 6.5; 7/108 |
| Moderate | 4.2; 13/312 | 4.5; 7/155 | 0.5; 1/214 | 1.9; 2/108 |
| Severe | 0.6; 2/312 | 0; 0/155 | 0; 0/214 | 0; 0/108 |
| **Swelling** | **22.8; 71/312** | **28.4; 44/155** | **15.0; 32/214** | **16.7; 18/108** |
| Mild | 11.9; 37/312 | 18.1; 28/155 | 10.3; 22/214 | 12.0; 13/108 |
| Moderate | 9.0; 28/312 | 9.7; 15/155 | 4.2; 9/214 | 3.7; 4/108 |
| Severe | 1.9; 6/312 | 0.6; 1/155 | 0.5; 1/214 | 0.9; 1/108 |
| **Tenderness to touch** | **24.7; 77/312** | **30.3; 47/155** | **15.0; 32/214** | **21.3; 23/108** |
| Mild | 15.4; 48/312 | 16.1; 25/155 | 10.3; 22/214 | 15.7; 17/108 |
| Moderate | 8.0; 25/312 | 13.5; 21/155 | 4.2; 9/214 | 5.6; 6/108 |
| Severe | 1.3; 4/312 | 0.6; 1/155 | 0.5; 1/214 | 0; 0/108 |
| **Other^{3}** | **5.1; 16/312** | **8.4; 13/155** | **3.3; 7/214** | **0.9; 1/108** |
Note: N = Number of subjects in analysis population with at least one entry in the diary. n (%) = Number and percentage of subjects reporting at least one injection site reaction with the specification among N. SAF = Safety Analysis Set. ISR = Injection Site Reaction.
Note: Injections site reactions were documented daily by subjects and per side of the midface treated. ISRs with the specification at either left side, right side, or both sides of the midface are displayed.
Note: Injection site reactions with intensity assessed as 'mild', 'moderate' or 'severe' were included. For computations of 'both', the maximum intensity of both sides of the midface was used.
Note: Injection site reactions with 'Other' type were excluded from the analysis.
$^{1}$ For subjects without touch-up treatment in the initial treatment phase, all diary entries were included in the analysis. For subjects who received touch-up treatment, all diary entries up to (and including) the last day before touch-up treatment were included in the analysis.
$^{2}$ Other than Redness or Bruising
$^{3}$ 'Other' was used in subject diary to describe a symptom that did not appear in the listed categories.
The maximum duration for any ISR reported was similar between treatments (see Table 9). After baseline treatment with saypha® ChIQ™, firmness, lumps/bumps, tenderness to touch, swelling, pain after injection and bruising were the ISRs that lasting up to 27 days, while redness, discoloration and itching disappeared much faster. The duration of ISRs after touch-up treatment by category was comparable to the duration of ISRs after baseline treatment.
A lower proportion of subjects (17% subjects overall) reported ISRs after repeat-treatment. The maximum duration for reported ISRs was similar between treatment groups and compared to initial treatment.
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Table 9. Initial Treatment Phase: Duration of ISR from Diary After Baseline Treatment by Categories (SAF)
| Type of ISR Duration Category | Subjects without* subsequent touch-up treatment | | Subjects with** subsequent touch-up treatment | | Subjects with or without*** subsequent touch-up treatment | |
| --- | --- | --- | --- | --- | --- | --- |
