A Randomized, Subject- and Evaluator-blinded, Controlled, Non-inferiority Multicenter, Parallel Group Comparison Study to Evaluate Effectiveness and Safety of Saypha® VOLUME Lidocaine for Midface Augmentation to Correct Volume Deficit
Phase: PHASE3
Conditions: Moderate to Severe Midface Volume Deficit
Sponsor: Croma-Pharma GmbH

 
 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 1 of 171 
Version 7.0 - 15-MAY-2024 
Volido – SAYPHA® VOLUME Lidocaine 
 
CLINICAL INVESTIGATION PLAN (CIP) 
Title of the clinical 
investigation: 
A randomized, subject- and evaluator-blinded, controlled, non-inferiority 
multicenter, parallel group comparison study to evaluate effectiveness 
and safety of saypha® VOLUME Lidocaine for midface augmentation in 
order to correct volume deficit 
Short title: 
Volido 
Investigation ID: 
CPH-301-201417 
IDE no.: 
G210347 
CIP version: 
7.0 
CIP version date: 
15-MAY-2024 
Sponsor: 
CROMA-PHARMA GmbH 
Industriezeile 6, 2100 Leobendorf, Austria 
Phone: +43 2262 684 680; Fax: +43 2262 68468 165 
E-mail: clinical.studies@croma.at; Web: www.croma.at 
Investigation site(s): 
Approximately 16 investigation sites located in the USA (an updated list of the 
sites, including names, addresses and positions of the corresponding Principal 
investigators, is kept separately from the CIP) 
Other institutions 
involved: 
 
 
 
 
An updated list of institutions that are involved in project management, 
monitoring, data management and statistics is kept separately from the CIP 
CONFIDENTIAL 
 
This clinical investigation plan is the property of CROMA-PHARMA GmbH and 
must be kept strictly confidential. Any unauthorized disclosure, copy or use of 
this document, or information contained herein, is prohibited. 
 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 3 of 171 
Version 7.0 - 15-MAY-2024 
Coordinating investigator agreement 
 
CIP identifier: CPH-301-201417 
 
I agree: 
• 
To assume responsibility for the proper conduct of the clinical investigation at the site specified 
below, and to conduct the investigation in compliance with this Clinical Investigation Plan (CIP), 
including any amendments thereof, any other study conduct procedures provided by the sponsor 
or their authorized representatives, the principles of Good Clinical Practice (GCP), and applicable 
regulatory requirements. 
• 
Not to implement any deviations from, or changes to, the CIP (including CIP amendments) without 
agreement from the sponsor, prior review and favorable opinion from the Ethics Committee, and 
approval from the Competent Authority, if applicable, except where necessary to eliminate an 
immediate hazard to the subject(s) or for administrative aspects of the clinical investigation (where 
permitted by all applicable regulatory requirements). 
• 
That I am familiar with the appropriate use of the medical devices under investigation as described 
in this CIP and any other information provided by the sponsor including, but not limited to, 
Investigator´s brochure (IB) and the Instructions for Use (IFU). 
• 
To ensure that all persons providing assistance during the clinical investigation are adequately 
informed about the medical devices under investigation and of their investigation-related duties 
and functions. 
• 
That I have been informed that certain regulatory authorities require the sponsor to obtain and 
supply details about the investigator’s ownership interest in the sponsor or the product under 
investigation, and more generally about his/her financial ties with the sponsor. The sponsor will 
use and disclose this information solely for the purpose of complying with regulatory requirements. 
 
Investigator's name: 
 
Investigation site: 
 
Address: 
  
 
 
Investigator's signature: 
 
 
 
Date: 
 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 4 of 171 
Version 7.0 - 15-MAY-2024 
Principal investigator agreement 
CIP identifier: CPH-301-201417 
I agree: 
• 
To assume responsibility for the proper conduct of the clinical investigation at the site specified 
below, and to conduct the investigation in compliance with this Clinical Investigation Plan (CIP), 
including any amendments thereof, any other study conduct procedures provided by the sponsor 
or their authorized representatives, the principles of Good Clinical Practice (GCP), and applicable 
regulatory requirements. 
• 
Not to implement any deviations from, or changes to, the CIP (including CIP amendments) without 
agreement from the sponsor, prior review and favorable opinion from the Ethics Committee, and 
approval from the Competent Authority, if applicable, except where necessary to eliminate an 
immediate hazard to the subject(s) or for administrative aspects of the clinical investigation (where 
permitted by all applicable regulatory requirements). 
• 
That I am familiar with the appropriate use of the medical devices under investigation as described 
in this CIP and any other information provided by the sponsor including, but not limited to, 
Investigator´s brochure (IB) and the Instructions for Use (IFU). 
• 
To ensure that all persons providing assistance during the clinical investigation are adequately 
informed about the medical devices under investigation and of their investigation-related duties 
and functions. 
• 
That I have been informed that certain regulatory authorities require the sponsor to obtain and 
supply details about the investigator’s ownership interest in the sponsor or the product under 
investigation, and more generally about his/her financial ties with the sponsor. The sponsor will 
use and disclose this information solely for the purpose of complying with regulatory requirements. 
Investigation site: 
 
Address: 
 
 
 
 
 
 
 
Principal Investigator's name: 
 
Principal Investigator's signature: 
 
Date: 
 
 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 5 of 171 
Version 7.0 - 15-MAY-2024 
Investigators and administrative structure of the clinical investigation  
 
Investigators: 
This is a randomized, subject- and evaluator-blinded, controlled, non-inferiority 
multicenter, parallel group comparison study to evaluate effectiveness and 
safety of saypha® VOLUME Lidocaine for midface augmentation in order to 
correct volume deficit, which will be conducted in the USA.  
An updated list of investigation sites and corresponding principal investigators 
will be kept separately from the CIP. 
Sponsor: 
CROMA-PHARMA GmbH 
The sponsor will be responsible for overall implementation and oversight of the 
clinical investigation.  
Sponsor’s address and other contact details are provided on the cover page.  
Other institutions: 
 
This is a contract research organization (CRO), also called sponsor’s 
representative elsewhere in this CIP. The address and other contact details of 
sponsor’s representative are provided on the cover page.  
Contact project management:
 
Contact for reportable events is provided in a separate manual 
An updated list of individuals responsible for various aspects of the investigation 
at sponsor’s representative will be kept separately from the CIP. 
An updated list of all key persons involved in the clinical investigation, including other institutions, if any, 
will be kept and maintained in the Trial Master File (TMF). 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 8 of 171 
Version 7.0 - 15-MAY-2024 
If an optimal aesthetic correction has not been achieved after the baseline 
treatment, as evaluated by the treating investigator, a touch-up treatment 
may be performed at Week 2 (Visit 3) using the same device as initially 
applied at Visit 2. 
At Week 48 (Visit 9 (SV1)) after last treatment of the initial treatment phase, 
subjects of both treatment groups (test device and comparator device) may 
qualify for optional repeat-treatment, which will be done with saypha® 
VOLUME Lidocaine only.  
Screening visits for repeat-treatment will be every 4 weeks up to 12 weeks 
after Visit 9 (SV1). As soon as the subject is eligible in MVDSS score, a full 
eligibility assessment for repeat-treatment will be done. 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. Again, the blinded evaluator at 
the site decides, if subject is eligible for the repeat-treatment (regarding 
MVDSS). 
Visit SV4 (12 weeks after Visit 9 (SV1) at the latest) 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 for repeat-treatment and 
further follow up in screening is not useful because the subject will apparently 
not qualify for repeat-treatment, Visit 9 (SV1), SV2 or SV 3 will be the end of 
study visit for the respective subject. 
Subjects who are eligible and willing to undergo optional repeat-treatment at 
Visit RT1 will enter the repeat-treatment follow-up phase.  
Follow-up visits on-site will occur at:  
• 
Initial treatment phase: Week 2 after baseline treatment, and 2, 4, 8, 
16, 24, 36, 48 weeks after last treatment, i.e., baseline or touch-up 
treatment, respectively (Visits 3 to 9 (SV1)) 
• 
Screening phase for repeat-treatment: Week 4, 8 and 12 after Visit 9 
(SV1) – (Visits SV2 to SV4) 
• 
Repeat-treatment phase: Week 2 after repeat-treatment, and 2, 4, 12 
and 24 weeks after last treatment, i.e., repeat- or touch-up treatment, 
respectively (Visit RT2 to RT5) 
In addition to the on-site follow-up visits, 24-48 hours after each treatment 
the subjects will be contacted by phone for safety checkup. If applicable, the 
incidence, severity, seriousness and type of adverse events resulting from 
device injection will be determined and closely followed up until resolution.  
Midface volume deficit will be evaluated (live assessment) by the blinded 
evaluator at the site using the 5-point MVDSS during follow-up visits of the 
initial and repeat-treatment phases. A central independent blinded 
photographic reviewer will assess the MVDSS for the same time points of the 
initial treatment phase based on photographs taken during the subject´s 
visits. In addition, volume change measurements will be done on 3D 
photographs. 
Severity of nasolabial folds (NLFs) will be assessed using the 4-point 
Nasolabial Folds Severity Rating Scale (NLF-SRS) during intial and repeat-
treatment phases, respectively, at each onsite visit by the blinded evaluator 
at the site (live assessment). 
Subject’s pain perception during treatment and recovery from treatment will 
be evaluated by means of a numerical pain rating scale (NPRS) immediately 
and for 60 min (in 15 minutes intervals) after each device administration.  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 10 of 171 
Version 7.0 - 15-MAY-2024 
the site 
3. 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). 
4. Healthy skin in the midface area and free of diseases that could 
interfere in cutaneous aging evaluation 
5. 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) 
6. Subjects who understand the purpose and conduct of the study and 
having given written informed consent and are willing and able to attend 
the study visits as judged by the investigator 
Exclusion criteria 
(baseline treatment) 
Subjects who meet ANY of the following criteria are NOT eligible for this study 
and must not be enrolled: 
1. Females, who are pregnant and/or, lactating or planning to become 
pregnant during the clinical investigation 
2. History of severe allergies manifested by a history of anaphylaxis or 
history or presence of multiple severe allergies  
3. History of hypersensitivity to hyaluronic acid preparations, lidocaine or 
any amide-based anesthetic 
4. Tendency to keloid formation and/or hypertrophic scars and/ or have 
pigment disorders  
5. Known human immune deficiency virus-positive individuals 
6. Presence of infectious, inflammatory or proliferative cancerous or pre-
cancerous lesions in the treatment area  
7. Re-current (three times a year over the last year) herpes simplex in the 
treatment area  
8. History or presence of any autoimmune or connective tissue disease, or 
current treatment with immuno-modulating therapy 
9. Uncontrolled (or unstable) Diabetes mellitus or systemic diseases as 
per investigator discretion  
10. 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 
11. Implantation of dermal fillers in the treatment area within the preceding 
24 months prior to Visit 1 (Screening) and during the entire investigation 
12. 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 
13. Facial lipolysis, including submental fat treatments, within the previous 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 11 of 171 
Version 7.0 - 15-MAY-2024 
12 months prior to Visit 1 (Screening) and during the entire investigation 
14. Bariatric surgery within 12 months prior to Visit 1 (Screening) and 
during the entire investigation 
15. History of bleeding disorder and/or use of anticoagulant, antiplatelet, 
thrombolytic medication, or anti-inflammatory drugs (oral/injectable 
corticosteroids or non-steroidal anti-inflammatory drugs, e.g.,
 
 or other substances known to increase coagulation time 
(vitamins or herbal supplements, e.g.,
, high doses of 
vitamin E supplements) from ten days pre- to seven days post injection 
(baseline treatment and touch-up treatment) 
16. 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 
17. Beard longer than three-day beard, or excessive facial hair that could 
interfere in evaluation of treatment as judged by the investigator 
18. 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. 
19. 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) 
20. Any medical condition prohibiting the inclusion in the study according to 
the judgment of the treating investigator 
21. Previous enrollment in this clinical investigation 
22. 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 
23. Midface volume deficit due to a congenital defect, trauma, or 
abnormalities in facial adipose tissue distribution such as those 
associated with HIV related lipodystrophy 
24. 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 
25. Any individual whose willingness to volunteer in this clinical 
investigation could be unduly influenced by the expectation, whether 
justified or not, of benefits associated with participation or of retaliatory 
response from senior members of a hierarchy in case of refusal to 
participate (e.g., persons with a legal custodian appointed due to 
mental disability, prisoners, soldiers and other members of the armed 
forces, civil servants). 
26. 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.  
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 12 of 171 
Version 7.0 - 15-MAY-2024 
0BEligibility criteria – Touch-up treatments (TUP1 and TUP2) 
Inclusion criteria 
(touch-up 
treatments) 
A subject must meet ALL of the following criteria to be ELIGIBLE each for 
touch-up-treatment: 
1. Females of childbearing potential must have a negative urine pregnancy 
test  
Exclusion criteria 
(touch-up 
treatments) 
Subjects who meet ANY of the following criteria are NOT eligible for each 
touch-up-treatment: 
1. Occurrence of a related Serious Adverse Event or Adverse Event of 
Special Interest (i.e., embolic events, with possible, probable, or causal 
relationship to an intravascular injection of the device, as changes in 
vision [loss of vision, blurriness, double vision, pain in or around the 
eye, blindness, blind spots, problems moving the eyes], skin changing 
color around the eyelids or around the site of injection, other embolic 
phenomenon, e.g., stroke, skin necrosis, or impending necrosis) during 
or after the previous injections  
2. Subjects who experienced visual changes considered abnormal 
clinically significant or other serious medical conditions during or after 
the previous injections 
3. Subjects who have one of the following assessments during the visual 
examinations: Snellen acuity test worse than 20/40 (with corrective 
eyewear, if applicable), abnormal confrontational visual field test, or 
abnormal ocular motility test.  
Eligibility criteria – Repeat-treatment  
Inclusion criteria 
(repeat-treatment) 
A subject must meet ALL of the following criteria to be ELIGIBLE for repeat-
treatment: 
1. Subjects with bilateral, approximately symmetric moderate to severe 
midface volume deficit (severity scores of 2 or 3 on the 5-point 
MVDSS), as assessed by the blinded evaluator at the site. The subject 
does not have to return to his baseline severity to be permitted to 
receive a repeat-treatment. 
2. Subject has completed initial treatment phase up to Visit 9 (SV1) and is 
willing to attend the study visits of the screening phase for repeat-
treatment and repeat-treatment phase 
3. Females of childbearing potential must have a negative urine 
pregnancy test  
4. Healthy skin in the midface area and free of diseases that could 
interfere in cutaneous aging evaluation 
Exclusion criteria 
(repeat-treatment) 
Subjects who meet ANY of the following criteria are NOT eligible for repeat-
treatment: 
1. Occurrence of a related Serious Adverse Event or Adverse Event of 
Special Interest (i.e., embolic events, with possible, probable, or causal 
relationship to an intravascular injection of the device, as changes in 
vision [loss of vision, blurriness, double vision, pain in or around the 
eye, blindness, blind spots, problems moving the eyes], skin changing 
color around the eyelids or around the site of injection, other embolic 
phenomenon, e.g., stroke, skin necrosis, or impending necrosis) during 
or after the baseline injection and/or touch-up injections 
2. Occurrence of a related Adverse Event that occurred during the initial 
treatment phase, and is ongoing at the time of the repeat treatment (i.e., 
relationship is classified as “possible”, “probable” or “causal 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 13 of 171 
Version 7.0 - 15-MAY-2024 
relationship”; outcome is “not recovered / resolved”, “recovering / 
resolving”, “recovered / resolved with sequelae” or “unknown”)  
3. Subjects who experienced visual changes considered abnormal 
clinically significant or other serious medical conditions during or after 
the baseline or touch-up injections, respectively 
4. Subjects who have one of the following assessments during the visual 
examinations: Snellen acuity test worse than 20/40 (with corrective 
eyewear, if applicable), abnormal confrontational visual field test, or 
abnormal ocular motility test 
5. Subjects who became pregnant since start of the study or planning to 
become pregnant during the clinical investigation 
6. Known human immune deficiency virus-positive individuals 
7. Presence of infectious, inflammatory or proliferative cancerous or pre-
cancerous lesions in the treatment area  
8. Development of re-current (three times a year over the last year) herpes 
simplex in the treatment area since study start 
9. Development of any autoimmune or connective tissue disease since 
study start, or current treatment with immuno-modulating therapy 
10. Development of uncontrolled (or unstable) diabetes mellitus or systemic 
diseases since study start as per investigator discretion  
11. Facial plastic surgery, tissue augmentation with silicone, fat or another 
non-absorbable substance (permanent fillers) and semi-permanent 
fillers (e.g., poly-L-lactic acid) in the area of device application and 
during the initial treatment phase of the investigation 
12. Implantation of dermal fillers (other than the test and comparator device 
used in the investigation) in the treatment area during the initial 
treatment phase of the investigation  
13. Subject has received any of the following aesthetic treatments in the 
midface area: e.g., laser therapy, absorbable and non-absorbable 
sutures (threads), dermabrasion, mesotherapy, micro-needling and/or 
botulinum toxin (including treatment of crow´s feet in the outer eye 
region), or chemical peeling during the initial treatment phase of the 
investigation or is planning to undergo such procedures during the 
repeat-treatment phase of the investigation 
14. Facial lipolysis, including submental fat treatments during the initial 
treatment phase of the investigation  
15. Bariatric surgery during the initial treatment phase of the investigation 
16. Development of bleeding disorder and/or use of anticoagulant, 
antiplatelet, thrombolytic medication, or anti-inflammatory drugs 
(oral/injectable corticosteroids or non-steroidal anti-inflammatory drugs, 
e.g., 
 or other substances known to increase 
coagulation time (vitamins or herbal supplements, e.g., St. John’s Wort, 
high doses of vitamin E supplements) from ten days pre- to seven days 
post injection (repeat-treatment and touch-up treatment) 
17. Planned dental/oral surgery or modification (bridge-work, implants) 
within four weeks prior to the injection and to a minimum of four weeks 
post injection  
18. Any medical condition prohibiting the inclusion for repeat-treatment 
according to the judgement of the treating investigator 
19. Beard longer than three-day beard, or excessive facial hair that could 
interfere in evaluation of treatment as judged by the investigator 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 14 of 171 
Version 7.0 - 15-MAY-2024 
20. Previous enrollment in initial treatment phase of this clinical 
investigation and early termination, or significant incompliance with the 
protocol requirements 
21. Current or previous treatment with another investigational drug and/or 
medical device or participation in another clinical study  
22. Midface volume deficit due to a trauma, or abnormalities in facial 
adipose tissue distribution such as those associated with HIV related 
lipodystrophy 
23. Subjects who experienced weight change for a minimum of 10% since 
study start or subjects who have the intention to change eating habits 
that result in a weight gain or loss >10% during the entire investigation 
24. Subjects with active COVID-19 infection and subjects with symptoms 
consistent with COVID-19 infection including any other respiratory 
symptoms/illnesses within the past 14 days unless tested negative prior 
to Visit RT1  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 17 of 171 
Version 7.0 - 15-MAY-2024 
Secondary 
effectiveness 
endpoints (initial 
treatment phase) 
Global aesthetic improvement based on modified GAIS 
• 
The percentage of subjects with a global aesthetic improvement over 
baseline (at Baseline visit) (subjects who have been rated as “much 
improved” or “improved”), based on subject´s assessment at Week 4, 
8, 16, 24, 36, and 48, after last injection of initial treatment phase using 
the 5-point modified GAIS. 
• 
The percentage of subjects with a global aesthetic improvement over 
baseline (at Baseline visit) (subjects who have been rated as “much 
improved” or “improved”), based on the blinded evaluator`s 
assessment at Week 4, 8, 16, 24, 36, and 48, after last injection of initial 
treatment phase using the 5-point modified GAIS.  
Subject’s satisfaction with outcome and appearance appraisal based on 
FACE-QTM assessments 
• 
The extent of subject´s satisfaction with overall treatment outcome at 
Week 4, 8, 16, 24, 36, and 48 after last injection of initial treatment 
phase as assessed by the subject using the Face-QTM Questionnaire 
“Satisfaction with Outcome”. 
• 
The extent of subject´s appearance appraisal at Week 4, 8, 16, 24, 
36, and 48 after last injection of initial treatment phase as assessed by 
the FACE-QTM questionnaire “Satisfaction with Cheeks” compared to 
Baseline visit. 
Subject´s pain assessment and injection volume 
• 
Subject evaluation of pain after each treatment (baseline and touch-up 
treatment) on an 11-point scale, where 0 is no pain and 10 is the worst 
pain imaginable 
• 
Injection volume required to achieve optimal aesthetic result at each 
treatment (baseline- and touch-up treatment together)  
Other endpoints 
(repeat-treatment 
phase) 
The investigational device during repeat-treatment phase (saypha® 
VOLUME Lidocaine) will be evaluated using the following other 
effectiveness endpoints:  
MVDSS and NLF-SRS  
• 
The percentage of responders on the 5-point MVDSS, based on the 
blinded evaluator´s live assessment at Week 4, 12 and 24 after last 
injection of repeat-treatment phase compared to the score at Visit RT1 
• 
Mean change in midface volume deficit measured on the 5-point 
MVDSS and based on the blinded evaluator´s live assessment at 
Week 4, 12, and 24 after last injection of repeat-treatment phase 
compared to the score at Visit RT1 
• 
Shift from baseline (Visit RT1) in NLF-SRS based on the blinded 
evaluator´s live assessment at Week 4, 12 and 24 after last injection 
during repeat-treatment phase  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 18 of 171 
Version 7.0 - 15-MAY-2024 
Other endpoints 
(repeat-treatment 
phase) 
Subject’s satisfaction with outcome and appearance appraisal based on 
FACE-QTM assessments  
• 
The extent of subject´s satisfaction with overall treatment outcome at 
Week 4, 12 and 24 after last injection of repeat-treatment phase as 
assessed by the subject using the Face-QTM Questionnaire “Satisfaction 
with Outcome” 
• 
The extent of subject´s appearance appraisal at Week 4, 12 and 24 
after last injection of repeat-treatment phase as assessed by the 
FACE-QTM questionnaire “Satisfaction with Cheeks” compared to the 
score at Visit RT1 
Subject´s pain assessment and injection volume 
• 
Subject evaluation of pain after each treatment (repeat and touch-up-
treatment) on an 11-point scale, where 0 is no pain and 10 is the worst 
pain imaginable 
• 
Injection volume required to achieve optimal aesthetic result at each 
treatment (repeat and touch-up treatment together) 
Safety endpoints 
The safety of the investigational device will be evaluated by treatment group 
including cross-over group (in repeat-treatment) and by treatment phase 
using the following endpoints: 
• 
Occurrence and frequency of adverse events during the entire study 
period including repeat-treatment phase (long-term safety). Symptoms 
of interest will be recorded in subject diary during the first 4 weeks (28 
days) after each treatment (i.e., either 4 weeks after baseline and 
repeat-treatment, respectively, and 6 weeks in case of touch-up 
treatment) and documented as AE by investigator. 
• 
Injection site reactions as recorded in the subject diaries during the first 
4 weeks (28 days) after each treatment (i.e., either 4 weeks after 
baseline and repeat-treatment, respectively, and 6 weeks in case of 
touch-up treatment). Injection site reactions will be assessed overall 
and for each side of the midface (i.e., left and right side separately). 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 20 of 171 
Version 7.0 - 15-MAY-2024 
General Statistical 
Considerations and 
Planned Statistical 
Analysis 
General Statistical Considerations 
Unless otherwise specified, all measurements will be summarized 
descriptively at each visit by treatment group .  
In general, continuous variables will be summarized using the following 
descriptive summary statistics: number of observations, arithmetic mean, 
standard deviation, minimum, lower quartile, median, upper quartile, 
maximum. Categorical data will be described using absolute and relative 
frequencies by category. Shift tables will be provided, where appropriate. 
For assessments over time, mean values may be plotted to explore the 
trajectory over time. All descriptive summaries and plots will be based on in-
trial data (i.e., without imputation) unless otherwise specified.  
In addition, estimated treatment differences will be presented together with 
two-sided confidence intervals and corresponding p-values, if appropriate. 
Effectiveness analyses 
The evaluation of the primary and secondary effectiveness endpoint(s) will 
be performed both in the PPS and in the FAS for the initial treatment phase, 
and only for the FAS for the repeat phase. 
• 
For the primary effectiveness endpoint, the PPS and the FAS will be 
both considered equally important for the primary analysis.The analysis 
of the primary effectiveness endpoint will be performed on the PPS 
(primarily) and FAS. Confirmatory testing will be performed in a 
hierarchical ordering. Non-inferiority is demonstrated only if the results 
are consistent for both analysis populations.  
Subjects with missing baseline MVDS score and / or missing MVDS 
score at Week 24 after last injection of the initial treatment phase will be 
considered as non-responders for the primary analysis on the FAS. To 
calculate the primary outcome measure, the improvement over Baseline 
in the MVDS score assessed live by the blinded evaluator at the site at 
Week 24 after last injection of the initial treatment phase by subtracting 
the Midface Scale grade obtained at Baseline. The proportion of 
subjects with MVDS score improvement of ≥1 point will be then 
calculated for each treatment group.  
The primary effectiveness endpoint will be evaluated by means of a 
one-sided two-group Farrington-Manning test of proportions with the 
following hypotheses: 
o 
H0: pA – pB ≤ d0 
o 
H1: pA – pB > d0.  
At this, pA is the response rate for saypha® VOLUME Lidocaine and pB 
is the response rate for
 
 
, and d0=-0.1. Thus, 
a negative value for this difference means that the response rate of 
saypha® VOLUME Lidocaine is lower than the response rate for 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 21 of 171 
Version 7.0 - 15-MAY-2024 
 
The non-inferiority margin is -10%. The study decision will be based on a 
Farrington-Manning-statistics with a one-sided type I error rate level of 
0.025. 
Sensitivity analyses of the primary effectiveness endpoint will be 
performed on the FAS addressing the different reasons for non-
adherence and covering the following aspects to underline the 
robustness of the results: 
o 
Complete case analysis: In this analysis only those subjects will be 
included for whom the primary endpoint could be calculated; 
o 
Subjects with non-allowed concomitant medication / treatments 
before Week 24 after last injection of the initial treatment phase 
may be regarded as non-responder.  
o 
Multiple imputation under MNAR assumption for imputing missing 
MVDS scores at Week 24 assessed live by the blinded evaluator. 
• 
All secondary effectiveness endpoints will be analyzed in an exploratory 
manner by means of descriptive statistics.  
The descriptive tables will show the statistics by time of assessments as 
well as for the changes from baseline (if applicable). Concerning the 
follow-up for initial treatment, the last measurements / assessments  
before first treatment are defined as baseline. Concerning the time after 
repeat-treatment, the measurements / assessments at Visit RT1 before 
first repeat-treatment are defined as baseline.  
Safety analyses  
Safety analyses will be based on the SAF.  
• 
Incidence of AEs will be summarized by Preferred Term and System 
Organ Class, and also by intensity (severity), causal relationship to the 
respective device or procedure, and seriousness.  
• 
The frequency and occurrence rate, maximum intensity, overall 
duration, and seriousness of injection site reactions within four weeks 
(28 days) after baseline treatment, after repeat-treatment injection, 
respectively, and 6 weeks in case of touch-up treatment will be 
summarized by device. 
Analysis of subgroups 
The primary analysis will be based on the total trial population. Besides the 
total study population, the following subgroups will be analyzed by 
descriptive statistical methods for the primary and the main secondary 
effectiveness endpoints: 
• 
Injection equipment: Needle versus cannula  
• 
Gender: Female versus male 
• 
Fitzpatrick skin type 
• 
Race and ethnicity 
• 
Age group 
In addition, incidence of AEs and injection site reactions in will be 
summarized by preferred term (PT) and system organ class (SOC) within all 
of the above-mentioned subgroups. Frequency and occurrence rate 
injection site reactions will be summarized within all of the above-mentioned 
subgroups. 
 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 22 of 171 
Version 7.0 - 15-MAY-2024 
Interim analysis (IA) 
An interim analysis (IA) assessing the safety and effectiveness will be 
performed after all subjects have completed the follow-up visit 48 weeks 
after their last injection during the initial treatment phase (Visit 9 (SV1)). 
 
A schedule of assessments for initial treatment phase is given in Table 1 (Visit 1 to Visit 9 (SV1)) for the 
screening phase for repeat-treatment (SV2 to SV4) in Table 2, and for optional repeat-treatment phase 
in Table 3 (Visit RT1 to Visit RT5).  
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
  
 
 
 
 
 
 
Page 25 of 171 
Version 7.0 - 15-MAY-2024 
* 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-QTM questionnaire “Satisfaction with Outcome” 
8 Evaluation of subject appearance appraisal using the FACE-QTM 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. 
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 (see section 6.3.5). 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 (see Table 
3).  
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 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
  
 
 
 
 
 
 
Page 26 of 171 
Version 7.0 - 15-MAY-2024 
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 (see section 6.3.5) 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 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
  
 
 
 
 
 
 
Page 29 of 171 
Version 7.0 - 15-MAY-2024 
* 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.  
6 Subject satisfaction will be determined using the FACE-QTM questionnaire “Satisfaction with Outcome” 
7 Evaluation of subject appearance appraisal using the FACE-QTM questionnaire “Satisfaction with Cheeks” 
8 
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. 
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) 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
  
 
 
 
 
 
 
Page 30 of 171 
Version 7.0 - 15-MAY-2024 
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 
 
 

 
 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 31 of 171 
Version 7.0 - 15-MAY-2024 
List of abbreviations 
ADE 
Adverse device effect 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AOI 
Anatomical Areas of Interest  
ATC 
Anatomical Therapeutical Chemical 
BDDE 
1,4-butanediol diglycidyl ether  
CDMS 
Clinical Data Management System 
CE 
Conformité Européene (European conformity) 
CI 
Coordinating Investigator 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
COVID-19 
Corona Virus Disease of 2019 
CRO 
Contract Research Organization 
CTR 
Common treatment site responses 
DCP 
Data Cleaning Plan  
DMP 
Data Management Plan 
DRM 
Data Review Meeting 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EU 
European Union 
ExC 
Exclusion criterion 
FAS 
Full Analysis Set 
FST 
Fitzpatrick skin type 
G 
Gauge 
GAIS 
Global Aesthetic Improvement Scale 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Directive  
HA 
Hyaluronic acid 
HIPAA 
Health Insurance Portability and Accountability Act 
IA 
Interim analysis 
IB 
Investigator’s brochure 
ICF 
Informed Consent Form 
IDE 
Investigational device exemption  
IFU 
Instructions for Use 
IMD 
Investigational medical device 
IMDRF 
International Medical Device Regulators Forum 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 32 of 171 
Version 7.0 - 15-MAY-2024 
IRB 
Institutional Review Board  
ISO 
International Organization for Standardization 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
MDD 
Medical Device Directive 
MDR 
Medical Device Regulation  
MedDRA 
Medical dictionary for regulatory activities 
MNAR 
Missing not at random 
MVDSS 
Midface Volume Deficit Severity Scale 
NLF-SRS 
Nasolabial Folds Severity Rating Scale 
NPRS 
Numerical Pain Rating Scale 
PPS 
Per-Protocol Set 
PT 
Preferred term 
RT 
Repeat Treatment 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SDV 
Source data verification  
SOC 
System organ class 
SOI 
Symptoms of interest  
SV 
Screening Visit 
TMF 
Trial master file 
TUP 
Touch-Up Treatment 
US(A) 
United States (of America) 
U(S)ADE 
Unanticipated (serious) adverse device effect 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
US(A) 
United States (of America) 
3D 
Three-dimensional 
 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 33 of 171 
Version 7.0 - 15-MAY-2024 
Glossary 
Definitions of terms used in this Clinical Investigation Plan are in accordance with ISO 14155:2020 if not 
indicated otherwise (e.g., study-specific definitions). Some of the definitions may be defined under 
national regulations. Therefore, there may be the need to check for definitions written down in 
regional / national guidance documents or regulations can:  
Adverse Device Effect 
(ADE) 
Adverse event related to the use of an investigational medical device. 
This definition includes  
- 
adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical 
device.  
- 
any event resulting from use error or from intentional misuse of 
the investigational medical device.  
- 
the ‘comparator’ if the comparator is a medical device. 
Adverse Event (AE) 
An adverse event (AE) is defined as any untoward medical 
occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the test device (IMD) or 
comparator device and whether anticipated or unanticipated. 
This definition includes events related to the test device or the 
comparator and events related to the procedures involved.  
For users or other persons, this definition is restricted to events 
related to the use of test device or comparator device. 
Study-specific addition: AEs initially observed beyond baseline 
treatment or worsening of pre-existing AEs are defined as treatment-
emergent AEs (TEAEs). 
(serious or non-serious) - 
Adverse Events of 
Special Interest (AESI) 
(study-specific definition) 
AESIs are defined as scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor could be 
appropriate. Such events may require further investigation in order to 
characterize and understand them. Depending on the nature of the 
event, rapid communication by the sponsor to other parties may also 
be needed. AEs of special interest are defined in section 14.1. 
Blinded evaluator at the 
site (study-specific 
definition) 
Only responsible for live MVDSS, NLF-SRS and modified GAIS 
evaluations at the site.  
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 until final database lock.  
Blinding  
Blinding is a procedure in which one or more parties to the clinical 
investigation are kept unaware of the treatment assignment(s). This 
clinical investigation is termed ‘evaluator blind’, i.e., at least the 
primary endpoint is assessed without knowledge of whether an IMD 
or comparator has been used to treat a subject. 
Case Report Form (CRF) 
A CRF is a set of printed, optical or electronic documents for each 
subject on which information to be reported to the sponsor is 
recorded, as required by the CIP. 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 34 of 171 
Version 7.0 - 15-MAY-2024 
Central independent 
blinded photographic 
reviewer (study-specific 
definition) 
Person responsible for MVDSS evaluations; will be dislocated from 
the investigation sites and will not discuss any findings with the 
investigators during the investigation 
Clinical Investigation 
The terms ‘clinical trial’ or ‘clinical study’ are synonymous with ‘clinical 
investigation’. 
Clinical Investigation 
Plan (CIP) 
Document that states the rationale, objectives, design and pre-
specified analysis, methodology, organization, monitoring conduct 
and record-keeping of the clinical investigation.  
Study-specific addition: For the purpose of this document “protocol” is 
synonymous with “CIP”.  
Comparator (device) 
Medical device, therapy (e.g., active treatment, normal clinical 
practice), used in the control group in a clinical investigation.  
Coordinating Investigator 
(CI) 
A Coordinating Investigator is appointed by the sponsor to assist in 
coordinating the work in a multicentre clinical investigation. 
Concomitant Treatment 
(study-specific definition) 
All medications taken and non-pharmacological procedures applied 
by a subject during the course of a clinical study. Further details see 
“Prior Treatment”. 
Deviation 
Instance(s) of failure to follow, intentionally or unintentionally, the 
requirements of the CIP. 
Device Deficiency 
A device deficiency is an inadequacy of a medical device with respect 
to its identity, quality, durability, reliability, usability, safety or 
performance.  
Device deficiencies include malfunctions, use errors, and inadequacy 
in the information supplied by the manufacturer including labelling.  
This definition includes device deficiencies related to the test device 
or the comparator device. 
Effectiveness 
Achievement of a clinically significant intended result in a defined 
portion of the target population when the investigational medical 
device is used within its intended uses and according to its 
instructions for use, the investigator’s brochure and the CIP, as 
determined by documented scientific evidence 
Ethics Committee (EC) 
The Ethics Committee (EC) is an independent body whose 
responsibility it is to review clinical investigations in order to protect 
the rights, safety and well-being of human subjects participating in a 
clinical investigation.  
For the purposes of this document, “ethics committee” is synonymous 
with “research ethics committee”, “independent ethics committee” or 
“institutional review board”. The regulatory requirements pertaining to 
ethics committees or similar institutions vary by country or region. 
Independent 
A person not involved in the development of the investigational 
device or the conduct of a clinical investigation, except for their 
specifically assigned responsibilities, in order to avoid bias or a 
conflict of interest. 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 35 of 171 
Version 7.0 - 15-MAY-2024 
Investigational Medical 
Device (IMD) 
Medical device being assessed for clinical performance, effectiveness 
or safety or performance in a clinical investigation. This includes 
medical devices already on the market that are being evaluated 
within their intended use in a post-market clinical investigation 
(interventional or non-interventional). 
Study-specific addition: For the purpose of this document “IMD” is 
synonymous with “test device”.  
Investigator 
An individual member of the investigation site team designated and 
supervised by the Principal Investigator at an investigation site to 
perform clinical-investigation-related procedures or to make important 
clinical investigation-related and medical treatment decisions. An 
individual member of the investigation site team can also be called 
‘sub-investigator’ or ‘co- investigator’.  
Investigator’s Brochure 
(IB) 
Compilation of the current clinical and non-clinical information on the 
investigational medical device(s), relevant to the clinical investigation. 
Institutional Review 
Board (IRB) 
See definition for Ethics Committee. 
Investigation site 
Institution or site where the clinical investigation is carried out. Note: 
“investigation site” is synonymous with “study site”. 
Investigator site file (ISF) 
Binder(s) maintained at the study site containing all regulatory and 
study specific documents. 
Malfunction 
Failure of a medical device to perform in accordance with its intended 
purpose when used in accordance with the instructions for use, IB or 
CIP. 
Medical History (study-
specific definition) 
Medical history includes prior and ongoing concomitant diseases and 
possibly recurring conditions. 
New concomitant diseases, not pre-existing at Screening visit or a 
worsening in the concomitant diseases will be documented as 
adverse event (AE).  
Point of Enrollment 
Time at which, following recruitment but before any clinical 
investigation-related procedures are undertaken, a subject signs and 
dates the informed consent form. 
Principal Investigator (PI) 
The Principal Investigator (PI) is a qualified person responsible for 
conducting the clinical investigation at an investigation site. If a 
clinical investigation is conducted by a team of individuals at an 
investigation site, the PI is responsible for leading the team. Whether 
this is the responsibility of an individual or an institution can depend 
on national regulations. 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 36 of 171 
Version 7.0 - 15-MAY-2024 
Prior Treatment (study-
specific definition) 
All medications (prescription and over-the-counter products) taken 
and non-pharmacological procedures applied prior to Screening Visit 
that was stopped before the first use of the device (at Baseline) is 
classified as 'prior treatment'.  
Treatments used at least once after the first use of a device are 
classified as 'concomitant treatment'. Note, that a treatment classified 
as 'concomitant' could already be taken prior to first application of 
device. 
Randomization 
Randomization is a process of assigning subjects to the test device or 
comparator device using an established recognized statistical method 
using an element of chance to determine the unforeseeable 
assignment in order to reduce bias. 
Serious Adverse Device 
Effect (SADE) 
A SADE is an adverse device effect that has resulted in any of the 
consequences characteristic of a SAE. 
Serious Adverse Event 
(SAE)  
A SAE is an adverse event that led to any of the following 
a) death, 
b) serious deterioration in the health of the subject, users, or other 
persons as defined by one or more of the following: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body 
function including chronic diseases, or 
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening 
illness or injury, or permanent impairment to a body 
structure or a body function, 
c) 
fetal distress, fetal death, a congenital abnormality, or birth defect 
including physical or mental impairment 
Planned hospitalization for a pre-existing condition, or a procedure 
required by the CIP, without serious deterioration in health, is not 
considered a SAE.  
Serious health threat 
Signal from any adverse event or device deficiency that indicates an 
imminent risk of death or a serious deterioration in the health in 
subjects, users or other persons, and that requires prompt remedial 
action for other subjects, users or other persons. This would include 
events that are of significant and unexpected nature such that they 
become alarming as a potential serious health hazard or possibility of 
multiple deaths occurring at short intervals (according to ISO 14155). 
Source Data  
 
