Radiesse® Post Approval Safety Study For the Treatment of Hands With Moderate to Very Severe Dorsal Volume Loss
Phase: NA
Conditions: Volume Loss in the Dorsum of the Hand
Sponsor: Merz North America, Inc.



Merz North America, Inc. 
CLINICAL STUDY PROTOCOL – Version 0.5 
Protocol # P151009; Version 18-SEP-2017 
Table of Contents 
1 
SYNOPSIS ...................................................................................................................6 
2 
STUDY ADMINISTRATIVE STRUCTURE ..........................................................8 
2.1 
Internal responsibilities ............................................................................................8 
3 
ETHICS .......................................................................................................................9 
3.1 
Institutional Review Board ......................................................................................9 
3.2 
Ethical conduct of the study .....................................................................................9 
3.3 
Informed consent .....................................................................................................9 
4 
INTRODUCTION  ...................................................................................................11 
4.1 
Study background  .................................................................................................11 
4.2 
Study rationale  ......................................................................................................11 
4.3 
Risk-benefit assessment  ........................................................................................11 
5 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................13 
5.1 
Objectives  .............................................................................................................13 
5.2 
Endpoints  ..............................................................................................................14 
6 
INVESTIGATIONAL PLAN  .................................................................................16 
6.1 
Overall study design ..............................................................................................16 
6.1.1 
Study visits  ......................................................................................................16 
6.1.2 
End of study  ....................................................................................................17 
6.1.3 
Study flow chart  ..............................................................................................17 
6.1.4 
Study timeline  .................................................................................................18 
7 
STUDY POPULATION  ..........................................................................................19 
7.1 
Selection of study population  ................................................................................19 
7.2 
Inclusion criteria  ...................................................................................................19 
7.3 
Exclusion criteria  ..................................................................................................20 
7.4 
Removal of subjects from treatment or assessment  ..............................................21 
7.4.1 
Discontinuation of subjects  .............................................................................21 
7.4.2 
Premature termination or suspension of the study or a study site  ...................21 
8 
TREATMENTS  .......................................................................................................23 
8.1 
Investigational product(s)  .....................................................................................23 
8.1.1 
Description of investigational product(s)  ........................................................23 
8.1.2 
Disposition of investigational product(s)  ........................................................23 
8.2 
Treatment administration  ......................................................................................23 
8.2.1 
Randomization Procedures  .............................................................................23 
8.2.2 
Treatment method  ...........................................................................................23 
9 
STUDY ASSESSMENTS  ........................................................................................28 
9.1 
Clinical evaluations  ...............................................................................................28 
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CLINICAL STUDY PROTOCOL – Version 0.5 
Protocol # P151009; Version 18-SEP-2017 
List of Tables 
1 
Global Aesthetic Improvement Scale (GAIS) ........................................................18 
2 
Schedule of Events ....................................................................................................34 
List of Figures 
1 
Merz Hand Grading Scale (MHGS) ........................................................................15 
2 
Study Flow Chart ......................................................................................................18 
3 
Radiesse Mixing Components ..................................................................................24 
4 
Removal of Cap from Radiesse Syringe .................................................................25 
5 
Connecting Radiesse Syringe to the Mixing Syringe .............................................25 
6 
Mixing Strokes ..........................................................................................................25 
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CLINICAL STUDY PROTOCOL – Version 0.5 
Protocol # P151009; Version 18-SEP-2017 
2 STUDY ADMINISTRATIVE STRUCTURE 
2.1 
Internal responsibilities 
Name 
Function 
Address 
Merz North America, Inc. 
Sponsor 
Merz North America, Inc. 
6501 Six Forks Road 
Raleigh, NC 27615 
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CLINICAL STUDY PROTOCOL – Version 0.5 
Protocol # P151009; Version 18-SEP-2017 
3 ETHICS 
3.1 
Institutional Review Board 
The following documents must be submitted to the responsible Institutional Review 
Board (IRB):  this protocol, the Informed Consent Form (ICF), relevant supporting 
information, and all types of subject recruitment or advertisement information. These 
documents must be approved by the appropriate IRB before the study is initiated. Any 
amendments to the protocol must also be approved, where necessary, by the IRB prior to 
implementing changes in the study. Documentation of these approvals must be provided 
to the Sponsor prior to the initiation of the amendment. The IRB used must comply with 
current Good Clinical Practice (GCP) and guidelines. 