| | saypha® ChIQ™ (N = 99) (%; n/N) | Control (N = 49) (%; n/N) | saypha® ChIQ™ (N = 213) (%; n/N) | Control (N = 106) (%; n/N) | saypha® ChIQ™ (N = 312) (%; n/N) | Control (N = 155) (%; n/N) |
| At least one ISR | 25.3; 25/99 | 28.6; 14/49 | 30.0; 64/213 | 36.8; 39/106 | 28.5; 89/312 | 34.2; 53/155 |
| 1-3 days | 8.1; 8/99 | 12.2; 6/49 | 12.2; 26/213 | 17.0; 18/106 | 10.9; 34/312 | 15.5; 24/155 |
| 4-7 days | 3.0; 3/99 | 2.0; 1/49 | 6.1; 13/213 | 5.7; 6/106 | 5.1; 16/312 | 4.5; 7/155 |
| 8-14 days | 5.1; 5/99 | 6.1; 3/49 | 10.3; 22/213 | 14.2; 15/106 | 8.7; 27/312 | 11.6; 18/155 |
| 15-28 days | 9.1; 9/99 | 8.2; 4/49 | 1.4; 3/213 | 0; 0/106 | 3.8; 12/312 | 2.6; 4/155 |
| Bruising | 22.2; 22/99 | 18.4; 9/49 | 19.2; 41/213 | 24.5; 26/106 | 20.2; 63/312 | 22.6; 35/155 |
| 1-3 days | 9.1; 9/99 | 12.2; 6/49 | 7.5; 16/213 | 11.3; 12/106 | 8.0; 25/312 | 11.6; 18/155 |
| 4-7 days | 5.1; 5/99 | 0; 0/49 | 4.7; 10/213 | 4.7; 5/106 | 4.8; 15/312 | 3.2; 5/155 |
| 8-14 days | 4.0; 4/99 | 0; 0/49 | 6.6; 14/213 | 8.5; 9/106 | 5.8; 18/312 | 5.8; 9/155 |
| 15-28 days | 4.0; 4/99 | 6.1; 3/49 | 0.5; 1/213 | 0; 0/106 | 1.6; 5/312 | 1.9; 3/155 |
| Discoloration¹ | 11.1; 11/99 | 8.2; 4/49 | 9.4; 20/213 | 8.5; 9/106 | 9.9; 31/312 | 8.4; 13/155 |
| 1-3 days | 8.1; 8/99 | 2.0; 1/49 | 6.6; 14/213 | 5.7; 6/106 | 7.1; 22/312 | 4.5; 7/155 |
| 4-7 days | 1.0; 1/99 | 2.0; 1/49 | 1.4; 3/213 | 1.9; 2/106 | 1.3; 4/312 | 1.9; 3/155 |
| 8-14 days | 1.0; 1/99 | 4.1; 2/49 | 1.4; 3/213 | 0.9; 1/106 | 1.3; 4/312 | 1.9; 3/155 |
| 15-28 days | 1.0; 1/99 | 0; 0/49 | 0; 0/213 | 0; 0/106 | 0.3; 1/312 | 0; 0/155 |
| Firmness | 20.2; 20/99 | 20.4; 10/49 | 26.8; 57/213 | 31.1; 33/106 | 24.7; 77/312 | 27.7; 43/155 |
| 1-3 days | 9.1; 9/99 | 8.2; 4/49 | 13.6; 29/213 | 17.9; 19/106 | 12.2; 38/312 | 14.8; 23/155 |
| 4-7 days | 0; 0/99 | 4.1; 2/49 | 5.2; 11/213 | 5.7; 6/106 | 3.5; 11/312 | 5.2; 8/155 |
| 8-14 days | 3.0; 3/99 | 4.1; 2/49 | 6.6; 14/213 | 7.5; 8/106 | 5.4; 17/312 | 6.5; 10/155 |
| 15-28 days | 8.1; 8/99 | 4.1; 2/49 | 1.4; 3/213 | 0; 0/106 | 3.5; 11/312 | 1.3; 2/155 |
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| Type of ISR Duration Category | Subjects without* subsequent touch-up treatment | | Subjects with** subsequent touch-up treatment | | Subjects with or without*** subsequent touch-up treatment | |
| --- | --- | --- | --- | --- | --- | --- |
| | saypha® ChIQ™ (N = 99) (%; n/N) | Control (N = 49) (%; n/N) | saypha® ChIQ™ (N = 213) (%; n/N) | Control (N = 106) (%; n/N) | saypha® ChIQ™ (N = 312) (%; n/N) | Control (N = 155) (%; n/N) |
| **Itching** | **4.0; 4/99** | **8.2; 4/49** | **4.7; 10/213** | **6.6; 7/106** | **4.5; 14/312** | **7.1; 11/155** |
| 1-3 days | 2.0; 2/99 | 8.2; 4/49 | 3.3; 7/213 | 6.6; 7/106 | 2.9; 9/312 | 7.1; 11/155 |
| 4-7 days | 0; 0/99 | 0; 0/49 | 0.9; 2/213 | 0; 0/106 | 0.6; 2/312 | 0; 0/155 |
| 8-14 days | 1.0; 1/99 | 0; 0/49 | 0.5; 1/213 | 0; 0/106 | 0.6; 2/312 | 0; 0/155 |
| 15-28 days | 1.0; 1/99 | 0; 0/49 | 0; 0/213 | 0; 0/106 | 0.3; 1/312 | 0; 0/155 |
| **Lumps/Bumps** | **21.2; 21/99** | **22.4; 11/49** | **24.9; 53/213** | **30.2; 32/106** | **23.7; 74/312** | **27.7; 43/155** |