Source data are all information in original records, certified copies of 
original records of clinical findings, observations, or other activities in 
a clinical investigation, necessary for the reconstruction and 
evaluation of the clinical investigation. This includes electronic source 
data initially recorded in an electronic format. 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 37 of 171 
Version 7.0 - 15-MAY-2024 
Source Document  
 
Source documents are printed, optical or electronic document 
containing source data. Examples include: Hospital records, 
laboratory notes, device accountability records, photographic 
negatives, radiographs, records kept at the investigation site, at the 
laboratories and at the medico-technical departments involved in the 
clinical investigation. 
Source Records 
Collection of source documents containing source data. 
Sponsor 
Is an individual, company, institution or organization taking 
responsibility and liability for the initiation and management of a 
clinical investigation, and arranging the financial setup. 
Subject 
Is an individual who is or becomes a participant in a clinical 
investigation either as a recipient of the test device or the comparator 
device.  
Treatment (phase)  
(study-specific definition)  
Baseline treatment: Treatment at Visit 2 is defined as “baseline 
treatment”;  
Touch-up treatment 1: Optional treatment at Visit 3 is defined as 
“touch-up treatment 1” (TUP1) 
Initial treatment (phase): Baseline treatment and touch-up treatment 
together are defined as “initial treatment”; The study phase between 
Baseline visit and Visit 9 (SV1) is defined as initial treatment phase. 
For initial treatment either saypha® VOLUME Lidocaine (test device) 
or the comparator device
 
 
 are 
administered (according to randomization of the subject) 
Repeat-treatment (phase): Optional treatment (with saypha® 
VOLUME Lidocaine only) at Visit RT1 is defined as “repeat-
treatment”. The study phase beginning with repeat-treatment at Visit 
RT1 and up to Visit RT5 is defined as repeat-treatment phase. 
Touch-up treatment 2: Optional treatment at Visit RT2 is defined as 
“touch-up treatment 2” (TUP2) 
For repeat-treatment only saypha® VOLUME Lidocaine (test device) 
is administered. 
Treating (unblinded) 
investigator (study-specific 
definition) 
Responsible for all study related assessments and procedures 
(except those allocated to the blinded evaluator at the site and the 
central independent blinded photographic reviewer).  
Trial Master File (TMF) 
Binder(s) maintained at the sponsor’s (CRO´s) office containing all 
regulatory and study specific documents including the essential 
documents according to the ISO-GCP Guideline. 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
An USADE is a serious adverse device effect which by its nature, 
incidence, severity (intensity) or outcome has not been identified in 
the current risk assessment and the current version of the 
Investigator´s brochure (adapted according to ISO 14155) 
Anticipated serious adverse device effect (ASADE) is an effect which 
by its nature, incidence, severity or outcome has been identified in 
the risk assessment. 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 38 of 171 
Version 7.0 - 15-MAY-2024 
For the USA only: 
Unanticipated Adverse 
Device Effect (UADE) 
The investigational device exemption (IDE) regulations define an 
unanticipated adverse device effect (UADE) as “any serious adverse 
effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity (intensity), or 
degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects. (according to investigational 
device exemption (IDE) regulations / 21 CFR 812.3(s)) 
Use error 
A user action or lack of user action while using the medical device 
that leads a different response than that intended by the 
manufacturer or expected by the user.  
Use error includes the inability of the user to complete a task. Use 
errors can result from a mismatch between the characteristics of the 
user, user interface, task or use environment. Users might be aware 
or unaware that a use error has occurred. An unexpected 
physiological response of the subject is not by itself considered a use 
error: A malfunction of a medical device that causes an unexpected 
result is not considered a use error. 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 39 of 171 
Version 7.0 - 15-MAY-2024 
Table of contents 
Approval and signature pages ............................................................................................................. 2 
Coordinating investigator agreement.................................................................................................. 3 
Principal investigator agreement ......................................................................................................... 4 
Investigators and administrative structure of the clinical investigation ......................................... 5 
Synopsis ................................................................................................................................................. 6 
Schedule of procedures and assessments ...................................................................................... 23 
List of abbreviations............................................................................................................................ 31 
Glossary ............................................................................................................................................... 33 
Table of contents ................................................................................................................................. 39 
List of text tables ................................................................................................................................. 45 
1 
Background .................................................................................................................................. 46 
1.1 
Dermal Fillers ............................................................................................................................ 46 
1.2 
Indication and intended use ...................................................................................................... 47 
2 
Identification and description of the investigational devices ................................................. 48 
2.1 
saypha® VOLUME Lidocaine ................................................................................................... 48 
2.2 
 
 ...................................................................................................... 50 
3 
Justification for the design of the clinical investigation ......................................................... 51 
3.1 
Non-clinical data and biocompatibility ...................................................................................... 51 
3.1.1 
saypha® VOLUME Lidocaine .............................................................................................. 51 
3.1.2 
 
 
 ................................................................................................. 51 
3.2 
Clinical data .............................................................................................................................. 51 
3.2.1 
saypha® VOLUME Lidocaine .............................................................................................. 51 
3.2.2 
 
 
 ................................................................................................. 52 
3.3 
Justification for the clinical investigation ................................................................................... 53 
4 
Risks and benefits of the devices and clinical investigation .................................................. 53 
4.1 
Anticipated clinical benefits ....................................................................................................... 53 
4.2 
Anticipated adverse device effects ........................................................................................... 54 
4.2.1 
saypha® VOLUME Lidocaine .............................................................................................. 54 
4.2.2 
 
 
 ................................................................................................. 56 
4.2.3 
Lidocaine hydrochloride ....................................................................................................... 61 
4.3 
Possible interactions with concomitant medical treatments ..................................................... 61 
4.4 
Risk mitigation strategy ............................................................................................................. 61 
4.5 
Risk-to-benefit rationale ............................................................................................................ 63 
5 
Purpose and objectives of the clinical investigation ............................................................... 64 
5.1 
Intended purpose of the clinical investigation ........................................................................... 64 
5.2 
Objectives ................................................................................................................................. 64 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 40 of 171 
Version 7.0 - 15-MAY-2024 
5.2.1 
Primary objective ................................................................................................................. 64 
5.2.2 
Secondary effectiveness and other objectives .................................................................... 64 
5.2.3 
Safety objectives .................................................................................................................. 65 
5.3 
Endpoints: Criteria for evaluation .............................................................................................. 65 
5.3.1 
General information on effectiveness endpoints ................................................................. 65 
5.3.2 
Primary effectiveness endpoint ........................................................................................... 65 
5.3.3 
Secondary effectiveness and other endpoints .................................................................... 66 
5.3.4 
Safety endpoints .................................................................................................................. 67 
5.4 
Risks and anticipated adverse device effects that are to be assessed .................................... 67 
6 
Design of the clinical investigation ............................................................................................ 68 
6.1 
Design description .................................................................................................................... 68 
6.1.1 
Visit Overview ...................................................................................................................... 68 
6.1.2 
Randomization ..................................................................................................................... 71 
6.1.3 
Blinding ................................................................................................................................ 71 
6.1.4 
Discussion of clinical investigation design ........................................................................... 73 
6.2 
Handling and Administration of the medical devices ................................................................ 75 
6.2.1 
Packaging, labelling and storage ......................................................................................... 75 
6.2.2 
Administration (test and comparator devices) ..................................................................... 76 
6.2.3 
Applied volume of the devices ............................................................................................. 80 
6.2.4 
Precautions and warnings for the investigator .................................................................... 80 
6.2.5 
Rescue medication and emergency plan ............................................................................ 82 
6.2.6 
Device accountability ........................................................................................................... 82 
6.2.7 
Handling of deficient devices ............................................................................................... 83 
6.3 
Subjects .................................................................................................................................... 83 
6.3.1 
Number of subjects and duration of the clinical investigation ............................................. 83 
6.3.2 
Recruitment strategy............................................................................................................ 83 
6.3.3 
Eligibility criteria – Baseline treatment ................................................................................. 84 
6.3.4 
Eligibility criteria  – Touch-up treatments (TUP1 and TUP2)............................................... 86 
6.3.5 
Eligibility criteria – Repeat-treatment (with saypha® VOLUME Lidocaine only).................. 86 
6.3.6 
Withdrawal criteria and procedures ..................................................................................... 88 
6.3.7 
Replacement of subjects ..................................................................................................... 88 
6.3.8 
Life-style and other restrictions ............................................................................................ 88 
6.3.9 
Prohibited treatments........................................................................................................... 89 
6.3.10 
Medical care upon termination of the clinical investigation ................................................. 90 
6.3.11 
Screening failures, withdrawals, and completer .................................................................. 90 
6.3.12 
Subject identification, privacy and confidentiality ................................................................ 91 
6.4 
Assessments and procedures .................................................................................................. 91 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 41 of 171 
Version 7.0 - 15-MAY-2024 
6.4.1 
Demographic data ............................................................................................................... 92 
6.4.2 
Fitzpatrick skin types ........................................................................................................... 92 
6.4.3 
Body weight measurement .................................................................................................. 92 
6.4.4 
Pregnancy test ..................................................................................................................... 93 
6.4.5 
Medical history ..................................................................................................................... 93 
6.4.6 
Aesthetic history .................................................................................................................. 93 
6.4.7 
Prior and concomitant treatments (medication and non-pharmacological procedures ) ..... 93 
6.4.8 
Visual examinations ............................................................................................................. 94 
6.4.9 
Neurological examination (F.A.S.T) ..................................................................................... 95 
6.4.10 
Injection volume, injection technique and injection equipment ........................................... 96 
6.4.11 
Clinical photography ............................................................................................................ 96 
6.4.12 
Volume change measurements ........................................................................................... 97 
6.4.13 
Midface Volume Deficit Severity Scale (MVDSS) - Grading of midface volume deficiency 97 
6.4.14 
Nasolabial Folds Severity Rating Scale (NLF-SRS) ............................................................ 99 
6.4.15 
Numeric Pain Rating Scale (NPRS) - Pain assessment ................................................... 100 
6.4.16 
Modified Global Aesthetic Improvement Scale (GAIS) - “Global aesthetic improvement” 100 
6.4.17 
FACE-QTM Questionnaire – “Satisfaction with overall outcome” ....................................... 101 
6.4.18 
FACE-QTM Questionnaire – “Satisfaction with Cheeks” .................................................... 101 
6.4.19 
Subject diary: Injection site reactions and symptoms of interest ....................................... 102 
6.4.20 
Safety monitoring ............................................................................................................... 104 
6.5 
Schedule of procedures .......................................................................................................... 105 
6.5.1 
Visit 1 – Screening (Day -14 up to Day 0) ......................................................................... 105 
6.5.2 
Visit 2 – Baseline (Day 0) .................................................................................................. 106 
6.5.3 
Visit 2a - Telephone Visit (24 to 48 hours (±4 hours) after baseline treatment) ................ 106 
6.5.4 
Visit 3 – Week 2 (after baseline injection) ± 3 days ........................................................... 106 
6.5.5 
Visit 3a - Telephone Visit (24 to 48 hours (±4 hours) after touch-up treatment) ............... 107 
6.5.6 
Visit 3b – Safety follow-up (2 weeks (±3 days) after touch-up treatment) ......................... 108 
6.5.7 
Visit 4 to 8 – Week 4 to Week 36 (after last injection) ....................................................... 108 
6.5.8 
Visit 9 (SV1) – Week 48 (after last injection) ±7days ........................................................ 109 
6.5.9 
Visit SV2 to SV4 – Week 4 to Week 12 after Visit 9 (SV1) ............................................... 109 
6.5.10 
Visit RT1 - Up to 12 weeks after Visit 9 (SV1) ±7days ...................................................... 110 
6.5.11 
Visit RT1a - Telephone Visit (24 to 48 hours days (±4 hours) after repeat-treatment) ..... 111 
6.5.12 
Visit RT2 – Week 2 (after repeat-treatment injection) ± 3 days) ....................................... 111 
6.5.13 
Visit RT2a - Telephone Visit (24 to 48 hours (±4 hours) after touch-up treatment) .......... 112 
6.5.14 
Visit RT2b – Safety follow-up (2 weeks (±3 days) after touch-up treatment) .................... 112 
6.5.15 
Visit RT3 to RT5 - Week 4 to Week 24 (after last injection) .............................................. 112 
6.5.16 
Early Termination Visit ....................................................................................................... 113 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 42 of 171 
Version 7.0 - 15-MAY-2024 
6.5.17 
Unscheduled Visit .............................................................................................................. 113 
6.6 
Factors that may compromise the outcome ........................................................................... 114 
6.7 
Monitoring and Monitoring plan .............................................................................................. 114 
6.8 
Audits and inspections ............................................................................................................ 115 
6.9 
Quality and risk management ................................................................................................. 115 
7 
Statistical considerations ......................................................................................................... 116 
7.1 
Sample size and hypothesis ................................................................................................... 116 
7.2 
Analysed data sets.................................................................................................................. 117 
7.3 
Methods of analysis ................................................................................................................ 117 
7.3.1 
Interim analysis .................................................................................................................. 118 
7.3.2 
Final analysis ..................................................................................................................... 118 
7.3.3 
Subject disposition ............................................................................................................. 118 
7.3.4 
Demographics and baseline characteristics ...................................................................... 118 
7.3.5 
Medical and aesthetic procedures history ......................................................................... 118 
7.3.6 
Prior and concomitant treatments ...................................................................................... 118 
7.3.7 
Effectiveness endpoints ..................................................................................................... 119 
7.3.8 
Safety endpoints ................................................................................................................ 121 
7.3.9 
Multicentre trial .................................................................................................................. 121 
7.3.10 
Analysis of subgroups........................................................................................................ 121 
7.4 
Subject data listings ................................................................................................................ 122 
7.5 
Missing data ............................................................................................................................ 122 
7.6 
Software used for statistical analysis ...................................................................................... 122 
7.7 
Deviations from the planned statistical analysis ..................................................................... 122 
7.8 
Amendments ........................................................................................................................... 122 
7.9 
Randomization ........................................................................................................................ 122 
8 
Data handling and data management ...................................................................................... 122 
8.1 
Source documents and other records maintained by the investigator ................................... 122 
8.2 
Case report forms ................................................................................................................... 122 
8.3 
Data management procedures ............................................................................................... 123 
8.4 
Data retention ......................................................................................................................... 124 
8.5 
Report of the clinical investigation (CIR)................................................................................. 124 
9 
Amendments to the clinical investigation plan (CIP) ............................................................. 124 
10 Deviations from the clinical investigation plan ...................................................................... 124 
11 Device accountability ................................................................................................................ 125 
12 Statements of compliance ........................................................................................................ 125 
13 Informed consent process ........................................................................................................ 125 
14 Adverse events, adverse device effects and device deficiencies ........................................ 126 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 43 of 171 
Version 7.0 - 15-MAY-2024 
14.1 
Definitions ............................................................................................................................... 126 
14.2 
Method of detecting AEs ......................................................................................................... 128 
14.3 
AE/SAE documentation .......................................................................................................... 128 
14.4 
AE assessment ....................................................................................................................... 129 
14.4.1 
Seriousness ....................................................................................................................... 129 
14.4.2 
Intensity ............................................................................................................................. 129 
14.4.3 
Causality ............................................................................................................................ 129 
14.4.4 
Outcome assessment ........................................................................................................ 131 
14.5 
AE/SAE and pregnancy reporting requirements ..................................................................... 131 
14.5.1 
General AE/SAE reporting requirements........................................................................... 131 
14.5.2 
Serious Adverse Events (SAE) and Serious Adverse Device Effects (SADE) reporting .. 132 
14.5.3 
Reporting of visual disturbances ....................................................................................... 132 
14.5.4 
AESIs and other embolic events reporting ........................................................................ 132 
14.5.5 
Pregnancy .......................................................................................................................... 132 
14.6 
AE/SAE and pregnancy follow-up ........................................................................................... 133 
14.7 
Foreseeable AEs and anticipated ADEs ................................................................................ 133 
14.8 
Risk assessment process for potentially unacceptable risks ................................................. 133 
14.9 
Device deficiency .................................................................................................................... 133 
14.9.1 
Device deficiency documentation ...................................................................................... 133 
14.9.2 
Device deficiency reporting requirements ......................................................................... 134 
14.10 Data monitoring committee ..................................................................................................... 134 
15 Vulnerable populations ............................................................................................................. 134 
16 Suspension or premature termination of the clinical investigation ..................................... 134 
16.1 
Clinical investigation stopping rules in case of vascular occlusion ......................................... 134 
17 Publication policy, financing and other agreements ............................................................. 135 
17.1 
Registration and Publication in Publicly Accessible Database ............................................... 135 
17.2 
Scientific Publication ............................................................................................................... 135 
17.3 
Financing ................................................................................................................................ 135 
17.4 
Agreements ............................................................................................................................. 135 
18 Bibliography ............................................................................................................................... 135 
19 Protocol Amendments ............................................................................................................... 138 
19.1 
Protocol Amendment 1 ........................................................................................................... 138 
19.2 
Protocol Amendment 2 ........................................................................................................... 150 
19.3 
Protocol Amendment 3 ........................................................................................................... 153 
19.4 
Protocol Amendment 4 ........................................................................................................... 156 
19.5 
Protocol Amendment 5 ........................................................................................................... 157 
19.6 
Protocol Amendment 6 ........................................................................................................... 165 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 44 of 171 
Version 7.0 - 15-MAY-2024 
20 Annex .......................................................................................................................................... 167 
20.1 
Croma Midface Volume Deficit Severity Scale (MVDSS) ....................................................... 167 
20.2 
Croma Nasolabial Folds Severity Rating Scale (NLF-SRS) ................................................... 168 
20.3 
saypha® VOLUME Lidocaine: Visual instructions how to attach needle / cannula to syringe169 
20.4 
 
: Visual instructions how to attach needle / cannula to syringe .. 170 
20.5 
Assessment of Symptoms of Interest (SOIs) .......................................................................... 171 
20.5.1 
Not Clinically Significant SOIs (examples) ........................................................................ 171 
20.5.2 
Diagnoses resulting from SOI Assessment (examples) .................................................... 171 
 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 45 of 171 
Version 7.0 - 15-MAY-2024 
List of text tables 
Table 1. Schedule of procedures and assessments for the initial treatment phase (Visit 1-to Visit 9 (SV1) 
(all subjects) ........................................................................................................................................... 23 
Table 2. Schedule of procedures and assessments for screening phase for repeat-treatment (Visit SV2 
to SV4) 27 
Table 3. Schedule of procedures and assessments for repeat-treatment phase (Visits RT1 to RT5) .. 28 
Table 4. Description of saypha® VOLUME Lidocaine. ......................................................................... 48 
Table 5. Main components of saypha® VOLUME Lidocaine. ............................................................... 49 
Table 6. Main components of
 ................................................................. 50 
Table 7. Adverse effects of hyaluronic acid dermal fillers[23] ............................................................... 55 
Table 8. Common treatment site responses after initial treatment with 
 as 
reported by the subjects (N=265) in the diary. ...................................................................................... 56 
Table 9. Device- and injection-related adverse events reported by treating investigator and subjects 
occurring in subjects treated with
 (N = 270) ........................................... 57 
Table 10. Common treatment site responses after repeat-treatment with
 
as reported by the subjects (N=167) in the diary (occurring in > 5% of subjects). ................................ 58 
Table 11. Device- and injection-related adverse events reported by treating investigator and subjects 
occurring in > 1% of subjects treated with 
 (N = 167). ............................ 58 
Table 12. Common treatment site responses after treatment with 
 as 
reported by > 5% the subjects (N = 60) in the diary. ............................................................................. 59 
Table 13. Post-market surveillance for 
 with and without Lidocaine with a 
frequency ≥ 5 and were not observed in the clinical studies.[14] .......................................................... 60 
Table 14. Storage and packaging of the devices. ................................................................................. 75 
Table 15. Description of injection technique and injection equipment used in the investigation .......... 77 
Table 16. Administration of saypha® VOLUME Lidocaine and 
 ............... 78 
Table 17. Volume of the devices administered in the clinical investigation per treatment and overall . 80 
Table 18. Fitzpatrick skin types. ............................................................................................................ 92 
Table 19. F.A.S.T. Warning Signs and Instructions for Use (adapted per [27, 28]) .............................. 95 
Table 20. Croma - Midface Volume Deficit Severity Scale (MVDSS) ................................................... 98 
Table 21. Croma - Nasolabial Folds Severity Rating Scale (NLF-SRS) ............................................... 99 
Table 22. Modified Global Aesthetic Improvement Scale (GAIS) ....................................................... 100 
Table 23. FACE-QTM Questionnaire – “Satisfaction with outcome” ................................................... 101 
Table 24. FACE-QTM appearance appraisal scale – “Satisfaction with cheeks”. .............................. 102 
Table 25. Injections site reactions assessment by the subject. .......................................................... 103 
Table 26. Symptoms of interest to be assessed by the subject .......................................................... 104 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 46 of 171 
Version 7.0 - 15-MAY-2024 
1 
Background  
1.1 
Dermal Fillers 
Age is the most significant factor contributing to the overall change in the appearance of an individual’s 
face over time. The young face is full and rounded, especially in the upper and middle parts, and 
perceived as healthy. Facial aging is a multifactorial process including thinning of the skin, decreased 
skin elasticity, collagen degradation, bone resorption, and fat pad atrophy. During the ageing process, 
midface tissues lose volume, the excess of cheek skin occurs and as a result flattening and furrowing of 
the mid-cheek is observed. The face is no longer perceived as young but as sad, heavy, and long.[1] 
Perception of age and health is critical in the judgement of attractiveness. Forming an impression in 
other humans about facial attractiveness is fast, automatic and mandatory, and impacts impressions of 
other social traits of a person with real-world consequences.[2] 
Attractiveness influences both the self-perception and behaviour toward others and is related to traits 
such as self-confidence and social acceptance. It is not surprising, therefore, that aesthetic interventions 
can improve the psychological well-being and quality of life in people who elect to undergo such 
procedures due to aging. Common positive changes include increased satisfaction with self-
appearance, reduced depression or anxiety, improved emotional well-being and increased self-
confidence.[3]  
Dermal fillers are used for facial rejuvenation and correction of deep wrinkles (e.g., nasolabial folds) and 
also to correct midface volume deficits. These treatments provide desirable aesthetic outcomes with 
minimal invasiveness and without the downtime associated with surgery.  
Hyaluronic acid 
Hyaluronic acidis a naturally occurring glycosaminoglycan that consists of repeating non-sulfated 
disaccharide units of glucuronic acid and N-acetylglucosamine. It is an essential component of the 
animal and human extracellular matrix, present in all tissues, most abundantly in the skin. Hyaluronic 
acid has a considerable water-binding capacity, and by this mechanism it increases dermal volume and 
compressibility.[4] Furthermore, it stimulates collagen synthesis and up-regulation of elastin, possibly by 
mechanical stretching of the skin, which in turn leads to stretching and activation of dermal fibroblasts.[5] 
Hyaluronic acid is degraded by enzymatic depolymerization via hyaluronidases and oxidation by free 
radicals. Native chains have a short half-life of 24-48 h, which may be significantly extended by cross-
linking of the chains. The most commonly used cross-linking agent is 1,4-butanediol diglycidyl ether 
(BDDE). The cross-linked hyaluronic acid is degraded via the same mechanisms as native chains, but 
at a much slower rate, extending the clinical effect of BDDE-cross-linked hyaluronic acid for up to one 
year.[6] 
Hyaluronic acid dermal filler for aesthetic use  
Soft tissue fillers are nowadays widely used for smoothing skin wrinkles and folds, and volumizing facial 
contours. Various fillers are available on the market, but hyaluronic acid (HA) gels are most popular 
because of their versatility, ease of administration, predictable effectiveness, safety track record 
established during decades of use, and quick subject recovery after administration.[1, 7]  
Since the launch of the first BDDE-cross-linked hyaluronic acid dermal filler for aesthetic use in Europe 
in 1996, over 50 clinical studies have been conducted with this type of medical device, which included 
more than 9,000 subjects.[6] Hyaluronic acid gels are currently considered as the gold standard for 
dermal fillers and are widely used in aesthetic dermatology for facial rejuvenation and re-contouring, 
with a remarkable track record of performance and safety.[5] Over time, their use was extended to 
medical reconstructive purposes in the treatment of pathologic conditions such as facial lipoatrophy, 
morphologic asymmetry of the face, and depressed scars.  
Lidocaine hydrochloride 
In order to improve the comfort of filler injections, novel formulations containing a local anaesthetic, 
lidocaine hydrochloride, have been developed to reduce procedural pain and to bypass the need for 
additional anaesthesia.[8] 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 47 of 171 
Version 7.0 - 15-MAY-2024 
Lidocaine hydrochloride is a well-known local anaesthetic, which has been in clinical use for over 60 
years. It is currently one of the most widely used local anaesthetics. Lidocaine exerts its anaesthetic 
effects by blocking fast voltage-gated sodium channels in the cell membrane of postsynaptic neurons, 
which prevents depolarization and inhibits the generation and propagation of nerve impulses.[9]  
When used for infiltrative anaesthesia, lidocaine hydrochloride has fast onset of action (< 2min) and 
moderate duration of effect lasting 1.5-2 h.[10] Absorbed lidocaine is metabolized in the liver and 
eliminated via the kidneys with a half-life of around 90 minutes.[11] Lidocaine is generally well tolerated 
and safe. Adverse reactions are rare and usually result from high plasma concentrations due to 
accidental intravascular injection, excessive dosage (>400 mg), or rapid absorption from highly vascular 
areas. Early symptoms of toxicity include a metallic taste, tinnitus, light-headedness, and confusion, and 
may be followed by tremors, shivering, seizures and, ultimately, respiratory arrest. Cardiovascular 
toxicity may be manifested by hypotension, bradycardia, arrhythmia and cardiac arrest.[10], [11]  
In soft tissue fillers the addition of lidocaine hydrochloride reduces pain and distress and provides a 
more comfortable injection experience.[12] The performance and safety of hyaluronic acid dermal fillers 
supplemented with lidocaine hydrochloride have been studied in several randomized clinical trials, which 
were mostly designed as split face trials, where the same dermal filler was administered with and without 
ancillary lidocaine. A detailed analysis of nine randomized clinical trials with the equivalent devices 
 has confirmed a statistically significant reduction in pain with 
formulations which contained lidocaine. The pain reduction was consistent across the studies, and 
present irrespective of the dermal filler tested. The frequency and severity of adverse events (AEs) was 
not different for dermal fillers with or without lidocaine, indicating no incremental safety risk.[13] 
saypha® VOLUME Lidocaine – the test investigational medical device (IMD) - is an injectable hyaluronic 
acid gel implant produced by CROMA-PHARMA GmbH in Austria.
 
 
 (known 
as
 with Lidocaine in Europe[14]) was chosen as comparator device.  
The indication for saypha® VOLUME Lidocaine to be studied in this clinical investigation is correction of 
moderate to severe midface volume deficit. There are no known data for use of saypha® VOLUME 
Lidocaine for bilateral midface augmentation available yet. However, there have been a few studies 
published over the last 2 years using hyaluronic acid fillers aimed at restoring midface volume. Jung et 
al. investigated in a total of 88 subjects with moderate to severe age-related midface volume deficit to 
evaluate the efficacy and safety of
 Volume Lidocaine compared to 
. The results 
showed that
 Volume Lidocaine was not inferior to
 in temporarily restoring midface 
volume at 24 weeks after treatment with all ADEs being mild or moderate in severity.[15] 
Jones et al. evaluated the safety and efficacy of large gel particle hyaluronic acid with lidocaine. Sixty 
subjects with mild to substantial loss of midface fullness were treated to optimal correction; improvement 
in the Global Aesthetic Improvements Scale (GAIS) were reported for the majority of subjects (≥98.3% 
for investigator-assessed and ≥91.5% for subject-assessed) for up to 16 weeks. At 8 weeks, the Medicis 
Midface Volume Scale responder rate was 100% and subject satisfaction scores (5/6 questions) in the 
FACE-QTM were ≥91.5%. Only five AEs were reported in this study, with one being considered injection 
procedure-related (mild presyncope). No serious AEs were reported.[16]  
Moreover, Huh et al. conducted a randomized, active-controlled, 52-week study of hyaluronic acid fillers 
 in one side and 
 for anteromedial malar region 
augmentation. The HA fillers injected maintained the volume well for up to 52 weeks in the anteromedial 
malar augmentation. Additionally, both 
 showed similar effectiveness and safety 
profiles.[17] 
1.2 
Indication and intended use 
The saypha® VOLUME Lidocaine device is not yet approved in the US, while in Europe (and other 
countries worldwide) the label is stating the following (approved labeling incl. EU, dated 06/2020; [18]):  
o 
The device saypha® VOLUME Lidocaine is indicated to correct moderate to severe nasolabial 
folds. It is indicated to be injected into the deep dermis or subcutis  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 48 of 171 
Version 7.0 - 15-MAY-2024 
o 
The intended purpose of the device is to create volume in order to correct wrinkles and folds 
and to correct moderate to severe nasolabial folds to treat signs of ageing. 
Within this clinical investigation (CPH-301-201417) the device will be used for midface augmentation 
in order to correct moderate to severe volume deficit. Saypha® VOLUME Lidocaine is to be administered 
by injection into the zygomaticomalar region, anteromedial cheek region and submalar region. The 
device has to be administered by subcutaneous and/or supraperiosteal injection.[46] 
 
 
 is indicated for injection for cheek augmentation to correct age-related 
volume deficit in the midface and for augmentation of the chin region to improve the chin profile in adults 
over the age of 21. The device is administered by deep (subcutaneous and/or supraperiosteal) 
injection.[14] 
In this clinical investigation, both medical devices will only be used to treat midface volume deficit.  
2 
Identification and description of the investigational devices 
2.1 
saypha® VOLUME Lidocaine  
The following text gives a summary on the characteristics of the test device. Refer to the saypha® 
VOLUME Lidocaine Investigator’s brochure (IB) for detailed information on the test device.[46] 
Note: saypha® VOLUME Lidocaine and Princess® Volume Lidocaine are the same product marketed 
under different brand names in different countries. For consistency, the brand name of saypha® 
VOLUME Lidocaine will be used in this CIP. 
Device description 
Table 4 shows the main characteristics of saypha® VOLUME Lidocaine and Table 5 tabulates the single 
components of saypha® Volume Lidocaine.  
Table 4. Description of saypha® VOLUME Lidocaine.  
Saypha® VOLUME Lidocaine 
• is a class III medical device FA incorporating the ancillary medicinal substance lidocaine hydrochloride as an integral 
part 
• is a sterile, biodegradable, viscoelastic, clear, transparent, isotonic, and homogenized and injectable gel implant 
provided in pre-filled 1 mL glass syringes for subcutaneous and/or supraperiosteal injection 
• is designed for single use. No materials of human or animal origin are used during manufacture or as raw materials; 
Moreover, the non-animal origin reduces any potential for hypersensitivity. 
• In general, HA fillers are degraded. They may provide volume for a period of four to twelve months after treatment 
before undergoing degradation.[20] For the test device the lifetime is anticipated to last up to nine months after 
treatment. 
 
 
 
 
A Classification according to its field of application (MDD 93/42/EEC, Annex IX; Class III rule 8: 
implantable device which is wholly or mainly absorbed; and rule 13: incorporating, as an integral part, 
an ancillary medicinal product. The conformity assessment route complies with MDD 93/42 Annex II.3. 
(Quality System) and Annex II.4. (Design Examination for Class III Medical Devices).  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 49 of 171 
Version 7.0 - 15-MAY-2024 
Table 5. Main components of saypha® VOLUME Lidocaine. 
Component 
Concentration 
Description 
Hyaluronic acid (HA) 
(Sodium hyaluronate) 
23 mg/g (2.3%) 
• 
HA, a natural polysaccharide, is obtained from Streptococcus 
equi bacteria is highly cross-linked using 1,4-Butanediol 
Diglycidyl Ether (BDDE) 
• 
BDDE covalently binds native HA molecules to each other 
with repeating bridges, creating a polymer ‘network’, 
transforming the viscous liquid into a gel.  
• 
Compared with native HA, the highly crosslinked HA gel is 
considerably more resistant against enzymatic and free 
radical breakdown, so that its tissue residence time is 
dramatically increased.  
• 
Native HA is added in order to adjust the rheological 
properties and injectability of the fillers.  
• 
HA is a natural component of human skin, hence the device is 
naturally absorbed and excreted by the liver. 
Lidocaine hydrochloride  
3 mg/g (0.3%) 
• 
Lidocaine hydrochloride (a medicinal product) is a well-known 
local anesthetic; it is added to saypha® VOLUME Lidocaine 
as an ancillary substance for reduction of procedural pain and 
to improve the comfort of filler injections thus bypassing the 
need for additional anesthesia  
• 
Lidocaine hydrochloride is rapidly released from the implant 
and quickly eliminated from the body, with a half-life of around 
90 minutes.[11] 
 
Manufacturing of saypha® VOLUME Lidocaine 
saypha® VOLUME Lidocaine is manufactured in compliance with applicable Regulatory Requirements 
according to MDD 93/42/EEC (see section 10 of the IB for complete listing [46]).  
All steps of the device preparation (design, manufacture, primary packaging, secondary packaging, 
labelling inspection, final inspection, moist heat sterilization, and release) are performed at the facilities 
of CROMA-PHARMA GmbH, Industriezeile 6, 2100 Leobendorf, Austria, in accordance with EN ISO 
13485:2016.  
Needles and cannulas for application  
• 
The device is delivered with two sterile single use needles (27G ½’’) per syringe. The needles are 
Ethylene oxide sterilized; they are medical devices according to their field of application, under class 
IIa (MDD 93/42/EEC, Annex IX, rule 6). The CE manufacturer is
 
. 
• 
 25G 1½” cannulas may be used (will be provided by the sponsor´s 
representative). 
Regulatory status 
• 
EU: saypha® VOLUME Lidocaine received the CE mark in 2016 in compliance with the COUNCIL 
DIRECTIVE 93/42/EEC (Medical Device Directive, MDD). Saypha® VOLUME is marketed in the 
European Union (EU). 
• 
USA: saypha® VOLUME Lidocaine is not approved for use in the USA yet. 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 50 of 171 
Version 7.0 - 15-MAY-2024 
2.2 
 
 
  
General information 
 
 
 was chosen as comparator device. The following text gives a summary on 
the characteristics of the comparator device. Detailed information on the comparator device
 
 is given in the current IFU (dated 06/2020).[14]  
Table 6 shows the main components and main characteristics of
 
: 
Table 6. Main components of
  
 
  
• 
20 mg/mL crosslinked HA in a physiologic buffer; obtained from Streptococcus equi bacteria 
• 
0.3% (w/w) lidocaine hydrochloride 
  
• 
is a class III medical device incorporating the ancillary medicinal substance lidocaine hydrochloride as an integral 
part 
• 
is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, colorless, homogenized gel implant pre-filled in 2x1 mL 
syringes (made of Cycloolefin-Copolymer [COC polymer]) and four 27G ½” needles 
• 
The contents of the syringe are sterile and non-pyrogenic.  
Manufacturer 
• 
 
• 
 
 
Needles and cannulas for application  
• 
The device is delivered with four 27G ½” needles. The CE manufacturer is
 
 
 
 25G 1½” cannula may be used (will be provided by the sponsor´s 
representative). Note: The safety and effectiveness of cannula injection of 
 
 has only been clinically evaluated with the 
 25G 1½” cannulas 
Note: The device may be injected with a 25G 1” needle according to the IFU.[14] However, use of 
other needles than 27G ½” is not allowed within this clinical investigation  
Regulatory status 
• 
EU: 
 is commercially available in the European Union (EU) known as 
with Lidocaine, which is CE certified (CE 0549) in accordance with the 
Medical Device Directive (93/42/EEC). 
• 
USA: 
 is commercially available in the United States (see section 1.2). 
It has been marketed in the USA since 2013. It is also approved for midface-injection via 
cannula.[14]  
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 53 of 171 
Version 7.0 - 15-MAY-2024 
Details and results for all above-mentioned studies are summarized in the IFU.[14] 
Post-market surveillance 
Adverse events that were received during post-market surveillance are summarized in section 4.2.2. 
Details are given in the IFU.[14] 
Literature  
Several clinical data from published clinical studies confirmed the effectiveness and safety profile in 
treating midface volume deficit.[21, 22] 
3.3 
Justification for the clinical investigation 
In the present clinical investigation, saypha® VOLUME Lidocaine (test device) and 
 
 (comparator device) will be used for correction of moderate to severe volume deficiency 
of the midface. There are no known data for use of saypha® VOLUME Lidocaine for bilateral midface 
augmentation available yet. However, depending on the following non-clinical and clinical data, the 
investigation is justified:  
• 
Non-clinical biocompatibility studies have confirmed that saypha® VOLUME Lidocaine was well 
tolerated and with only a slight reaction observed in the implantation study (also see section 3.1.1 
for details).  
• 
saypha® VOLUME Lidocaine received the CE mark in compliance with the COUNCIL DIRECTIVE 
93/42/EEC (Medical Device Directive, MDD) in 2016.  
• 
Two clinical studies for the correction of nasolabial folds (CPH-401-201258, ‘VINO’ and CPH-101-
201477, ‘SAVINO’) were conducted. Saypha® VOLUME Lidocaine was shown to be effective (i.e., 
indicating a general improvement in the NLF severity rating scale grading) and was deemed safe 
and well tolerated (see section 3.2.1 for details). 
• 
Safety data are also available from post-market surveillance since market entry in 2016 confirming 
the favourable risk/benefit ratio for the device. No new adverse reactions were found in the 
complaints listing. In addition, post-market surveillance and complaints from competent authority 
data did not reveal new adverse reactions and events (see section 3.2.1 for details). 
The comparator device, 
 
 
, has a well-established record of safety and 
effectiveness and is approved for marketing for correcting volume deficit in the midface and hence an 
appropriate comparator as a positive control in this non-inferiority study design (see section 3.1.2 and 
section 3.2.2 for summaries, and IFU [14] for details).  
Overall, non-clinical and clinical data indicate that both devices are well established. In addition, the 
assessment is based on a sufficient number of treatments.  
4 
Risks and benefits of the devices and clinical investigation 
4.1 
Anticipated clinical benefits 
The treatment with saypha® VOLUME Lidocaine may remove or reduce a distressing aesthetic defect 
in subjects with volume deficiency of the midface (“none/minimal” to “very severe” volume deficit of the 
midface, see section 6.4.13), thereby improving their psychological and social wellbeing. 
This is achieved by a minimally invasive procedure with a short downtime. The treatment will correct 
volume in the midface area immediate and a long-lasting effect is anticipated to last up to nine months 
after treatment.[46] 
The comparator device, 
 
 
 is approved by the FDA for the treatment of 
condition under investigation (including the use of cannula) and was shown to be effective and safe over 
years.[14] 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 54 of 171 
Version 7.0 - 15-MAY-2024 
4.2 
Anticipated adverse device effects 
In general, physicians must inform the subject that there are potential side effects and/or incompatibilities 
associated with implantation of this device, which may occur immediately or may be delayed.  
 