The investigator’s responsibilities (at a minimum) regarding the IRB are as follows: 
•
Obtain IRB approval of the protocol, informed consent, and any advertisements to
recruit subjects prior to their use.
•
Obtain IRB approval for any protocol amendments and ICF revisions before
implementing the changes.
•
Provide the IRB with any required information before and during the study.
•
Submit progress reports to the IRB, as required, during the conduct of the study;
request re-review and approval of the study, as needed; provide copies of all IRB
re-approvals and relevant communication to the Sponsor.
•
Notify the IRB within 10 days of all serious and unexpected AEs related to the
study device that are reported to the investigator by the Sponsor.  The investigator
is responsible for updating the IRB on the progress of the study and of any
changes made to the protocol as deemed appropriate, but (in any case) at least
once a year.  The investigator must also keep the IRB informed of any AEs of
interest, according to the IRB policy.
3.2 
Ethical conduct of the study 
This study will be conducted in accordance with all applicable local and federal 
regulations. Regulatory authorities will be notified and consulted, as required, prior to, 
during, and after the conduct of the study. 
This clinical trial will be conducted in compliance with the protocol, International 
Conference on Harmonisation (ICH), GCP guidelines, and other applicable regulatory 
requirements. 
3.3 
Informed consent 
The investigator is responsible for obtaining written informed consent from each 
individual participating in this study after adequate explanation in layman’s terms 
regarding the nature of the study, along with the aims, methods, objectives, and any 
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Protocol # P151009; Version 18-SEP-2017 
potential risks. The ICF must be appropriately signed and dated by the subject or the 
subject’s legally authorized representative and the person obtaining the consent (if 
required by the IRB) prior to conducting/obtaining any study-related assessments, 
including the discontinuation of any medications prohibited for the study. The subject 
will be given a copy of the signed and dated written ICF as well as all ICF updates (if 
applicable). 
If the ICF is amended during the study, the investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF by the IRB and use of 
the amended form (including for ongoing subjects). 
During the course of the study, the subject will be informed in a timely manner if 
information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study. In case of AEs, the subject should inform the 
investigator, who then will make a judgment whether continuing in the study serves the 
subject’s best interests. The subject, however, is free to withdraw consent at any time 
and for any reason, whether expressed or not. 
Each ICF will contain contact information with a phone number the subject should 
contact if they have medical concerns 24 hours a day. 
The original and any amended signed and dated ICF must be retained at the study site; 
and a copy must be given to the subject or subject’s legally authorized representative(s). 
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4 INTRODUCTION 
4.1 
Study background 
The clinical study is a PAS being conducted to satisfy a condition of the June 4, 2015, 
PMA-S (P050052/S049) approval of Radiesse injectable implant indicated for hand 
augmentation to correct volume loss in the dorsum of the hand, to provide safety and 
effectiveness data in subjects with more severe volume loss (MHGS grade 4) than those 
subjects evaluated in the pre-market study. The pre-market (Merz protocol #P110607) 
study cohort excluded subjects with baseline grade 4 hands. This study will also provide 
additional data specific to safety of multiple retreatments. 
4.2 
Study rationale 
Radiesse dermal filler was demonstrated to be safe and effective in the pre-market study 
for treatment of hands with moderate to severe dorsal volume loss. On the validated 
MHGS (Figure 1), these were hands rated as grade 2 or grade 3 at baseline, or before 
treatment.  On the MHGS, these hands had moderate to severe dorsal volume loss. 
Subjects with MHGS grade 4 (MHGS4) hands at baseline, or very severe dorsal volume 
loss, were excluded from the pre-market study.  With the Food and Drug Administration 
(FDA) approval of Radiesse for treatment of the hands, it is anticipated that patients that 
present with MHGS4 hands will seek treatment.  This PAS will evaluate the safety and 
effectiveness of Radiesse treatment in MHGS4 hands with very severe dorsal volume 
loss.  Subjects will receive an initial Radiesse hand treatment and have the opportunity to 
receive up to 3 repeat treatments over 2 years of follow-up. 