| 1-3 days | 8.1; 8/99 | 10.2; 5/49 | 13.1; 28/213 | 20.8; 22/106 | 11.5; 36/312 | 17.4; 27/155 |
| 4-7 days | 3.0; 3/99 | 2.0; 1/49 | 4.7; 10/213 | 1.9; 2/106 | 4.2; 13/312 | 1.9; 3/155 |
| 8-14 days | 4.0; 4/99 | 2.0; 1/49 | 5.6; 12/213 | 7.5; 8/106 | 5.1; 16/312 | 5.8; 9/155 |
| 15-28 days | 6.1; 6/99 | 8.2; 4/49 | 1.4; 3/213 | 0; 0/106 | 2.9; 9/312 | 2.6; 4/155 |
| **Pain after injection** | **20.2; 20/99** | **24.5; 12/49** | **20.2; 43/213** | **27.4; 29/106** | **20.2; 63/312** | **26.5; 41/155** |
| 1-3 days | 11.1; 11/99 | 16.3; 8/49 | 13.1; 28/213 | 17.0; 18/106 | 12.5; 39/312 | 16.8; 26/155 |
| 4-7 days | 4.0; 4/99 | 6.1; 3/49 | 3.3; 7/213 | 7.5; 8/106 | 3.5; 11/312 | 7.1; 11/155 |
| 8-14 days | 1.0; 1/99 | 0; 0/49 | 3.3; 7/213 | 2.8; 3/106 | 2.6; 8/312 | 1.9; 3/155 |
| 15-28 days | 4.0; 4/99 | 2.0; 1/49 | 0.5; 1/213 | 0; 0/106 | 1.6; 5/312 | 0.6; 1/155 |
| **Redness** | **15.2; 15/99** | **16.3; 8/49** | **19.2; 41/213** | **26.4; 28/106** | **17.9; 56/312** | **23.2; 36/155** |
| 1-3 days | 10.1; 10/99 | 12.2; 6/49 | 15.0; 32/213 | 18.9; 20/106 | 13.5; 42/312 | 16.8; 26/155 |
| 4-7 days | 2.0; 2/99 | 2.0; 1/49 | 2.8; 6/213 | 4.7; 5/106 | 2.6; 8/312 | 3.9; 6/155 |
| 8-14 days | 1.0; 1/99 | 0; 0/49 | 1.4; 3/213 | 2.8; 3/106 | 1.3; 4/312 | 1.9; 3/155 |
| 15-28 days | 2.0; 2/99 | 2.0; 1/49 | 0; 0/213 | 0; 0/106 | 0.6; 2/312 | 0.6; 1/155 |
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| Type of ISR Duration Category | Subjects without* subsequent touch-up treatment | | Subjects with** subsequent touch-up treatment | | Subjects with or without*** subsequent touch-up treatment | |
| --- | --- | --- | --- | --- | --- | --- |
| | saypha® ChIQ™ (N = 99) (%; n/N) | Control (N = 49) (%; n/N) | saypha® ChIQ™ (N = 213) (%; n/N) | Control (N = 106) (%; n/N) | saypha® ChIQ™ (N = 312) (%; n/N) | Control (N = 155) (%; n/N) |
| Swelling | 20.2; 20/99 | 24.5; 12/49 | 23.9; 51/213 | 30.2; 32/106 | 22.8; 71/312 | 28.4; 44/155 |
| 1-3 days | 11.1; 11/99 | 18.4; 9/49 | 13.6; 29/213 | 18.9; 20/106 | 12.8; 40/312 | 18.7; 29/155 |
| 4-7 days | 3.0; 3/99 | 4.1; 2/49 | 7.0; 15/213 | 8.5; 9/106 | 5.8; 18/312 | 7.1; 11/155 |
| 8-14 days | 1.0; 1/99 | 0; 0/49 | 2.8; 6/213 | 2.8; 3/106 | 2.2; 7/312 | 1.9; 3/155 |
| 15-28 days | 5.1; 5/99 | 2.0; 1/49 | 0.5; 1/213 | 0; 0/106 | 1.9; 6/312 | 0.6; 1/155 |
| Tenderness to touch | 22.2; 22/99 | 24.5; 12/49 | 25.8; 55/213 | 33.0; 35/106 | 24.7; 77/312 | 30.3; 47/155 |
| 1-3 days | 9.1; 9/99 | 10.2; 5/49 | 10.3; 22/213 | 16.0; 17/106 | 9.9; 31/312 | 14.2; 22/155 |
| 4-7 days | 5.1; 5/99 | 4.1; 2/49 | 6.6; 14/213 | 6.6; 7/106 | 6.1; 19/312 | 5.8; 9/155 |
| 8-14 days | 2.0; 2/99 | 2.0; 1/49 | 8.0; 17/213 | 10.4; 11/106 | 6.1; 19/312 | 7.7; 12/155 |
| 15-28 days | 6.1; 6/99 | 8.2; 4/49 | 0.9; 2/213 | 0; 0/106 | 2.6; 8/312 | 2.6; 4/155 |
Note: N = Number of subjects in analysis population with at least one entry in the diary. n (%) = Number and percentage of subjects reporting at least one Injection Site Reaction with the specification among N. SAF = Safety Analysis Set. ISR = Injection Site Reaction.