The anticipated ADEs for saypha® VOLUME Lidocaine are given in the current version of the IB.[46] 
Safety data are available from two clinical studies, post-market surveillance (given in section 3.2.1) and 
from observations with devices similar to saypha® VOLUME Lidocaine. These are summarized in the 
following paragraphs.  
Post-market study (CPH-401-201258, VINO) 
‘VINO’ (CPH-401-201258) was a prospective, open label, multicentre, post-marketing clinical follow-up 
study evaluating Princess® VOLUME LidocaineFB for the correction of nasolabial folds. Overall, 62 
subjects were included in the investigation, 61 of whom completed the investigation. A total of twelve 
subjects (19.4%) reported 18 AEs.  
All 18 reported AEs were mild, and none of the AEs were judged by the investigator to have a definite, 
probable, or possible relationship to the investigational medical device. Ten AEs reported by eight 
subjects (12.9%) had a definite (nine AEs) or probable (one AE) relationship to the procedure and were 
classified as adverse device effects (ADEs) according to the sponsor’s assessment.  
The reported ADEs included injection site hypoesthesia (six subjects), injection site pain (two subjects), 
injection site hematoma (one subject), and syncope (one subject). All ADEs were mild and had resolved 
within a maximum of 13 days of their onset. General disorders and administration site disorders were 
the most frequently reported AEs. Injection site hypoesthesia and injection site pain were the only AEs 
reported by more than one subject. No AEs were assessed as serious, and no deaths occurred in the 
investigation. 
SAVINO study (CPH-101-201477) 
SAVINO (CPH-101-201477) was a prospective, randomized, multicenter study evaluating saypha® 
VOLUME Lidocaine for the correction of NLFs. 
A total of 39 TEAEs was reported in 30 of 109 subjects (28%). 3 of the TEAEs were SAEs (appendicitis, 
vertebral foraminal stenosis and intervertebral disc protrusion) which were considered to be not related 
to the device or procedure. All other TEAEs were non-serious, 15 of them were local TEAEs, mainly of 
mild intensity. 14 of the 15 TEAEs were considered to be related to IMD (definite N=2 and probable N=8) 
and/or to procedure (definite N=6 and probable N=6).  
All local TEAEs belonged to the system organ class ‘general disorders and administration site conditions’ 
according to MedDRA. The most frequently patient reported terms according to MedDRA class were 
‘administration site pain’ and ‘injection site pain’ (3%, each), followed by ‘administration site hematoma’ 
and ‘administration site swelling’ (1%, each). All non-local TEAEs were considered not related to IMD or 
procedure. Most of the TEAEs had ‘resolved’ at the end of the investigation. The low number of mainly 
mild local TEAEs, considered to be related to IMD and/or to procedure was clearly lower than generally 
described in the literature. No other clinically relevant observations related to safety raised any concerns 
and no specific risks or precautions were required to be mentioned over those already known and 
described.[46] 
 
 
 
 
B Note: saypha® VOLUME Lidocaine and Princess® Volume Lidocaine are the same product marketed 
under different brand names in different countries. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 55 of 171 
Version 7.0 - 15-MAY-2024 
 
Overview: Adverse effects of hyaluronic acid dermal fillers 
Adverse effects of hyaluronic acid dermal fillers  are described in detail in the IB for saypha® VOLUME 
Lidocaine [46] and are summarized in Table 7.  
Table 7. Adverse effects of hyaluronic acid dermal fillers [46]  
Commonly reported treatment 
related AEs  
(also refer to Section 8.2.1 of the IB) 
Rare AEs  
 
(also refer to Section 8.2.2 of the IB) 
Very rare (S)AEs  
 
(refer to Section 8.2.3 of the IB) 
• Bruise/contusion (incl. hematoma) 
• Hemorrhage/bleeding (incl. 
ecchymosis) 
• Hypoesthesia (incl. numbness) 
• Itching sensation 
• Medical device site induration (incl. 
firmness) 
• Pain (incl. discomfort, tenderness, 
sensitivity to hot/cold liquids and 
foods) 
• Skin discoloration (incl. 
discoloration, dyspigmentation, 
erythema, redness, telangiectasia) 
• Skin inflammation/irritation 
• Subcutaneous nodule (incl. implant 
site mass (beading, lumpiness) 
implant visibility)  
• Swelling/edema (incl. malar edema) 
• Tactile disorder 
• Angioedema  
• Device dislocation  
• Dizziness (incl. vasovagal reaction 
during injection)  
• Malaise  
• Nausea  
• Nerve damage  
• Paresthesia  
• Peeling  
• Puncture marks 
• Presyncope  
• Rash   
• Sebaceous hyperplasia  
• Skin burning sensation  
• Skin disorders (incl. scar 
sarcoidosis, scleroderma, 
scleromyxedema)  
• Vasculitis  
For more details refer to section 8.2.2 
of the IB 
• Abscess  
• Bacterial infection  
• Capsular contracture  
• Fever  
• Fibrosis  
• Granuloma 
• Headache  
• Physical asymmetry 
• Herpes simplex reactivation  
• Hypersensitivity/allergic reaction 
• Syncope/fainting  
• Vascular obstruction/occlusion (incl. 
changes in vision, stroke, skin 
changing color or crusty or scabby 
skin around the eyelids, 
vasospasm, white appearance (or 
blanching) of the skin)  
• Vasoconstriction  
 The following very rare device-related 
serious AEs have been reported after 
use of the device or similar devices: 
• Necrosis  
• Vascular compromise/arterial 
occlusion  
• Retinal artery occlusion  
For more details refer to section 8.2.3 
of the IB. 
These minor AEs are commonly 
reported after the treatment procedure 
and are typically managed with the 
application of ice. 
These events are typically mild in 
intensity and should resolve within 
one to two days after injection. 
For more details refer to section 8.2.1 
of the IB. 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 57 of 171 
Version 7.0 - 15-MAY-2024 
Table 9. Device- and injection-related adverse events reported by treating investigator and subjects occurring in subjects 
treated with
 (N = 270)  
Adverse Event  
Treated Subjects  
% (n) 
> 1% of subjects 
Treatment site mass  
18.9% (51/270) 
Treatment site induration  
14.1% (38/270) 
Treatment site swelling  
7.0% (19/270) 
Treatment site pain  
5.9% (16/270) 
Treatment site hematoma  
3.7% (10/270) 
Treatment site discoloration  
2.2% (6/270) 
Treatment site erythema  
1.9% (5/270) 
Treatment site reaction  
1.5% (4/270) 
≤ 1% of subjects 
Injection site hypertrophy, nodule 
0.7% [each AE] 
Inflammation, injection site anesthesia, injection site dryness, injection site erosion, mass, 
contusion and syncope 
0.4 % [each AE] 
N = number of subjects who device- and injection-related adverse events after the initial treatment. 
n = number of subjects treated. 
These AEs were seen more frequently in subjects that received injection volumes greater than 9 mL, 
and in subjects older than 60 years of age.  
Two subjects (0.7%; 2/270) reported 3 serious adverse events (SAEs) that were considered to be related 
to the device (see IFU for details). 
Among the 270 subjects treated, 32.6% (88/270) experienced device- and injection-related AEs 
following initial and touch-up treatment. Of these 99% (624/627) were reported at a treatment site. 
Information on AEs following repeat-treatment was collected as part of the post-approval study (see 
below). 
Post-approval study: One-Year Post-Approval Study of 
 for Cheek 
Augmentation 
Safety data from subjects who underwent repeat-treatment with
 as part of 
the pivotal study were analyzed. Again, CTRs were reported by the subjects within the pre-printed 
subject´s diary for 30 days after repeat-treatment. Data are summarized in Table 10.  
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 58 of 171 
Version 7.0 - 15-MAY-2024 
Table 10. Common treatment site responses after repeat-treatment with
 as reported by the 
subjects (N=167) in the diary (occurring in > 5% of subjects).  
Common Treatment Site Response 
% (n) 
Any Treatment Site Response 
90.1% (146/162) 
Tenderness 
76.5% (124/162) 
Swelling 
67.9% (110/162) 
Firmness 
67.9% (110/162) 
Bruising 
62.3% (101/162) 
Lumps/Bumps 
58.0% (94/162) 
Redness 
56.8% (92/162) 
Pain 
54.9% (89/162) 
Itching 
32.7% (53/162) 
Discoloration 
26.5% (43/162) 
N=number of subjects who recorded responses in the diaries after the repeat-treatment. 
n= number of subjects who experienced responses after the repeat-treatment. 
The incidence of treatment site responses after repeat-treatment was lower than the incidence after 
initial/touch-up treatment. The reported treatment site responses were generally less severe and shorter 
in duration after repeat-treatment compared to initial/touch-up treatment (usually resolved within 2 
weeks).  
Again, treatment site responses reported in subject diaries lasting longer than 30 days were considered 
AEs and, where applicable, other AEs were reported by the treating investigator at all follow-up visits. 
These device- and injection-related AEs are summarized in Table 11. 
Table 11. Device- and injection-related adverse events reported by treating investigator and subjects occurring in > 1% of 
subjects treated with 
 (N = 167).  
Adverse Event  
Treated Subjects  
% (n) 
Total 
8.4% (14/167) 
Injection site mass  
4.2% (7/167) 
Injection site induration  
4.2% (7/167) 
Injection site bruising 
1.2% (2/167) 
N = number of subjects who device- and injection-related adverse events after the repeat-treatment. 
n = number of subjects treated. 
Device/injection-related AEs were lower and less severe after repeat-treatment compared to 
initial/touch-up treatment. Most of those AEs resolved within three months. There were no 
device/injection-related SAEs after repeat-treatment.  
Cannula study for cheek augmentation 
At total of 60 subjects seeking correction of age-related midface volume deficit underwent treatment in 
a randomized, within-subject, controlled clinical trial to evaluate the safety and effectiveness of 
C using a 
 25G 1½” cannula in one cheek and a needle 
in the other cheek. Again, the subjects completed a pre-printed diary forms for 30 days after treatment. 
These device- and injection-related AEs are summarized in Table 12. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 59 of 171 
Version 7.0 - 15-MAY-2024 
Table 12. Common treatment site responses after treatment with
 as reported by > 5% the 
subjects (N = 60) in the diary.  
Common Treatment Site Response 
Cannula % (n) 
Needle % (n) 
Any Treatment Site Response 
100.0% (60/60) 
100.0% (60/60) 
Tenderness to touch 
91.7% (55/60) 
96.7% (58/60) 
Firmness 
83.3% (50/60) 
90.0% (54/60) 
Swelling 
81.7% (49/60) 
85.0% (51/60) 
Lumps/Bumps 
70.0% (42/60) 
83.3% (50/60) 
Pain after injection 
66.7% (40/60) 
83.3% (50/60) 
Bruising 
60.0% (36/60) 
71.7% (43/60) 
Redness 
55.0% (33/60) 
61.7% (37/60) 
Discoloration 
36.7% (22/60) 
43.3% (26/60) 
Itching 
18.3% (11/60) 
20.0% (12/60) 
N=number of subjects who recorded responses in the diaries after the repeat-treatment. 
n= number of subjects who experienced responses after the repeat-treatment. 
All subjects reported experiencing a local treatment site response after treatment with 
 
. Subjects rated treatment site responses as being mostly mild or moderate in severity 
(about 90% for cannula and needle, respectively). About 60% of the treatment site responses resolved 
within 2 weeks.  
Post-Market Surveillance for 
 
 
 with and without Lidocaine 
The events listed in Table 13 were received from post-market surveillance for 
 
with and without lidocaine with a frequency ≥5 and were not observed in the clinical studies (during the 
6-13 months that subjects were monitored in the chin and cheek studies, respectively); this includes 
reports received globally from all sources including scientific journals and voluntary reports. Note, that 
 without lidocaine has been marketed outside the USA since 2005.[14] 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 60 of 171 
Version 7.0 - 15-MAY-2024 
Table 13. Post-market surveillance for 
 with and without Lidocaine with a frequency ≥ 5 and were 
not observed in the clinical studies.[14]   
Note: AEs are listed in order of number of reports received. 
• Inflammatory reaction 
• Lack of correction 
• Infection 
• Migration 
• Allergic reaction 
• Abscess 
• Paresthesia 
• Vascular occlusion 
• Drainage 
• Necrosis 
• Vision abnormalities * 
• Malaise 
• Scarring 
• Nausea 
• Granuloma 
• Deeper wrinkle 
• Dyspnea 
* Vision abnormalities have been reported following injection into the nose, glabella, periorbital area, and/or cheek, with a 
time to onset ranging from immediate to one week following injection. Reported treatments include anticoagulants, 
sympathomimetics, steroids, and surgery.  
Outcomes ranged from resolved to ongoing at the time of last contact.  
Note, that events requiring medical intervention, and events where resolution information is not 
available, were reported after injection in the highly vascularized areas of the glabella, nose, and 
periorbital area, which are outside the device indication for use (see Warnings section in the IFU [14]). 
General Warnings for 
 
 
• 
Introduction of 
 into the vasculature may lead to embolization, 
occlusion of the vessels, ischemia, or infarction. 
• 
Treatment site reactions consist mainly of short-term inflammatory symptoms and generally resolve 
within 2 to 4 weeks.  
In general, rare but serious adverse events associated with the intravascular injection of soft tissue 
fillers in the face have been reported and include [14]   
o 
temporary or permanent vision impairment 
o 
blindness 
o 
cerebral ischemia or cerebral hemorrhage 
o 
leading to stroke 
o 
skin necrosis 
o 
damage to underlying facial structures.  
Please see IFU of
 
 
 [14]  and section 6.2.4.2 for further General Precautions 
and Warnings when using the comparator device. 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 61 of 171 
Version 7.0 - 15-MAY-2024 
 
In order to improve the comfort of HA filler injections, the local anesthetic lidocaine hydrochloride (a 
medicinal product) [11] has been included in their formulation to reduce procedural pain and to bypass 
the need for additional anesthesia.  
Randomized controlled clinical trials, many of which have been split face trials, have compared the same 
dermal filler with and without lidocaine. The studies have been designed appropriately, with suitable 
outcome measures and appropriate analysis and have confirmed that treatment with dermal fillers with 
lidocaine resulted in a statistically and clinically significant reduction in pain (p <0.0001).  
The collective data has demonstrated unequivocal clinical benefit for dermal fillers incorporating 
lidocaine with no additional risks, since the frequency and severity of AEs was not different for dermal 
fillers with or without lidocaine.[24, 25], [26] 
4.3 
Possible interactions with concomitant medical treatments 
No studies on drug interactions with saypha® VOLUME Lidocaine have been conducted in humans. 
• 
Both devices must not be used in subjects on immunosuppressive therapy (also see Exclusion 
Criterion (ExC) #8; section 6.3.3; ExC#9 in section 6.3.5). 
• 
Use of anticoagulant, antiplatelet, nonsteroidal anti-inflammatory drugs or thrombolytic drugs may 
increase the risk of bleeding or bruising (such as acetylsalicylic acid, clopidogrel, ticagrelor, and 
warfarin, heparin, enoxaparin, or apixaban). The subject should be asked about use of such 
medications (also see ExC #15; section 6.3.3, ExC#16 in section 6.3.5). 
• 
Sodium hyaluronate is incompatible with quaternary ammonium compounds such as benzalkonium 
chloride solutions, hence the device should never be placed in contact with these substances or 
with medical-surgical instruments that have been in contact with these substances. 
4.4 
Risk mitigation strategy 
The risks will be mitigated by  
• 
Careful selection of subjects and exclusion of those who may have an increased risk of developing 
certain types of adverse events (AEs) (see section 4.2 and section 6.3.3).  
• 
Engagement of experienced investigators who are familiar with soft tissue fillers, and who are 
appropriately trained to ensure correct and safe application of the test and the comparator devices 
(including treatment of potential safety issues). The sponsor has chosen only board-certified 
specialists (dermatologists or plastic surgeons) as principal investigators for this investigation who 
in addition to board certification have years in experience with dermal fillers, both in clinical 
investigations as well as in daily routine activities. An updated list of investigation sites and 
corresponding principal investigators and their qualifications will be kept separately from the CIP. 
• 
In particular, the investigators must be familiar with the signs and symptoms associated with 
vascular occlusion and have a plan detailing how to treat the subject in the event of vascular 
occlusion; this may include on-site treatment and/or immediate referral to another health care 
professional for specialized treatment. For instance, in the event of blindness, subjects have to 
undergo immediate evaluation by an ophthalmology specialist.  
Ophthalmology specialists near each investigational site who are able to immediately examine 
subjects should be identified and informed about the clinical investigation procedure. 
A board-certified ophthalmologist will do a training to the treating investigators at the sites. 
Additionally, a specific treatment protocol in case of unintended intravascular injection that is 
consistent with those recognized by national, professional societies should be in place at each 
investigational site.  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 62 of 171 
Version 7.0 - 15-MAY-2024 
Additionally, a basic neurological examination (F.A.S.T [27, 28]) will be performed in all subjects 
who show signs of ophthalmic complications due to filler injection to ensure patient safety (see 
sections 6.4.8 and 6.4.9).  
Investigation sites will also be required to have an emergency plan in place and a minimum 
medication readily available to promptly react in case a suspected vascular occlusion or allergic 
reaction occurs (see section 6.2.5). 
The subjects will be instructed to immediately contact the treating investigator in case of any health 
concern occurring between the scheduled visits including special focus on experience of any 
signs/symptoms of vision changes or stroke since the injection (see section 6.4.8). 
• 
Evaluation of vision changes through visual examinations before and after treatment and protocols 
at each investigational site for immediate intervention in the event of unintended vascular injection. 
• 
Regular follow-up of the subjects, which allows for timely recognition and management of potential 
AEs, including phone calls for safety follow-up. The subjects will be contacted by phone 24 to 48 
hours after each treatment to check their health condition.  
• 
Careful selection of the comparator device (
 
 
) that´s use, safety and 
effectiveness is very well established and that is approved for the indication investigated in the EU 
and in the USA including the use of cannulas for application (see section 3.2.2 and section 4.2.2). 
• 
Ensuring the safety and ensuring the rights of participants, site personnel and other persons involved 
in conducting the study (e.g., the clinical monitors) also during the COVID-19 (coronavirus) 
pandemic is paramount. Guidance documents of the EMA [29, 30], the European Commission [31] 
and the FDA [32], national supplementary recommendations and laws, and guidance from IRBs/ECs 
regarding management of clinical studies during the COVID-19 pandemic will be followed in their 
respective current versions and as applicable. 
Mitigation measures already taken 
Several mitigation measures have already been taken: 
o 
An exclusion criterion referring to an infection with SARS-CoV-2 was included into the 
investigation design (see section 6.3.3.2).  
o 
To minimize the risk for the subjects, in this investigation design, the safety follow-up 24 to 48 
hours after each device injection will be performed as phone contact. Only in case of an AE or 
an unbearable injection site reaction an unscheduled on-site visit should be performed (see 
section 6.5.17). 
o 
The number of study sites planned to be included in the study was increased during study-set-
up to mitigate the risk of COVID-19. 
o 
Each site is required to carry out all procedures and to have their own process how to manage 
the subjects that come into their clinic in light of COVID-19 (e.g., social distancing needs as far 
as possible, particular attention to the specific sanitation rules).  
In addition, at time of each scheduled on-site visit post-screening the study site may take into 
consideration to ask subjects repeatedly (alternatively by phone contact prior to the respective 
on-site visit or as a first measure during the on-site visit) if he/she currently suffers from active 
COVID-19 disease, from common signs and/or symptoms of COVID-19, if he/she had close 
contact to a person with confirmed COVID-19 within the last 14 days or since the last visit, or if 
they had been in a currently designated risk area.   
In case of a suspected infection with SARS-CoV-2 at any time during the clinical investigation, 
it is recommended to ask subjects to perform a test on SARS-CoV-2. This should be done in an 
official Corona test center or at the subject’s family physician and / or in line with national / local 
provisions. Until the negative test result is available, remaining assessments planned for the 
respective study visit will be postponed. 
Of note, depending on the respective national regulation, SARS-CoV-2, may be a notifiable 
infection. If infection with SARS-CoV-2 is suspected or diagnosed, the investigator or the 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 63 of 171 
Version 7.0 - 15-MAY-2024 
laboratory may be required to report this by name (not pseudonymized) to the responsible health 
authority. 
Possible Mitigation Measures in Case of Restrictions During the Pandemic 
It is possible that, with the escalation of the pandemic, local circumstances lead to a local change in 
risk assessment. Certain study procedures may need to be adapted to then existing pandemic 
situation, e.g., when study sites are not accessible to subjects or clinical monitors, or individual 
subjects are unable to attend single visits, e.g., due to current active infection with SARS-CoV-2 and 
related quarantine, movement restrictions, subject´s concerns or site closure. An overview about 
the possible mitigation measures in case of restrictions during the pandemic is outlined in an 
addendum to the CIP. 
All decisions to adjust the conduct of the clinical investigation will be based on the risk assessment 
(see section 6.9). The sponsor will continuously re-assess risks with special focus on the COVID-
19 pandemic. This risk assessment will be based on relevant parties’ input and should be 
documented on an ongoing basis. Investigators involved should initiate and/or be involved in risk 
assessment and planning of mitigation measures.  
All measures taken, their prospective impact and their outcomes will be documented as part of the 
study-specific risk management documentation. Necessary changes will be agreed with and 
communicated clearly to investigators and study sites. Study subjects will be informed by the 
investigator about the possible changes in the conduct of the clinical study relevant to them 
(cancellation of on-site visits, etc.). In general, information process will be in line with information 
given in section 13. 
4.5 
Risk-to-benefit rationale 
Hyaluronic acid-based dermal fillers, such as saypha® VOLUME Lidocaine as well as 
 
, are generally considered very safe and effective (see sections 3.1 and 3.2, and sections 
4.2.1 to 4.2.3 for details).  
When using saypha® VOLUME Lidocaine, only a very low number of product quality and adverse event 
complaints compared to the total number of devices sold have been reported since its first market entry 
(see section 3.2.1). All adverse events are described in the IB as commonly reported after use of dermal 
fillers. Based on similarity to other crosslinked HA fillers and an acceptable non-clinical safety profile, 
saypha® VOLUME Lidocaine is expected to be as safe as other HA fillers including the comparator 
device.  
The risk assessment for saypha® VOLUME Lidocaine has been performed according to ISO 14971. 
Results of the risk assessment are described in the IB (section 9). The overall residual design, 
manufacturing, and use risks, and the benefit-risk-ratio of the device when used on subjects by 
experienced and trained physicians, according to the manufacturer’s instructions for use, are considered 
to be fully acceptable.[46] 
The safety of the subjects is of primary importance, and challenges due to COVID-19, were weighed 
against anticipated benefit for the subjects and society and respective measures are to be taken as 
appropriate (see section 4.4). Overall, the study subjects are healthy persons who desire a filler injection 
procedure for correction of moderate to severe volume deficiency of the midface and are not considered 
to be at an increased risk for virus infections nor at increased risk for a severe course of a COVID-19 
due to participation in the investigation. Based on the current knowledge and available information on 
risks associated with the COVID-19 pandemic, treatment of adult subjects enrolled in the study seems 
justified. Therefore, the overall Risk-to Benefit assessment in regard to COVID-19 and in regard to 
related assessments is considered to be acceptable in view of a potential spread of the virus. 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 64 of 171 
Version 7.0 - 15-MAY-2024 
It is reasonable to conclude that potential benefits of participation in the investigation, including treatment 
with either the test device or comparator device, outweighs potential risks described in section 4.2 when:  
• 
considering the potential benefits of correction, in particular the immediate and long-lasting 
improvement of distressing aesthetic defect (see section 4.1), and 
• 
taking into account the risk mitigation measures (see section 4.4).  
In conclusion, the overall risk-benefit-ratio for subjects participating in the study is justified.  
5 
Purpose and objectives of the clinical investigation 
5.1 
Intended purpose of the clinical investigation 
The purpose of the current clinical investigation is to evaluate the effectiveness, safety and long-term 
safety of saypha® VOLUME Lidocaine for the correction of age-related moderate to severe volume 
deficit in the midface (augmentation of midface volume deficit), and to demonstrate its non-inferiority to 
one of the devices approved for the same indication 
 
 
 In addition, the 
duration of the aesthetic effect after implantation will be studied. 
5.2 
Objectives 
 
• 
To demonstrate non-inferiority in the effectiveness of saypha® VOLUME Lidocaine for midface 
augmentation in order to correct moderate to severe volume deficit versus
 
 
 based on the blinded evaluator´s live assessment at Week 24 after last injection of initial 
treatment phase and compared to baseline assessments.  
 
5.2.2.1 General Aspects 
The following general topics are applicable for all below defined objectives:  
• 
For the initial treatment phase: 
o 
all secondary effectiveness objectives will be evaluated for saypha® VOLUME Lidocaine 
versus
 
 
o 
evaluation in general will be assessed for Visits 4 to 9 (SV1): Week 4, 8, 16, 24, 36, and 48 
after last injection of initial treatment phase  
• 
For the repeat-treatment phase: 
o 
 Other objectives will be evaluated descriptively for saypha® VOLUME Lidocaine, only 
o 
evaluation will be assessed at Visits RT3 to Visit RT5 (Week 4, 12 and 24 after last injection of 
repeat-treatment phase)  
5.2.2.2 Objectives  
Midface volume deficit and nasolabial fold improvement 
• 
To further assess effectiveness of saypha® VOLUME Lidocaine 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) 
• 
To assess the effectiveness of saypha® VOLUME Lidocaine for correction of moderate to severe 
midface volume deficit based on the independent blinded photographic reviewer´s assessment 
(initial treatment phase only) 
• 
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) 
• 
To assess the effect of midface treatment with saypha® VOLUME Lidocaine on the nasolabial 
folds based on the blinded evaluator´s live assessment  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 65 of 171 
Version 7.0 - 15-MAY-2024 
Global aesthetic improvement 
• 
To evaluate global aesthetic improvement based on subject’s assessments (initial treatment 
phase only) 
• 
To evaluate global aesthetic improvement based on the blinded evaluator’s assessments (initial 
treatment phase only) 
Subject’s satisfaction with outcome and appearance appraisal 
• 
To assess subject´s satisfaction with overall treatment outcome  
• 
To assess subject´s appearance appraisal after treatment 
Subject’s pain assessment and injection volume 
• 
To evaluate subject’s perception of pain after each treatment  
• 
To assess total injection volume needed for optimal correction   
 
• 
To assess safety of saypha® VOLUME Lidocaine during the entire study period including subject 
complaints as recorded in the subject diaries  
• 
To evaluate long term safety of saypha® VOLUME Lidocaine after repeat-treatment  
• 
To assess safety of saypha® VOLUME Lidocaine when used in cross over treatment referring to 
initial and repeat treatment 
 
 in initial treatment phase switched to 
saypha® VOLUME Lidocaine in repeat-treatment phase) 
5.3 
Endpoints: Criteria for evaluation  
 
• 
The subjects pain assessment, nasolabial folds, and volumetric change measurement will be 
assessed and analyzed for the left and right side of the face separately.  
• 
All other endpoints will be assessed and analyzed globally (i.e., left and right side together / 
combined) 
• 
For MVDSS in general: Subjects are defined as a ‘responder’ if they are showing an ≥1 point 
improvement on the 5-point MVDSS, based on the respective score at a given visit relative to the 
respective baseline score. The grade assigned at the respective baseline visit (either Baseline visit 
or Visit RT1) will represent the baseline value for derivation of the responder status at a given visit 
during the initial treatment phase or repeat-treatment phase. Assessments will be evaluated by 
either the blinded evaluator at the site or by the central independent blinded photographic 
reviewer.  
 
The effectiveness of the investigational device will be evaluated using the following primary endpoint:  
• 
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 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 66 of 171 
Version 7.0 - 15-MAY-2024 
 
5.3.3.1 Initial treatment phase 
The effectiveness of the investigational device during initial treatment phase will be further evaluated 
using the following secondary effectiveness endpoints:  
MVDSS, NLF-SRS and Volumetric Change measurement  
• 
The percentage of responders on the 5-point MVDSS, based on the blinded evaluator´s live 
assessment at Week 4, 8, 16, 36, and 48 after last injection of initial treatment phase compared to 
the score at Baseline visit.  
• 
The percentage of responders on the 5-point MVDSS, based on the independent blinded 
photographic reviewer´s assessment by using Baseline photographs at Week 4, 8, 16, 24, 36 
and 48 after last injection of initial treatment phase compared to the score at Baseline visit  
• 
Mean change in midface volume deficit measured on the 5-point MVDSS and based on the 
blinded evaluator´s live assessment at Week 4, 8, 16, 24, 36 and 48 after last injection of initial 
treatment phase compared to the score at Baseline visit 
• 
Mean change in midface volume deficit as measured by volumetric change measurement by 
using 3D digital photographic images at Week 4, 8, 16, 24, 36 and 48 after last injection of initial 
treatment phase compared to Baseline visit  
• 
Shift from baseline (Baseline visit) in nasolabial folds measured by NLF-SRS based on the blinded 
evaluator´s live assessment at Week 4, 8, 16, 24, 36, and 48 after last injection of initial treatment 
phase  
Global aesthetic improvement based on modified GAIS 
• 
The percentage of subjects with a global aesthetic improvement over baseline (at Baseline visit) 
(subjects who have been rated as “much improved” or “improved”), based on subject´s 
assessment at Week 4, 8, 16, 24, 36, and 48, after last injection of initial treatment phase using 
the 5-point modified GAIS. 
• 
The percentage of subjects with a global aesthetic improvement over baseline (at Baseline visit) 
(subjects who have been rated as “much improved” or “improved”), based on the blinded 
evaluator`s assessment at Week 4, 8, 16, 24, 36, and 48, after last injection of initial treatment 
phase using the 5-point modified GAIS.  
Subject’s satisfaction with outcome and appearance appraisal based on FACE-QTM assessments 
• 
The extent of subject´s satisfaction with overall treatment outcome at Week 4, 8, 16, 24, 36, 
and 48 after last injection of initial treatment phase as assessed by the subject using the Face-QTM 
Questionnaire “Satisfaction with Outcome”. 
• 
The extent of subject´s appearance appraisal at Week 4, 8, 16, 24, 36, and 48 after last injection 
of initial treatment phase as assessed by the FACE-QTM questionnaire “Satisfaction with Cheeks” 
compared to Baseline visit. 
Subject´s pain assessment and injection volume 
• 
Subject evaluation of pain after each treatment (baseline and touch-up treatment) on an 11-point 
scale, where 0 is no pain and 10 is the worst pain imaginable 
• 
Injection volume required to achieve optimal aesthetic result at each treatment (baseline- and 
touch-up treatment together)  
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 67 of 171 
Version 7.0 - 15-MAY-2024 
5.3.3.2 Repeat-treatment phase 
The investigational device during repeat-treatment phase (saypha® VOLUME Lidocaine) will be 
evaluated using the following other effectiveness endpoints:  
MVDSS and NLF-SRS  
• 
The percentage of responders on the 5-point MVDSS, based on the blinded evaluator´s live 
assessment at Week 4, 12 and 24 after last injection of repeat-treatment phase compared to the 
score at Visit RT1 
• 
Mean change in midface volume deficit measured on the 5-point MVDSS and based on the 
blinded evaluator´s live assessment at Week 4, 12, and 24 after last injection of repeat-treatment 
phase compared to the score at Visit RT1 
• 
Shift from baseline (Visit RT1) in NLF-SRS based on the blinded evaluator´s live assessment at 
Week 4, 12 and 24 after last injection during repeat-treatment phase  
Subject’s satisfaction with outcome and appearance appraisal based on FACE-QTM assessments  
• 
The extent of subject´s satisfaction with overall treatment outcome at Week 4, 12 and 24 after 
last injection of repeat-treatment phase as assessed by the subject using the Face-QTM 
Questionnaire “Satisfaction with Outcome” 
• 
The extent of subject´s appearance appraisal at Week 4, 12 and 24 after last injection of repeat-
treatment phase as assessed by the FACE-QTM questionnaire “Satisfaction with Cheeks” 
compared to the score at Visit RT1 
Subject´s pain assessment and injection volume 
• 
Subject evaluation of pain after each treatment (repeat and touch-up-treatment) on an 11-point 
scale, where 0 is no pain and 10 is the worst pain imaginable 
• 
Injection volume required to achieve optimal aesthetic result at each treatment (repeat and 
touch-up treatment together) 
 
The safety of the investigational device will be evaluated by treatment group including cross-over group 
(in repeat-treatment) and by treatment phase using the following endpoints: 
• 
Occurrence and frequency of adverse events during the entire study period including repeat-
treatment phase (long-term safety). Symptoms of interest will be recorded in subject diary during 
the first 4 weeks (28 days) after each treatment (i.e., either 4 weeks after baseline and repeat-
treatment, respectively, and 6 weeks in case of touch-up treatment) and documented as AE by 
investigator. 
• 
Injection site reactions as recorded in the subject diaries during the first 4 weeks (28 days) after 
each treatment (i.e., either 4 weeks after baseline and repeat-treatment, respectively, and 6 weeks 
in case of touch-up treatment). Injection site reactions will be assessed overall and for each side of 
the midface (i.e., left and right side separately). 
5.4 
Risks and anticipated adverse device effects that are to be assessed 
Based on the equivalence of saypha® VOLUME Lidocaine with these products and available non-clinical 
and clinical safety data of the device under investigation, it is anticipated that it will share the same safety 
profile (details described in section 4).  
Risks and anticipated ADEs for the test device are given in the current version of the IB.[46] All 
anticipated ADEs according to the IB section 8.2 have to be documented and reported as described in 
section 14.  
For precautions to be taken to avoid occurrence of adverse events associated with the test device refer 
to section 6.2.4 and the current IB.[46] 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 68 of 171 
Version 7.0 - 15-MAY-2024 
6 
Design of the clinical investigation 
6.1 
Design description 
 
This is a randomized, subject and evaluator-blinded, active treatment controlled, parallel group, non-
inferiority, multicenter study with a dermal filler for the correction of moderate to severe midface volume 
deficit.  
The clinical investigation will comprise randomization to two treatment groups:  
• 
Test device: saypha® VOLUME Lidocaine 
• 
Comparator device: 
 
 
  
Eligible subjects will be randomized at Baseline visit in a 2:1 ratio to undergo bilateral treatment with 
saypha® VOLUME Lidocaine or
 
, respectively. 
The Screening visit (Visit 1) will be performed within 2 weeks prior to randomization and will entail 
informed consent and screening assessments as specified in section 6.5.1. During this visit the treating 
investigator will determine eligibility of subjects based on study inclusion and exclusion criteria (see 
section 6.3.3). Screening and Baseline visit (Visit 2 / Day 0) can be combined and performed at one day.  
Baseline severity of midface volume deficit will be determined at Visit 1 by the blinded evaluator using 
the 5-point MVDSS. In addition, the subjects face will be photographed to document baseline condition 
for further assessments. 
At Visit 2, eligible subjects will be randomized and undergo bilateral midface augmentation treatment 
with either saypha® VOLUME Lidocaine or
 
 
 (baseline treatment).  
If an optimal aesthetic correction has not been achieved after the baseline treatment, as evaluated by 
the treating investigator, a touch-up treatment may be performed at Week 2 (Visit 3) using the same 
device as initially applied at Visit 2. 
At Week 48 (Visit 9 (SV1)) after last treatment of the initial treatment phase, subjects of both treatment 
groups (test device and comparator device) may qualify for optional repeat-treatment, which will be done 
with saypha® VOLUME Lidocaine only.  
Screening visits for repeat-treatment will be every 4 weeks up to 12 weeks after Visit 9 (SV1). As soon 
as the subject is eligible in MVDSS score, a full eligibility assessment for repeat-treatment will be done. 
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 (see section 6.3.5). Again, the blinded evaluator at the site decides, if subject is eligible 
for the repeat-treatment (regarding MVDSS). 
Visit SV4 (12 weeks after Visit 9 (SV1) at the latest) 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 for 
repeat-treatment and further follow up in screening is not useful because the subject will apparently not 
qualify for repeat-treatment, Visit 9 (SV1), SV2 or SV 3 will be the end of study visit for the respective 
subject. 
Subjects who are eligible and willing to undergo optional repeat-treatment at Visit RT1 will enter the 
repeat-treatment follow-up phase.  
Follow-up visits on-site (see Figure 1.) will occur at:  
• 
Initial treatment phase: Week 2 after baseline treatment, and 2, 4, 8, 16, 24, 36, 48 weeks after 
last treatment, i.e., baseline or touch-up treatment, respectively (Visits 3 to 9 (SV1)) 
• 
Screening phase for repeat-treatment: Week 4, 8 and 12 after Visit 9 (SV1) – (Visits SV2 to 
SV4) 
• 
Repeat-treatment phase: Week 2 after repeat-treatment, and 2, 4, 12 and 24 weeks after last 
treatment, i.e., repeat- or touch-up treatment, respectively (Visit RT2 to RT5)  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 71 of 171 
Version 7.0 - 15-MAY-2024 
The safety will be evaluated based on occurrence of adverse events, which will be collected at each visit 
(on-site and telephone visits) throughout the clinical investigation, beginning after signature of the ICF 
until the last visit. In order to identify potential adverse events post-administration a safety evaluation 
after 15 minutes needs to take place (see section 6.4.20).  
In order to evaluate any potential vision changes, visual examinations (including Snellen visual acuity, 
confrontational visual fields and ocular motility) will be additionally performed at treatment visits (prior to 
and 30 min after any treatment) and at all follow-up visits of the initial and repeat-treatment phase. A 
basic neurological examination (F.A.S.T) will be performed for all subjects who show signs of ophthalmic 
complications due to filler injection.  
Abnormal clinically significant changes in visual examination or experience of neurological symptoms 
indicative of a vaso-occlusional event after any treatment will lead to withdrawal of the subject from 
further treatment(s) in case an eye specialist or neurologist confirm that the result is related to a vascular 
injection of the dermal filler. The subjects may remain in the study for at least safety assessments during 
the scheduled study visits. Further activities following a related vascular event are described in 
section 16.1. 
A subject diary will be used to record injection site reactions, and symptoms of interest over the first four 
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 – see section 6.4.19. 
A detailed schedule of procedures is given in section 6.5 and the “Schedule of procedures and 
assessments”. Detailed descriptions of assessments and procedures can be found in section 6.4. 
 