A non-inferiority hypothesis test will be conducted for the primary study endpoint. The 
hypothesis test will compare the 6-month rate of device/injection-related severe AEs in 
the MHGS4 subjects (Group A) versus a subjects with baseline MHGS grade 2 or grade 3 
(MHGS2-3, Group B). 
4.3 
Risk-benefit assessment 
Potential risks associated with the injection of Radiesse into the dorsum of the hand to 
restore volume loss are similar to injections performed with any other commercially 
available cosmetic dermal filler, such as bruising, swelling and redness.  For complete 
safety and risk information, see the Instructions For Use (IFU, Appendix A).  Lidocaine 
is approved as a local and regional anesthetic and will be mixed in-office with Radiesse. 
Potential side effects associated with lidocaine are a risk of participating in this study and 
include lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, 
drowsiness, ringing noise in the ears, blurred or double vision, vomiting, sensations of 
heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory 
depression and arrest, slow heartbeat, hypotension, and cardiovascular collapse, which 
may lead to cardiac arrest.  However, these side effects are unlikely to occur at the low 
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doses of lidocaine being used in this investigation. Lidocaine is beneficial in terms of 
pain reduction during and after the study procedure. 
A potential benefit of participating in this study is to have correction of volume loss and 
reduction of the prominence of veins and tendons in the dorsum of one or both hands. 
Additional potential benefits of improving the appearance of the hands could include 
enhanced emotional well-being with improved satisfaction with the appearance of the 
hands, or the perception of having a more youthful appearance. 
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The Visits will include a Screening/Enrollment/Baseline Visit in which the subject 
receives their first injections of Radiesse. After Enrollment, there will be a 72-hour 
follow-up phone call made to each subject to assess AEs and/or any changes in 
concomitant medications. Subjects will be seen at the study site for follow up visits at 
Months 1, 3, 6, 12, 18, and 24. If they are administered repeat injections at any of the 
Months 6, 12 and 18 visits, they will receive a 72-hour follow-up phone call following 
each injection and return for follow up visits 1 month post-injection at Months 7, 13, 
and/or 19 respectively. 
6.1.2 
End of study 
The end of study will be defined as completion of all study visits by all enrolled subjects 
during the 24-month participation period. If an unforeseen device-related serious adverse 
event (SAE) or unanticipated serious device effect (USADE) occurs, the end of the study 
will be prolonged until clinical resolution of the event, or considered permanent as 
determined by the treating investigator. 
The study or parts of the study may be discontinued by Merz North America, Inc. (Merz) 
or at the recommendation of an investigator after consultation with Merz at any time. 
This may be based on a significant number of AEs of a similar nature that warrant such 
action or at the request of Merz. 
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CLINICAL STUDY PROTOCOL – Version 0.5 
Protocol # P151009; Version 18-SEP-2017 
7 STUDY POPULATION 
The study will enroll adults at least 22 years of age. There will be 2 study groups, with 
approximately 125 subjects enrolled into each group. Group A subjects will be required 
to present with MHGS grade 4 hands at baseline. Grade 4 hands are defined as, in the 
dorsal hand: very severe loss of fatty tissue and marked visibility of veins and tendons. 
Group B subjects will be required to present with MHGS grade 2 or 3 hands at baseline. 
Grade 2 and 3 hands are defined as, in the dorsal hand: moderate to severe loss of fatty 
tissue and mild to moderate visibility of veins and tendons. Group A subjects will 
provide safety and effectiveness of Radiesse treatment of MHGS grade 4 hands, which 
might receive higher injection volumes than hands of Group B subjects. Every effort will 
be made to have all enrolled subjects complete the study. If subjects are withdrawn or 
lost to follow during the study, they will not be replaced. 
7.1 
Selection of study population 
Presenting subjects will be screened to the selection criteria identified in sections 7.2 and 
7.3 below. The investigational site will recruit candidates and perform the screening, 
which could include use of patient databases, phone calls, email or postal mail 
distribution, and advertisements. 
7.2 
Inclusion criteria 
Only subjects meeting all of the following inclusion criteria will be considered for study 
enrollment: 
1. Has hands rating 2, 3, or 4 on the validated MHGS as determined by a live, masked
evaluator.
•
Left and right hand with a rating of 4 of the validated MHGS will be assigned
to Group A.