Note: Injection site reactions were documented daily by subjects and per side of the midface treated.
Note: The duration in time [days] was computed as: Last stop date – First start date +1. This definition comprised both sides of the midface.
Note: Injection site reactions with 'Other' type were excluded from the analysis.
¹ Other than Redness or Bruising
* For subjects without touch-up treatment in the initial treatment phase, all diary entries were included in the analysis (maximum documentation after baseline treatment: 28 days)
** For subjects who received touch-up treatment (14±3 days) after baseline treatment, all diary entries up to (and including) the last day before touch-up treatment were included in the analysis.
*** For subjects without touch-up treatment in the initial treatment phase, all diary entries were included in the analysis. For subjects who received touch-up treatment, all diary entries up to (and including) the last day before touch-up treatment were included in the analysis.
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### Treatment-Emergent Adverse Events After Initial and Repeat-Treatments
Adverse events documented during the initial treatment phase are summarized in Table 10. The most commonly reported adverse device effects (ADEs) by MedDRA SOC are presented in Table 12.
142 AEs in 15.7% (76/483) subjects were considered by the investigator to have a relationship to the medical device itself and/or the procedure and were categorized as ADE. A higher proportion of subjects in the Control group (17.4%; 28/161 subjects) was affected by an ADE compared to the saypha® ChIQ™ group (14.9%; 48/322 subjects).
Overall, 1 subject (saypha® ChIQ™ group) terminated the investigation prematurely due to a TEAE. One other subject (saypha® ChIQ™ group) experienced a TEAE, which led to discontinuation of the injection (i.e., the subject was discontinued from further treatment with the medical device).
In total, 2 adverse events of special interest (AESIs) were reported in 2 subjects. One (cerebrovascular accident of unknown mechanism) was assessed as not related to medical device nor to procedure approximately 6 months after baseline treatment. One (external vascular occlusion on left side of face) was assessed as possibly related to medical device and procedure with onset on study day 5 after baseline treatment.
In total, 6 serious adverse events (SAEs) were reported in 1.2% (6/483) subjects. One SAE ('vascular skin disorder'; saypha® ChIQ™ group) was assessed by the investigator as possibly related to medical device and procedure.
Six AEs due to persisting injection-site reactions (pISR; i.e., ISR lasting more than 28 days) were reported in 2 subjects (0.4%) during initial treatment and in 1 subject (0.8%) during repeat treatment. All events were mild, non-serious, classified within the SOC General disorders and administration-site conditions, and resolved without sequelae.