The randomization will be performed at the Baseline visit (Visit 2), after final confirmation of subject’s 
eligibility. Treatment assignment will be pre-planned according to a computer-generated randomization 
schedule in a 2:1 ratio (test device : comparator device). The schedule will contain the following 
treatment assignments, which will be randomly allocated to sequential randomization scheme: 
• 
Test device: saypha® VOLUME Lidocaine 
• 
Comparator device: 
 
 
  
The randomization information will assign the subject to one of the treatment groups. In addition, a 
minimum of 100 subjects randomized to the test device will be treated with either needle or cannula.  
Only unblinded site staff performs the randomization via a randomization function of the eCRF.  
Neither the blinded evaluator at the site nor the central independent photographic reviewer will have 
access to the randomization system (see section 6.1.3 for details). The randomization number will be 
documented in the eCRF.  
The exact procedure for obtaining a randomization number/treatment assignment for a subject will be 
provided to each investigational site before the study is initiated by training and will be described in a 
separate manual or other appropriate document.  
 
The blinded evaluator at the site, who will perform live assessments of treatment effectiveness, as well 
as the central independent blinded photographic reviewer will be blinded to the treatment administered.  
Subjects will also be blinded to the treatments they received until finalization of Visit 9 (SV1). 
Measurements to keep the blinding are described below.  
Subjects  
• 
Subjects will be blinded to the treatment administered 
o 
Subjects will be blind-folded during treatment. Subjects might be unblinded via label or design 
of the syringe/backstop of both devices that are different in appearance. Before removing the 
blind-folds, the respective device (incl. all needles/cannulas used, the surrounding 
boxes/blisters, etc.) must be removed from the treating room or covered (e.g., with a 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 72 of 171 
Version 7.0 - 15-MAY-2024 
nontransparent box) before the sleep mask is removed). The way of blinding (e.g., goggles, 
masks, other) has to be documented in the subject’s source record and in the eCRF. 
o 
Also, the sites must ensure, that before, during and after the treatment there can be no specific 
information found in the clinical and especially the treating room (e.g., logos on the device or on 
the outer boxes; the subject must have no view on the computer screen during randomization 
process)  
o 
The treating investigator and other site staff must not disclose the device injected to the 
subject  
Blinded evaluator at the site 
The blinded evaluator at the site will be independent of the study conduct and blinded against the 
randomization code of each subject until data base lock.FC The following measures will be taken to ensure 
the blinded evaluator at the site throughout the clinical investigation: 
• 
Each site has to install two types of study personnel:  
o 
Unblinded site staff (i.e., treating investigator, other site staff) 
o 
Blinded evaluator at the site.  
Of note, unblinded site staff as well as CRO staff (including Clinical Research Associates (CRAs)), 
data managers, medical monitor and biostatistician) and sponsor will be unblinded to the treatment 
group assignment. 
• 
The treating investigator, all other unblinded site and CRO / sponsor staff must not disclose the 
blinded evaluator at the site the identity of the treatment group the subjects belong to. Especially the 
treating investigator must ensure that the blinded evaluator at the site is not inadvertently unblinded 
when evaluating the subjects. 
• 
The blinded evaluator at the site will not be present during treating investigator’s evaluation of the 
subject or vice versa.  
• 
The treating investigator and the blinded evaluator at the site will not discuss any details or guesses 
about the treatment assignment, potential touch-up or repeat-treatment, or results of assessments 
in individual subjects during the course of the investigation and until the final database lock. The 
same applies to any discussions between blinded evaluators at the site. 
• 
The treating investigator will explain to each subject that they should not discuss, any side-effects 
or complaints, nor personal views on treatment success with the blinded evaluator at the site, in 
order to assure scientific rigor and unbiased results of the trial.  
• 
Results of ratings will be documented on Rating Sheets by the blinded evaluator at the site (see 
section 6.4.12 for details).  
• 
The blinded evaluator at the site will not have access to the subject´s source records during the 
course of the investigation and until the final database lock. If this will not be technically feasible, 
e.g., in case of electronic source records, the blinded evaluator will commit to abstain from accessing 
these records and will maintain the list of prohibited medical files to avoid accidental access 
• 
The blinded evaluator at the site will not have access to the eCRF to keep the blinding towards the 
treatment assignment of the subject. Results of the ratings will be transferred into the eCRF by an 
 
 
C Note: The blinded evaluator at the site is not blinded for treatment allocation during the repeat-treatment 
phase. However, he/she will be blinded for the treatment a subject received during the initial treatment phase 
until final database lock. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 73 of 171 
Version 7.0 - 15-MAY-2024 
unblinded team member. However, the blinded evaluator at the site will have an emergency access 
to the eCRF/IWRS for emergency unblinding (also see below). 
• 
The blinded evaluator at the site will not have access to the data of the interim analysis or the interim 
clinical investigation report (iCIR).  
• 
The site staff will be trained by the CRA on the required procedures to maintain the blinding of the 
blinded evaluator at the site. 
In the event that the treatment group allocation for a subject becomes known to blinded evaluator at the 
site, the sponsor must be notified immediately (i.e., within 24 hours).  
Unblinding a subject’s treatment group to the blinded evaluator at the site must be recorded in the 
subject’s source record, in the eCRF indicating the date and will be considered a protocol deviation. The 
evaluability of such subjects will be discussed at the data review meeting (DRM). 
Central independent blinded photographic reviewer and volumetric change measurement 
A central independent blinded photographic reviewer (see section 6.4.13) and staff at the photo provider 
conducting the volume changes measurement (see section 6.4.12) will:  
• 
be dislocated from the investigation sites 
• 
will have no access to randomization schedule / eCRF or information on treatment assignment, and 
• 
will not discuss any findings with the treating investigators and blinded evaluators at the sites during 
the investigation until after the final study database lock.  
Emergency unblinding 
There will be no special procedure for emergency unblinding because the treating investigator and other 
study staff will be aware of the treatment allocation. In case, only the blinded evaluator at the site is 
available in case of an emergency situation, and an unblinding is required, he/she should contact the 
Medical Monitor or the Sponsor first before accessing the subject´s medical records for unblinding. 
The subjects will know that they have received a hyaluronic acid dermal filler with lidocaine, which is, 
sufficient level of information needed in case of emergency. However, the subjects will receive a 
participant card with 24/7 emergency telephone numbers.  
Any cases of unblinding will be documented by the site staff. 
 
This clinical investigation is undertaken to evaluate the effectiveness, safety and long-term safety of 
saypha® VOLUME Lidocaine for the correction of moderate to severe midface volume deficit, and to 
demonstrate its non-inferiority to one of the devices approved for the same indication 
 
. In addition, the duration of the global aesthetic improvement and subject´s satisfaction 
after implantation will be assessed.  
The investigation is designed to minimize potential bias during collection of clinical observations and to 
allow for interpretation of results in the context of available treatment options. 
Approximately 486 subjects will be randomized in this investigation (324 test device and 162 comparator 
device) in order to get a sufficient number of evaluable subjects per treatment group (437 in total). The 
sample size selection is justified in section 7.1. The method of randomization is used to minimize the 
bias arising from the assignment of subjects to treatment groups (see section 6.1.2).   
The primary and several secondary and other effectiveness endpoints (see section 5.3) are based on 
the 5-grade MVDSS, a validated instrument for semi-quantitative assessment of volume deficit in the 
midface as assessed live by the blinded evaluator at the site.[33] Blinded outcome assessment by a 
blinded rater is a common practice to reduce bias arising from the expectations of individuals collecting 
data. The sites will make their best efforts to assign the same blinded evaluator for evaluation activity 
throughout the clinical investigation to maintain consistency of effectiveness evaluation (see 
section 6.4.12).  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 74 of 171 
Version 7.0 - 15-MAY-2024 
In view of multicenter conduct of the investigation, the validated MVDSS assessment will be also 
evaluated centrally, by experienced independent blinded photographic reviewers.[34] This will allow for 
unified assessment of treatment responses across the sites and checking if any bias was introduced by 
inter-observer variability between the sites.  
The rater blinding regarding treatment group in initial treatment will remain in effect until study data base 
lock. The blinded evaluator at the site will be trained on the MVDSS and NLF-SRS prior to start of the 
investigation during the investigator meeting, a live WebEx with a sponsor medical consultant, or through 
review of a recording of the WebEx. Open questions by on-site located raters will be answered during 
the pre-study visits; further training on the scale will be also performed during site pre-study visits, if 
needed. The independent blinded photographic reviewers will be trained on the MVDSS prior to their 
assessments of the photographs.  
In addition, the improvement of midface volume deficit will also be evaluated centrally by using 
computerized volume change measurement based on the 3D photographic images. The quantified data 
of the volume change measurement provide additional evidence confirming the effectiveness of the test 
device for the indication to be treated (see section 6.4.12). 
The time point for definition of the primary endpoint (Week 24 after  last injection of the initial treatment 
phase) was selected based on clinical experience with other HA fillers and will be corroborated by earlier 
and later observations (see Table 1 and Table 3 for details). Difference of one grade on this scale is 
considered to be clinically meaningful since it can be visually recognized by various observers as 
demonstrated during validation of the scale.  
The clinical relevance of the investigation will be also supported by several (other) secondary 
effectiveness endpoints (see section 5.3), related to global aesthetic improvement (by using the modified 
GAIS) [35] and subject’s satisfaction with outcome (overall and the cheeks by using FACE-QTM 
scales).[36, 37]  
Information on occurrence of pain will be primarily obtained by collection of AEs, with additional insight 
into pain intensity being obtained directly after the injection using a semi-quantitative 11-point Numeric 
Pain Rating Scale (NRPS).[38]. 
Touch-up treatments are allowed in the investigation, and the treating investigator will determine the 
appropriate injection volume and injection technique and equipment (i.e., needle/cannula) based on 
his/her clinical experience (see sections 6.2). A minimum of 100 subjects randomized to the test device 
will be treated with either needle or cannula. Use of either needle or cannula is based on the treating 
investigator´s medical decision.  
Finally, it is well known that in routine clinical practice many patients choose for repeating treatments 
with HA dermal fillers to maintain the aesthetic improvement achieved with the first one.[39-41] A 
repeat-treatment at one of the later time points (earliest Week 48 after baseline treatment) has been 
therefore added, not only to improve subject retention in the investigation, but also to collect safety data 
after repeated administration of the test device. This actually allows the sponsor to determine if subjects 
previously treated with a different device behave differently with exposure to saypha® VOLUME 
Lidocaine. 
Safety and long-term safety of saypha® VOLUME Lidocaine for the correction of moderate to severe 
midface volume deficit will be monitored by documentation of safety parameters (AEs, injection site 
reactions and device deficiencies; see section 6.4.19).  
Overall, the proposed design for this investigation is considered ethically and scientifically justified. 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 75 of 171 
Version 7.0 - 15-MAY-2024 
6.2 
Handling and Administration of the medical devices 
A description of both devices is given in section 2.  
 
Labelling and traceability of the devices 
The study labels will comply with appropriate information as mandated by applicable guidelines and 
national regulatory requirements, as appropriate.  
Label text will be available into local languages and a copy will be filed in the TMF.  
Study labels will include the batch number (lot number) and a kit number. Both devices are identified 
and tracked by those batch numbers. To ensure the traceability of each device, the batch numbers must 
be documented in the source medical record of the subject treated with the device.  
Table 14. Storage and packaging of the devices. 
 
Saypha® VOLUME Lidocaine  
  
Packaging 
Per carton box (= one kit) 
• 
One prefilled syringe of 1.0 mL filler 
solution 
• 
two 27G ½” disposable sterile needles  
Per carton box (= one kit) 
• 
Two prefilled syringes of 1.0 mL filler 
solution, each 
• 
four 27G ½” disposable sterile needles  
Note: The volume in each syringe is as stated 
on the syringe label and on the carton. 
Optional / additional 
injection equipment 
 25G 1½” cannula   
 25G 1½” cannula 
Note: Cannulas will be provided by the sponsor´s representative. 
Batch number 
Batch number will be on the study label 
Batch number will be on the study label 
Kit number 
Kit number will be on the study label.  
Kit number will be on the study label 
Storage 
Store at + 2 to + 25 °C/ +36 to +77 °F in a dry 
place in the original box and protected from 
light, heat and frost.  
Store at room temperature (up to 25°C/77°F).  
DO NOT FREEZE. 
Finished sterilized saypha® VOLUME 
Lidocaine product has a shelf life of 36 months 
at 2 to 25°C. 
 injectable gel 
must be used prior to the expiration date 
printed on the label. 
Note: The safety and effectiveness of cannula injection of 
 has only been clinically evaluated 
with the 
 25G 1½” cannulas 
Note: 
 may be injected with a 25G 1” needle according to the IFU.  However, use of needles 
other than 27G ½” is not allowed within this clinical investigation. 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 76 of 171 
Version 7.0 - 15-MAY-2024 
 
Anatomic areas of midface treatment 
The anatomic areas of midface treatment are defined as follows:  
• 
Anteromedial cheek (left and right) 
• 
Submalar (left and right) 
• 
Zygomaticomalar (left and right) 
A visual depiction of the anatomic areas of midface treatment is given in Figure 3. 
Figure 3. Anatomic areas treated.  
 
Treatment occasions 
Each subject may be treated on up to four occasions: 
• 
Baseline treatment will be administered at Visit 2 (Day 0). Each eligible subject (see section 6.3.3) 
will receive either saypha® VOLUME Lidocaine or 
 into the midface 
region, according to the randomization scheme (see section 6.1.2).  
• 
Touch-up treatment after baseline treatment (optional) may be administered at Visit 3 (2 weeks 
after baseline treatment)  
• 
Repeat-treatment (optional) will be administered once during the clinical investigation, at Visit RT1, 
in eligible subjects (see section 6.3.5) using the saypha® VOLUME Lidocaine only even if the subject 
was treated with the comparator device before.  
• 
Touch-up treatment after repeat-treatment (optional) may be administered at Visit RT2 (2 weeks 
after repeat-treatment) 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
 
Page 77 of 171 
Version 7.0 - 15-MAY-2024 
In general, a touch-up treatment may be administered if an optimal aesthetic correction has not been 
achieved after baseline and / or repeat-treatment in the discretion of the treating investigator and if 
none of the exclusion criteria are met (see section 6.3.5). 
The touch-up treatment may be performed on one or both sides of the midface. In any case, it must 
be performed using the same device (either test device or comparator device) which was initially 
applied to the subject. 
Injection technique and injection equipment 
Table 15 describes the injection techniques and injection equipment to be used in the investigation. 
Table 15. Description of injection technique and injection equipment used in the investigation 
 
saypha® VOLUME Lidocaine [46] 
 [also see IFU] 
[14] 
Injection technique 
For each treatment, the injection technique used will be selected by the treating investigator. 
The technique used is essential for the success of the treatment. The following injection 
techniques should be employed based on investigator’s preference and characteristics of 
the defect under correction. 
• 
Every injection technique may be 
selected within this clinical investigation  
 
• 
Tunneling, fanning, crosshatching, and 
ferning techniques may be used with 
needle or cannula  
• 
Serial puncture may be used with a 
needle.  Injection may be administered 
in an antegrade or retrograde fashion. 
• 
The injection technique for regard to 
the angle and orientation of the bevel, 
the depth (subcutaneous and/or 
submuscular/ supraperiosteal) of 
injection, and the quantity administered 
may vary depending on the area being 
treated. Injection of the filler too 
superficially (intradermally), or in large 
volumes over a small area, may result 
in visible and persistent lumps and/or 
discoloration. 
Injection equipment 
Either needle or cannula will be used (see below) in the discretion of the treating investigator. 
A minimum of 100 subjects randomized to the test device will be treated with either needle or 
cannula.  
• 
27G ½’’ needle (provided with the 
syringe) 
• 
25G 1 ½’’ cannula 
 
 provided separately) 
• 
27G ½” needle (provided with the 
syringe)  
• 
25G 1½” cannula 
 
 provided separately) 

 
 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
  
 
 
 
 
 
 
Page 78 of 171 
Version 7.0 - 15-MAY-2024 
 
Administration of saypha® VOLUME Lidocaine and 
  
Table 16 gives detailed instructions how to administer the test device and the comparator device.  
Table 16. Administration of saypha® VOLUME Lidocaine and 
  
Step 
saypha® VOLUME Lidocaine [also see current version of IB]  
 [also see IFU] [14] 
Prior to administration 
• 
The device must be injected into non-inflamed, disinfected, healthy skin 
• 
After ensuring that the subject has thoroughly washed the treatment area with soap and water, the area should be prepped with alcohol or another antiseptic. 
Note: IB for saypha® VOLUME Lidocaine  (section 8.1.5 therein) and IFU for
 [14] (section B. Health Care Professional Instructions 
#5) read that topical anaesthetic patch or cream or injectable anesthesia may be used to manage pain during and after injection. However, injectable anaesthesia 
is not allowed to manage pain during and after injection.  
Whenever possible (i.e., if the subject agrees) additional topical anaesthetic (patch or cream) should be avoided in this investigation to not falsify the pain 
assessment (as collected via Numerical Pain Rating Scale; see section 6.4.14).  
In case additional local anesthesia is used, this has to be documented as concomitant treatment in the subject’s records and the eCRF. 
Preparation for 
administration 
Instructions incl. visual illustration how to attach needle / cannula to the 
syringe is given in section 20.3.  
Instructions incl. visual illustration how to attach needle / cannula is given in 
section 20.4 and in the IFU [14] 
Note: Failure to comply with the needle attachment instructions could result in 
needle disengagement and/or product leakage at the
 and needle 
hub connection. In such case follow instructions given in section 14.9. 
Administration 
The following applies to saypha® VOLUME Lidocaine and
 (according to IFU of
 [14]) 
• 
If the needle/cannula is blocked, do not increase the pressure on the plunger rod. Instead, stop the injection and replace the needle/cannula 
• 
When using a cannula, an entry point is made in the skin, e.g., with a sharp needle of appropriate size  
• 
After insertion of the needle, and just before injection, the plunger rod should be withdrawn slightly to aspirate and verify the needle is not intravascular. 
• 
After the first small amount of material has been injected into the patient, wait a full 3 seconds to allow the lidocaine to take effect before proceeding with the 
rest of the injection. 
• 
Distribute in small aliquots (small boluses of 0.1 mL to 0.2 mL) over a large area to reduce the risk of persistent lumpiness. 
• 
With submuscular/supraperiosteal injection, the number of times the needle passes through the muscle should be minimized to reduce the risk of bruising. It 
is important to stop injecting before the needle tip reaches the level of the deep dermis to prevent material from being placed too superficially in the skin. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
  
 
 
 
 
 
 
Page 79 of 171 
Version 7.0 - 15-MAY-2024 
Table 16. Administration of saypha® VOLUME Lidocaine and 
  
Step 
saypha® VOLUME Lidocaine [also see current version of IB]  
[also see IFU] [14] 
• 
Correct to 100% of the desired volume effect. Do not overcorrect. The degree and duration of the correction depend on the character of the defect treated, 
the tissue stress at the implant site, the depth of the implant in the tissue, and the injection technique. Markedly indurated defects may be difficult to correct.  
• 
If immediate blanching occurs, the injection should be stopped, and the area massaged until it returns to a normal color. Blanching may represent a vessel 
occlusion. If normal skin coloring does not return, do not continue with the injection. Treat in accordance with the guidelines, which include hyaluronidase 
injection as given in section 6.2.5. Also see sections 6.3.6, 14.5.4 and 16.1. 
• 
The maximum volume to be applied per treatment and the overall investigation is given in section 6.2.3. 
Completion of 
administration 
• 
After the injection, doctors may apply a light massage in order to 
distribute the product uniformly. 
 
• 
The area of lost facial volume should be lifted by the end of the injection. 
When injection is completed, the treated site may be gently massaged to 
mold the product to the contour of the surrounding tissue and assure that 
it is evenly distributed and conforms to the contour of the surrounding 
tissues. If overcorrection occurs, massage the area between your fingers 
or against an underlying superficial bone to obtain optimal results. 
After administration 
• 
After use, treatment syringes and needles may be potential biohazards. Handle and dispose of these items in accordance with accepted medical practice 
and applicable local, state, and federal requirements (please also see sections 6.2.6 and 6.2.7).   
• 
Pain intensity will be assessed immediately after injection, and at 15 min-intervals for 60 min post-treatment by using the NPRS (see section 6.4.14 for 
details).  
• 
In order to identify potential AEs (especially, to detect blanching caused by arterial occlusions) post-administration of device (baseline treatment, touch-up 
treatment and repeat-treatment) a safety evaluation 15 minutes after the administration needs to take place (see section 6.4.19).  
• 
Should any of the vision assessments (Snellen visual acuity, confrontational visual test field, or ocular motility – see section 6.4.76.4.8) suddenly worsen 
after the injection of the device, the treating investigator must examine the subject to exclude vascular injection and contact an eye specialist, if necessary. 
• 
A basic neurological examination (F.A.S.T) will be performed for all subjects who show signs of ophthalmic complications due to filler injection (see 
section 6.4.9). 
• 
Prior to discharge the subject should be advised to follow restrictions specified in section 6.3.8 and to inform their investigator as soon as possible about 
any unwanted event.  
• 
Details for each treatment will be documented in the subject’s records and the eCRF with the same level of details (see section 6.4.10).  

 
 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 80 of 171 
Version 7.0 - 15-MAY-2024 
 
The volume administered is at the discretion of the treating investigator and depends on the severity of 
the midface volume deficit to be corrected.  
However, the maximum volume (left and right side of the midface together) must not exceed 10 mL in 
total per treatment phase (initial and repeat-treatment, respectively, including touch-up treatments) or 
20 mL per 60 kg (130 lbs) body mass per year.  
A maximum of 6.0 mL on one side of the midface is allowed total per treatment phase (i.e., a maximum 
of 4.0 mL on the other side).  
Table 17 gives an overview of the average volume of the devices administered in the clinical 
investigation.  
Table 17. Volume of the devices administered in the clinical investigation per treatment and overall 
Treatment Session 
saypha® VOLUME Lidocaine 
  
Initial treatment phase per 
subject  
(baseline treatment plus touch-up 
treatment)  
Total volume must not exceed 10 mL 
per 60 kg (130 lbs) body mass in total 
(baseline plus touch-up treatment; left 
and right side of the midface together) 
Total volume must not exceed 10 mL 
per 60 kg (130 lbs) body mass in total 
(baseline plus touch-up treatment; left 
and right side of the midface together) 
Repeat-treatment phase per 
subject  
(repeat-treatment plus touch-up 
treatment) 
Total volume must not exceed 10 mL 
per 60 kg (130 lbs) body mass in total 
(repeat-treatment plus touch-up 
treatment; left and right side of the 
midface together) 
Total volume must not exceed 10 mL 
per 60 kg (130 lbs) body mass in total 
(repeat-treatment plus touch-up 
treatment; left and right side of the 
midface together) 
Total volume per subject during 
the entire study 
Total volume must not exceed 20 mL 
per 60 kg (130 lbs) body mass in total  
Total volume must not exceed 20 mL 
per 60 kg (130 lbs) body mass in total  
Note 1: ‘Year’ means rolling 365 days, starting with study start / baseline injection. 
Note 2: Based on preclinical studies and a toxicological risk assessment, subjects should be limited to 20 mL of 
 per 60 kg (130 lbs) body mass per year. The safety of injecting greater amounts has not 
been established. [14]   
However, for this investigation, the above given limit must be followed for both devices. 
After each administration, the actual volume of the device injected will be recorded in the subject´s 
source records and in the eCRF (also see section 6.4.10).  
 
Only precautions and warnings that require a study-specific action during the investigation are listed 
below. For the complete list of precautions and warnings please refer to current IB [46] (section 8.1.5) 
for saypha® VOLUME Lidocaine and to the respective IFU of the comparator device.[14]  
Each treating investigator has to familiarize himself / herself with the CIP and the detailed precautions 
and warnings in the above-mentioned documents.  
6.2.4.1 saypha® VOLUME Lidocaine  
Precautions and Warnings  
• 
According to the IB (section 8.1.5), sensitive skin may be pre-treated using a local anesthetic patch 
or cream (also see section 6.2.2).  
Note: Whenever possible (i.e., if the subject agrees) additional topical anesthetic (patch or cream) 
should be avoided in this investigation to not falsify the pain assessment (see section 6.4.14). In 
case additional local anesthesia is used, this has to be documented as concomitant treatment in the 
subject’s records and the eCRF. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 81 of 171 
Version 7.0 - 15-MAY-2024 
• 
The device must not be used if the expiry date has lapsed, or if the integrity of the syringe cannot 
be verified, of if packaging or contents are damaged (open or shifted tip cap or in an opened or 
damaged blister, syringe is not stored in its originally sealed blister, needle with a damaged 
container). In such case follow instructions given in section 14.9.  
• 
The device should only be used with the needles / cannulas and syringe provided by the 
manufacturer / sponsor´s representative (also see section 2.1 and section 6.4.19). 
• 
Do not inject into blood vessels, bones, tendons, ligaments, nerves or muscles. Do not inject the 
device into naevi. In such cases, subjects should receive prompt medical attention and possibly 
evaluation by an appropriate health care practitioner specialist should an intravascular injection 
occur. Also see section 6.2.5 and section 14 for documentation and reporting obligations for AEs. 
Also see sections 6.3.6, 14.5.4 and 16.1. 
• 
Subjects should be advised not to apply make-up for twelve hours after injection and to avoid 
prolonged exposure to sunlight and UV; also subjects should not use saunas or Turkish baths for 
one Week after the injection (also see section 6.3.8).  
• 
Subjects should be advised not to massage the treatment site for a few days following the injection, 
to avoid the possible risk of product mobility (also see section 6.3.8).  
• 
The device should never be placed in contact with quaternary ammonium compounds (such as 
benzalkonium chloride solutions) or with medical-surgical instruments that have been in contact with 
these substances (also see section 4.3).  
6.2.4.2 
  
Warnings 
• 
The product must not be injected into blood vessels. Introduction of 
 into 
the vasculature may lead to embolization, occlusion of the vessels, ischemia, or infarction. Take 
extra care when injecting soft tissue fillers, for example, after insertion of the needle, and just before 
injection, the plunger rod can be withdrawn slightly to aspirate and verify the needle is not 
intravascular, inject the product slowly and apply the least amount of pressure necessary.  
Rare but serious adverse events associated with the intravascular injection of soft tissue fillers in 
the face have been reported and include temporary or permanent vision impairment, blindness, 
cerebral ischemia or cerebral hemorrhage, leading to stroke, skin necrosis, and damage to 
underlying facial structures. Immediately stop the injection if a subject exhibits any of the following 
symptoms, including changes in vision, signs of a stroke, blanching of the skin, or unusual pain 
during or shortly after the procedure (see section 6.4.8 for information on visual examinations to be 
performed). 
Subjects should receive prompt medical attention and possibly evaluation by an appropriate health 
care practitioner specialist should an intravascular injection occur. Also see section 6.2.5 and section 
14 for documentation and reporting obligations for AEs. Also see sections 6.3.6, 14.5.4 and 16.1. 
• 
Product use at specific sites in which an active inflammatory process (skin eruptions such as cysts, 
pimples, rashes, or hives) or infection is present should be deferred until the underlying process has 
been controlled. The treating investigator must document subject´s temporary discontinuation and 
the reason in the subject’s source records and on the electronic Case Report Form (eCRF). 
• 
Treatment site reactions consist mainly of short-term inflammatory symptoms and generally resolve 
within 2 to 4 weeks (also see section 4.2.2).  
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 83 of 171 
Version 7.0 - 15-MAY-2024 
Empty or used syringes will not be returned to the sponsor, but will be destroyed by the investigation 
site, in line with their routine procedure for medical waste disposal. Used needles/cannulas should be 
disposed immediately after the use as per routine procedure for medical waste disposal at the site.  
According to the underlying monitoring plan (see also section 6.7) the monitor will regularly check study 
documentation and inventory of devices held by the investigator to verify accountability of all devices 
used. 
 
Any device alleged to be deficient must not be used by the investigator and must be returned to the 
sponsor´s designee. In case of device deficiencies also instructions in section 14.9 must be followed.  
6.3 
Subjects 
 
Up to 486 subjects are planned to be randomized in a 2:1 ratio (test device: 324, comparator device: 
162) and treated. Approximately 516 subjects will need to be screened to reach 486 subjects 
randomized (accounting for a screening failure rate of approx. 6%) and to ensure that 437 subjects will 
be evaluable for the primary endpoint. Approximately 300 subjects are estimated to qualify for repeat 
treatment. 
Inclusion of subjects is planned to be as equally distributed as possible between the sites. The clinical 
investigation is planned to be conducted at approximately 16 study sites with enrolment target of 
approximately 20 to 30 subjects per site. The maximum expected number of subjects to be enrolled per 
each site will be 45 but may be higher if agreed with the Sponsor. 
Each subject will take part in the investigation for up to 92 weeks.  
The total anticipated duration of the investigation, from the first-subject-first visit to the last-subject-last-
visit, is around 114 weeks, based on expected recruitment period of about 22 weeks. 
 
Subjects will be recruited by sites located in the USA (a list of the sites, including names, addresses and 
positions of the corresponding Principal Investigators, is kept separately from the CIP).  
The investigator may also offer participation in the study to potential candidates identified in their subject 
database. The investigation may be advertised as requested by the sites. In such case, the advertising 
strategy and materials will be submitted to the Institutional Review Board (IRB) / Ethics Committee 
(EC)for prior review and approval.  
Every effort will be made to include individuals with all Fitzpatrick skin types (FST, see section 6.4.2 for 
details) in a proportional pattern adequately include patients of diverse skin colcor and background in 
this study.  
The FST enrollment levels planned to be achieved are as follows: 
• 
FST I to III: approximately 80% of subjects 
• 
FST IV to VI: at least 20% of subjects  
• 
FST V and VI: approximately 10% of subjects  
These FST enrollment levels will not be seen in each investigation site, i.e., there will be over-
representation at some sites and underrepresentation at other sites. However, enrollment of the different 
FST levels will be monitored during the enrollment period via the eCRF system (report) by the project 
management team at the CRO. Details how to monitor enrollment levels via the eCRF system will be 
described in the project management plan.  
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 84 of 171 
Version 7.0 - 15-MAY-2024 
 
6.3.3.1 Inclusion criteria 
A subject must meet ALL of the following criteria to be ELIGIBLE for the study: 
1. Male or female subjects aged 22 – 75 years (inclusive) of age at Screening 
2. Subjects with bilateral, approximately symmetric moderate to severe midface volume deficit 
(severity scores of 2 or 3 on the 5-point Midface Volume Deficit Severity Scale), as assessed by 
the blinded evaluator at the site 
3. Females of childbearing potential FD must have a negative urine pregnancy test and must agree to 
use an effectiveFE 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). 
4. Healthy skin in the midface area and free of diseases that could interfere in cutaneous aging 
evaluation 
5. 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) 
6. 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 
6.3.3.2 Exclusion criteria 
A subject who meets ANY of the following criteria is NOT eligible for the study and must not be enrolled: 
1. Females, who are pregnant and/or, lactating or planning to become pregnant during the clinical 
investigation 
2. History of severe allergies manifested by a history of anaphylaxis or history or presence of multiple 
severe allergies  
3. History of hypersensitivity to hyaluronic acid preparations, lidocaine or any amide-based 
anesthetic 
4. Tendency to keloid formation and/or hypertrophic scars and/ or have pigment disorders  
5. Known human immune deficiency virus-positive individuals 
6. Presence of infectious, inflammatory or proliferative cancerous or pre-cancerous lesions in the 
treatment area  
7. Re-current (three times a year over the last year) herpes simplex in the treatment area  
8. History or presence of any autoimmune or connective tissue disease, or current treatment with 
immuno-modulating therapy 
9. Uncontrolled (or unstable) Diabetes mellitus or systemic diseases as per investigator discretion  
 
 
D A woman is considered to be of childbearing potential (WOCBP) if fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause. 
E Effective methods of birth control include: combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), 
intrauterine hormone-releasing system (IUS), bilateral tubal occlusion), vasectomized partner (provided that is the 
sole sexual partner of the subject and that the vasectomized partner has received medical assessment of the 
surgical success) and sexual abstinence (if in line with the preferred and usual lifestyle of the subject and defined 
as refraining from heterosexual intercourse during the entire period of the trial).  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 85 of 171 
Version 7.0 - 15-MAY-2024 
10. 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 
11. Implantation of dermal fillers in the treatment area within the preceding 24 months prior to Visit 1 
(Screening) and during the entire investigation 
12. 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 
13. Facial lipolysis, including submental fat treatments, within the previous 12 months prior to Visit 1 
(Screening) and during the entire investigation 
14. Bariatric surgery within 12 months prior to Visit 1 (Screening) and during the entire investigation 
15. 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., 
) 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) 
16. 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) 
17. Beard longer than three-day beard, or excessive facial hair that could interfere in evaluation of 
treatment as judged by the investigator 
18. 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. 
19. 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) 
20. Any medical condition prohibiting the inclusion in the study according to the judgment of the 
treating investigator 
21. Previous enrollment in this clinical investigation 
22. 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 
23. Midface volume deficit due to a congenital defect, trauma, or abnormalities in facial adipose tissue 
distribution such as those associated with HIV related lipodystrophy 
24. 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 
25. Any individual whose willingness to volunteer in this clinical investigation could be unduly 
influenced by the expectation, whether justified or not, of benefits associated with participation or 
of retaliatory response from senior members of a hierarchy in case of refusal to participate (e.g., 
persons with a legal custodian appointed due to mental disability, prisoners, soldiers and other 
members of the armed forces, civil servants). 
26. 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.  
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 86 of 171 
Version 7.0 - 15-MAY-2024 
 
6.3.4.1 Inclusion Criteria 
A subject must meet ALL of the following criteria to be ELIGIBLE for each touch-up-treatment: 
1. Females of childbearing potential must have a negative urine pregnancy test  
6.3.4.2 Exclusion criteria 
A subject who meets ANY of the following criteria is NOT eligible for each touch-up treatment: 
1. Occurrence of a related Serious Adverse Event or Adverse Event of Special Interest (i.e., embolic 
events, with possible, probable, or causal relationship to an intravascular injection of the device, 
as changes in vision [loss of vision, blurriness, double vision, pain in or around the eye, blindness, 
blind spots, problems moving the eyes], skin changing color around the eyelids or around the site 
of injection, other embolic phenomenon, e.g., stroke, skin necrosis, or impending necrosis) during 
or after the previous injections  
2. Subjects who experienced visual changes considered abnormal clinically significant or other 
serious medical conditions during or after the previous injections 
3. Subjects who have one of the following assessments during the visual examinations: Snellen 
acuity test worse than 20/40 (with corrective eyewear, if applicable), abnormal confrontational 
visual field test, or abnormal ocular motility test.  
 