•
Left and right hands with a rating of 2 or 3 on the validated MHGS will be
assigned to Group B.
2. Has left and right hands with a rating of 2 or 3 on the validated MHGS as determined
by a live, masked evaluator if screened for Group B.
3. Is at least 22 years of age.2 
4. Has signed an ICF.
2  Pediatric populations or subpopulations generally do not suffer from the hand condition the device is 
intended to treat in the study protocol. 
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5. Understands and accepts the obligation not to receive any other procedures in the
dorsum of the hands through the end of the study.
6. Understands and accepts the obligation and is logistically able to present for all
scheduled follow-up visits and meet all study requirements.
7.3 
Exclusion criteria 
Subjects having any of the following criteria, either at screening or at baseline, will not 
be included in the study: 
1. Was a participant in the Radiesse hands pre-market clinical study (Merz #P110607).
2. Has been treated with fat injections or Radiesse in the hands, has hand deformities, or
has received surgery in the dorsum of the hands.
3. Has received within the past 6 months or plans to receive during the study dermal
resurfacing procedures (e.g. chemical peel, dermabrasion, ablative laser resurfacing)
or non-invasive skin-tightening (e.g. Thermage, Ulthera) in the dorsum of the hands
during the study.
4. Has received in the past 2 weeks or plans to receive during the study, prescription
wrinkle therapies, topical steroids, skin irritating topical preparations, or pigmenting
agents (self-tanning agents) in the dorsum of the hands during the study.
5. Has received in the past 2 months, or plans to receive immunosuppressive
medications or systemic steroids (intranasal / inhaled steroids acceptable) during the
study.
6. Has an acute inflammatory process or infection, or history of chronic or recurrent
infection or inflammation with the potential to interfere with the study results or
increase the risk of AEs.
7. Has a known bleeding disorder or is receiving medication that will likely increase the
risk of bleeding as the result of injection.
8. Has a known history of allergic / anaphylactic reactions, including hypersensitivity to
lidocaine or anesthetics of the amide type, or any of the device components.
9. Has a known history of hyper- or hypo-pigmentation, keloid formation, or
hypertrophic scarring.
10. Is a female of child bearing potential3 and not using medically effective4 birth control
or is pregnant or lactating.
3 Childbearing potential is defined as NOT premenarche, permanently sterilized or postmenopausal (i.e., 12 
months with no menses without an alternative medical cause). 
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11. Has any other medical condition with the potential to interfere with the study or
increase the risk of AEs, such as: autoimmune disease affecting the hand, hand
implants, Dupuytren’s contracture, history of hand tumor, vascular malformations,
Raynaud’s disease, and patients at risk for tendon rupture.
12. Is enrolled or plans to enroll in an interfering study.
13. Is an employee or direct relative of an employee of the investigational site or of the
study Sponsor.
7.4 
Removal of subjects from treatment or assessment 
7.4.1 
Discontinuation of subjects 
The subject may discontinue from the study at any time without any penalty or loss of 
benefits to which the subject is otherwise entitled. Date and discontinuation 
circumstances should be recorded. 
Subjects must be discontinued from the study by the investigator at any time for any of 
the following reasons: 
•
Withdrawal of informed consent.
•
Pregnancy.
•
Any AE for which treatment continuation would constitute an unacceptably high
risk for the subject.
Before discontinuation, every effort should be made to ensure that the subject returns for 
a final study visit. In the case of loss to follow-up subjects, every effort should be made 
to contact subjects lost to follow-up, and all such efforts should be documented in the 
subject file. 
7.4.2 
Premature termination or suspension of the study or a study site 
The study or the study site can be prematurely terminated or suspended by the sponsor. If 
and when certain issues arise affecting the conduct of this Post Approval Study, the 
possibility of early study termination will be discussed with the FDA prior to termination. 
Reasons for termination of the study or a study site may include, but are not limited to, 
the following: 
•
Subject enrollment is unsatisfactory.
4 Defined as a method that results in a low failure rate (i.e., less than 1% per year) when used consistently 
and correctly, such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence, 
or vasectomized partner. 
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•
The risks and benefits of continuing the study have been reassessed, and the risks
outweigh any potential benefits.
•
The incidence of AEs constitutes a potential health hazard to the subjects.