**Table 10. Initial Treatment Phase: Overview of Adverse Events (SAF)**
| Subjects with Occurrence of | saypha® ChIQ™ (N=322) (%; n/N) [AE] | Control (N=161) (%; n/N) [AE] | Overall (N=483) (%; n/N) [AE] |
| --- | --- | --- | --- |
| **Adverse Events (AEs)** | **(39.4; 127/322) [300]** | **(36.6; 59/161) [162]** | **(38.5; 186/483) [462]** |
| **Treatment Emergent^{1} AEs (TEAEs)** | **(39.1; 126/322) [299]** | **(36.6; 59/161) [161]** | **(38.3; 185/483) [460]** |
| TEAEs of Special Interest (AESIs) | (0.6; 2/322) [2] | (0; 0/161) [0] | (0.4; 2/483) [2] |
| Dermatological TEAEs | (12.7; 41/322) [75] | (13.7; 22/161) [34] | (13.0; 63/483) [109] |
| TEAEs leading to withdrawal from investigation | (0.3; 1/322) [1] | (0; 0/161) [0] | (0.2; 1/483) [1] |
| TEAEs leading to discontinuation of injection | (0.3; 1/322) [1] | (0; 0/161) [0] | (0.2; 1/483) [1] |
| **Adverse device effects^{2} (ADEs)** | **(14.9; 48/322) [94]** | **(17.4; 28/161) [48]** | **(15.7; 76/483) [142]** |
| ADEs related to device | (9.0; 29/322) [65] | (12.4; 20/161) [35] | (10.1; 49/483) [100] |
| ADEs related to procedure | (14.0; 45/322) [83] | (17.4; 28/161) [46] | (15.1; 73/483) [129] |
| **Serious AEs (SAEs)** | **(1.2; 4/322) [4]** | **(1.2; 2/161) [2]** | **(1.2; 6/483) [6]** |
| **Serious ADEs^{2} (SADEs)** | **(0.3; 1/322) [1]** | **(0; 0/161) [0]** | **(0.2; 1/483) [1]** |
| SADEs related to device | (0.3; 1/322) [1] | (0; 0/161) [0] | (0.2; 1/483) [1] |
| SADEs related to procedure | (0.3; 1/322) [1] | (0; 0/161) [0] | (0.2; 1/483) [1] |
| **AEs due to a Persisting Injection Site Reaction (pISRs)** | **(0.3; 1/322) [5]** | **(0.6; 1/161) [1]** | **(0.4; 2/483) [6]** |
Note: N = Number of subjects in analysis population. n (%) = Number and percentage of subjects reporting at least 1 AE with the specification among N. [AE] = Number of individual AEs which occurred among the n subjects. SAF = Safety Analysis Set.
$^{1}$ TEAE = AE with a start date on or after the first use of medical device or pre-existing AEs which worsened in intensity.
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$^{2}$ All AEs assessed with ‘possible’, ‘probable’ or ‘causal’ relationship were classified as ‘related’ (i.e., as adverse device effect [ADE]).
An overview of all AEs reported during the repeat-treatment phase is given in Table 11 for subjects in the mSAF (N=192) separated by treatment group and overall.
In total, 16 AEs in 3.6% (7/192) subjects overall were considered by the investigator to have a relationship to the medical device itself and/or the procedure and were categorized as ADE with 5.4% (4/74) subjects affected by an ADE in the Control group compared to 2.5% (3/118) subjects in the saypha® ChIQ™ group.
Overall, 1 subject (saypha® ChIQ™ group) terminated the investigation prematurely due to a TEAE during the repeat-treatment phase. One other subject (saypha® ChIQ™ group) experienced a TEAE, which led to discontinuation of the injection, i.e., the subject was discontinued from further treatment with the medical device.
In total, 2 serious adverse events (SAEs) were reported in 1.7% (2/118) subjects of the saypha® ChIQ™ group during the repeat-treatment phase. Both events were reported as non-related to medical device and procedure.
Seven AEs due to persisting ISRs (pISRs) were documented in 0.8% (1/118) subjects of the saypha® ChIQ™ group.
**Table 11. Repeat-Treatment Phase: Overview of Adverse Events (mSAF)**
| Subjects with Occurrence of | saypha® ChIQ™ (N=118) (%; n/N) [AE] | saypha® ChIQ™ (initial treatment with Control) (N=74) (%; n/N) [AE] | Overall (N=192) (%; n/N) [AE] |
| --- | --- | --- | --- |
| **Adverse Events (AEs)** | **(15.3; 18/118) [51]** | **(27.0; 20/74) [39]** | **(19.8; 38/192) [90]** |
| **Treatment Emergent^{1} AEs (TEAEs)** | **(15.3; 18/118) [51]** | **(27.0; 20/74) [39]** | **(19.8; 38/192) [90]** |
| TEAEs of Special Interest (AESIs) | (0; 0/118) [0] | (0; 0/74) [0] | (0; 0/192) [0] |
| Dermatological TEAEs | (4.2; 5/118) [13] | (12.2; 9/74) [15] | (7.3; 14/192) [28] |
| TEAEs leading to withdrawal from investigation | (0.8; 1/118) [1] | (0; 0/74) [0] | (0.5; 1/192) [1] |
| TEAEs leading to d…