 
The eligibility criteria given in section 6.3.5.1 and section 6.3.5.2 must be assessed for repeat-treatment. 
6.3.5.1 Inclusion criteria 
A subject must meet ALL of the following criteria to be ELIGIBLE for repeat-treatment: 
1. Subjects with bilateral, approximately symmetric moderate to severe midface volume deficit 
(severity scores of 2 or 3 on the 5-point MVDSS), as assessed by the blinded evaluator at the site. 
The subject does not have to return to his baseline severity to be permitted to receive a repeat-
treatment. 
2. Subject has completed initial treatment phase up to Visit 9 (SV1) and is willing to attend the study 
visits of the screening phase for repeat-treatment and repeat-treatment phase 
3. Females of childbearing potential must have a negative urine pregnancy test  
4. Healthy skin in the midface area and free of diseases that could interfere in cutaneous aging 
evaluation 
6.3.5.2 Exclusion criteria 
Subjects who meet ANY of the following criteria are NOT eligible for repeat-treatment: 
1. Occurrence of a related Serious Adverse Event or Adverse Event of Special Interest (i.e., embolic 
events with possible, probable, or causal relationship to an intravascular injection of the device, as 
changes in vision [loss of vision, blurriness, double vision, pain in or around the eye, blindness, 
blind spots, problems moving the eyes], skin changing color around the eyelids or around the site 
of injection, other embolic phenomenon, e.g., stroke, skin necrosis, or impending necrosis) during 
or after the baseline injection and/or touch-up injections 
2. Occurrence of a related Adverse Event that occurred during the initial treatment phase, and is 
ongoing at the time of the repeat treatment (i.e., relationship is classified as “possible”, “probable” 
or “causal relationship”; outcome is “not recovered / resolved”, “recovering / resolving”, “recovered 
/ resolved with sequelae” or “unknown”)   
3. Subjects who experienced visual changes considered abnormal clinically significant or other 
serious medical conditions during or after the baseline or touch-up injections, respectively 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 87 of 171 
Version 7.0 - 15-MAY-2024 
4. Subjects who have one of the following assessments during the visual examinations: Snellen 
acuity test worse than 20/40 (with corrective eyewear, if applicable), abnormal confrontational 
visual field test, or abnormal ocular motility test 
5. Subjects who became pregnant since start of the study or planning to become pregnant during the 
clinical investigation 
6. Known human immune deficiency virus-positive individuals 
7. Presence of infectious, inflammatory or proliferative cancerous or pre-cancerous lesions in the 
treatment area  
8. Development of re-current (three times a year over the last year) herpes simplex in the treatment 
area since study start 
9. Development of any autoimmune or connective tissue disease since study start, or current 
treatment with immuno-modulating therapy 
10. Development of uncontrolled (or unstable) diabetes mellitus or systemic diseases since study start 
as per investigator discretion  
11. Facial plastic surgery, tissue augmentation with silicone, fat or another non-absorbable substance 
(permanent fillers) and semi-permanent fillers (e.g., poly-L-lactic acid) in the area of device 
application and during the initial treatment phase of the investigation 
12. Implantation of dermal fillers (other than the test and comparator device used in the investigation) 
in the treatment area during the initial treatment phase of the investigation  
13. Subject has received any of the following aesthetic treatments in the midface area: e.g., laser 
therapy, absorbable and non-absorbable sutures (threads), dermabrasion, mesotherapy, micro-
needling and/or botulinum toxin (including treatment of crow´s feet in the outer eye region), or 
chemical peeling during the initial treatment phase of the investigation or is planning to undergo 
such procedures during the repeat-treatment phase of the investigation 
14. Facial lipolysis, including submental fat treatments during the initial treatment phase of the 
investigation  
15. Bariatric surgery during the initial treatment phase of the investigation 
16. Development of bleeding disorder and/or use of anticoagulant, antiplatelet, thrombolytic 
medication, or anti-inflammatory drugs (oral/injectable corticosteroids or non-steroidal anti-
inflammatory drugs, e.g.,
) or other substances known to increase coagulation 
time (vitamins or herbal supplements, e.g., St. John’s Wort, high doses of vitamin E supplements) 
from ten days pre- to seven days post injection (repeat-treatment and touch-up treatment) 
17. Planned dental/oral surgery or modification (bridge-work, implants) within four weeks prior to the 
injection and to a minimum of four weeks post injection  
18. Beard longer than three-day beard, or excessive facial hair that could interfere in evaluation of 
treatment as judged by the investigator 
19. Any medical condition prohibiting the inclusion for repeat-treatment according to the judgement of 
the treating investigator  
20. Previous enrollment in initial treatment phase of this clinical investigation and early termination, or 
significant incompliance with the protocol requirements 
21. Current or previous treatment with another investigational drug and/or medical device or 
participation in another clinical study  
22. Midface volume deficit due to a trauma, or abnormalities in facial adipose tissue distribution such 
as those associated with HIV related lipodystrophy 
23. Subjects who experienced weight change for a minimum of 10% since study start or subjects who 
have the intention to change eating habits that result in a weight gain or loss >10% during the 
entire investigation  
24. Subjects with active COVID-19 infection and subjects with symptoms consistent with COVID-19 
infection including any other respiratory symptoms/illnesses within the past 14 days unless tested 
negative prior to Visit RT1  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 88 of 171 
Version 7.0 - 15-MAY-2024 
 
The subject MUST be withdrawn from the investigation for any of the following reasons: 
1. Withdrawal of consent: At any time during the investigation and without giving reasons, a subject 
may decline to participate further. The subject will not suffer any disadvantage as a result. 
The subject MAY be withdrawn from the investigation for any of the following reasons: 
1. Occurrence of an AE which requires a premature termination of the treatment or precludes follow-
up of the subject (e.g., COVID-19) 
2. A major CIP deviation, which may interfere with evaluation of the treatment outcome (e.g., 
additional aesthetic correction of the defect during the course of the investigation, use of prohibited 
medication, or similar) 
3. Investigator’s decision, triggered by safety, behavioural or administrative reasons 
4. Pregnancy; Note: pregnant women must be withdrawn from further treatment; However, 
pregnant women may remain in the study for safety assessments during the scheduled study 
visits.  
5. Subjects with abnormal clinically significant changes in visual examination after treatment must be 
withdrawn from further treatment in case an eye specialist confirms that the result is related to a 
vascular injection of the dermal filler (see section 6.4.8 and section 16.1).  
The subjects may remain in the study at least for safety assessments during the scheduled study 
visits. 
6. Subjects who experience neurological symptoms indicative of a vaso-occlusional event after 
treatment must be withdrawn from further treatment in case a neurologist confirms that the result 
is related to a vascular injection of the dermal filler (see section 6.4.9, also see section 16.1).  
The subjects may remain in the study at least for safety assessments during the scheduled study 
visits. 
Reasons, circumstances and findings related to early withdrawal should be fully described in the 
subject’s source records and the eCRF respecting the subject’s rights.  
Attempts should be made to perform an early termination visit, which should consist of the assessments 
planned for Visit 9 (SV1), Visit SV2 to SV4 or Visit RT5 (depending on the study phase) – also see 
section 6.5.16. In the event that the withdrawal is caused by an AE, the procedures stated in section 14 
must be followed. 
Efforts should be made, however, to get in touch with subjects who did not attend a scheduled visit and 
clarify the reason for default. The two attempts with also sending a registered letter to subject must be 
made and documented to try and make contact. If the subject is unreachable, a corresponding note 
should be provided in the subject´s source record. 
Depending on the time point of withdrawal, a withdrawn subject is referred to as either “screening failure” 
or “withdrawal” (see section 6.3.11).  
 
Subjects withdrawn from the investigation or lost for follow-up will not be replaced.  
No re-screening is allowed. An exception may be granted with prior approval of the sponsor in case that 
subjects are withdrawn due to restrictions that might occur in the context of the ongoing COVID-19 
pandemic (e.g., in case conduction of the clinical investigation in a protocol-conformal manner is no 
longer possible due to a new pandemic situation comparable to the COVID-19 pandemic in spring 2020). 
 
Contraception 
Women of childbearing potential participating should not be pregnant and should use effective 
contraception methods throughout the clinical investigation or avoid unprotected sexual intercourse. Any 
pregnancy occurring in study subjects should be reported and followed-up as described in section 14. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 89 of 171 
Version 7.0 - 15-MAY-2024 
Note 1: A woman is considered to be of childbearing potential (WOCBP) if fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. 
Note 2: Effective methods of birth control include: combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), 
intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (provided that is the 
sole sexual partner of the subject and that the vasectomized partner has received medical assessment of the 
surgical success and sexual abstinence (if in line with the preferred and usual lifestyle of the subject and defined as 
refraining from heterosexual intercourse during the entire period of the trial).  
Male subjects should use an effective contraceptive method as a reproductive damage on the seminal 
fluid cannot be ruled out. Male fertile participants need to ensure safe contraception to prevent their 
female partner of childbearing potential from becoming pregnant. Contraceptive methods include 
surgical sterilization or a physical barrier such as a condom when having penile-vaginal intercourse. 
This applies from throughout the clinical investigation. Males will be counseled to inform their female 
partner about the participation in the clinical investigation. 
Other restrictions  
The following restrictions apply to all subjects: 
• 
Make-up should not be applied for 12 hours after each device injection 
• 
Within the first 24 hours after each device injection, subjects should avoid strenuous exercise and 
extensive sun or heat exposure. Exposure to any of the above may cause temporary redness, 
swelling, and/or itching at the treatment sites.  
Note: If the treated area is swollen, an ice pack may be applied to the site for a short period. 
• 
Prolonged exposure to sunlight or ultraviolet (UV) radiation must be avoided for one week after 
each device injection. 
• 
To minimize the risk of product mobility, the subject should be advised to avoid massaging the 
treatment site or applying pressure to this area for one week following each device injection 
(exception: a light massage may be applied after injection of the device for uniform distribution of 
the filler by the investigator – see Table 15 in section 6.2.2) 
• 
Use of saunas or Turkish baths is prohibited for one week after each device injection. 
• 
Beard longer than three-day beard, or excessive facial hair that could interfere in evaluation of 
treatment as judged by the investigator (see ExC#17 in see section 6.3.3 and ExC#18 in section 
6.3.5) 
 
The following medications and treatments are prohibited prior to start of the investigation (Visit 1) and 
during the entire investigation, if not stated otherwise below (also refer to the respective ExC in 
section 6.3.3 to 6.3.5): 
• 
History or presence of any autoimmune or connective tissue disease, or current treatment with 
immune therapy  
• 
Previous facial plastic surgery, tissue augmentation with silicone, fat or another non-absorbable 
substance (permanent fillers) 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.  
o 
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 and during the entire investigation 
o 
chemical peeling within the last three months prior to Visit 1 and during the entire 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 90 of 171 
Version 7.0 - 15-MAY-2024 
investigation,  
or is planning to undergo such procedures during the 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  
• 
Anticoagulant, antiplatelet, or thrombolytic drugs, or anti-inflammatory drugs (oral/injectable 
corticosteroids or non-steroidal anti-inflammatory drugs, e.g., Motrin® or Advil®) or other 
substances known to increase coagulation time (vitamins or herbal supplements, e.g., St. John’s 
Wort, high doses of vitamin E supplements) from ten days pre- until seven days after each 
injection of the device  
• 
Planned dental/oral surgery or modification (bridge-work, implants) within four weeks prior to 
baseline and repeat-treatment device injection and to a minimum of four weeks post device 
injections  
• 
Current or previous treatment with another investigational drug and/or medical device or 
participation in another clinical study (within 30 days of Visit 1 (Screening) and entire investigation) 
• 
Change in eating habits that result in a weight gain or loss >10% during the entire investigation  
• 
According to IB (section 8.1.5) and IFU for
 [14] (section B. Health 
Care Professional Instructions #5) sensitive skin may be pre-treated using a local anaesthetic 
patch or cream or injectable anesthesia. However, injectable anaesthesia is not allowed to 
manage pain during and after injection in this investigation. Additional topical anaesthetic (patch 
or cream) is allowed but should be avoided possible (i.e., if the subject agrees) to not falsify the 
pain assessment (as collected via Numerical Pain Rating Scale; see section 6.4.14).  
 
The study participants will not receive any study-specific treatment after their final study visit. Any further 
treatment, if needed, will be proposed to the subject by the investigator at their discretion. 
 
Initial treatment phase 
• 
Subjects who have signed the ICF but are not randomized and are not treated for any reason will 
be considered as screening failures. Data for screening failures will be documented in appropriate 
forms (e.g., Subject Screening/Enrollment Log). Screening data for these subjects will be kept in the 
Investigator’s File. The type of data to be entered in the eCRF, if any, will be defined in the eCRF 
Completion Guidelines.  
• 
Subjects who prematurely discontinue the investigation after receiving at least one dose of the 
device and who are not screening failures will be defined as withdrawals / dropouts.  
• 
Subjects who complete the initial treatment phase (incl. Visit 9 (SV1)) but do not participate in the 
optional repeat-treatment phase are defined as completer (initial treatment phase).  
Optional repeat-treatment phase including screening phase for repeat-treatment 
• 
Subjects who enter the screening phase for optional repeat-treatment and  
o 
who are not eligible for the repeat-treatment phase and who are not treated for any reason 
during repeat-treatment phase will be considered as screening failures for repeat-treatment 
(SV1, SV2, SV3, SV4, RT1) 
o 
who are eligible but do not participate in the optional repeat-treatment phase will be 
considered as completer (initial treatment phase) 
• 
Subjects who prematurely discontinue the investigation after receiving at least one dose of the 
device at Visit RT1 will be defined as withdrawals / dropouts.  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 91 of 171 
Version 7.0 - 15-MAY-2024 
• 
Subjects who complete the repeat-treatment phase (incl. Visit RT 5) are defined as completer 
(repeat-treatment phase). 
 
Subjects’ privacy and data confidentiality will be protected in line with the principles of Good Clinical 
Practice (GCP), the European General Data Protection Directive (GDPR), Health Insurance Portability 
and Accountability Act (HIPAA) and other applicable international and national requirements. Personal 
subject data transferred to CROMA-PHARMA GmbH in Austria should be in compliance with the 
European GDPR. Subjects will provide authorization for use of their personal data in accordance with 
the applicable regulations regarding privacy and data protection. 
A unique numerical subject identification code will be assigned to each subject at screening. The format 
of the codes will be defined in the CRF Completion Guidelines. The investigator will assign the codes in 
ascending order, in line with the order of the informed consent date and time.  
The investigator must ensure that anonymity of the subjects will be maintained and that their identities 
are protected from unauthorized parties.  
In the eCRF or any other document submitted to the sponsor or sponsor’s representative, subjects must 
be identified only by their identification codes; use of names, initials, complete birthdates, addresses, 
telephone numbers, electronic addresses or similar information is prohibited.  
The investigator will keep the Subject Identification Log (including complete name, date of birth, and 
contact details of each subject). The investigator must maintain these documents in strict confidence. 
For GCP compliance, all subjects will be informed and consented regarding the access to their personal 
investigation-related data by the monitors, auditors and inspectors of the clinical investigation, as well 
as transmission of their coded data to the sponsor or sponsor’s representative and data retention for the 
duration defined in section 8.4. Professionals with access to subjects’ data for monitoring, audits and 
inspections are bound to preserve strict confidentiality. 
This CIP, other investigation-related documentation, collected data and all other information generated 
will be held in strict confidence. No information concerning the clinical investigation, nor the data 
collected will be released to any unauthorized third party without prior written approval of the sponsor. 
Clinical photography 
Besides live assessments by the blinded evaluator at the site, midface volume deficit will additionally be 
assessed by a central independent blinded photographic reviewer using photographs (see 
section 6.4.13). In addition, the photographs will be used for volumetric change measurement (see 
section 6.4.12) and modified GAIS assessment by the blinded evaluator at the site and subject (see 
section 6.4.16).  
All photographs are submitted to the photo provider in a non-masked manner. During the study, all 
photographs will be stored in the data base of the photo provider in a non-masked and a masked version, 
respectively, to allow for review and assessments as required. Image masking will occur during the 
monitoring process and a 100% quality check will be completed by the photo provider to ensure all 
images are de-identified before they are forwarded to the sponsor. Details will be given in a separate 
manual. 
Photographs used for publication purposes will not reveal the subject´s identity. For this purpose, 
subject’s eyes will either not appear on the photographs or will be masked with e.g., a black bar; other 
attributes visible on the photographs that could identify a subject (e.g., characteristic scars, tattoos).  
Subjects will be explicitly informed about these matters when obtaining written informed consent.  
6.4 
Assessments and procedures 
Assessments and procedures that will be performed during the investigation are described below. The 
exact timing of each assessment is indicated in Table 1 to Table 3 and in section 6.5. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 92 of 171 
Version 7.0 - 15-MAY-2024 
It is the treating investigator’s obligation to assure documentation of all relevant data in the subject’s 
source record and the eCRF, such as medical history and concomitant diseases, date of enrollment into 
the clinical investigation, visit dates, results of examinations, application of the device, AEs and device 
deficiencies. 
All subject questionnaires assessing improvement and satisfaction with appearance and outcome (i.e., 
modified GAIS, FACE-QTM) should preferably be done at the beginning of the respective visit to avoid 
potential influence of investigator’s comments on subject’s perception during the visit.  
Important note: The assessments and procedures described in the following sections must ONLY be 
conducted by the treating investigator (or trained site staff, if applicable), except for the MVDSS, 
NLF-SRS and modified GAIS rating, that will be done by the blinded evaluator at the site. The central 
independent blinded photographic reviewer will conduct MVDSS assessment (see section 6.4.13).  
To ensure consistency of effectiveness assessments over the study duration, it is preferred that the 
same person performs the same assessments on the same subject across all visits. 
Treatment-related procedures are described in section 6.2.2, AE and device deficiency collection 
procedure in section 14.9. All other assessments and procedures are described below. 
Actions during ongoing COVID-19 pandemic 
During COVID-19 pandemic situation, special risk mitigation procedures need to be performed to protect 
the safety of subjects, site personnel and other persons involved. Possible mitigation measures to be 
taken into consideration by the study sites are described in section 4.4.  
In addition, a separate CIP addendum (see section 4.4) gives detailed information about the possible 
mitigation measures and alternative procedures in case of restrictions during the pandemic. 
If the conduct of visits or assessments of a specific subject is affected by the COVID-19 situation this 
should be documented in the subject´s source records.  
 
Information on subject’s year of birth, gender, race and ethnicity will be collected. All demographic data 
will be documented in the subject´s source record and in the eCRF. 
 
The Fitzpatrick skin type (FST) scale [44] is a widely used numerical classification scheme for human 
skin color shown in Table 18. 
Table 18. Fitzpatrick skin types. 
Skin type  
Characteristics 
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 
Rarely burns, tans very well (moderate brown) 
VI 
Never burns, deeply pigmented 
Skin type of the subject will be documented in the subject´s source record and in the eCRF.  
Note: Enrollment levels for subjects of all FST is encouraged (see section 6.3.2 for details). 
 
For body weight measurement, the subject must stand barefoot and wear light indoor clothing. Body 
weight will be recorded to the nearest kilogram in the subject´s source record and the eCRF. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 93 of 171 
Version 7.0 - 15-MAY-2024 
Any findings in the body weight measurement at Screening (Visit 1) will be recorded in the subject´s 
source record and in the eCRF as medical history (see section 6.4.5).  
Any changes of clinical relevance (significant weight loss or weight gain) compared to the Screening 
(Visit 1) measurement may represent an AE. The Investigator will evaluate if the change is due to a 
medical reason (e.g., an accompanying disease like metabolism disorders or cancer, unintended 
appetite gain/loss, edema), and - if medically reasonable - will record the diagnosis in the subject´s 
source record and document in the eCRF as an AE (see section 14). 
 
In females of childbearing potential, including women who are postmenopausal for less than twelve 
months, urine pregnancy tests will be performed using a dipstick test. The result will be recorded in the 
subject’s source record and the eCRF. 
In case of positive test result at Screening (Visit 1) the subject must not be enrolled. Any female subject 
who becomes pregnant while participating in the investigation must be withdrawn from the study (also 
see section 6.3.6).  
The Investigator will collect pregnancy information on any female subject who becomes pregnant while 
participating in this study. Pregnancy needs to be reported and followed-up as described in section 14.5 
and section 14.5.5. 
 
Relevant medical history findings (including major surgeries) will be collected at Screening (Visit 1) from 
subject interview and source records (if available). An update will be collected at Baseline (Visit 2).  
Special attention should be paid to diseases and conditions assessed in exclusion criteria (see section 
6.3.3), especially findings of clinical significance in visual examinations prior to the first treatment at 
Baseline visit (Visit 2) (see section 6.4.7).  
Any medical condition / disease that is still present (ongoing) at Screening (Visit 1) should also be 
considered as concomitant disease. If such condition, however, deteriorates after Screening (Visit 1), at 
any time during the investigation, it should be documented as an AE (see section 14). 
Medical history findings will be documented in the subject´s source record and in the eCRF by diagnosis 
and time of diagnosing (start date and end date, if applicable). 
 
Aesthetic history is defined as aesthetic findings limited to procedures on the face.  
Aesthetic history will be collected at Screening (Visit 1) from subject interview and source records (if 
available). An update will be collected at Baseline (Visit 2). Special attention should be paid to aesthetic 
procedures relevant for exclusion criteria (see section 6.3.3).  
Findings will be documented in the subject´s medical record and in the eCRF by diagnosis and time of 
diagnosing (start date and end date, if applicable). 
 
All medications (prescription and over-the-counter products) taken and non-pharmacological procedures 
applied from 10 days prior to Screening (Visit 1) up to the End of Study Visit will be documented in the 
subject´s source record and in the eCRF. 
Medications will be classified by drug generic name / trade name or active substance (in case no generic 
name is available).  
Prohibited concomitant medications and non-pharmacological procedures (including surgeries or 
aesthetic procedures, see section 6.4.6) are listed in section 6.3.9. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 94 of 171 
Version 7.0 - 15-MAY-2024 
 
Visual examinations (including Snellen visual acuity, confrontational visual fields and ocular motility) will 
be performed at the study site by treating investigator or authorized designee as indicated in the 
“Schedule of procedures and assessments” (Table 1 and Table 3).  
If device is administered during a visit, the examination will be performed both before and 30 min after 
each injection.  
Overview of visual examinations 
• 
Snellen acuity test: Visual acuity is the eye’s ability to detect subtle details and is the measure of 
the eye’s ability to see a sharp image at a specific distance. Visual acuity is determined by using a 
letter board. 
• 
Confrontational visual field test: A confrontation visual field test is a quick and easy way to 
measure overall field of vision. This diagnostic test is also commonly known as the finger counting 
exam because the examiner may use his own fingers during the test. In general, human vision is 
divided into 4 quadrants (superior, inferior, nasal and temporal) in brain. The examiner will check 
the field of vision in each quadrant. 
In normal individuals  
o 
Superior field extends 55 to 60 deg from fixation  
o 
Nasal field extends from 60 to 65 deg from fixation 
o 
Inferior field extends from 70 to 75 deg from fixation 
o 
Temporal field extends 90 to 95 deg from fixation 
• 
Ocular motility: Normal ocular motility is considered as the conjugate, full and painless movements 
of both eyes in all directions. It includes the study of 12 extra-curricular muscles and their impact on 
eye movement. To be more specific each eye has 6 muscles, four recti and two obliques, which 
when functioning normally allow the eyes to work together in a wide range of gaze. Restriction of 
movement in particular gaze          signifies the involvement of a specific muscle.  
All visual examination results and the use of corrective eyewear (i.e., glasses/contact lenses) will be 
documented in the subject´s source record and in the eCRF.  
Note: The subject should wear the same corrective eyewear (i.e., glasses/contact lenses) at each 
assessment, if appropriate. Details how to conduct visual examinations will be given in a separate 
manual.  
Abnormal Visual Examinations at Baseline (Visit 2) 
Any abnormal findings in visual examinations prior to the first treatment at Baseline visit (Visit 2) will be 
recorded as medical history (see section 6.4.5) in the subject´s medical record and in the eCRF. Special 
attention should be paid to ExC#18 (see section 6.3.3). 
The following results from visual examinations at Baseline (Visit 2) will be considered abnormal and will 
exclude the subject from participation in the study: 
• 
Snellen acuity test: Abnormality is defined as any result worse than 20/40 (with corrections, if 
applicable) 
• 
Confrontational visual field test: Any abnormality at baseline will be considered if the subject 
fails to identify or count the finger(s) 
• 
Ocular motility: Any deviation in the eye movement from the above given normal is considered as 
abnormal at baseline.  
Abnormal Visual Examinations after Baseline visit (Visit 2)  
Any clinically significant change compared to prior each device application will be recorded as AE 
according to section 14 in the subject´s source record and the eCRF. Special focus must be on the 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 95 of 171 
Version 7.0 - 15-MAY-2024 
Adverse event of special interest (AESIs) as defined in section 14.1.Any of the following changes in 
visual examinations after respective Baseline result will be considered abnormal clinically significant: 
• 
Snellen acuity test: Any worsening of 2 lines or more in best corrected visual acuity (i.e., with 
glasses/contact lenses) 
• 
Confrontational visual field test: Any change to the peripheral vision 
• 
Ocular motility: Any change in the normal ocular motility  
Respective Baseline results are defined as follows:  
• 
Results at each visit will be compared to the results prior to first injection of each treatment phase, 
i.e., Visit 2 for initial treatment phase and Visit RT1 for repeat-treatment phase.  
• 
At treatment visits, visual examinations will be performed before the injection and 30 min after the 
injection. The result post-injection (30 min after) will be compared to the results prior the injection.  
If any of the above changes occur at any assessment, the treating investigator must refer the subject to 
an eye specialist to evaluate if the result is related to a vascular injection of the dermal filler. If the eye 
specialist confirms that the result is related to a vascular injection of the dermal filler, the subject must 
be withdrawn from further treatment(s) (see section 6.3.6) and further activities following a related 
vascular event will be reviewed (see section 16.1).  
The subjects may remain in the study at least for safety assessments during the scheduled study visits. 
 
The “F.A.S.T” examination is a basic neurological examination that will be performed by treating 
investigator (or authorized designee) according the instructions given in Table 19 for all subjects who 
show signs of ophthalmic complications due to filler injection.[27, 28] 
Table 19. F.A.S.T. Warning Signs and Instructions for Use (adapted per [27, 28]) 
Symptom 
Instructions for Use 
F - Facial 
drooping 
Ask the patient to smile or show teeth. Look for lack of symmetry.  
Does one side of the face droop or is it numb?  
Is the person's smile uneven? 
A - Arm weakness 
Lift the patient´s arms together to 90° if sitting; 45° if supine and ask him/her to hold the position for 5 
seconds then let go. Or ask the person to raise both arms. 
Is one arm weak or numb?   
Does one arm drift downward or fall rapidly? 
S - Speech 
difficulty 
Look for disturbance of speech.  
Look for slurred speech.  
Look for word-finding difficulties. This can be confirmed by asking the patient to name commonplace 
objects that may be nearby, such as a cup, chair table, keys, pen. 
If there is a severe visual disturbance, place an object in the patient´s hand and ask him/her to name it.  
T - Time  
Time to call emergency services 
More ways to spot a stroke [27] 
• 
Sudden weakness or numbness of face, arm or leg, especially on one side. 
• 
Sudden confusion, trouble speaking or understanding. 
• 
Sudden trouble seeing in one or both eyes. 
• 
Sudden trouble walking, dizziness, loss of balance or coordination. 
• 
Sudden, severe headache with no known cause. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 96 of 171 
Version 7.0 - 15-MAY-2024 
If any of the symptoms above are showing, time is of the essence; call the emergency services and 
redirect the patient to the hospital / acute stroke unit immediately. 
Any clinically significant change compared to prior of each device application will be recorded as AE 
according to section 14 in the subject´s source record and the eCRF. Special focus must be on the 
AESIs as defined in section 14.1. 
If any of the above changes occurs at any assessment, the treating investigator must refer the subject 
to a neurologist to evaluate if the result is related to a vascular injection of the dermal filler.  
If the neurologist confirms that the result is related to a vascular injection of the dermal filler, the subject 
must be withdrawn from further treatment(s) (see section 6.3.6) and further activities following a related 
vascular event will be reviewed (see section 16.1). The subjects may remain in the study at least for 
safety assessments during the scheduled study visits. 
 
The following information will be documented in the subject´s source record and the in eCRF:  
• 
Injection volume (see section 6.2.3 for details) 
o 
the volume injected will be calculated by the investigator based on the number of syringes used 
and the estimated amount of the gel remaining in each of the syringes used)  
o 
the injection volume will be documented separately  
- 
for right and left side of the midface  
- 
for each anatomical area of the midface (see section 6.2.2 for details) 
- 
per each treatment (i.e., for baseline- and repeat treatment and each touch-up treatment (if 
applicable) 
• 
Kit numbers of kits used (see section 6.2.1 for details) 
• 
Injection technique (see section 6.2.2 for details) 
• 
Injection equipment used (i.e., needle or cannula (see 6.2.2 for details). Note: A minimum of 100 
subjects randomized to the test device will be treated with either needle or cannula. Use of either 
needle or cannula is based on the treating investigator´s medical decision. Details how to monitor 
enrollment levels via the eCRF system will be described in the project management plan. 
• 
Exact start time and end time of injection 
For detailed instructions on administration of the devices refer to section 6.2.2. 
 
Photographs of the subject´s full face subject´s and neck will be taken by the investigator or designee 
using a digital 3D (three-dimensional) camera (provided by 
 the photo provider). 
Note: In addition to clinical photography (3D photos), another baseline photo (2D) should be taken 
on-site at Visit 1 (for details refer to a separate photography manual). This 2D photo will be used 
as baseline photo to evaluate the global aesthetic improvement (see below) in case of restrictions 
during the COVID-19 pandemic. Details are outlined in an addendum to the CIP. 
If device is administered at the respective visit, photography must be conducted before the application 
of the device. 
The photographs will be used  
• 
for publication purposes (see section 6.3.12) 
• 
for volume change measurements (see section 6.4.12)  
• 
for evaluation of severity of midface volume deficiency using the 5-point MVDSS by a central 
independent blinded photographic reviewer (see section 6.4.13) 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 97 of 171 
Version 7.0 - 15-MAY-2024 
• 
for assessment of global aesthetic improvement using the modified GAIS by the blinded evaluator 
at the site and subject (see section 6.4.16) 
Any excessive or distracting make-up has to be removed before photos are taken. A standardized 
procedure will be applied to ensure consistency of the background, camera settings, lighting, and subject 
position between the visits and across the sites.  
Details will be given in a photography manual provided by
. 
 
Computerized volume change measurements (
 will be used to evaluate the 
volume changes following injection of the device.  
The volume changes quantified by measuring the difference between the 3D photography images taken 
at follow-up visits as indicated in the “Schedule of procedures and assessments” (post-treatment) 
relative to baseline pre-treatment pictures (taken at Visit 1) in the specified areas of interests (AOIs). 
The anatomical areas of interest (AOIs) are given below and shown in Figure 4:  
• 
Anteromedial cheek (left and right) 
• 
Submalar (left and right) 
• 
Zygomaticomalar (left and right) 
The analysis script will produce measurements of positive, negative, and total volume change in 
comparison to the Screening (Visit 1) image for each AOI and for the combined AOIs of the left and right 
sides of the face. The left and right midface will be evaluated separately. 
Figure 4. Anatomical areas of interest (AOI) for volume change measurements. 
Once the photography images are received at the photography provider at the end of the initial treatment 
phase (i.e., all subjects have completed Visit 9 (SV1)), they will be analyzed based on scripts and 
procedures unique to the underlying application.  
 
The severity of midface deficit will be evaluated based on the Midface Volume Deficit Severity Scale 
(MVDSS), which is a validated 5-point rating scale ranging from grade 0 (none/minimal) to grade 4 (very 
severe).  
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 98 of 171 
Version 7.0 - 15-MAY-2024 
The scale is briefly described in Table 20. The detailed MVDSS is provided in section 20.1. 
Table 20. Croma - Midface Volume Deficit Severity Scale (MVDSS) 
Note: No separate assessments will be performed for the right and left midface region. Only subjects 
with approximately symmetrical deficit will be included into the study (see InC#2 in section 6.3.3), so the 
left and the right cheek will not be graded separately. If asymmetry emerges during follow-up, which is 
unlikely, the grade will be assigned according to the side with a larger deficit, and asymmetry will be 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 99 of 171 
Version 7.0 - 15-MAY-2024 
recorded as an AE. If InC#2 is violated and asymmetry is already present at Day 0, the grade will also 
be assigned according to the side with the larger deficit. The same applies to eligibility for repeat-
treatment (see InC#1 in see section 6.3.5).  
Blinded evaluator at site: 
• 
The blinded evaluator at the site will perform a live assessment of midface volume deficit based 
on the MVDSS before each treatment and at each follow up visit (see Table 1 and Table 3)  
The assessments of the blinded evaluator will be documented in a MVDSS Rating Sheet indicating: 
• 
the date and visit of the assessment  
• 
the subject ID 
The MVDSS Rating Sheets will be filed in the subject´s source record and results will be transferred in 
the eCRF by an unblinded member of the investigation site (see section 6.1.3). 
Central independent blinded photographic reviewer 
The severity of volume deficiency will additionally be assessed by central independent blinded 
photographic reviewers using MVDSS on photographs (see section 6.4.11) before baseline treatment 
and at each follow up visit of the initial treatment phase (see Table 1). 
This assessment is performed after the photo has been uploaded and after all subjects have completed 
Visit 9 (SV1). The central independent blinded photographic reviewer will be dislocated from the 
investigation sites and will not discuss any findings with the investigators during the investigation. Further 
details will be described in a separate manual.  
Note: For both, the blinded evaluator at the site and the central independent blinded photographic 
reviewer, the rater blinding regarding treatment group in initial treatment phase will remain in effect 
during the repeat-treatment phase until study data base lock.  
 
The severity of nasolabial folds (NLFs) will be assessed using the Nasolabial Folds Severity Rating 
Scale (NLF-SRS). The NLF-SRS is a 5-point rating scale ranging from grade 0 (none/minimal) to grade 4 
(extreme). Separate assessments will be performed for the right and left NLFs.  
The scale is briefly described in Table 21. The detailed NLF-SRS is provided in section 20.2. 
Table 21. Croma - Nasolabial Folds Severity Rating Scale (NLF-SRS)  
The blinded evaluator at the site will perform a live assessment of nasolabial folds severity based on 
the NLF-SRS before each treatment and at each follow up visit (see Table 1 and Table 3).  
The assessment of the blinded evaluator will be documented in the NLF-SRS Rating Sheet indicating: 
• 
the date and visit of the assessment  
• 
the subject ID 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 100 of 171 
Version 7.0 - 15-MAY-2024 
The NLF-SRS Rating Sheets will be filed in the subject´s source record and results will be transferred 
in the eCRF by an unblinded member of the investigation site (see section 6.1.3). 
 
After each treatment with the device, the subject will be asked by the treating investigator to quantify the 
pain associated with the procedure by means of a semi-quantitative 11-point Numeric Pain Rating Scale 
(NPRS), where “0” corresponds to no pain, and “10” to the worst pain imaginable.[38] Separate pain 
assessments will be performed for the right and left midface area treated. 
Pain intensity will be assessed immediately after injection (approx. +3 min), and at 15 min-intervals 
(approx. ±3 min) after end time of the device administration for 60 min post-treatment by asking the 
subject one of the following questions, as appropriate: 
• 
“How would you rate the pain you have felt during the treatment, if “0” is no pain at all, and “10” is 
the worst pain you can imagine?” 
• 
“How would you rate the pain you have felt during recovery from the treatment, if “0” is no pain at 
all, and “10” is the worst pain you can imagine?” 
Subject’s response will be recorded on the Pain Assessment Form. If additional local anesthesia is used, 
this has to be documented on the Pain Assessment Form as well. The subject will be provided with the 
appropriate questionnaire in local language.  
Completed subject’s Pain Assessment Form will be considered as source documents and archived in 
the subject’s source record. The results will be transferred into the eCRF.  
 
The global aesthetic improvement after correction of midface volume deficit will be independently 
evaluated by the blinded evaluator at the site and the subject using the modified Global Aesthetic 
Improvement Scale (modified GAIS; based on [35]), a widely-used instrument presented in Table 22. 
Table 22. Modified Global Aesthetic Improvement Scale (GAIS) 
Subject 
The subject will be asked to evaluate the global aesthetic improvement by reviewing the photographs 
taken at the current visit relative to photographs taken at the Baseline visit. For the assessment, the 
subject will answer the modified GAIS shown in Table 22 in local language. 
Completed subject’s modified GAIS will be considered as source documents archived in the subject’s 
source record. The results will be transferred into the eCRF.  
Blinded evaluator at the site 
The blinded evaluator at the site will evaluate the global aesthetic improvement by reviewing the 
photographs taken at the current visit relative to photographs taken at the Baseline visit. Results will be 
recorded using the modified GAIS rater form (to be filed in the subject´s source record) transferred into 
the eCRF (see section 6.1.3).  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 101 of 171 
Version 7.0 - 15-MAY-2024 
 
Subject’s satisfaction with the overall treatment will be assessed using the FACE-QTM Questionnaire 
“Satisfaction with Outcome” (Patient experience scale: Outcome) in order to evaluate the performance 
of the devices and consistency in alignment with subject expectation. 
The questionnaire is a validated instrument for evaluation of subject´s satisfaction with the overall 
outcome of the treatment.[36, 37] It comprises 6 positively worded items that ask the subjects to indicate 
how they feel about the result of their most recent facial aesthetic procedure.  
Four response options are provided (i.e., ‘definitely agree’, ‘somewhat agree’, ‘somewhat disagree’, and 
‘definitely disagree’). For each statement, the subject may circle only one answer. The scale is described 
in Table 23 below. 
Table 23. FACE-QTM Questionnaire – “Satisfaction with outcome” 
The subject will be provided with the appropriate questionnaire in local language.  
Completed questionnaires will be considered as source documents and archived in the subject’s source 
records. The results will be transferred into the eCRF.  
 
Subject’s satisfaction with overall midface augmentation will be evaluated using the respective 
FACE-QTM Questionnaire (Appearance appraisal scale: Cheeks).  
The scale is a validated instrument for evaluation of subject´s satisfaction with cheeks. It comprises 5 
items. The scale measures the appearance of cheeks (side of the face below cheekbones) with items 
that ask about fullness, symmetry and attractiveness.[37]  
Four response options are provided (i.e., ‘very dissatisfied, ‘somewhat dissatisfied’, ‘somewhat 
satisfied’, and ‘very satisfied’). For each statement, the subject may circle only one answer. The scale 
is described in Table 24 below. 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 102 of 171 
Version 7.0 - 15-MAY-2024 
Table 24. FACE-QTM appearance appraisal scale – “Satisfaction with cheeks”. 
The subject will be provided with the appropriate questionnaire in local language.  
Completed questionnaires will be considered as a source document and archived in the subject’s source 
records. The results will be transferred into the eCRF.  
 