•
New scientific data do not justify a continuation of the study.
•
The investigator or study site exhibit serious and/or persistent non-adherence to the
clinical study protocol and/or applicable regulatory requirements.
•
The Sponsor decides to terminate the study at any time for any other reason.
Furthermore, the study may be prematurely ended if the regulatory authority or the IRB 
makes a recommendation to terminate or suspend approval for the study, the study site, or 
the investigator. 
If the study is prematurely terminated or suspended for any reason, the investigator must 
inform the subjects and assure appropriate follow-up treatment. Within the timeframes 
noted in applicable regulations, the Sponsor will promptly inform the investigators, study 
sites, the IRB, and regulatory authorities of the termination or suspension of the study, as 
appropriate. 
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8 TREATMENTS 
8.1 
Investigational product(s) 
8.1.1 
Description of investigational product(s) 
Radiesse injectable implant is an opaque, sterile, non-pyrogenic, semi-solid, cohesive 
implant. The principle component is synthetic calcium hydroxylapatite suspended in a 
gel carrier that consists primarily of water (sterile water for injection USP), glycerin 
(USP), sodium carboxymethylcellulose (USP). Radiesse injectable implant (1.5cc 
syringe unit) has a CaHA particle size range of 25-45 microns and should be injected 
with a 25 gauge Outer Diameter (O.D.) to 27 gauge Inner Diameter (I.D.) needle. The 
same size needle should be utilized throughout the trial for an individual subject and 
needle size will be collected in the electronic case report form. 
8.1.2 
Disposition of investigational product(s) 
Radiesse has been FDA approved for injection into the face since 2006 (PMA P050037 
and PMA P005052), and was approved for hand augmentation to correct volume loss in 
the dorsum of the hand in 2015 (PMA P050052/S049, see IFU Appendix A). This same 
Radiesse formulation will be used in the study for injection, as approved in the indication 
for hand augmentation to correct volume loss in the dorsum of the hand. Radiesse will be 
mixed with 2% lidocaine HCl prior to injection – an approved use of Radiesse. 
8.2 
Treatment administration 
8.2.1 
Randomization Procedures 
The study is not a randomized trial, and there are no randomization procedures. 
8.2.2 
Treatment method 
Prior to injection, Radiesse will be mixed with 0.26cc of 2% Lidocaine HCl. Volume 
injected as well as any observed AEs will be recorded. A maximum of 2 1.5cc Radiesse 
syringes will be injected per hand, per treatment visit. Treatment and retreatment visits 
will be scheduled per Table 2. There will be no touch-up treatments performed in the 
study. Subjects are to be given a 30-day take-home diary on which to record AEs that 
may occur before their next visit (copy provided in Appendix B). 
Step-by-step injection instructions are as indicated below from the IFU in Appendix A. 
Technique for Mixing Radiesse injectable implant and 2% Lidocaine HCl 
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Injection Procedure for Hand Augmentation 
1. Prepare subject for percutaneous injection using standard methods. Have the
subject wash both hands with soapy water producing friction for 5-10 minutes and
then prepare hands with suitable antiseptic. The treatment injection site may be
marked for planned injection sites. Jewelry should be removed prior to injection
and until post-procedure swelling has resolved.
2. Using the syringe of Radiesse injectable implant that has been mixed with
lidocaine using the procedure described in “Mixing Instructions” above, and fitted
with the injection needle, slowly push the syringe plunger until Radiesse
injectable implant extrudes from the end of the needle performing aspiration
before bolus injection to avoid intravascular injection. If leakage is noted at the
luer fitting, wipe it clean with sterile gauze. It may be necessary to tighten the
needle, remove the needle and clean the surfaces of the luer fitting or, in extreme
cases, replace both the syringe and the needle. A new injection needle may be
used for each syringe, or the same injection needle may be connected to each new
syringe.
3. Locate the initial site for injection. Subjects are to receive injections in the
dorsum of the hands between the 1st and 5th metacarpals. Injection should initially
occur between the 2nd and 4th metacarpals, taking care not to inject close to the
metacarpophalangeal joints. If necessary to achieve optimal correction, injection
is also allowed between the 1st and 2nd, and 4th and 5th metacarpals.