The subjects will be asked to document predefined injection site reactions and symptoms of interest in a 
web-based electronic diary (eDiary).  
Access to the eDiary needs to be initiated by site staff for each subject at the end of the initial and repeat-
treatment session. Site staff will thoroughly train the subjects on completing the eDiary. Details on 
handling of the eDiary (e.g., initiation of accounts, training and instruction for the subjects, cancel access 
rights) will be provided to the site staff in a separate manual.  
All injection site reactions / symptoms of interest documented by the subject in the eDiary will be directly 
available in the eCRF. The treating investigator (or designated staff) at the site will thoroughly review 
the entries for completeness at the next on-site visit after each treatment. Subjects who are non-
compliant will be counseled and re-trained. The subjects will receive detailed instructions for completion 
and handling of the eDiary in local language.  
To confirm that entries have been reviewed at a respective on-site visit, the treating investigator (or 
designated site staff) needs to document the review in the subject´s source record and in the eCRF.  
All data will be considered as a source document. 
Injection site reactions 
The subjects will be asked to record injection site reactions 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). Injection site reactions include:  
• 
Redness 
• 
Pain after injection 
• 
Tenderness to touch 
• 
Firmness 
• 
Swelling 
• 
Lumps/Bumps 
• 
Bruising 
• 
Itching 
• 
Discoloration (not redness or bruising) 
• 
Other (other symptoms at the injection site not listed above) [with possibility to answer ‘Yes’ or 
‘No’ and a free-text field to add a symptom at the injection site if answered ‘Yes’] 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 103 of 171 
Version 7.0 - 15-MAY-2024 
The presence and intensity of these symptoms per side of the midface (left and right side of the midface) 
will be documented and scored by the subject using a 5-grade scale for the left and right side separately 
on a daily basis within the diary (see Table 25).  
Table 25. Injections site reactions assessment by the subject. 
Score 
Intensity code Definition 
0 
No reaction 
No injection site reaction 
In case there is an injection site reaction the rating is as follows (left and right side of the midface):  
1 
None 
No observation. 
2 
Mild 
Symptoms barely noticeable and does not cause discomfort.  No influence on 
performance or functioning. 
Treatment of symptoms is not needed. 
3 
Moderate 
Symptoms very noticeable and/or causes discomfort. Performance of daily activities is 
influenced. 
Treatment of symptoms may be needed. 
4 
Severe 
Symptoms cause severe discomfort. Performance of daily activities is compromised. 
Treatment of symptoms is needed. 
In case, the injection site reaction is not resolved after 4 weeks (28 days) it must be documented and 
reported (if applicable) as an AE as described in section 14. Note, that injection site reactions that are 
considered serious (see section 14) will be collected and processed as AE regardless of the occurrence 
date (see section 14).  
Injection site reactions the subject is not specifically asked about in the subject diary (i.e., ‘Other’ 
symptoms at the injection site not listed above) need to be assessed and documented by the treating 
investigator: 
• 
If an ‘Other’ symptom at the injection site is synonymous to one of the injection site reactions listed 
above, the treating investigator needs to document this fact in the subject´s source record. The 
synonymous ‘Other’ symptom at the injection site does not need to be transferred to the eCRF. 
• 
If the ‘Other’ symptom at the injection site does not meet one of the injection site reactions listed 
above, it should be further assessed by the treating investigator and documented as AEs in the 
subject´s source record and in the eCRF (in English language) as described in section 14. 
Symptoms of interest  
Furthermore, the subjects will be asked if they have experienced any of the following symptoms of interest 
(SOIs) potentially associated with the unintended intravascular injection of the device during the first four 
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):  
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 104 of 171 
Version 7.0 - 15-MAY-2024 
 
Table 26. Symptoms of interest to be assessed by the subject 
Symptoms of interest (diary term) 
• 
Changes in vision:  
o 
loss of vision 
o 
blurriness 
o 
double vision 
o 
pain in or around your eye 
o 
blindness 
o 
blind spots 
o 
problems moving the eyes 
• 
Skin changing color around the eyelids   
• 
Crusty or scabby skin around the eyelids   
• 
Headache   
• 
Fever   
• 
Dizziness   
• 
Confusion   
• 
Weakness or numbness in the arms or legs  
• 
Changes to consciousness or alertness  
• 
Difficulty speaking/speech impairment  
• 
Face droop  
• 
Changes to chewing and drinking  
• 
Discomfort with palpation  
• 
Sensitivity to hot/cold liquids and foods   
SOI(s) documented by the subject in the eDiary will be directly available in the eCRF. The study site will 
closely monitor the SOI(s) in the eCRF between the on-site visits and - if deemed necessary – proactively 
contact the subject for safety reasons. If required, an unscheduled on-site visit may be performed (see 
section 6.5.17). The eDiary will include specific instructions for the subject to seek immediate medical 
attention if any of the above symptoms or signs are observed. 
At each visit during eDiary period, the SOI(s) documented by the subject in the eDiary will be discussed 
with the subject.  
All SOI(s) should be carefully verified by the investigator for their clinical significance (see section 14.2). 
If clinical significance is verified, the investigator will attempt to establish a diagnosis based on SOIs 
documented by the subject in the eDiary and/or additional clinical information the subject may report 
(see section 20.5.2). The diagnosis will be documented and assessed as AE(SI) rather than single 
SOI(s). If no diagnosis can be established the SOI term should be only documented and assessed as 
AE(SI). See sections 14.3 and 14.4 for details regarding documentation and assessment of AE(SI)s. 
Note: SOIs that turn out to be not clinically significant due to any reason (see section 20.5.1) are not 
considered as AE(SI) and need not to be documented as AE(SI) in the eCRF. However, the investigator 
should add a statement in the subject’s source records why the SOI was not considered clinically 
significant / as AE(SI).  
Note: All AESIs (serious and non-serious, see section 14.1 for definition) and any other embolic event 
(regardless of seriousness and / or relationship to device or procedure) resulting from SOI assessment 
have to be reported by the investigator to the sponsor’s representative within 24 hours of awareness of 
the event (see section 14.5).  
 
The safety of the subjects will be monitored throughout the investigation, from Screening (Visit 1) until 
their End of Study visit. The follow-up period will be prolonged outside the investigation, if a related AE 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 105 of 171 
Version 7.0 - 15-MAY-2024 
is ongoing and not stabilized after 24 weeks after last injection of the repeat-treatment phase (see 
section 14.6 for details). 
The subjects will be instructed to immediately contact the investigator by phone in case of occurrence 
of any untoward event between the visits (including visual examinations after treatment visits).  
In order to identify potential AEs immediately post-administration a safety evaluation 15 min after each 
treatment needs to take place. Furthermore, subject diaries will be provided to the subjects, and they 
will be instructed to note injection site reactions, and symptoms of interest (see section 6.4.19).   
Any subject with an (S)AE or clinically significant abnormal test result will be evaluated by the treating 
investigator and will be treated and/or followed up as per local clinical practice. Where appropriate, 
medical tests and examinations may be performed to ensure that an AE has fully resolved.  
The procedure for collection, recording and reporting of AEs and device deficiencies is described in 
section 14. Device deficiencies will be documented as well at each device treatment (see section 14.9).  
6.5 
Schedule of procedures 
The “Schedule of procedures and assessments” in Table 1 to Table 3 gives an overview of study 
procedures during study conduct. The following sections tabulate the procedures to be performed by 
visit.  
Actions during ongoing COVID-19 pandemic 
During COVID-19 pandemic situation, special risk mitigation procedures need to be performed to protect 
the safety of subjects, site personnel and other persons involved. Possible mitigation measures to be 
taken into consideration by the study sites are described in section 4.4.  
In addition, a separate CIP addendum (see section 4.4) gives detailed information about the possible 
mitigation measures and alternative procedures in case of restrictions during the pandemic. 
If the conduct of visits or assessments of a specific subject is affected by the COVID-19 situation this 
should be documented in the subject´s source records.  
 
 
Note: Screening visit (Visit 1) and Baseline visit (Visit 2) may be performed as one visit. 
o 
Provide subject information / Obtain written informed consent (see section 13) 
o 
Assign the subject number by entering subject data into eCRF (see CRF Completion Guidelines) 
o 
Collect demographic data (see section 6.4.1) 
o 
Define Fitzpatrick skin type of the subject (see section 6.4.2) 
o 
Perform body weight measurement (see section 6.4.3) 
o 
Women of child-bearing potential:  
o 
Urine dipstick pregnancy test (see section 6.4.4) 
o 
Instruction about [highly] effective methods of contraception (see section 6.3.8) 
o 
Record relevant medical history (i.e., prior and concomitant diseases, incl. major surgeries) (see 
section 6.4.5) 
o 
Record relevant aesthetic history (i.e., information on prior facial aesthetic procedures) (see 
section 6.4.6) 
o 
Record AEs from signature of the ICF onwards (see section 14) 
o 
Record prior and concomitant treatments (see section 6.4.7)  
o 
Midface volume deficit severity scale (MVDSS) – blinded evaluator at the site (see section 6.4.13) 
o 
NLF-SRS – blinded evaluator at site (see section 6.4.14) 
o 
Review and evaluate eligibility criteria (see section 6.3.3) including wash out periods for prohibited 
treatment (see section 6.3.8)  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 106 of 171 
Version 7.0 - 15-MAY-2024 
o 
Perform clinical photography (2D and 3D photos) (see section 6.4.11) 
o 
Upload the 3D photos for independent blinded photographic reviewer (MVDSS) (see 
section 6.4.13) and volumetric change measurement (see section 6.4.12) 
o 
Upload the 2D photo (see section 6.4.11) 
o 
Schedule an appointment for the next on-site visit. 
 
 
o 
Record any new AE or changes of AEs (see section 14). Note: this includes AESIs (see section 
14.1) 
o 
Record changes in concomitant treatments (see section 6.4.7), medical and aesthetic history (see 
section 6.4.5 and 6.4.6) 
o 
Perform visual examinations prior to device administration (see section 6.4.8) with special focus on 
eligibility criterion on visual examinations (ExC #18, see section 6.3.3.2) 
o 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4) – prior to 
device administration 
o 
FACE-QTM - Satisfaction with cheeks (see section 6.4.18) – prior to device administration 
o 
Re-assess and evaluate eligibility criteria (see section 6.3.3)  
o 
For eligible subjects perform randomization (see section 6.1.2) 
o 
Device administration (baseline treatment):  
o 
See section 6.2.2 to section 6.2.4 for detailed instructions for injection  
o 
Document information on injection (see section 6.4.9) 
o 
Record any device deficiencies (see section 14.9) 
o 
Pain assessment (during treatment) using the NPRS by subject immediately (approx.+3 min) after 
end time of device administration (see section 6.4.14) 
o 
Pain assessment (during recovery from treatment) using the NPRS by subject every 15 min (approx. 
±3 min) after end time of the device administration for 60 min post-treatment (see section 6.4.14) 
o 
Perform visual examinations approximately 30 min after device administration (see section6.4.8). 
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
o 
Initiate access to eDiary and explain diary use incl. documentation of injection site reactions / 
symptoms of interest to the subject (see section 6.4.19) 
o 
Advise the subject prior to discharge to follow restrictions specified in section 6.3.8. 
o 
Schedule an appointment for the telephone visit and the next on-site visit. 
 
 
The time of the telephone call has to be documented; it has to be conducted 24 to 48 hours 
(±4 hours) after the end of injection at Visit 2 (see section 6.4.9) 
o 
Ask for any changes in AEs and new AEs (see section 14) including AESIs (see section 14.1) 
In case of an AE including vision changes, neurological issues, or an unbearable injection site 
reaction an unscheduled on-site visit must be performed (see section 6.5.17)  
o 
Ask for changes in concomitant treatments (see section 6.4.7)  
o 
Remind the subject to document injection site reactions / symptoms of interest in the diary (see 
section 6.4.19) 
 
 
o 
Record any new AE or changes of AEs (see section 14) including AESIs (see section 14.1) 
o 
Record changes in concomitant treatments (see section 6.4.7)  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 107 of 171 
Version 7.0 - 15-MAY-2024 
o 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4) – prior to 
device administration  
o 
Review subject diary regarding injection site reactions / symptoms of interest; confirm review (see 
section 6.4.19) 
o 
Perform visual examinations prior to device administration (see section 6.4.8) and review 
respective exclusion criteria (see section 6.3.5) 
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
o 
MVDSS –blinded evaluator at the site (see section 6.4.13) – prior to device administration 
o 
NLF-SRS – blinded evaluator at site (see section 6.4.14) – prior to device administration 
Subjects not receiving the optional touch-up treatment:  
o 
Remind subject regarding further documentation of injection site reactions / symptoms of interest 
in the diary (see section 6.4.19) 
o 
Schedule an appointment for the next on-site visit. 
Optional touch-up treatment:  
Note: The touch-up treatment may be conducted if an optimal aesthetic correction has not been 
achieved after baseline treatment (i.e., at Visit 2) in the discretion of the treating investigator (see 
section 6.2.2 for criteria).  
The touch-up treatment is optional and must only be conducted if the respective exclusion criteria are 
not met (see section 6.3.4). 
The following assessments must be conducted for the respective subjects:  
o 
Device administration (touch-up treatment)  
o 
See section 6.2.2 to section 6.2.4 for detailed instructions for injection  
o 
Document information on injection (see section 6.4.9) 
o 
Record any device deficiencies (see section 14.9) 
o 
Pain assessment (during treatment) using the NPRS by subject immediately (approx.+3 min) after 
end time of device administration (see section 6.4.14)  
o 
Pain assessment (during recovery from treatment) using the NPRS by subject every 15 min 
(approx.±3 min) after end time of the device administration for 60 min post-treatment (see 
section 6.4.14) 
o 
Perform visual examinations approximately 30 min after device administration (see section 6.4.8) 
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
o 
Explain again diary use to the subject and documentation of injection site reactions / symptoms of 
interest (see section 6.4.19)  
o 
Advise the subject prior to discharge to follow restrictions specified in section 6.3.8. 
o 
Schedule an appointment for telephone visit and the next on-site visit. 
 
 
Only in case of touch-up treatment at Visit 3 
The time of the telephone call has to be documented; it has to be conducted 24 to 48 hours 
(±4 hours) after the end of injection at Visit 3 (see section 6.4.9) 
o 
Ask for any changes in AEs and new AEs (see section 14) including AESIs (see section 14.1) 
In case of an AE including vision changes, neurological issues, or an unbearable injection site 
reaction an unscheduled on-site visit should be performed (see section 6.5.17).  
o 
Ask for changes in concomitant treatments (see section 6.4.7) 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 108 of 171 
Version 7.0 - 15-MAY-2024 
o 
Remind the subject to document injection site reactions / symptoms of interest in the diary (see 
section 6.4.19) 
 
 
Only in case of touch-up treatment at Visit 3 
o 
Record any changes in AEs and new AEs (see section 14) including AESIs (see section 14.1) 
In case of an AE including vision changes, neurological issues, or an unbearable injection site 
reaction an unscheduled on-site visit should be performed (see section 6.5.17).  
o 
Record changes in concomitant treatments (see section 6.4.7) 
o 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4)  
o 
Review subject diary regarding injection site reactions / symptoms of interest; confirm review (see 
section 6.4.19) 
o 
Perform visual examinations (see section6.4.8) and review respective exclusion criteria (see 
section 6.3.5) 
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
 
 
Through the follow-up phase of the initial treatment phase the following visits will be performed: 
• 
Visit 4 – Week 4 (± 5 d) after last injection 
• 
Visit 5 – Week 8 (± 5 d) after last injection 
• 
Visit 6 – Week 16 (± 7 d) after last injection 
• 
Visit 7 – Week 24 (± 7 d) after last injection 
• 
Visit 8 – Week 36 (± 7 d) after last injection  
Note: Last injection refers to either  
o 
Visit 2 for subjects without touch-up treatment, or  
o 
Visit 3 for subjects with touch-up treatment (i.e., TUP1) 
 
The following assessment will be performed:  
o 
Record any new AE or changes of AEs (see section 14) including AESIs (see section 14.1) 
o 
Record changes in concomitant treatments (see section 6.4.7)  
o 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4)  
o 
Review subject diary regarding injection site reactions / symptoms of interest; confirm review (see 
section 6.4.19) – only Visit 4  
o 
Perform body weight measurement (see section 6.4.3) 
o 
Perform visual examinations (see section 6.4.8) 
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
o 
Perform clinical photography (see section 6.4.11) 
o 
MVDSS –blinded evaluator at the site (see section 6.4.13)  
o 
NLF-SRS –blinded evaluator at site (see section 6.4.14)  
o 
Upload the photos for independent blinded photographic reviewer (MVDSS) (see section 6.4.13) 
and volumetric change measurement (see section 6.4.12). 
o 
Modified GAIS assessment –blinded evaluator at the site (see section 6.4.16) 
o 
Modified GAIS assessment – subject (see section 6.4.16) 
o 
FACE-QTM – Satisfaction with overall outcome of treatment (see section 6.4.17) – subject 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 109 of 171 
Version 7.0 - 15-MAY-2024 
o 
FACE-QTM – Satisfaction with cheeks (see section 6.4.18) – subject 
o 
Schedule an appointment for the next on-site visit. 
 
 
Note: Last injection refers to either  
o 
Visit 2 for subjects without touch-up treatment or  
o 
Visit 3 for subjects with touch-up treatment  
The following assessment will be performed:  
o 
Record any new AE or changes of AEs (see section 14) including AESIs (see section 14.1) 
o 
Record changes in concomitant treatments (see section 6.4.7)  
o 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4) – prior to 
device administration 
o 
Perform body weight measurement (see section 6.4.3) – prior to device administration 
o 
Perform clinical photography (see section 6.4.11) – prior to device administration 
o 
Perform visual examinations prior to device administration (see section 6.4.8) with special focus on 
eligibility criteria on visual examinations (see section 6.3.5)  
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
o 
MVDSS – blinded evaluator at the site (see section 6.4.13) 
Note:  
o 
If the subject already qualifies for optional repeat-treatment with regards to MVDSS at this visit 
proceed with Visit RT1 (see section 6.5.10). 
o 
In case it is already known at this Visit that an inclusion criterion will be not met / an exclusion 
criterion will be met for repeat-treatment (see section 6.3.5) and further follow up in screening 
is not useful because the subject will apparently not qualify for repeat-treatment, Visit 9 (SV1) 
will be End of Study visit for the respective subject. 
o 
NLF-SRS –blinded evaluator at site (see section 6.4.14)  
o 
Upload the photos for independent blinded photographic reviewer (MVDSS) (see section 6.4.13) 
and volumetric change measurement (see section 6.4.12).  
o 
Modified GAIS assessment – blinded evaluator at the site (see section 6.4.16) 
o 
Modified GAIS assessment – subject (see section 6.4.16) 
o 
FACE-QTM – Satisfaction with overall outcome of treatment (see section 6.4.17) – subject 
o 
FACE-QTM – Satisfaction with cheeks (see section 6.4.18) – subject 
 
 
Through the screening phase for optional repeat-treatment following visits will be performed: 
• 
Visit SV2 – Week   4 (± 7 d) after Visit 9 (SV1) 
• 
Visit SV3 – Week   8 (± 7 d) after Visit 9 (SV1) 
• 
Visit SV4 – Week 12 (± 7 d) after Visit 9 (SV1) 
The following assessment will be performed:  
o 
MVDSS – blinded evaluator at the site (see section 6.4.13).  
Note:  
o 
If the subject qualifies for optional repeat-treatment with regards to MVDSS at one of the visits, 
proceed with Visit RT1 (see section 6.5.10). 
o 
SV4 is the End of Study visit for subjects who do not qualify for repeat-treatment.  
o 
In case an inclusion criterion is not met / an exclusion criterion is met for repeat-treatment (see 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 110 of 171 
Version 7.0 - 15-MAY-2024 
section 6.3.5) and further follow up in screening is not useful because the subject will 
apparently not qualify for repeat-treatment, either Visit SV 2 or SV 3 will be End of Study visit 
for the respective subject. 
o 
Record any new AE or changes of AEs (see section 14) including AESIs (see section 14.1) 
o 
Record changes in concomitant treatments (see section 6.4.7)  
o 
Schedule an appointment for the next on-site visit 
 
 
For optional repeat-treatment only saypha® VOLUME Lidocaine will be used.  
The optional repeat-treatment must only be conducted if the respective eligibility criteria are 
fulfilled (see section 6.3.5). 
The following assessments will be performed:  
Note: In case the subject qualifies for optional repeat-treatment the following assessments do 
not need to be done twice at the respective visit: 
o 
Visit 9 (SV1): pre-treatment assessments 
o 
Visits SV2 to SV4: MVDSS by blinded evaluator, concomitant treatments, adverse events 
o 
Record any new AE or changes of AEs (see section 14) including AESIs (see section 14.1) 
o 
Record changes in concomitant treatments (see section 6.4.7) MVDSS –blinded evaluator at the 
site (see section 6.4.13) – prior to device administration  
o 
NLF-SRS –blinded evaluator at site (see section 6.4.14) – prior to device administration 
o 
Perform visual examinations prior to device administration (see section 6.4.8) with special focus on 
eligibility criterion on visual examinations (ExC #3 and 4, see section 6.3.5.2) 
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
o 
Perform body weight measurement (see section 6.4.3) 
o 
Women of child-bearing potential:  
o 
Urine dipstick pregnancy test (see section 6.4.4) 
o 
Re-Instruction about [highly] effective methods of contraception (see section 6.3.8) 
o 
FACE-QTM – Satisfaction with overall outcome of treatment (see section 6.4.17) – subject – prior to 
device administration 
o 
FACE-QTM – Satisfaction with cheeks (see section 6.4.18) – subject – prior to device 
administration 
o 
Re-assess and evaluate eligibility criteria (see section 6.3.5); Note: In case an inclusion criterion is 
not met / an exclusion criterion is met, Visit RT1 will be End of Study visit for the respective 
subject.  
o 
Device administration (repeat-treatment):  
o 
See section 6.2.2 to section 6.2.4 for detailed instructions for injection  
o 
Document information on injection (see section 6.4.9) 
o 
Record any device deficiencies (see section 14.9) 
o 
Pain assessment (during treatment) using the NPRS by subject immediately (approx.+3 min) after 
end time of device administration (see section 6.4.14) 
o 
Pain assessment (during recovery from treatment) using the NPRS by subject every 15 min 
(approx.±3 min) after end time of the device administration for 60 min post-treatment (see 
section 6.4.14) 
o 
Perform visual examinations approximately 30 min after treatment (see section 6.4.8) 
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
o 
Initiate access to eDiary and explain diary use incl. documentation of injection site reactions / 
symptoms of interest to the subject (see section 6.4.19) 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 111 of 171 
Version 7.0 - 15-MAY-2024 
o 
Advise the subject prior to discharge to follow restrictions specified in section 6.3.8. 
o 
Schedule an appointment for the telephone visit and the next on-site visit. 
 
 
The time of the telephone call has to be documented; it has to be conducted 24 to 48 hours 
(±4 hours) after the end of injection at Visit RT1 (see section 6.4.9) 
o 
Ask for any changes in AEs and new AEs (see section 14) including AESIs (see section 14.1) 
In case of an AE including vision changes, neurological issues, or an unbearable injection site 
reaction an unscheduled on-site visit must be performed (see section 6.5.17).  
o 
Ask for changes in concomitant treatments (see section 6.4.7) 
o 
Remind the subject to document injection site reactions / symptoms of interest in the diary (see 
section 6.4.19) 
 
 
o 
Record any new AE or changes of AEs (see section 14) including AESIs (see section 14.1) 
o 
Record changes in concomitant treatments (see section 6.4.7)  
o 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4) – prior to 
device administration  
o 
Review subject diary regarding injection site reactions / symptoms of interest; confirm review (see 
section 6.4.19) 
o 
Perform visual examinations prior to device administration (see section 6.4.8) and review 
respective exclusion criteria (see section 6.3.5) 
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
o 
FACE-QTM – Satisfaction with overall outcome of treatment (see section 6.4.17) – subject – prior to 
device administration 
o 
FACE-QTM - Satisfaction with cheeks (see section 6.4.18) – subject – prior to device administration 
o 
MVDSS –blinded evaluator at the site (see section 6.4.13) – prior to device administration 
o 
NLF-SRS – blinded evaluator at site (see section 6.4.14) – prior to device administration 
Subjects not receiving the optional touch-up treatment (TUP2): 
o 
Remind subject regarding further documentation of injection site reactions / symptoms of interest 
in the diary (see section 6.4.19) 
o 
Schedule an appointment for the next on-site visit. 
Optional touch-up treatment:  
Note: The touch-up treatment may be conducted if an optimal aesthetic correction has not been 
achieved after repeat-treatment (i.e., at Visit RT1) in the discretion of the treating investigator (see 
section 6.2.2 for criteria).  
The touch-up treatment is optional and must only be conducted if the respective exclusion criteria are 
not met (see section 6.3.4). 
The following assessments must be conducted for the respective subjects:  
o 
Device administration (touch-up treatment)  
o 
See section 6.2.2 to section 6.2.4  for detailed instructions for injection  
o 
Document information on injection (see section 6.4.9) 
o 
Record any device deficiencies (see section 14.9) 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 112 of 171 
Version 7.0 - 15-MAY-2024 
o 
Pain assessment (during treatment) using the NPRS by subject immediately (approx.+3 min) after 
end time of device administration (see section 6.4.14)  
o 
Pain assessment (during recovery from treatment) using the NPRS by subject every 15 min (approx. 
±3 min) after end time of the device administration for 60 min post-treatment (see section 6.4.14) 
o 
Perform visual examinations approximately 30 min after device administration (see section 6.4.8) 
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
o 
Explain again diary use to the subject and documentation of injection site reactions /  symptoms of 
interest (see section 6.4.19)  
o 
Advise the subject prior to discharge to follow restrictions specified in section 6.3.8. 
o 
Schedule an appointment for telephone visit and the next on-site visit. 
 
Only in case of touch-up treatment at Visit RT2 
The time of the telephone call has to be documented; it has to be conducted 24 to 48 hours 
(±4 hours) after the end of injection at Visit RT2 (see section 6.4.9) 
o 
Ask for any changes in AEs and new AEs (see section 14) including AESIs (see section 14.1) 
In case of an AE including vision changes, neurological issues or an unbearable injection site 
reaction an unscheduled on-site visit should be performed (see section 6.5.17).  
o 
Ask for changes in concomitant treatments (see section 6.4.7) 
o 
Remind the subject to document injection site reactions / symptoms of interest in the diary (see 
section 6.4.19) 
 
 
Only in case of touch-up treatment at Visit RT2 
o 
Record any changes in AEs and new AEs (see section 14) including AESIs (see section 14.1) 
In case of an AE including vision changes, neurological issues, or an unbearable injection site 
reaction an unscheduled on-site visit should be performed (see section 6.5.17).  
o 
Record changes in concomitant treatments (see section 6.4.7) 
o 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4) 
o 
Review subject diary regarding injection site reactions / symptoms of interest; confirm review (see 
section 6.4.19) 
o 
Perform visual examinations (see section 6.4.8) and review respective exclusion criteria (see 
section 6.3.5) 
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
 
 
Through the follow-up phase after repeat-treatment the following visits will be performed: 
• 
Visit RT3 – Week 4 (± 5 d) after last injection 
• 
Visit RT4 – Week 12 (± 7 d) after last injection 
• 
Visit RT5 – Week 24 (± 7 d) after last injection 
Note: Last injection refers to either  
o 
Visit RT1 for subjects without touch-up treatment, or  
o 
Visit RT2 for subjects with touch-up treatment (i.e., TUP2) 
The following assessment will be performed:  
o Record any new AE or changes of AEs (see section 14) including AESIs (see section 14.1) 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 113 of 171 
Version 7.0 - 15-MAY-2024 
o 
Record changes in concomitant treatments (see section 6.4.7)  
o 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4) 
o 
Perform visual examinations (see section 6.4.8)  
o 
If applicable: Perform basic neurological examination (F.A.S.T) (see section 6.4.9) 
o 
Review subject diary and documentation of injection site reactions / symptoms of interest; confirm 
review (see section 6.4.19) – only Visit RT3  
o 
Perform body weight measurement (see section 6.4.3) 
o 
MVDSS – blinded evaluator at the site (see section 6.4.13)  
o 
NLF-SRS –blinded evaluator at site (see section 6.4.14)  
o 
FACE-QTM – Satisfaction with overall outcome of treatment (see section 6.4.17) – subject 
o 
FACE-QTM – Satisfaction with cheeks (see section 6.4.18) – subject 
o 
Schedule an appointment for the next on-site visit – Visits RT3 and RT4 only 
 
 
At Early Termination Visit all attempts should be made to perform the assessments described for  
o 
Visit 9 (SV1) if withdrawn during initial treatment phase (see section 6.5.8) 
o 
Visit SV2 to SV4 if withdrawn during screening phase for repeat-treatment (see section 6.5.9) 
o 
Visit RT5 if withdrawn during repeat-treatment phase (see section 6.5.15) 
The following assessments are recommended to be completed at a minimum:  
o 
Record any new AE or changes of AEs (see section 14) including AESIs (see section 14.1) 
o 
Record changes in concomitant treatments (see section 6.4.7)  
o 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4) 
o 
Perform visual examinations (see section 6.4.8)  
o 
If applicable perform neurological examination (F.A.S.T) (see section 6.4.9) 
o 
MVDSS – blinded evaluator at the site (see section 6.4.12)  
Only in case of Early Termination Visit during initial treatment phase (i.e., prior to Visit 9 (SV1)):   
o 
Perform clinical photography (see section 6.4.11)  
o 
Upload the photos for independent blinded photographic reviewer (MVDSS) (see section 6.4.13) 
and volumetric change measurement (see section 6.4.12)  
 
An unscheduled visit may be performed at any time during the study if judged necessary by the treating 
investigator, such as  
• 
severe or serious injection site reactions 
o 
clinically significant AE including AESIs ( see section 14.1) 
• 
suspected or confirmed pregnancy.  
In case the unscheduled visit results in early termination of the subject, the assessments for the Early 
Termination Visit should be performed (see section 6.5.16). Details of the event are to be recorded in 
the subject’s records and in the eCRF.  
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 114 of 171 
Version 7.0 - 15-MAY-2024 
 
6.6 
Factors that may compromise the outcome 
There are no foreseeable factors that may significantly compromise the outcome.  
Subject eligibility criteria and prohibition of concomitant treatments and aesthetic procedures that may 
affect the outcome are carefully defined.  
A substantial body weight change during the investigation period could possibly affect the results in 
individual subjects. This may obscure the effectiveness of the device at individual level. This factor will 
be controlled by monitoring body weight throughout the investigation (see section 6.3.8).  
Beard longer than three-day beard, or excessive facial hair as well as prolonged exposure to sunlight or 
ultraviolet (UV) radiation and may affect the assessments. Subjects will be advised to avoid and to use 
daily skin care with UV protection in face throughout the entire clinical investigation (see section 6.3.8).  
It is possible that women will prevail in the study population because they still more often seek facial 
aesthetic procedures than men. This potential gender imbalance will reflect common practice and is not 
considered relevant since available data on soft tissue fillers do not indicate any gender-related effect 
on treatment outcomes.  
It may also happen that persons of color are enrolled in less numbers. When selecting the study sites, 
however, care was taken to ensure that adequate numbers of subjects with Fitzpatrick Skin Types (FST) 
IV, V, or VI will be enrolled to evaluate the safety profile for the subjects with the darkest skin types. To 
avoid disproportionate enrollment patterns with potential influence on the results FST enrollment levels 
were implemented (see section 6.3.2). In any case, every effort possible will be taken to enroll males 
and all Fitzpatrick Skin Types. 
Changes in study visit schedules, missed visits, or patient discontinuations may lead to missing 
information for protocol-specified procedures. The sponsor will implement measurements to prevent an 
influence on the outcome measures due to COVID-19 pandemic, as appropriate (see section 4.4). 
However, if changes are unavoidable, specific information will be captured in the subject´s source 
records and in the eCRF that explains the relationship to COVID-19 for missing protocol-specified 
information. The information will be summarized in the clinical investigation report (see section 8.5) or 
in a separate study-specific document, as applicable.  
6.7 
Monitoring and Monitoring plan 
The conduct of this clinical investigation will be monitored by the sponsor’s representative, who will 
appoint one or more monitors. The extent of monitoring and source data verification will be specified in 
the Monitoring plan. 
Prior to initiation of the clinical investigation at any of the investigation sites, the Monitor will discuss the 
CIP, the eCRF and other investigation-related documents and forms with the investigator and their staff, 
and verify that all prerequisites for the initiation are met. No subject should be enrolled into the 
investigation before this site initiation visit.  
During the investigation, further monitoring visits will be performed according to GCP, the applicable 
standard operating procedures, and local regulations. At each visit the monitor will check the progress 
of enrolment, will review source data for adherence to the CIP, review eCRFs against source data for 
completeness, accuracy and consistency, and will also check if the device has been stored, dispensed 
and accounted for according to respective specifications.  
The monitor will inform the investigator or their authorized designee on any error in the eCRF and will 
ensure that appropriate data corrections or clarifications are made in appropriate manner. In case of any 
other observed default, the monitor will inform the investigator and, when appropriate, the sponsor as 
well. The monitor will discuss and agree with the investigator suitable corrective actions and will follow-
up their implementation.  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 115 of 171 
Version 7.0 - 15-MAY-2024 
Upon completion of the investigation, the monitor will ensure that all investigator’s records are accurate 
and complete, all documents needed for the sponsor’s files are retrieved, the remaining investigation 
supplies, including the device, are disposed of, and that all previously identified issues have been 
resolved. 
The investigator and their institution must permit the monitoring of the investigation and must provide 
the monitor a direct access to those portions of the subject’s source records, which directly concern this 
clinical investigation. Furthermore, key personnel at the site involved in the investigation must be 
available to assist the monitor during the monitoring visits. 
6.8 
Audits and inspections 
The investigator will permit study related audits, IRB/EC review, and regulatory inspections, providing 
direct access to source data / documents. 
Audits of the clinical investigation may be conducted by the sponsor or external organizations designated 
by the sponsor to evaluate compliance with the CIP, written procedures, GCP and the applicable 
regulatory requirements.  
A risk-based approach will be used for selection of investigator sites for an audit. The following criteria 
may be used as a guide for site selection (including but not limited to):  
• 
Study specific requirements.  
• 
Sites with high and/or rapid enrolment.  
• 
Negative outcome from regulatory inspections (e.g. Form FDA 483 issued). 
• 
Level of professional experience of the assigned Site Monitor/CRA.  
• 
Input from other sources (e.g., CROs, CRAs, project team members, centralized Monitoring findings, 
etc.).  
• 
Previous experience with the investigator and/or site, including, but not limited to:  
o 
Performance and/or regulatory history 
o 
Sites with high volume of clinical studies currently active 
o 
Sites with less experience in clinical studies 
o 
Sites with high incidences of (Serious) Adverse Events (S)AEs)  
o 
Sites without or low incidence of SAEs and/or AEs when SAEs and/or AEs are expected 
o 
Sites with high enrollment and no SAEs/AEs 
o 
Investigator sites in countries that Croma has not conducted studies previously 
o 
Frequency of deviations/violations 
o 
Sites with a high frequency of CRA turn-over or backlog of monitoring visits.  
• 
Sites that have not been the subject of other audits or inspections (e.g., Co-Visit Audit, Sponsor Site 
Audits, Regulatory Inspections) within the prior 6 months.  
• 
Sites with an adequate number of enrolled subjects to ensure sufficient data for review during the 
audit. 
A visit may be arranged by the sponsor or sponsor’s representative in order to audit the investigation 
site and the investigation documents, which originate there. The auditor(s) will usually be accompanied 
by the monitor or the project manager. The investigator will be informed about the outcome of the audit. 
In addition, inspections by health authority representatives, including foreign authorities, are possible at 
any time. The investigator should notify the sponsor and/or sponsor’s representative 
) of 
any such inspection immediately. 
6.9 Quality and risk management  
The sponsor will implement a system to manage quality throughout all stages of the study process in 
accordance with GCP, applicable regulations, and sponsor’s / CRO’s procedures (e.g., written SOPs).  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 116 of 171 
Version 7.0 - 15-MAY-2024 
The system implemented will focus on study activities essential to ensure human subject protection and 
the reliability of study results. The methods used to assure and control the quality of the investigation 
should be proportionate to the risks inherent in the investigation and the importance of the information 
collected. All aspects of the study should be operationally feasible and should avoid unnecessary 
complexity, procedures, and data collection. During Clinical Investigational Plan development processes 
and data that are critical to ensure human subject protection and the reliability of trial results were 
identified.  
In general, risks should be considered at both the system level (e.g., standard operating procedures, 
computerized systems, personnel) and clinical trial level (e.g., study design, data collection, informed 
consent process).  
The approach used to reduce risk to an acceptable level should be proportionate to the significance of 
the risk. Predefined quality tolerance limits will be established, taking into consideration the medical and 
statistical characteristics of the variables as well as the statistical design of the trial, to identify systematic 
issues that can impact subject safety or reliability of trial results. Detection of deviations from the 
predefined quality tolerance limits should trigger an evaluation to determine if action is needed. 
Quality management activities must be documented and communicated to those who are involved in or 
affected by such activities, to facilitate risk review and continual improvement during clinical trial 
execution.  
Details and consequences resulting from the ongoing risk management process are dealt with in the 
study specific risk management plan filed in the TMF. 
7 
Statistical considerations 
Planned statistical analyses are briefly summarized below. Data analyses will be described in detail in 
the Statistical Analysis Plan (SAP). 
7.1 
Sample size and hypothesis 
The primary outcome measures for effectiveness will be 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® VOLUME Lidocaine based on the blinded 
evaluator´s live assessment at Week 24 after last injection of initial treatment phase, while pB is the 
corresponding response rate for
 
 
. Thus, a negative value for this difference 
means that the response rate of saypha® VOLUME Lidocaine is lower than the response rate for 
 
.  
The non-inferiority margin is -10%. 
Further assumptions for sample size calculation: 
• 
Response rate at Week 24 for saypha® VOLUME Lidocaine is 85.6% 
• 
Response rate at Week 24 for
 
 is 85.6% 
• 
Randomization ratio 2:1 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 117 of 171 
Version 7.0 - 15-MAY-2024 
Based on these assumptions, 437 subjects (saypha® VOLUME Lidocaine: n=291, 
 
 
: n=146) will be necessary in order to achieve power exceeding 83%  with a one-sided 
 of 2.5%. Assuming 10% exclusion from PPS results in 486 subjects to be randomized. Adding 6% 
screen failures yields approximately 516 subjects to be enrolled. 
Concerning FAS, it is expected that only very few subjects will be regarded as non-responder due to 
missing data for the primary effectiveness endpoint. Response rates at Week 24 after last injection of 
the initial treatment phase may be slightly smaller than assumed above. Due to the increased sample 
size in the FAS (more than 10% compared to the PPS) it is expected that the power will be adhered as 
specified above. 
Sample size calculation was done using SAS® version 9.4. 
Approximately 300 subjects are estimated to qualify for repeat treatment. 
7.2 
Analysed data sets 
Safety Analysis Set (SAF)  
The SAF comprises all subjects who were randomized and received at least one treatment with device 
(test device or the comparator device). Subjects in the SAF will contribute to the evaluation “as treated” 
i.e., the subjects’ assignment to the treatment group will be based on the device administered. 
Full Analysis Set (FAS)  
The FAS consists of all randomized subjects who received at least one administration of the test 
device or the comparator device. The statistical evaluation of the FAS will follow the intention-to-treat 
(ITT) principle and subjects will contribute to the evaluation “as randomized”. 
Per-Protocol Set (PPS): 
The PPS is defined as a subset of the subjects in the FAS without major protocol deviation(s) affecting 
the primary effectiveness endpoint and assessed as ‘major excluding from PPS’.  
The relevance of protocol deviations will be assessed at the interim and final Data Review Meetings 
(DRMs). Protocol deviations will be assessed as either “minor” or “major”. Major protocol deviations that 
could directly interfere with analysis of the primary effectiveness endpoint will be further assessed as 
either ‘major excluding from PPS´ or `major not excluding from PPS´. Randomization errors will be 
considered ‘major excluding from PPS’.  
The criteria for this assessment will be defined before analysis in Protocol Deviation Manual. Listings 
will be prepared to assess the eligibility of all subjects during the (i)DRM. 
All effectiveness analyses for the initial treatment phase will be conducted using the PPS and the FAS. 
The effectiveness analysis for the repeat treatment phase will be conducted using the FAS only. Safety 
analyses will be based on the SAF. 
7.3 
Methods of analysis 
The evaluation of the primary and secondary effectiveness endpoint(s) will be performed both in the 
Per-Protocol Set (PPS) and in the Full Analysis Set (FAS) for the initial treatment phase, and only for 
the FAS for the repeat phase. 
Unless otherwise specified, all measurements will be summarized descriptively at each visit by treatment 
group. 
In general, continuous variables will be summarized using the following descriptive summary statistics: 
number of observations, arithmetic mean, standard deviation, minimum, lower quartile, median, upper 
quartile, maximum. Categorical data will be described using absolute and relative frequencies by 
category. Shift tables will be provided, where appropriate. For assessments over time, mean values may 
be plotted to explore the trajectory over time. All descriptive summaries and plots will be based on in-
trial data (i.e., without imputation) unless otherwise specified. 
In addition, estimated treatment differences will be presented together with two-sided confidence 
intervals and corresponding p-values, if appropriate. A statistical analysis plan (SAP) will be written in 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 118 of 171 
Version 7.0 - 15-MAY-2024 
addition to the protocol, including a more technical and detailed elaboration of the statistical analyses. 
The SAP will be finalized before database lock. 
 
An interim analysis (IA) assessing the safety and effectiveness will be performed after all subjects have 
completed the follow-up visit 48 weeks after their last injection during the initial treatment phase (Visit 9 
(SV1)).  
Summary tables and subject data listings will be provided for the SAF and the FAS and all variables that 
are outlined in detail in the IA section of the final SAP.  
The SAP has to be finalized prior to the IA database lock. The IA database will be cleaned and a data 
base lock prior to export for data analysis will be done.  
 
Final analysis will be done after completion of the investigation (i.e., Visit RT5) by all subjects.  
 
Summary tables will be provided for the following subject characteristics: 
• 
Number of subjects, both screened and received at least one administration of device, included in 
the study. 
• 
Number of subjects by visit.  
• 
Number of subjects included in the SAF, FAS and PPS. 
• 
Number of subjects withdrawn from the study and the reason for withdrawal 
Subjects who prematurely discontinue the investigation after receiving at least one dose of device will 
be defined as dropouts, see section 6.3.11. 
 
Summary statistics for demographic and baseline characteristics, including age, gender, race/ ethnicity, 
and other relevant study entry criteria will be prepared for the SAF. In addition, demographic and 
baseline characteristics including age, gender, race/ ethnicity as well as injection equipment will be 
presented by study site.  
 
Medical history (incl. concomitant diseases) and aesthetic procedures history will be encoded using the 
Medical Dictionary for Regulatory Activities (MedDRA) system. These data will be presented for the SAF 
using frequency tables. 
 
Prior and concomitant treatments (medication / non-pharmacological procedures) will be coded using 
MedDRA and the WHO DRUG Global, respectively. These data will be presented for the SAF using 
frequency tables. 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 119 of 171 
Version 7.0 - 15-MAY-2024 
 
 
Primary effectiveness endpoint 
The PPS and the FAS will be both considered equally important for the primary analysis.The analysis of 
the primary endpoint will be performed on the PPS (primarily) and FAS. Confirmatory testing will be 
performed in a hierarchical ordering. Non-inferiority is demonstrated only if the results are consistent for 
both analysis populations. 
Subjects with missing baseline MVDS score and / or missing MVDS score at Week 24 after last injection 
of the initial treatment phase will be considered as non-responders for the primary analysis on the FAS. 
To calculate the primary outcome measure, the improvement over Baseline in the MVDS score 
assessed live by the blinded evaluator at the site at Week 24 after last injection of the initial treatment 
phase by subtracting the Midface Scale grade obtained at Baseline. The proportion of subjects with 
MVDS score improvement of ≥1 point will be then calculated for each treatment group.  
The primary outcome measure for effectiveness will be evaluated by means of a one-sided two-group 
Farrington-Manning  test of proportions with the following hypotheses: 
o 
H0: pA – pB ≤ d0 
o 
H1: pA – pB > d0.  
At this, pA is the response rate for saypha® VOLUME Lidocaine and pB is the response rate for 
 
 
, and d0 equals to -0.1. Thus, a negative value for this difference means that 
the response rate of saypha® VOLUME Lidocaine is lower than the response rate for 
 
 In addition to this, the response rates for both treatment groups along with their Clopper-
Pearson exact 95% CIs will be tabulated. 
The study decision will be based on a Farrington-Manning-statistics with a one-sided type I error rate 
level of 0.025. 
In addition, sensitivity analyses of the primary effectiveness endpoint will be performed on the FAS 
addressing the different reasons for non-adherence and covering the following aspects (among others) 
to underline the robustness of the results: 
o 
Complete case analysis: In this analysis only those subjects will be included for whom the primary 
endpoint could be calculated; 
o 
Subjects with non-allowed concomitant medication / treatments before Week 24 after last 
injection of the initial treatment phase may be regarded as non-responder.  
o 
Multiple imputation under MNAR assumption for imputing missing MVDS scores at Week 24 
assessed live by the blinded evaluator. 
Secondary effectiveness endpoints 
All secondary effectiveness endpoints (see section 5.3.3) will be analyzed in an exploratory manner by 
means of descriptive statistics.  
The descriptive tables will show the statistics described at the top of section 7.3 by time of assessments 
as well as for the changes from baseline (if applicable). 
Concerning the follow-up for initial treatment, the last measurements / assessments before first 
treatment are defined as baseline. Concerning the time after repeat-treatment, the measurements / 
assessments at Visit RT1 before first repeat-treatment are defined as baseline.    
Assessments on the MVDSS (see section 6.4.13) as well on the modified GAIS (see section 6.4.16) will 
be presented for each possible category. In addition, shift tables from baseline will be provided for the 
assessments on the MVDSS.   

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 120 of 171 
Version 7.0 - 15-MAY-2024 
Concerning nasolabial folds measured by NLF-SRS based on the blinded evaluator’s live assessment, 
shift tables from baseline will be presented for Week 4, 8, 16, 24, 36, and Week 48 after last injection of 
initial treatment phase.  
Volume change measurements will be presented for each of the specified areas of interest (left side, 
right side, and total) at each time of assessment including change from baseline (see section 6.4.12). 
The subject’s satisfaction with overall treatment outcome will be evaluated based on the scores for 6 
positively worded items that ask the subjects to indicate how they feel about the result of their most 
recent facial aesthetic procedure (FACE-QTM “Satisfaction with Outcome”, see section 6.4.17).    
Correspondingly, the subject’s satisfaction with overall midface augmentation will be evaluated based 
on the scores for 5 items concerning the appearance of cheeks (FACE-QTM “Satisfaction with Cheeks”, 
see section 6.4.18).    
Concerning each injection, the subject’s assessment of pain intensity on the Numeric Pain Rating Scale 
will be described at each time of assessment (immediately after the injection and after 15-minute 
intervals up to 60 minutes post-treatment) (see section 6.4.14).   
The injection volume applied (right midface, left midface, and total), the duration of each injection as well 
as the injection technique and details concerning the injection equipment will be summarized for each 
injection time point and treatment group (see section 6.4.9). 
In addition, at least the following main secondary effectiveness endpoints will be compared between the 
treatment groups by means of 95% confidence intervals for the differences in 
• 
proportion of subjects with response on the MVDSS as assessed by the blinded evaluator at the 
site 
• 
proportion of subjects with response on the MVDSS as assessed by the independent blinded 
photographic reviewer 
• 
mean change in midface volume deficit measured on the 5-point MVDSS and based on the blinded 
evaluator´s live assessment  
• 
proportion of subjects with global aesthetic improvement (in modified GAIS) as assessed by the 
subject  
• 
proportion of subjects with global aesthetic improvement (in modified GAIS) as assessed by the 
blinded evaluator  
This will be done for each time of assessment during follow-up for initial treatment.  
The resulting 95% confidence intervals for proportions will be presented in forest plots and the 
boundaries of the confidence intervals evaluated with respect to their clinical relevance in an exploratory 
manner. 
The investigational device during repeat-treatment phase (saypha® VOLUME Lidocaine) will be 
evaluated descriptively using the following other endpoints:  
• 
The percentage of responders on the 5-point MVDSS, based on the blinded evaluator´s live 
assessment at Week 4, 12 and 24 after last injection of repeat-treatment phase compared to the 
score at Visit RT1 
• 
Mean change in midface volume deficit measured on the 5-point MVDSS and based on the 
blinded evaluator´s live assessment at Week 4, 12, and 24 after last injection of repeat-treatment 
phase compared to the score at Visit RT1 
• 
Shift from baseline (Visit RT1) in NLF-SRS based on the blinded evaluator´s live assessment at 
Week 4, 12 and 24 after last injection during repeat-treatment phase  
• 
The extent of subject´s satisfaction with overall treatment outcome at Week 4, 12 and 24 after last 
injection of repeat-treatment phase as assessed by the subject using the Face-QTM 
Questionnaire “Satisfaction with Outcome” 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 121 of 171 
Version 7.0 - 15-MAY-2024 
• 
The extent of subject´s appearance appraisal at Week 4, 12 and 24 after last injection of repeat-
treatment phase as assessed by the FACE-QTM questionnaire “Satisfaction with Cheeks” 
compared to the score at Visit RT1 
• 
Subject evaluation of pain after each treatment (repeat and touch-up-treatment) on an 11-point 
scale, where 0 is no pain and 10 is the worst pain imaginable 
• 
Injection volume required to achieve optimal aesthetic result at each treatment (repeat and touch-
up treatment together) 
 
AEs will be encoded using the MedDRA thesaurus in the most recent version available at the beginning 
of the study. This version will be used throughout the entire study. Updates of the MedDRA thesaurus 
will not be applied afterwards. 
All AEs will be listed by subject, user or other persons, date and time since last treatment. Incidence of 
AEs will be summarized by preferred term (PT) and system organ class (SOC), and also by intensity, 
duration causal relationship to the device or procedure, and seriousness.  
The frequency and occurrence rate, maximum intensity, overall duration, and seriousness of injection 
site reactions within four weeks (28 days) after baseline treatment, after repeat-treatment injection, 
respectively, and 6 weeks in case of touch-up treatment, will be summarized by device. 
The number and percentage of subjects, user or other persons with at least one device deficiency will 
be summarized. Details concerning device deficiencies will be listed by treatment group and subject. 
Urine pregnancy tests will be listed only.  
The data will be presented for the SAF using frequency tables.  
 
This study will take place in approximately 16 investigation sites. Inclusion of subjects is planned to be 
as equally distributed as possible between the sites (see section 6.3.1 for details). 
Possible country (or geographical cluster) and study site effects will not be included in the primary 
analysis, but will be evaluated on an exploratory level by tabulation of the primary and key secondary 
endpoints by country (or geographical cluster) and study site, respectively. 
Any pooling of study sites with few subjects as well as pooling of countries in geographical clusters will 
be agreed and specified in the SAP before database lock. 
 
The primary analysis will be based on the total trial population. Besides the total study population, the 
following subgroups will be analyzed by descriptive statistical methods for the primary and the main 
secondary effectiveness endpoints: 
• 
Injection equipment: Needle versus cannula  
• 
Gender: Female versus male 
• 
Fitzpatrick skin type 
• 
Race and ethnicity 
• 
Age groups 
In order to gather information on potential heterogeneity of treatment effects between the different 
subgroups, an exploratory analysis will be performed using logistic regression models with subgroup as 
covariate and a treatment by subgroup interaction. 95% confidence intervals will be calculated for the 
treatment difference in each subgroup and presented in a forest plot. 
In addition, incidence of AEs will be summarized by preferred term (PT) and system organ class (SOC) 
within all of the above-mentioned subgroups. Frequency and occurrence rate of injection site reactions 
will be summarized within all of the above-mentioned subgroups. 
The detailed statistical analysis of subgroups will be described in the statistical analysis plan (SAP).  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 122 of 171 
Version 7.0 - 15-MAY-2024 
7.4 
Subject data listings 
All recorded data will be presented in subject data listings. 
7.5 
Missing data 
Adverse events with unknown onset times will be counted as post device administration AEs. AEs with 
missing relationship to device will be counted as related AEs (ADEs). 
Concerning statistical evaluation of the primary effectiveness endpoint (primary analysis, sensitivity 
analyses) missing data may be regarded as non-response. 
In addition, there will be no imputation of missing values. All data will be analyzed as they appear in the 
data base. 
7.6 
Software used for statistical analysis 
The SAS software version 9.4 or higher will be used for the statistical analysis and for the reporting of 
this study. 
7.7 
Deviations from the planned statistical analysis 
Any deviations from the planned statistical analysis have to be discussed in the final study report and 
should be defined in the SAP. If the deviation has any impact on the effectiveness analysis, the deviation 
has to be specified in an amendment to the CIP. 
7.8 
Amendments 
If an amendment impacts the integrity of the clinical investigation, the data collected before and after the 
amendment must be analyzed statistically to assess the effect of the amendment on effectiveness or 
safety analysis. This analysis must be included in the clinical investigation report.  
7.9 
Randomization 
The randomization list will be prepared by a biostatistician using SAS, Procedure PLAN. The 
randomization list is a document that consists of randomization numbers, which uniquely assign each 
subject to one of the two devices at a 2:1 ratio (test device: comparator device). Randomization will be 
performed using randomly permuted blocks. 
8 Data handling and data management  
8.1 
Source documents and other records maintained by the investigator 
It is the treating investigators’ obligation to assure documentation of all relevant data in the subject’s 
source record, such as the informed consent process and date of enrollment into the clinical 
investigation, medical / aesthetic history, prior and concomitant treatments, visit dates, clinical 
observations including AEs (including reporting and follow-up of AEs), results of all assessments, 
information related to medical device application, and the date of subject’s exit from the investigation, 
including the reason. 
Any form completed by the subject (including the eDiary) is also considered as a source document and 
must be kept in the subject’s source record. The location of the source documents shall be documented.  
In addition, the investigator must maintain all other essential documents pertaining to the clinical 
investigation as defined by GCP and applicable regulatory requirements.  
8.2 
Case report forms 
A CRF will be completed for each subject who signed an ICF. Data on each subject screened / 
randomized in the investigation will be recorded pseudonymously in the web-based validated electronic 
CRF (eCRF), which is designed to accommodate the specific features of the clinical investigation design 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 123 of 171 
Version 7.0 - 15-MAY-2024 
and complies with regulatory requirements on electronic data transfer. The system is compliant with 21 
CFR Part 11 regulation. 
Only the treating investigator and their authorized designees are allowed to make entries in the eCRF. 
This will be regulated by appropriate read and write access. Completed eCRFs will be electronically 
signed by the treating investigator or their authorized designee.  
All site personnel, sponsor and CRO personnel seeking access must go through a thorough training 
process before they are granted access. Furthermore, all study personnel will be instructed how to fill in 
the CRFs. The CRF Completion Guide will provide additional information additional instructions for CRF 
documentation.   
Data required according to this protocol are to be recorded on the eCRFs as soon as possible. The 
Principal Investigator must assure that all data are entered completely, and accurately according to the 
CRF Completion Guide, and is ultimately responsible for conformance of CRF entries with source data. 
Completed eCRFs will be electronically signed by the Principal Investigator or their authorized designee 
(only treating investigators). 
Any subsequent change, deletion or addition will be recorded by an audit trail system, which will require 
re-signing of the CRF.  
Data recorded from screening failures  
The minimum data to be recorded for screening failures in the subject´s source records and in the CRF 
will be given in the CRF Completion Guide.  
8.3 
Data management procedures 
All data management activities will be conducted by the sponsor's representative following their standard 
operating procedures. They will build the database and handle the data cleaning process, including 
logical checks, medical checks, and query process. Subject data necessary for analysis and reporting 
will be transmitted into a validated database. Details on data handling and data cleaning will be described 
in the Data Management Plan (DMP).  
Procedures for verification, validation and securing of electronic clinical data management systems 
(CDMS) 
The study specific eCRF and ePRO are implemented on a validated CDMS. The validation requirement 
for the study specific eCRF and ePRO is served by the following components:  
• 
The data entry screen testing and edit check testing serve as evidence of a database that performs 
for its intended use of capturing and cleaning of clinical data (user acceptance testing).  
• 
The validation of electronic clinical data management systems will be done according to the 
regulatory requirements and respective SOPs. 
• 
Any validation is performed on a self-contained development and test environment of the CDMS, 
eCRF and other applications. These environments are identical to the productive version. The test 
data are not mixed with data of other environments. 
Procedures for Data Cleaning  
Computerized validated check programs on completeness, correctness, plausibility (such as range 
checks, cross-checks, edit checks) will verify the data according to the listing of all planned programmed 
data integrity checks, the Data Cleaning Plan (DCP). All identified discrepancies will be queried and 
addressed to the respective site staff. The investigator or their authorized designee must carefully 
answer any query issued by Data Management.  
Coding of concomitant diseases, adverse events and concomitant treatments will be coded using the 
MedDRA system and the WHO Drug Global. Device deficiencies will be coded using International 
Medical Device Regulators Forum (IMDRF) Annex A. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 124 of 171 
Version 7.0 - 15-MAY-2024 
Upon completion of data collection and all data cleaning activities, i.e., when the database is considered 
complete and accurate, it is considered soft locked and reviewed by the sponsor together with the clinical 
investigation team during the DRM.  
The database will be hard locked after sponsor’s approval. All changes will be tracked by audit trail. 
Once hard locked the final clean datasets will be exported for final statistical analysis.  
Interim analysis 
An interim analysis (IA) assessing the safety and effectiveness will be performed after all subjects have 
completed the follow-up visit at Week 48 after last injection of the initial treatment phase (Visit 9 (SV1)). 
For the interim analysis the database will be cleaned and a data base lock prior to export for data 
analysis will be done.  
8.4 
Data retention 
The investigator shall retain all clinical investigation records (including all individual subject-related 
documents (e.g., subject´s questionnaires, eDiary and ICF), device-related records, investigation-
related correspondence, and all other documents contained in the Investigator’s Site File) during the 
clinical investigation and for the period required by the applicable regulatory requirements, or the time 
period specified in the contract between the sponsor and the investigator, whichever is longer.  
In any case, the investigator must contact the sponsor in writing prior to destruction of any records 
pertaining to the clinical investigation, to get confirmation that these no longer need to be retained. In 
addition, the sponsor should be informed in writing if the investigator plans to leave the site or chooses 
to store the records at a different physical address than the site address, to ensure traceability of the 
records and appropriate arrangements for the transfer of custody. 
The source records of subjects taking part in the investigation must be retained in accordance with local 
legislation and the maximum period permitted by the hospital, institution or private practice. 
8.5 
Report of the clinical investigation (CIR) 
Following completion of the clinical investigation, the results will be evaluated, and the Clinical 
Investigation Report (CIR) will be generated. Based on the interim analysis results an interim Clinical 
Investigation Report (iCIR) will be generated. Both, the iCIR and CIR will include a summary of all 
available data, statistical measures, tabulated results, graphical results (if any), and interpretations. A 
complete list of all adverse events will be enclosed. The reports will be submitted to relevant authorities 
as appropriate, within the timeframes defined per national regulation and/or to the IRB/EC as applicable.  
9 
Amendments to the clinical investigation plan (CIP) 
Any change of this CIP can only be made in form of a written amendment. Such amendment must be 
discussed, agreed upon and signed by the sponsor, the Coordinating Investigator and the Principal 
Investigators before implementation. 
Any amendment which may affect the validity of the data or information resulting from original CIP, the 
risk-benefit ratio for the subject, the scientific soundness of the investigation, change of the principal 
investigator or the rights, safety or welfare of subjects taking part in the investigation will also have to be 
reviewed and approved by the IRB/EC and regulatory authorities, if applicable, prior to implementation. 
Amendments with impact on procedures to be performed, risk-benefit ratio for the subject and/or the 
well-being of the subjects require additional informed consent, which must be given in writing by all 
subjects enrolled in the clinical investigation who are affected by the amendment. 
10 Deviations from the clinical investigation plan  
A CIP deviation is a failure to follow, intentionally or unintentionally, the requirements of the CIP. As 
required by national regulation or guidelines, requests for deviations and reports of deviations will be 
provided to the IRB/EC if the deviation affects subject’s rights, safety and well-being, or the scientific 
integrity of the clinical investigation. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 125 of 171 
Version 7.0 - 15-MAY-2024 
Under emergency circumstances, deviations from the CIP may proceed without prior approval by the 
sponsor and favourable opinion of the IRB/EC if the rights, safety and well-being of human subjects 
need to be protected. Such deviations will - however - be documented and reported to the sponsor and 
the IRB/EC as soon as possible in accordance with national regulations. No waivers to the CIP will be 
granted by the sponsor. 
The investigator must maintain accurate, complete and current records of any deviation from the CIP, 
including the date and reason for each deviation. 
The investigator shall notify the sponsor and the reviewing IRB (as applicable) of any deviation from the 
CIP made to protect the life or physical well-being of a subject in emergency as soon as possible, but in 
no event later than five working days after the emergency occurred.  
All CIP deviations will be listed and their impact on evaluability of respective subjects will be discussed 
during the interim DRM and during DRM prior to the hard data base lock.  
11 Device accountability 
The device accountability is described in section 6.2.6. 
12 Statements of compliance 
This clinical investigation will be conducted in compliance with this CIP and the following standards and 
regulatory requirements:  
• 
International Standard ISO 14155:2020 Clinical investigation of medical devices for human subjects 
- Good Clinical Practice (GCP) 
• 
Declaration of Helsinki, in its currently adopted version 
• 
Applicable national medical device laws / regulations. 
By acting in accordance with this CIP, the investigators and the investigation site personnel fulfil the 
requirements of ISO 14155:2020. 
The clinical investigation will not commence until a favorable opinion from the respective EC has been 
received. All additional requirements imposed by the IRB/EC will be followed. A prior regulatory approval 
will also be sought, if required by national regulations. 
Insurance coverage for damages emerging from the clinical investigation will be provided according to 
applicable legal requirements. 
13 Informed consent process 
The informed consent form (ICF) must be notified to, or approved by, the IRB/EC and regulatory 
authorities, if required by local regulations.  
Written informed consent must be obtained from each subject prior to initiation of any of the investigation-
specific procedures.  
The investigator or their authorized designee must give each subject complete and adequate verbal and 
written information about the investigation. The investigator must ensure that the subject is fully informed 
about the aims, procedures, potential risks, any discomforts, and expected benefits of the clinical 
investigation. It must be emphasized that participation is voluntary and that the subject has the right to 
withdraw from the clinical investigation at any time without any justification and without prejudice. They 
also must be informed that the quality of their medical care will not be adversely affected if they decline 
to participate in the investigation or in case of subsequent consent withdrawal. Before consenting, the 
subject must be left with ample time to consider and ask questions.  
The subject must then sign and date the Informed Consent Form (ICF) prior to the conduct of any 
investigation-related procedures. The consent taker (the investigator or, according to local laws, their 
designee) must sign and date the ICF as well.  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 126 of 171 
Version 7.0 - 15-MAY-2024 
The investigator will document the entire informed consent process in the subject´s source record (e.g., 
date (and time as applicable) of informed consent / signature, who has informed the subject, and that 
s/he has informed the subject, that the subject had ample time to consider, that the subject and the 
investigator have signed the ICF). In addition, the date (and time as applicable) of informed consent / 
signature will be recorded in the eCRF.  
A signed and dated copy of the ICF will be given to the subject for their records. The other copy of the 
signed and dated ICF will remain in the Investigator´s Site File.  
If subject’s participation in the investigation or decision to participate in the investigation is or may be 
affected by an amendment to the CIP (e.g., a change in any procedure) or any other important new 
information, which may relate to the subject’s willingness to continue participation in the clinical 
investigation, the ICF must be amended accordingly, and the subject must sign the amended ICF 
indicating that they re-consent to participate in the clinical investigation. 
14 Adverse events, adverse device effects and device deficiencies 
14.1 Definitions 
Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury or untoward 
clinical sign (including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the device and whether anticipated or unanticipated. This definition includes events related 
to the test device, the comparator device and events related to the procedures involved.  
• 
For subjects taking part in the clinical investigation this definition includes events related to the 
device and procedures involved, as well as pregnancy in females.  
Note 1: The event of pregnancy meets the SAE criterion if it results in a spontaneous abortion or a 
congenital anomaly or it is suspected that the device or study procedure interacted with the 
contraceptive method and has led to pregnancy. Pregnancy is not considered an (S)AE per se. 
Note 2: Injection site reactions the subject is specifically asked about in the subject diary (see 
section 6.4.19) will not be collected as AEs during the first four 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). Any injection site reactions that continue for more than 28 days post-
administration will be assessed and documented as AEs by the treating investigator as described 
in the sections below.  
Note 3: Injection site reactions the subject is not specifically asked about in the subject diary (i.e., 
‘Other’ symptoms at the injection site not listed in section 6.4.19) and that are not synonymous to 
one of the pre-defined injection site reactions will be assessed and documented as AEs by the 
treating investigator as described in the sections below. 
• 
For users or other persons this definition is restricted to events related to the use of both devices 
(test device or comparator device). 
Adverse Device Effect (ADE) is an AE related to the use of the device. 
This includes This definition includes  
• 
AEs resulting from insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the device  
• 
any event resulting from use error or from intentional misuse of the investigational medical device.  
• 
the comparator device 
Serious Adverse Event (SAE) is an AE that led to any of the following conditions: 
• 
Death;  
• 
Serious deterioration in the health of the subject, users, or other persons as defined by one or more 
of the following: 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 127 of 171 
Version 7.0 - 15-MAY-2024 
o A life-threatening illness or injury, or 
o A permanent impairment of a body structure or a body function including chronic diseases, or 
o In-subject or prolonged hospitalization, or 
o Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function 
• 
Fetal distress, fetal death, a congenital abnormality, or birth defect including physical or mental 
impairment. 
Planned hospitalization for pre-existing condition or a procedure required by the CIP without a serious 
deterioration in health is not considered a SAE. 
Serious Adverse Device Effect (SADE) is an ADE that has resulted in any of the consequences 
characteristic of an SAE. 
Serious health threat is a signal from any adverse event or device deficiency that indicates an imminent 
risk of death or a serious deterioration in the health in subjects, users or other persons, and that requires 
prompt remedial action for other subjects, users or other persons. This would include events that are of 
significant and unexpected nature such that they become alarming as a potential serious health hazard 
or possibility of multiple deaths occurring at short intervals (according to ISO 14155). 
Adverse Events of Special Interest (AESI) (serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor could be appropriate. Such events may require further 
investigation in order to characterize and understand them. Depending on the nature of the event, rapid 
communication by the sponsor to other parties may also be needed (see section 14.5).  
For this clinical investigation, AEs of special interest are defined as embolic events, with possible, 
probable, or causal relationship to an intravascular injection of the device, as:  
• 
Changes in vision (i.e. loss of vision, blurriness, double vision, pain in or around your eye, 
blindness, blind spots, problems moving the eyes) 
• 
Skin changing color around the eyelids or around the site of injection 
• 
Other embolic phenomenons, e.g., stroke, skin necrosis, or impending necrosis 
Unanticipated (Serious) Adverse Device Effect:  
• 
Unanticipated Serious Adverse Device Effect (USADE) is defined as a SADE which by its 
nature, incidence, severity (intensity) or outcome has not been identified in the current risk 
assessment and the current version of the Investigator´s brochure (IB) (adapted according to 
ISO 14155) 
• 
For USA only: Unanticipated adverse device effect (UADE) is defined as any serious 
adverse effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously identified in nature, 
severity (intensity), or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with 
a device that relates to the rights, safety, or welfare of subjects” (according to investigational 
device exemption (IDE) regulations / 21 CFR 812.3(s)).  
Device deficiency is an inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, usability, safety or performance. Device deficiencies include malfunctions, use errors, and 
inadequacy in the information supplied by the manufacturer including labelling. This definition includes 
device deficiencies related to the test device or the comparator device. 
Device deficiency that might have led to a SAE if a) suitable action had not been taken, or b) 
intervention had not been made, or c) if circumstances had been less fortunate, is classified as a special 
type of deficiency and is handled under the SAE reporting system. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 128 of 171 
Version 7.0 - 15-MAY-2024 
14.2 Method of detecting AEs 
AEs will be detected by observation and by asking the subject about the occurrence of AEs. Care should 
be taken not to introduce bias when eliciting AE information from the subject. Open-ended and non-
leading verbal questioning is the preferred method and appropriate questions include: 
• 
“How are you feeling?” 
• 
“Have you had any medical problems since your last visit/contact?” 
• 
“Have you taken any new medication since your last visit/contact?” 
In order to identify potential AEs post-administration of device safety evaluation 15 minutes after the 
device administration needs to take place (see section 6.4.20).  
All SOI(s) documented by the subject in the eDiary (see section 6.4.19) must be verified by the 
investigator either by specific questioning of the subject and/or physical examination or visual inspection. 
SOI(s) considered clinically significant should be documented as AE(SI)(s). SOIs that turn out to be not 
clinically significant (see section 20.5.1 for examples) due to any reason are not considered as AE(SI) 
and need not to be documented as AE(SI) in the eCRF. However, the investigator should add a 
statement in the subject’s source records why the SOI was not considered clinically significant, i.e., as 
AE(SI). 
All AESIs (serious and non-serious, see section 14.1 for definition) and any other embolic event 
(regardless of seriousness and / or relationship to device or procedure) resulting from SOI assessment 
have to be reported by the investigator to the sponsor’s representative within 24 hours of awareness of 
the event (see section 14.5).  
In addition, the subjects will be instructed to immediately contact the investigator/investigation site in 
case of occurrence of any untoward event between visits and an unscheduled visit will be performed 
(see section 6.5.17). Throughout the entire investigation the investigator should also verify results of all 
assessments with respect to possible AEs.  
14.3 AE/SAE documentation 
For each AE the following must be reported:  
• 
Description of the event (event term) 
• 
Seriousness  
• 
Start date 
• 
Intensity 
• 
Action taken with subject (none, medical and/or surgical / non-pharmaceutical procedure) 
• 
Action taken with device (none [no action taken], device withdrawn [no touch-up treatment(s) / 
repeat-treatment due to AE], device interrupted [touch-up treatment(s) / repeat-treatment later than 
required by study design due to AE or injection interrupted due to AE during treatment session]) 
• 
Outcome 
• 
End date (if applicable) 
• 
The relationship to the device and procedure, respectively 
The information will be documented in subject´s source record and in the eCRF. 
Each AE and any new information concerning these events has to be documented, even if the 
investigator feels that it is not connected with the device or procedure.  
The AE will be described in precise, standard medical terminology. The investigator will attempt to 
establish a diagnosis of the event based on signs, symptoms, and/or other clinical information (including 
affected body site(s)). In such cases, the diagnosis will be documented as the AE and not the individual 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 129 of 171 
Version 7.0 - 15-MAY-2024 
signs/symptoms. In case of any injection site reaction the exact location (e.g., upper or lower lips) should 
be clearly noted. 
Each AE should be reported separately. The investigator will record all AEs in subject´s (medical) record 
and on the ”Adverse Events” page of the eCRF. For SAEs, the “Serious Adverse Event Reporting Form” 
must also be completed. Complete description of all AEs should be also available in source documents 
of the subject.  
Adverse events will be documented beginning after provision of informed consent until the last visit of 
the subject. The follow-up period will be prolonged outside the investigation, if a related AE is ongoing 
and not stabilized after 24 weeks after last injection of the repeat-treatment phase (see section 14.6 for 
details). 
AEs initially observed during or after baseline treatment are defined as treatment-emergent AEs 
(TEAEs). AEs occurring after informed consent but before baseline treatment will be defined as non-
TEAEs. Any medical condition that is present prior to day of screening should be considered as medical 
history (i.e., concomitant disease) and not recorded as an AE. If such condition, however, deteriorates 
after the device administration, at any time during the investigation, it should be reported as an AE.  
If the intensity or seriousness of an AE changes over time, the most severe intensity or seriousness of 
the AE will be recorded and included in the analysis. No separate AEs will be recorded for each intensity 
or seriousness level.  
Changes in causality assessment should also be clearly documented. AEs related to the device as well 
as to investigation procedure must be documented. Any medication and non-pharmacological procedure 
necessary for the therapy of an AE must be recorded on the respective page of the eCRF. 
Adverse events in users or other persons 
• 
For any AE in users or other persons the Adverse Event (AE) Documentation Form for Users / Other 
Persons must be completed according to the Instructions for Completion.  
• 
If the AE fulfills one of the criteria for seriousness the SAE Report Form must be completed, 
additionally and reporting responsibilities have to be fulfilled (see section 14.5).  
• 
If the AE is related to a device deficiency, the corresponding Device Deficiency Form has to be 
completed, too (see section 14.9).  
14.4 AE assessment 
All AEs will be assessed in terms of seriousness, intensity, relationship to the device or clinical 
investigation procedures, and outcome. 
 
The seriousness of an AE is assessed by comparing AE features against the SAE definition provided in 
section 14.1. 
 
The intensity of an AE will be graded as follows: 
Mild: 
The AE is easily tolerated and does not interfere with daily activity. 
Moderate: The AE interferes with daily activity, but the subject is still able to function. 
Severe: 
The AE is incapacitating and/or requires medical intervention. 
 
The investigator is obligated to estimate the relationship between each AE/SAE and the test device, the 
comparator device or clinical investigation procedure. Clinical judgement should be used and relevant 
documents like Instructions for Use or Investigator´s brochure consulted.  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 130 of 171 
Version 7.0 - 15-MAY-2024 
The presence of confounding factors, such as concomitant treatment, the natural history of the 
underlying disease, other concurrent illness or risk factors shall also be considered.  
For the final analysis all AEs assessed with the relationship “possible”, “probable” or “causal relationship” 
will be classified as “related”. 
The relationship should be determined using one of the following causality levels:[45]  
Causal 
relationship: 
 
The AE/SAE is associated with the test device, comparator device or with 
procedures beyond reasonable doubt when: 
• 
the event is a known side effect of the product category the device belongs 
to or of similar devices and procedures 
• 
the event has a temporal relationship with the device use/application or 
procedures 
• 
the event involves a body-site or organ that 
o 
the devices or procedures are applied to 
o 
the devices or procedures have an effect on 
• 
the event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
• 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the event (when clinically feasible) 
• 
other possible causes (e.g. an underlying or concurrent illness/ clinical 
condition or/and an effect of another device, drug or treatment) have been 
adequately ruled out 
• 
harm to the subject is due to error in use and/or 
• 
the event depends on a false result given by the investigational device used 
for diagnosis, when applicable 
Note: In order to establish the relatedness, not all the criteria listed above might 
be met at the same time, depending on the type of device/procedures and the 
event. 
Probable: 
The relationship with the use of the test or comparator device, or the relationship 
with procedures, seems relevant and/or the event cannot be reasonably 
explained by another cause. 
Possible: 
The relationship with the use of the test or comparator device, or the relationship 
with procedures, is weak but cannot be ruled out completely.  
Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment).  
Cases where relatedness cannot be assessed, or no information has been 
obtained should also be classified as possible. 
Not related: 
Relationship to the test device, comparator device or procedures can be 
excluded when: 
• 
the event has no temporal relationship with the use of the device, or the 
procedures related to application of the device 
• 
the event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible 
• 
the discontinuation of medical device application or the reduction of the level 
of activation/exposure - when clinically feasible - and reintroduction of its use 
(or increase of the level of activation/exposure), do not impact on the event 
• 
the event involves a body-site or an organ that cannot be affected by the 
device or procedure 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 131 of 171 
Version 7.0 - 15-MAY-2024 
• 
the event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other 
risk factors) 
• 
the event does not depend on a false result given by the device used for 
diagnosis, when applicable 
Note: In order to establish the non-relatedness, not all the criteria listed above 
might be met at the same time, depending on the type of device/procedures and 
the serious adverse event. 
 
The outcome of an AE will be assessed as follows: 
Recovered / Resolved: 
The subject has fully recovered from the event. 
Not recovered / resolved (Ongoing): 
The subject has not recovered from this event.  
Recovering / Resolving: 
The subject is recovering from the event. 
Recovered / Resolved with 
sequelae: 
The subject is experiencing the aftereffects of a condition 
or injury (sequelae). 
Fatal (Death): 
The subject died due to this event. 
Unknown: 
The outcome of this event is unknown  
14.5 AE/SAE and pregnancy reporting requirements  
 
Note: For any AE (including a SAE) all appropriate sections of the eCRF must be completed.  
Any SAE must be reported by the investigator to the sponsor’s representative immediately but not 
later than 24 hours of awareness of the event via Email. Contact details will be provided in a separate 
manual.  
This also applies to serious and non-serious AESIs (see section 14.1 for definition), any other embolic 
event (regardless of seriousness and / or relationship to device or procedure), and any significant AE, 
which in the investigator’s opinion could affect the safety of the subjects taking part in the investigation 
or the conduct of the investigation.  
In general, information about an SAE will be collected and recorded on the SAE Reporting Form. The 
SAE Reporting Form will be provided by the sponsor´s representative to the investigational sites and 
will contain additional process information for how to report.  
The investigator will be requested to supply as much detailed information as possible regarding the SAE 
that is available at the time of the initial contact. The investigator should also complete missing or 
requested information and submit follow-up reports until the SAE has resolved or, in the case of 
permanent impairment, until the SAE has stabilized.  
The sponsor’s representative will inform the sponsor about any SAEs immediately after becoming aware 
of the respective SAE report from the investigator.  
Should an SAE occur after the final visit, which is considered at least possibly related to the device or 
procedure, such events should always be reported to CROMA-PHARMA GmbH or its representative, 
even after the end of the clinical investigation.  
At the end of the clinical investigation, a reconciliation of all reported SAEs will take place and be 
enclosed as a list in the Clinical Investigation Report.  
For further information on reporting and notification requirements per country for Investigators see 
sections below.  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 132 of 171 
Version 7.0 - 15-MAY-2024 
Detailed reporting by the sponsor or sponsor’s representative to IRBs/ECs, all Investigators and 
regulatory authorities will follow pertinent national legislation described in detail in Safety Management 
Plan (SMP).  
Signals from adverse events or device deficiencies that might indicate a serious (public) health threat 
(see section 14.1) can be detected by either the sponsor or principal investigator but will be evaluated 
by the sponsor / sponsor´s representative. If required, occurrence of a serious (public) health threat will 
be reported according to regulatory requirements.  
 