4. Skin tenting should be performed to separate the skin from vascular and tendinous
structures by using the thumb and forefinger of the non-injecting hand to lift skin
over the dorsal aspect of the hand being treated.
5. Advance the needle between the subcutaneous layer and superficial fascia with
the syringe parallel to the dorsum of the hand. Carefully push the plunger of the
Radiesse injectable implant syringe to start the injection and inject the Radiesse
injectable implant material in small boluses, 0.2 – 0.5cc/bolus. No more than
0.5cc should be injected per bolus. The number of boluses will vary depending
on the extent of treatment desired. No more than 3cc of Radiesse injectable
implant (2 syringes) will be injected per hand, per treatment session.
6. If significant resistance is encountered when pushing the plunger, the injection
needle may be moved slightly to allow easier placement of the material or it may
be necessary to change the injection needle.
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7. Immediately after injection, cover the injection site with a sterile 4x4 gauze and
have the subject sit on this hand while the contralateral hand is being injected.
This warms the Radiesse injectable implant making it more malleable for later
massaging.
8. Treat the contralateral hand in the same manner as described in steps 2 through 6
above.
9. Immediately after injection of the contralateral hand, cover the injection site with
a sterile 4x4 gauze and have the subject sit on this hand.
10. While the contralateral hand is warming, remove the gauze from the hand that
was initially injected, have the subject make a fist with this hand, and gently
massage the dorsum of the hand until Radiesse has been evenly spread across the
dorsum, remaining 
distal to the 
wrist crease 
and 
proximal to the
metacarpophalangeal joints.
11. Use a 1:1 correction factor. No overcorrection is needed.
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Hand function testing performed in the study will include: 
•
Range of Motion (ROM). The rROM will be assessed using a Jamar finger
goniometer (Sammons Preston Rolyan, Bolingbrook, IL). This test will passively
and actively measure the angle of motion of all 5 metacarpophalangeal joints in
each hand by determining the flexion and extension angles. The flexion will
determine how far each finger can be flexed at the metacarpophalangeal joint
towards the palm. The extension will determine how each finger can be extended
at the metacarpophalangeal joint away from the palm.
•
Sensation. Sensation in the dorsum of each hand will be Semmes-Weinstein
monofilament touch test whereby the subject will be asked to report when a light
touch is felt at different areas of the dorsum of each hand.
•
Dexterity. Fine motor skills (dexterity) will be assessed using the Functional
Dexterity Test (FDT) which assesses one’s ability to use the hand for daily tasks
requiring 3-jaw chuck prehensions, i.e. buttoning, tying shoelaces, screwing a nut
and bolt and lacing yarn. Dexterity will be measured using a 16-hole peg board
(North Coast Medical, Inc., Morgan Hill, CA).
•
Strength.   Hand strength will be assessed in 2 ways; grip and pinch strengths.
The grip strength will be assessed using a standard, adjustable-handle Jamar
hydraulic hand dynamometer (Sammons Preston Rolyan, Bolingbrook, IL). The
pinch strength will be assessed in three different ways; tip (two-point) pinch, key
(lateral) pinch and palmar (three-jaw chuck) pinch using the Jamar hydraulic
pinch gauge (Sammons Preston Rolyan, Bolingbrook, IL).
For the first 10 subjects enrolled at each site, hand function testing will be performed by 
2 independent evaluators. After the first 10 subjects, only one evaluator will be 
performing the hand function testing at the required timepoints. This data will provide an 
assessment of intra and inter-rater variability in hand function measures within and 
between sites. A minimum of 50 subjects across all sites will be evaluated by two 
independent hand function testers. 
Training of the investigators who will be conducting the hand function tests on subjects 
will be provided by an instructional video of a hand surgeon and hand therapist. Sponsor 
trainers will be qualified by direct interaction with the hand surgeon who created and co- 
demonstrates the testing in the instructional video. Sponsor trainers worked closely with 
the hand surgeon during the creation of instructional video and creation of the hand 
function test protocol (Appendix E). To qualify, investigator trainees will be required to 
complete the instructional video and demonstrate to the Sponsor trainer the required 
competencies in accordance with the protocol for hand function testing during the 
Sponsor-monitored on-site training. Selection of trainees will include targeting 
investigators who plan to remain on staff for at least two years. Training certificates will 
be issued upon completion of trainee qualification. Only staff members who have been 
trained and qualified will be allowed to perform hand function testing during the study. 