The investigator must report any SAE/SADE to the sponsor´s representative immediately but not 
later than 24 hours of awareness of the event via Email.  
The sponsor will report the results of UADE evaluation to all investigators, to the reviewing IRBs and to 
the respective competent authority (FDA) within ten working days after receipt of the first notice of the 
effect.  
 
For reports received by the sponsor´s representative containing any event relating to incidences of visual 
disturbances, the following information must be urgently requested.  
The request will be made in the form of a query to the site (by using the ‘Device Safety Query for 
Additional Information’ form): 
• 
Depth of injection (i.e., subcutaneous or supraperiosteal)  
• 
The injection volume 
• 
The symptoms that were observed 
• 
The time to event onset, and resolution 
• 
Any interventions that were implemented 
• 
The symptoms that were observed 
• 
The time to event onset, and resolution 
• 
Any interventions that were implemented 
If a response to the aforementioned queries is not received within 24 hours, a follow-up reminder will 
be sent, and the queries escalated to the Medical Monitor and Project Manager at the sponsor´s 
representative. 
 
All AESI (serious and non-serious) and any other embolic event (regardless of seriousness and / or 
relationship to device or procedure) have to be reported by the investigator to the sponsor’s 
representative within 24 hours of awareness of the event via Email using the SAE Reporting Form.  
The sponsor's representative will report all AESIs and any other embolic event (regardless of 
seriousness and / or relationship to device or procedure) to the respective competent authority (FDA) in 
an expedited manner (see sections 14.5.1 to 14.5.3). 
 
Any pregnancy must be notified to the contact given above within the same timelines as an SAE (within 
24 hours after being made aware of the pregnancy). The Pregnancy and Lactation Exposure Form will 
be provided by the sponsor´s representative to the investigational sites and will contain additional 
process information for how to report. If pregnancy is associated with an SAE (e.g., if the mother is 
hospitalized for hemorrhage), a separate SAE Reporting Form must be filed in addition to Pregnancy 
and Lactation Exposure Form. The pregnant subject must be withdrawn immediately from further 
treatment, if applicable. The pregnant subject may remain in the study for safety assessments during 
the scheduled study visits.  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 133 of 171 
Version 7.0 - 15-MAY-2024 
14.6 AE/SAE and pregnancy follow-up 
The investigator will take all appropriate and necessary measures required for resolution of the AE. 
All AEs must be followed-up by the investigator until recovery, or until the investigator determines that 
the subject’s condition is stable, or subject’s last day of the clinical investigation at the site, whichever 
occurs first. All subjects excluded from repeat-treatment should continue to be followed until the 
resolution of all ongoing, related AEs. 
All SAEs/AESIs judged to be related to the device (SADEs) must be followed by the investigator until 
the subject has recovered, recovered with sequelae, died, or until the investigator determines that the 
subject’s condition is stable, whichever occurs first.  
In addition, those subjects who have a related AE ongoing (i.e., not recovered / not resolved) and not 
stabilized (i.e., recovering / resolving) after 24 weeks after last injection of the repeat-treatment phase 
will be followed for a longer follow-up outside the investigation. The follow-up for these subjects would 
continue until resolution (i.e., recovered / resolved) or stabilization of the condition (i.e., recovered / 
resolved with sequelae).  
AEs to be followed outside the investigation will be reported to the sponsor´s vigilance department using 
the Post-Study-AE-Follow-Up Form. Contact details and additional process information for how to report 
will be given on the respective form.  
Any pregnancy must be followed-up until the pregnancy outcome at least once in each trimester and 
pregnancy outcome (including pregnancy duration and health status of a newborn or cause of premature 
termination, as applicable) will be reported to the sponsor´s representative using a Pregnancy Query 
Form for the status of pregnancy. If it is still on-going at the end of the clinical investigation, follow-up 
will be continued outside of the context of clinical investigation.  
14.7 Foreseeable AEs and anticipated ADEs 
Foreseeable AEs and anticipated ADEs are listed in section 4.2. Reporting requirements are given in 
section 14.5. 
14.8 Risk assessment process for potentially unacceptable risks 
Any person identifying an event or information that could have an impact on subjects’, users’ or other 
persons’ safety, has an obligation to inform the principal investigator and the sponsor of their concerns. 
All potentially unacceptable risks arising during the course of the clinical investigation will be managed 
by the sponsor / sponsor´s representative following pertinent national legislations.  
14.9 Device deficiency 
 
At least the following items need to be documented with in the subject´s source records and the eCRF 
for each device deficiency: 
• 
Date of device deficiency or detection date of device deficiency 
• 
Description of the device deficiency 
• 
Nature of device deficiency (i.e., malfunction, use error, and inadequate labelling) 
• 
If an individual is affected by the device deficiency (subject, user, or other persons) 
• 
Relationship to an (S)AE, if any 
• 
If the device deficiency could have led to a SADE (including the circumstances) 
• 
Relationship between study intervention and device deficiency 
• 
Action taken with the deficient device  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 134 of 171 
Version 7.0 - 15-MAY-2024 
This includes device deficiencies related to the test device or the comparator device. 
 
All device deficiencies must be recorded on a Device Deficiency Reporting Form. The Device Deficiency 
Reporting Form will be provided by the sponsor´s representative to the investigational sites and will 
contain additional process information for how to report.  
Device deficiencies should be reported by the treating investigator to the sponsor’s representative within 
24 hours after the site became aware of the deficiency using the same contact as for SAEs (see 
section 14.5). 
If a device deficiency is associated with an AE, the corresponding AE documentation (see section 14.4) 
and reporting procedures (see section 14.5) must be adhered to as well. 
The sponsor’s representative will forward the Device Deficiency Reporting Form to the sponsor within 
24 hours after receipt of the respective report from the investigator.  
14.10 Data monitoring committee 
Not applicable. 
15 Vulnerable populations 
Vulnerable populations will not be included in this clinical investigation. 
16 Suspension or premature termination of the clinical investigation 
The sponsor reserves the right to terminate the clinical investigation for any reason (e.g., safety, new 
data on the risk/benefit, ethical or administrative reasons). Written notice, outlining the reasons for the 
termination, will be submitted to the investigators in advance of such termination. The sponsor will 
provide instructions if assessments beyond the regular per protocol procedures should be necessary. 
The sponsor may suspend enrollment or terminate the study at a specific site for reasons including, but 
not limited to, inadequate data collection, low subject enrollment rate, achievement of the total 
enrollment, or non-compliance with the CIP or other clinical research requirements. 
The investigator, IRB/EC, or regulatory authority (if applicable) may also suspend or prematurely 
terminate the clinical investigation at the investigational sites for which they are responsible.  
If the clinical investigation is prematurely terminated, the sponsor or the sponsor’s representative will 
promptly inform the relevant authority (if applicable) of the termination and its reason(s); the investigator 
or the sponsor (or representative) will promptly inform the IRB/EC, as specified in applicable regulations. 
16.1 Clinical investigation stopping rules in case of vascular occlusion 
In the event of any vascular occlusion secondary to dermal filler injection, or other adverse events 
secondary to such vascular occlusion, and which are avoided or prevented only by urgent treatment, 
the enrollment and treatment will be suspended, and a root cause investigation has to be conducted to 
determine the cause of the event. Such investigation will involve the investigator who treated the affected 
subject and the sponsor or designee.  
Such cases, which may include e.g., impending necrosis, subjects with early signs of a stroke, or 
subjects with vision loss, all of whom undergo urgent treatment and have resolution of their necrosis, 
stroke, or vision loss symptoms, will result in actions as defined above, during which further enrolment 
and treatment will be on hold. 
• 
If the treating investigator didn’t properly follow the treatment procedure, he/she will be re-trained 
before being allowed to recruit further subjects.  
• 
In case this event was unanticipated (see section 4.2 for foreseeable AEs and anticipated ADEs) 
and the investigator did follow the treatment procedure correctly, the entire clinical investigation has 
to be immediately suspended and no subjects should be enrolled until the event can be properly 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 135 of 171 
Version 7.0 - 15-MAY-2024 
characterized and an appropriate treatment strategy to avoid this unanticipated event can be 
devised. 
17 Publication policy, financing and other agreements 
This CIP, other investigation-related documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the clinical investigation, or the data will be released 
to any unauthorized third party without prior written approval by the sponsor. 
All data, results and all intellectual property rights in the data and results derived from the study will be 
the property of the sponsor who may utilize them in various ways, such as for submission to government 
regulatory authorities or disclosure to other investigators. 
Regarding public disclosure of study results, the sponsor will fulfill its obligations according to all 
applicable laws and regulations. 
17.1 Registration and Publication in Publicly Accessible Database 
In accordance with the applicable regulations, a description of the clinical investigation will be registered 
in a publicly accessible database before recruitment of the first subject. If required by the national 
regulations, the content will be updated throughout the conduct of the clinical investigation and the 
results entered at completion of the clinical investigation. 
Irrespective of the outcome, positive, inconclusive and negative results of the clinical investigation will 
be entered in a publicly accessible database where the clinical investigation was registered within the 
timeframes required by the respective regulations. It shall be accompanied by a summary written in a 
manner that is understandable to laypersons as applicable. 
The clinical investigation will be posted on the “clinicaltrials.gov” site. 
17.2 Scientific Publication 
The results of the clinical investigation may be published and/or presented at scientific meetings. 
However, results should not be published without prior written consent by the sponsor and such consent 
will not be unreasonably withheld. All manuscripts and abstracts, which refer to data originating from the 
clinical investigation, must be submitted to the sponsor for comments within a time period specified in 
the contract between the sponsor and the investigator prior to submission for publication. 
If the proposed publication contains any invention related to the clinical investigation, the sponsor is 
entitled to file respective patent applications and – on this ground – to delay the submission for 
publication or presentation of medical results. 
17.3 Financing 
The financial aspects of the investigation will be documented in a separate agreement between the 
sponsor and the investigator/institution. All expenses arising in connection with the investigation, the 
remuneration of the investigators for performance of the investigation and the indemnification of the 
subjects for their participation will be reimbursed in accordance with the respective contracts. 
17.4 Agreements 
There will be an agreement between the sponsor and the Principal Investigator(s)/investigation site(s) 
and any other relevant parties (e.g., investigators, CRO(s)), which defines the responsibilities of each 
party in this clinical investigation. All agreements will be in writing and signed and dated by all parties 
involved. 
18 Bibliography 
1. 
Macierzynska, A., E. Pierzchala, and W. Placek, Volumetric techniques: three-dimensional 
midface modeling. Postepy Dermatol Alergol, 2014. 31(6): p. 388-91. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 136 of 171 
Version 7.0 - 15-MAY-2024 
2. 
DeFatta, R.J. and E.F. Williams, 3rd, Evolution of midface rejuvenation. Arch Facial Plast Surg, 
2009. 11(1): p. 6-12. 
3. 
Sadick, N.S., The impact of cosmetic interventions on quality of life. Dermatol Online J, 2008. 
14(8): p. 2. 
4. 
Gold, M., What's New in Fillers in 2010? The Journal of clinical and aesthetic dermatology, 2010. 
3(8): p. 36-45. 
5. 
Wang, F., et al., In vivo stimulation of de novo collagen production caused by cross-linked 
hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol, 2007. 
143(2): p. 155-63. 
6. 
De Boulle, K., et al., A review of the metabolism of 1,4-butanediol diglycidyl ether-crosslinked 
hyaluronic acid dermal fillers. Dermatol Surg, 2013. 39(12): p. 1758-66. 
7. 
Sjerobabski-Masnec, I. and M. Situm, Skin aging. Acta Clin Croat, 2010. 49(4): p. 515-8. 
8. 
Goldman, A. and U. Wollina, Facial rejuvenation for middle-aged women: a combined approach 
with minimally invasive procedures. Clin Interv Aging, 2010. 5: p. 293-9. 
9. 
Cummins, T.R., Setting up for the block: the mechanism underlying lidocaine's use-dependent 
inhibition of sodium channels. The Journal of physiology, 2007. 582(Pt 1): p. 11-11. 
10. 
Achar, S. and S. Kundu, Principles of office anesthesia: part I. Infiltrative anesthesia. Am Fam 
Physician, 2002. 66(1): p. 91-4. 
11. 
Becker, D.E. and K.L. Reed, Essentials of local anesthetic pharmacology. Anesth Prog, 2006. 
53(3): p. 98-108; quiz 109-10. 
12. 
Ballin, A.C., A. Cazzaniga, and F.S. Brandt, Long-term efficacy, safety and durability of 
Juvederm® XC. Clin Cosmet Investig Dermatol, 2013. 6: p. 183-9. 
13. 
Smith, L. and K. Cockerham, Hyaluronic acid dermal fillers: can adjunctive lidocaine improve 
patient satisfaction without decreasing efficacy or duration? Patient preference and adherence, 
2011. 5: p. 133-139. 
14. 
Allergan: INSTRUCTIONS FOR USE for JUVÉDERM VOLUMA™ XC [USA]. 2020. 
15. 
Jung, J.M., et al., "A Multi-center, randomized, double blinded, comparative study of two 
hyaluronic acid fillers for temporary restoration of mid-face volume in Asians". J Cosmet 
Dermatol, 2020. 19(7): p. 1619-1626. 
16. 
Jones, D.H., et al., Microcannula Injection of Large Gel Particle Hyaluronic Acid for Cheek 
Augmentation and the Correction of Age-Related Midface Contour Deficiencies. Dermatologic 
Surgery, 2020. 46(4): p. 465-472. 
17. 
Huh, C.-H., et al., A Randomized, Active-Controlled, 52-Week Study of Hyaluronic Acid Fillers 
for Anteromedial Malar Region Augmentation. Plastic and Reconstructive Surgery – Global 
Open, 2020. 8(2): p. e2648. 
18. 
CROMA-PHARMA GmbH: Instructions for use, saypha® VOLUME Lidocaine [approved 
labeling w/o USA]. 2020. 
20. 
Carruthers, A. and J. Carruthers, Non-animal-based hyaluronic acid fillers: scientific and 
technical considerations. Plast Reconstr Surg, 2007. 120(6 Suppl): p. 33s-40s. 
21. 
Baumann, L., et al., Volumizing Hyaluronic Acid Filler for Midface Volume Deficit: Results After 
Repeat Treatment. Dermatol Surg, 2015. 41 Suppl 1: p. S284-92. 
22. 
Glaser, D.A., et al., Duration of effect by injection volume and facial subregion for a volumizing 
hyaluronic acid filler in treating midface volume deficit. Dermatol Surg, 2015. 41(8): p. 942-9. 
24. 
Weinkle, S.H., et al., A multi-center, double-blind, randomized controlled study of the safety and 
effectiveness of Juvéderm injectable gel with and without lidocaine. J Cosmet Dermatol, 2009. 
8(3): p. 205-10. 
25. 
Joo, H.J., et al., A Randomized Clinical Trial to Evaluate the Efficacy and Safety of Lidocaine-
Containing Monophasic Hyaluronic Acid Filler for Nasolabial Folds. Plast Reconstr Surg, 2016. 
137(3): p. 799-808. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 137 of 171 
Version 7.0 - 15-MAY-2024 
26. 
Sharma, P.P., D.K. Sharma, and A. Carr, Comparative Study of UMA Jeunesse Classic(®) and 
UMA Jeunesse Ultra(®). Aesthetic Plast Surg, 2018. 42(4): p. 1111-1118. 
27. 
https://www.stroke.org/en/about-stroke/stroke-symptoms [accessed: 13-Oct-2021]. 
28. 
Harbison, J., et al., Diagnostic accuracy of stroke referrals from primary care, emergency room 
physicians, and ambulance staff using the face arm speech test. Stroke, 2003. 34(1): p. 71-6. 
29. 
EMA: Points to consider on implications of Coronavirus disease (COVID-19) on methodological 
aspects of ongoing clinical trials. 25-MAR-2020. DRAFT. 
30. 
GUIDANCE ON THE MANAGEMENT OF CLINICAL TRIALS DURING THE COVID-19 
(CORONAVIRUS) PANDEMIC. 28-APR-2020. Version 3.0. 
31. 
European Commission: Coronavirus - Commission issues guidance to mitigate clinical trial 
disruption in the EU. 28-APR-2020. 
32. 
FDA: Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency. March 2020;  Updated on August 30, 2021. 
33. 
CROMA PHARMA GmbH: Validation Report - Test-Retest Reliability Croma Midface Volume 
Deficit Severity Scale (MVDSS) - Live assessment. February 2018. 
34. 
CROMA PHARMA GmbH: Validation Report - Test-Retest Reliability Croma Midface Volume 
Deficit Severity Scale (MVDSS) - Photographic assessment. September 2017. 
35. 
Narins, R.S., et al., A randomized, double-blind, multicenter comparison of the efficacy and 
tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg, 
2003. 29(6): p. 588-95. 
36. 
Klassen, A.F., et al., FACE-Q scales for health-related quality of life, early life impact, 
satisfaction with outcomes, and decision to have treatment: development and validation. Plast 
Reconstr Surg, 2015. 135(2): p. 375-86. 
37. 
Memorial Sloan Kettering Cancer Center: FACE-Q | Aesthetics© - A Guide for Researchers and 
Clinicians - USER’S GUIDE. January 2015. VERSION 1.0  
38. 
Breivik, H., et al., Assessment of pain. Br J Anaesth, 2008. 101(1): p. 17-24. 
39. 
Carruthers, J., et al., Volumizing with a 20-mg/mL smooth, highly cohesive, viscous hyaluronic 
acid filler and its role in facial rejuvenation therapy. Dermatol Surg, 2010. 36 Suppl 3: p. 1886-
92. 
40. 
Hoffmann, K., Volumizing effects of a smooth, highly cohesive, viscous 20-mg/mL hyaluronic 
acid volumizing filler: prospective European study. BMC Dermatol, 2009. 9: p. 9. 
41. 
Kestemont, P., et al., Sustained efficacy and high patient satisfaction after cheek enhancement 
with a new hyaluronic acid dermal filler. J Drugs Dermatol, 2012. 11(1 Suppl): p. s9-16. 
42. 
Urdiales-Galvez, F., et al., Treatment of Soft Tissue Filler Complications: Expert Consensus 
Recommendations. Aesthetic Plast Surg, 2018. 42(2): p. 498-510. 
43. 
Alam, M., et al., ASDS guidelines of care: injectable fillers. Dermatol Surg, 2008. 34 Suppl 1: p. 
S115-48. 
44. 
Fitzpatrick, T.B., The validity and practicality of sun-reactive skin types I through VI. Arch 
Dermatol, 1988. 124(6): p. 869-71. 
45. 
MDCG 2020-10/1: Safety reporting in clinical investigations of medical devices under the 
Regulation (EU) 2017/745. May 2020. 
46. 
CROMA-PHARMA GmbH: Investigator’s brochure, PRINCESS® FILLER LIDOCAINE / 
SAYPHA® FILLER LIDOCAINE. 2024. IB-0003 - version 6.0. 
 
 
 
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 139 of 171 
Version 7.0 - 15-MAY-2024 
Change 
CIP Sections 
affected 
Rationale 
Austria only: and Ssexual abstinence (if in 
line with the preferred and usual lifestyle of 
the subject and defined as refraining from 
heterosexual intercourse during the entire 
period of the trial).  
Note: Sexual abstinence is defined as highly 
effective for Austria only.  
InC#5 and ExC#12-14, #22 and #24 
(Baseline treatment): 
InC: 
5. Willingness to abstain from any 
aesthetic or surgical procedures in 
the treatment area for the duration of 
the entire investigation study, […] 
ExC:  
12. […] or is planning to undergo such 
procedures during the trial entire 
investigation 
13. […] and during the trial entire 
investigation 
14. […] and during the trial entire 
investigation 
22. […] and the entire investigation 
24. […] during the study entire 
investigation  
Synopsis 
Section 6.3.3 
Specification in wording to point out that 
the treating investigator has to ensure 
prior to enrollment that the subject does 
not plan to undergo any of the 
procedures during the entire period of 
the investigation (i.e., Visit 1 up to 24 
weeks after last injection of repeat-
treatment). 
Corresponding exclusion criteria were 
added to re-check the eligibility of the 
subject for repeat-treatment (see below). 
ExC #3 (Baseline treatment): 
History of hypersensitivity to hyaluronic 
acid preparations, lidocaine or any 
amide-based anesthetic 
Synopsis 
Section 6.3.3 
Specification of wording to clarify the 
exclusion criterion. 
 
ExC#10 (Baseline treatment): 
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 
Synopsis 
Section 6.3.3 
Semi-permanent / long-lasting fillers (like 
 
, an injectable PLLA) 
are completely excluded.  
PLLA and PMMA products are semi-
permanent / long-lasting fillers and would 
make the injection of HA fillers more 
difficult due to the fibrosis. 
ExC#16 (Baseline treatment): 
Planned dental/oral surgery or 
modification (bridgework, implants) within 
four weeks prior to each injection and to a 
minimum of four weeks post injection 
(baseline treatment and touch-up 
treatment treatment, touch-up and re-
treatment) 
Synopsis 
Section 6.3.3 
Wording updated. This is an ExC for the 
initial treatment phase.  
The ExC is to be checked again 
separately in the repeat-treatment 
phase, because the subject cannot plan 
dental treatments one year in advance. 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 144 of 171 
Version 7.0 - 15-MAY-2024 
Change 
CIP Sections 
affected 
Rationale 
Global Aesthetic Improvement Scale 
(GAIS): 
1. GAIS was replaced by a modified 
GAIS:  
The modified GAIS is a 5-point scale 
with a balanced distribution of 
categories as follows: “much worse” – 
“worse” – “no change” – “improved”- 
“much improved”. 
Synopsis 
Schedule of 
procedures and 
assessments  
(Table 1) 
Glossary 
Section 5.2 
Section 5.3 
Section 6.1.1 
Section 6.4.11 
Section 6.4.16 
Section 6.5 
Per FDA comment: Initial version of the 
GAIS did not appear to be balanced, as 
there are 3 “improved” categories, one 
“no change” category, and one “worse” 
category. 
Now, there are 2 “improved” categories, 
one “no change” category, and 2 “worse” 
categories. 
2. The modified GAIS will be not 
evaluated for the repeat-treatment 
phase.  
The repeat-treatment part is mainly 
focusing on safety.  
3. There will be no comparison of the 
appearance in the mirror (subject) or 
live (blinded evaluator) at the current 
visit vs. photographs. Instead, both 
will review the photographs taken at 
the current and the Baseline visit  
The comparison of two photos is more 
suitable to get a valid statement than the 
comparison between mirror /live against 
a photo. 
4. In addition to clinical photography (3D 
photos), another baseline photo (2D) 
should be taken on-site at Visit 1, 
e.g., by using a smart phone or a 
digital camera. 
This 2D photo will be used as baseline 
photo to evaluate the aesthetic 
improvement (GAIS) in case of 
restrictions during the COVID-19 
pandemic.  
In case a personal meeting between the 
subject and the site representative is not 
possible in a protocol conformal manner 
at a follow-up visit of the initial treatment 
phase, the subject will be asked to take a 
current (2D) photo of his/her face and to 
evaluate the aesthetic improvement by 
comparing the appearance on the 
current photo against this baseline 
photo.  
Details are outlined in an addendum to 
the CIP 
Nasolabial Folds Severity Rating Scale 
(NLF-SRS) was added to assess the 
effect of midface treatment with saypha® 
VOLUME Lidocaine on the nasolabial 
folds based on the blinded evaluator´s 
live assessment. 
Correspondingly, additional objective and 
endpoint were added.  
 
Synopsis 
Schedule of 
procedures and 
assessments  
(Table 1, Table 3) 
Glossary 
Section 5.2 
Section 5.3 
Section 6.1.1 
Section 6.4.15 
Section 6.5 
Section 20.2 
Midface treatment has the potential to 
influence nasolabial folds and many 
Physicians prefer to indirectly influence 
nasolabial folds via a midface treatment 
over direct treatment of the nasolabial 
folds. Therefore, an exploratory objective 
and endpoint were added, respectively.  
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 146 of 171 
Version 7.0 - 15-MAY-2024 
Change 
CIP Sections 
affected 
Rationale 
a visual depiction (see Figure 3) of the 
areas of midface treatment were added.  
This was added for patient safety and to 
ensure investigators are provided with 
clear and standardized administration 
instructions for the subject device and 
comparator. 
Administration of test device was 
specified: Instructions given for the 
administration of
 
 apply now for saypha® VOLUME 
Lidocaine, too. 
Section 6.2.2 
(Table 16)  
To provide same level of instruction 
given to treating investigators to ensure 
patient safety and comparable results 
between the 2 devices. 
Applied volume of the devices per side 
and documentation was specified 
Synopsis 
Section 6.2.3 
Section 6.4.10 
Per FDA comment: FDA raised a safety 
concern in the event of exaggerated 
asymmetric injection. Therefore, a 
maximum volume of device per side of 
the midface was defined to ensure an 
appropriate volume is injected per 
treatment area for the safety of study 
participants. 
As the CIP allows subjects with slight 
asymmetries to be enrolled (per InC#2), 
the expected outcome of an optimal 
aesthetic result will potentially require 
moderate differences in treatment 
volumes by side. This was considered 
when the maximum volume of 6.0 mL for 
one side (and 4.0 mL for the second 
one) was introduced. 
Kit numbers of kits used will be 
documented in the eCRF. 
Section 6.4.10 
To have complete documentation of 
injection-related data available. 
No stratification between needle and 
cannula (1:1) will be performed. 
Instead, it will be ensured via monitoring 
of data management overview to get a 
minimum of 100 subjects randomized to 
the test device treated with either needle 
or cannula.  
Synopsis 
Section 6.1.2 
Section 6.2.2 
Section 6.3.1  
Section 6.4.10 
In general, in this study the use of needle 
or cannula is based on the treating 
investigator´s medical decision.  
Originally it was planned to stratify in a 
1:1 ratio (needle versus cannula).  
The approach was changed to have a 
setting which is more similar to real-life 
situation but ensures a minimum of 100 
subjects treated with test device via 
needle or cannula, each, to collect 
adequate safety data. 
If an optimal aesthetic correction has 
not been achieved after the baseline 
treatment, as evaluated by the treating 
investigator, a touch-up treatment at 
Week 2 (Visit 3) (and any following 
injection during the repeat-treatment 
Synopsis 
Section 6.1.1 
Section 6.2.2 
 
It should be in the discretion of the 
investigator, which approach is used for 
each injection to have a setting which is 
more similar to real-life situation. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 154 of 171 
Version 7.0 - 15-MAY-2024 
Change 
CIP Sections 
affected 
Rationale 
Global aesthetic improvement will be 
evaluated by reviewing these current 
photographs relative to the 
photographs taken at the Baseline 
visit (using the modified GAIS). 
improvement relative to baseline 
photographs (taken at the Baseline visit). 
2. Both – the blinded evaluator at the 
site and the subject – will assess the 
global aesthetic improvement (using 
the modified GAIS) at each on-site 
visit after last injection of the initial 
and repeat treatment phase, 
respectively. 
Synopsis 
Section 6.1.1 
 
Correction: Global aesthetic 
improvement will only be evaluated 
during the initial treatment phase (not 
during the repeat-treatment phase). 
3. Modified GAIS is a scale to assess 
the global aesthetic improvement. 
Wording was specified where 
required to avoid errors, including the 
objectives and endpoints covering the 
global aesthetic improvement:  
Objectives:  
Global aesthetic Aesthetic improvement 
• 
To evaluate global aesthetic 
improvement based on subject’s 
assessments (initial treatment phase 
only) 
• 
To evaluate global aesthetic 
improvement based on the blinded 
evaluator’s assessments (initial 
treatment phase only) 
Endpoints:  
Global aesthetic Aesthetic improvement 
based on modified GAIS 
• 
The percentage of subjects with an 
global aesthetic improvement over 
baseline (at Baseline visit) (subjects 
who have been rated as “much 
improved” or “improved”), based on 
subject´s assessment at Week 4, 8, 
16, 24, 36, and 48, after last injection 
of initial treatment phase using the 5-
point modified GAIS. 
• 
The percentage of subjects with an 
global aesthetic improvement over 
baseline (at Baseline visit) (subjects 
who have been rated as “much 
improved” or “improved”), based on 
the blinded evaluator`s assessment 
at Week 4, 8, 16, 24, 36, and 48, 
after last injection of initial treatment 
Synopsis 
Schedule of 
procedures and 
assessments  
(Table 1) 
Section 5.2.2.2 
Section 5.3.3.1 
Section 6.1.4 
Section 6.4.11 
Section 6.4.16 
Section 7.3.7 
Clarification to avoid errors.  

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 158 of 171 
Version 7.0 - 15-MAY-2024 
Change 
CIP Sections 
affected 
Rationale 
• 
Results at each visit will be compared 
to the results prior to first injection of 
each treatment phase, i.e., Visit 2 for 
initial treatment phase and Visit RT1 
for repeat-treatment phase. 
• 
At treatment visits, visual 
examinations will be performed 
before the injection and 30 min after 
the injection. The result post-injection 
(30 min after) will be compared to the 
results prior injection.  
Definition for AESI was clarified: 
For this clinical investigation, AEs of 
special interest are defined as embolic 
events, with possible, probable, or 
causal relationship to an intravascular 
injection of the device, as  
• 
Changes in vision (i.e. loss of vision, 
blurriness, double vision, pain in or 
around your eye, blindness, blind 
spots, problems moving the eyes) 
• 
Skin changing color around the 
eyelids or around the site of injection 
• 
Other embolic phenomenons, e.g., 
stroke, skin necrosis 
Consequently, ExC#1 (Touch-up 
treatments and Repeat-treatment) were 
updated:  
1. Occurrence of a related Serious 
Adverse Event or Adverse Event of 
Special Interest (i.e., embolic 
events, with possible, probable, or 
causal relationship to an 
intravascular injection of the 
device, as changes in vision […], 
skin changing color around the 
eyelids or around the site of injection, 
other embolic phenomenon, e.g., 
stroke, skin necrosis) during or after 
the previous injections  
Section 6.3.4.2 
Section 6.3.5.2 
Section 14.1 
 
Clarification reasons.  
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 159 of 171 
Version 7.0 - 15-MAY-2024 
Change 
CIP Sections 
affected 
Rationale 
In general, symptoms of interest asked 
for in the eDiary may indicate embolic 
events to be assessed and documented 
as AE(SI) if clinically significant.  
Also, other (non-embolic) diagnoses 
resulting from investigator´s assessment 
of the symptoms of interest are to be 
assessed and documented as AE if 
clinically significant. Examples how to 
assess SOIs and how to establish 
diagnoses are given in new section 20.5. 
Schedule of 
procedures and 
assessments 
(Table 1 / Table 3) 
Section 6.4.19 
Section 6.5 (incl. 
applicable sub-
sections) 
Section 14.2 
Section 20.5 
Clarification reasons: A clarification was 
included that a symptom of interest may 
be an AE(SI) and how these might be 
detected. 
Included to help investigators to identify 
clinically significant 
symptoms/diseases/worsenings and 
document these as AEs/AESIs. 
Reporting of AESIs and other embolic 
events was clarified: 
All AESI (serious and non-serious) and 
any other embolic event (regardless of 
seriousness and / or relationship to 
device or procedure) have to be 
reported by the investigator to the 
sponsor’s representative within 24 hours 
of awareness of the event via Email 
using the SAE Reporting Form.  
In case, any of the abovementioned 
criteria apply (i.e., seriousness, 
anticipation criteria), t The sponsor's 
representative will report the event all 
AESIs and any other embolic event 
(regardless of seriousness and / or 
relationship to device or procedure) to 
the respective competent authority 
(FDA) in an expedited manner. 
Section 14.5.1 
Section 14.5.4 
Per FDA comment: The clinical 
investigation plan was updated to specify 
the reporting of AESI and other AEs 
indicating other embolic events 
(regardless of relatedness or 
seriousness) to the Agency. 
Clarification: Other Symptom of interest 
(SOI).  
This includes also wording of one of the 
safety endpoints:  
Occurrence and frequency of adverse 
events during the entire study period 
including repeat-treatment phase (long-
term safety). Other Symptoms of interest 
will be recorded in subject diary during 
the first 4 weeks (28 days) after each 
treatment (i.e., either 4 weeks after 
baseline and repeat-treatment, 
respectively, and 6 weeks in case of 
touch-up treatment) and documented as 
AE by investigator. 
Synopsis 
Schedule of 
procedures and 
assessments 
(Table 1 / Table 3) 
List of abbreviations 
Section 5.3.4 
Section 6.4.19 
Section 6.5 (incl. 
applicable sub-
sections) 
Clarification reasons. These are 
symptoms of interest to identify potential 
AEs / AESIs.   
 
 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 162 of 171 
Version 7.0 - 15-MAY-2024 
Change 
CIP Sections 
affected 
Rationale 
Clarification for use of PPS:  
All effectiveness analyses for the initial 
treatment phase will be conducted for 
using the PPS and the FAS. The 
effectiveness analysis for the repeat 
treatment phase will be conducted 
using the FAS only. Safety analyses will 
be based on the SAF. 
The evaluation of the primary and 
secondary effectiveness endpoint(s) will 
be performed both in the Per-Protocol Set 
(PPS) and in the Full Analysis Set (FAS) 
for the initial treatment phase, and 
only for the FAS for the repeat phase. 
Section 7.2 
Section 7.3 
Clarification reasons: Section 7.3 (and 
sub-sections concerned) already 
restricted use of PPS for analysis of the 
primary and secondary effectiveness 
endpoints (i.e., endpoints analyzed 
during the initial treatment phase up to 
Visit 9). 
With this amendment to the CIP, this 
was clarified.  
Note: Endpoints for used to analyze 
effectiveness in the repeat-treatment 
phase are ‘Other endpoints’ and were 
therefore never covered by these 
statements.  
Adaption of sample size justification to 
match planned analysis of the primary 
effectiveness endpoint defined in section 
7.3.7:  
The primary outcome measures for 
effectiveness will be evaluated by means 
of a one-sided two-group Farrington-
Manning test for non-inferiority large
sample normal approximation test of 
proportions with the following 
hypotheses: […] 
Based on these assumptions, 437 
subjects (saypha® VOLUME Lidocaine: 
n=291,
 
 
: 
n=146) will be necessary in order to 
achieve a power exceeding 83%of 80% 
with a one-sided  of 2.5%. […] 
Synopsis 
Section 7.1 
Farrington-Manning test for non-
inferiority, as defined in section 7.3.7 for 
the analysis of the primary effectiveness 
endpoint, did not match the method used 
for sample size calculation (i.e., one-
sided two-group large-sample normal 
approximation test of proportions).  
Therefore, sample size justification (but 
not the sample size itself) was adapted. 
This modification resulted in a slightly 
higher power of the planned primary 
analysis for non-inferiority (83% instead 
of 80%). 
At this, pA is the response rate for 
saypha® VOLUME Lidocaine and pB is 
the response rate for
 
 
, and d0 equals to -0.1. 
Thus, a negative value for this difference 
means that the response rate of saypha® 
VOLUME Lidocaine is lower than the 
response rate for
 
 
 The non-inferiority margin is -10%.In 
addition to this, the response rates for 
both treatment groups along with their 
Clopper-Pearson exact 95% CIs will be 
tabulated. 
Synopsis 
Section 7.3.7 
For clarity, the information on non-
inferiority margin was added here as 
well.  
Clopper-Pearson exact confidence 
intervals were added for a more 
informative presentation of the estimated 
results. The point estimates can only be 
correctly interpreted if their confidence 
intervals are also presented. 
Sensitivity analyses of the primary 
effectiveness endpoint were adapted:  
Sensitivity analyses of the primary 
effectiveness endpoint will be performed 
on the FAS addressing the different 
reasons for non-adherence and covering 
Synopsis 
Section 7.3.7 
The first method for sensitivity analysis 
was deleted because single imputations 
are usually biased, and because it was 
too conservative. A multiple imputation 
with MNAR assumption was added 
instead. 

 
 
CONFIDENTIAL 
 
 
Clinical Investigation Plan 
CPH-301-201417 
 
  
 
 
 
 
 
Page 169 of 171 
Version 7.0 - 15-MAY-2024 
20.3 saypha® VOLUME Lidocaine: Visual instructions how to attach needle / cannula to syringe 
 
Hold the Luer-Lock adapter as shown in ❶. To remove the tip cap, twist ❷ and pull carefully ❸. Following the instruction above will prevent the formation of 
air bubbles. Hold the syringe as shown in ❹. Open the enclosed needle case and insert the needle firmly ❺ (do not use any other needle). Tightly secure the 
needle by twisting it clockwise ❻ 
 
 

 
 
CONFIDENTIAL 
________________________________________________________________________________________________________________________________________ 
 
Clinical Investigation Plan 
CPH-301-201417 
 
Page 171 of 171 
Version 7.0 - 15-MAY-2024 
20.5 Assessment of Symptoms of Interest (SOIs) 
 
Not clinically significant SOIs are those SOIs that cannot be verified e.g., through targeted subject 
questioning and/or examinations (also see section 14.2).  
The below list is included as a guide and is not intended to be all inclusive:  
• 
The subject is dissatisfied with treatment effect and reports SOI ‘Face droop’ because the 
lifting/volume effect did not turn out as desired,  
• 
An anxious subject observes him/herself closely and reports an apparent feeling of ‘Weakness or 
numbness in the arms or legs’ but this cannot be verified in neurologic examination and subject 
confirms retrospectively that his/her mobility and sensitivity were not really restricted. 
• 
The subject is unsure and selects an SOI by misinterpretation (e.g., ‘difficulty speaking/speech 
impairment’ although neither dysarthria nor aphasia occurred but he/she did not dare to speak 
normally to ‘protect’ the cheeks 
• 
The SOI ‘skin changing colour around eyes’ corresponds to a local reaction that is already 
recorded in the diary as injection site reaction (e.g., ‘bruising’),  
• 
The SOI ‘blurriness’ is caused by a pre-existing underlying disease or treatment (e.g., due to dry 
eyes in a contact lens wearer). 
• 
Technical failure(s). The subject ticked a SOI by mistake.  
 
Verified diagnoses will be documented and assessed as AE(SI) (see section 14.3 and section 14.4 for 
details).  
The below list is included as a guide and is not intended to be all inclusive:  
• 
Symptoms of headache and fever might be symptoms of e.g., a ‘common cold’, ‘influenza’ or ‘Covid-
19’ and shall be reported as the respective diagnosis. 
• 
Symptoms of headache, difficulty speaking/speech impairment and face droop might be symptoms 
of e.g., ‘stroke’ and shall be reported as the respective diagnosis, if such.