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10 SAFETY ASSESSMENTS 
All AEs observed by study subjects, investigators or other study staff from informed 
consent through last study follow up visit will be recorded. If a SAE or unanticipated 
serious device related effect (USADE) occurs, study subjects may be requested to appear 
for unscheduled follow up visits for AE assessment and hand photographs. 
The following information, at minimum, must be recorded: 
•
AE description
•
AE type (serious, expected, unexpected) – Refer to definitions below
•
Start and Stop Dates
•
Intensity (mild, moderate, severe) – Refer to definitions below
•
Causal relationship (not related, related) – Refer to definitions below
•
Treatment description, if any
10.1 Definition of intensity 
The clinical intensity of an AE will be classified as: 
Mild: Signs and symptoms that can be easily tolerated. Symptoms can be ignored and 
disappear when the subject is distracted. 
Moderate: Signs and symptoms that cause discomfort and interfere with normal 
functioning, but are tolerable. They cannot be ignored and do not disappear when the 
subject is distracted. 
Severe: Signs and symptoms that affect usual daily activity and incapacitate the subject, 
thereby interrupting his/her daily activities. 
The definitions above are difficult to apply for some data (e.g., clinically relevant 
laboratory values that are documented and evaluated on the CRF AE report form). In 
such situations, the investigator should make a judgment based on personal experience. 
10.2 Definition of causal relationship 
An AE is considered to be “related” to investigational product (IP) if a causal relationship 
between the IP and an AE is at least a reasonable possibility (i.e., the relationship cannot 
be ruled out) in the opinion of the investigator. 
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The expression “reasonable causal relationship” is meant to convey that there are facts 
(evidence) or arguments to suggest a causal relationship (ICH E2A guideline). 
Otherwise, the relationship should be considered as “not related.” 
10.3 Definition of type 
10.3.1 Adverse event 
The general definition for an AE is an untoward medical occurrence which does not 
necessarily have a causal relationship to the investigational product. 
10.3.2 Serious adverse event 
A SAE is an AE that meets at least 1 of the following 6 criteria: 
(1)
Results in death.
(2)
Is life-threatening.5
(3)
Requires inpatient hospitalization, or prolongation of existing hospitalization.
(4)
Results in persistent or significant incapacity or substantial disruption of the ability
to conduct normal life functions.
(5)
Is a congenital anomaly/birth defect.
(6)
Is an important medical event6, including an event that requires medical or surgical
intervention necessary to preclude permanent impairment of a body function or
permanent damage to a body structure.
All SAEs that occur during the study period, whether considered to be related to the IP or 
not must be reported by e-fax (1-336-458-5983) or e-mail sent within 24 hours of 
knowledge of the event. 
Please send completed SAE forms to: adverse.events@merz.com 
Product Safety Department 
Merz North America, Inc. 
6501 Six Forks Road 
Raleigh, North Carolina 27615 
5 Defined as the subject being at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
6 According to ICH E2A, CPMP/ICH/377/95: “Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient/subject or may require intervention to prevent one of the other outcomes listed in the definition 
above. These should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse.” 
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Although all information required for completion of an SAE report form may not be 
available within the specified time period, the following minimal initial information 
should be reported: Subject ID #, Site #, name and contact information (of 
investigator/study coordinator), and which of the 6 SAE criteria identified above resulted 
in the event being deemed “serious”. 
IRB reporting requirements may also apply for SAEs. 
10.3.3 Unanticipated adverse device effect 
An unanticipated adverse device effect is 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, or degree of 
incidence in the IFU or Radiesse labeling, or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
10.3.4 Expected adverse events 
An expected AE is an experience listed in the current IFU (Appendix A). 
10.3.5 Unexpected adverse events 
An unexpected AE is an experience not previously reported in nature, severity, or 
incidence in the current IFU.  IRB reporting requirements may also apply. 
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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1   Monitoring 
This study will be monitored in accordance with GCP and regulatory guidelines.  By 
signing this protocol, the investigator agrees to periodic, on-site monitoring of all 
appropriate study documentation.  The progress of the study will be monitored by 
periodic on-site visits and frequent communications between the Sponsor (or designee) 
and the investigator (either by phone, fax, email, or post). During these contacts, the 
monitor will: 
•
Check and assess the progress of the study.
•
Conduct source document verification to ensure data are authentic, accurate, and
complete.
•
Identify any issues and address their resolution.
•
Ensure the safety and rights of subjects are being protected.
•
Verify that the study is being conducted in accordance with the currently
approved protocol (and any amendments) per GCP and all applicable regulatory
requirements.
In addition, the monitor will check whether all AEs and SAEs have been reported 
appropriately within the time periods required. 
The investigator and all staff will be expected to cooperate with the monitor by providing 
any missing information whenever possible. The investigator must be available to answer 
questions arising during regular monitoring visits. 
11.2   Audits / Inspections 
Audits may be performed, including the possibility that a member of the sponsor’s 
quality assurance function or their representative may arrange to visit the investigator in 
order to audit the performance of the study at the study site, as well as all study 
documents originating there. 
Inspections by regulatory authority representatives and IRBs are possible at any time, 
even after the end of study. The investigator is to notify the Sponsor immediately of any 
such inspection. The investigator and institution will permit study-related monitoring, 
audits, reviews by the IRB and/or regulatory authorities, and will allow direct access to 
source data and source documents for such monitoring, audits, and reviews. 
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12 
STATISTICAL METHODS 
This section describes the statistical analyses foreseen at the time of study planning. 
Any deviations from planned analyses, the reasons for such deviation, and all alternative 
or additional statistical analyses that may be performed before database close will be 
summarized in the clinical study report. 
12.1 Determination of sample size 
The primary endpoint will be based on a non-inferiority hypothesis test comparing the 6- 
month rate of device/injection-related severe AEs in the MHGS4 (Group A) subjects 
versus the MHGS2-3 (Group B) subjects.  Based on the pre-market study data, an 
expected rate of severe adverse events is 17% for both groups, and the test will be based 
on a 12% non-inferiority margin. This margin allows for adequate power of the planned 
hypothesis test with a reasonable sample size and will provide assurance that the severe 
AE rate in the MHGS4 subjects is not unacceptably higher given the expected benefit in 
these subjects. The test will be based on a one-sided Farrington-Manning likelihood score 
test of binomial proportions at a one-sided 0.05 alpha level.  A maximum of 250 subjects 
with MHGS grades 2, 3 and 4 at baseline (at least 50% with both hands rated MHGS 4) 
will be enrolled in at least 5 sites and a maximum of 12 sites in the US. Allowing for 
some attrition, a total of 244 subjects (122 in each group) at 6 months will provide 
approximately 80% power to conduct the hypothesis test. Based on an expected attrition 
rate of 5% per year, a minimum of 225 evaluable subjects are required to provide 2-year 
follow-up data. Safety and effectiveness data that are collected after 6 months and up to 
2 years will be presented descriptively. 
12.2 Analysis sets 
The  safety  and  per  protocol  analysis  sets  will  be  used  for  analysis  of  the  study. 
Differences in results between analysis sets will be explored. 
12.2.1 Safety Evaluation Set (SES) 
The SES is the subset of all subjects who were exposed to the study device at enrollment. 
This will be the basis of the primary analysis of the primary safety endpoint. 
12.2.2 Per Protocol Set (PPS) 
The PPS is the subset of subjects in the SES without major protocol deviations. 
Examples of a major protocol deviation would be absence of Radiesse hand treatment or 
receiving an exclusionary hand procedure during the study. 
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13 
DATA HANDLING AND RECORDKEEPING 
By signing and dating the CRF, or electronic signature of the electronic case report form 
(eCRF) if an Electronic Data Capture (EDC) system is used, the investigator will confirm 
that all investigations have been completed and conducted in compliance with the clinical 
study protocol, and that reliable and complete data have been entered into the CRF. 
All data required by this clinical study protocol are to be recorded on CRFs, or eCRFs, as 
soon as possible. If paper-based, entries on the CRF must be legible and made with a 
blue or black ballpoint pen: pencils are not permitted. The monitor is not allowed to 
make entries into CRF or eCRF. 
For paper-based CRFs, it is not permitted to erase, overwrite, or use correction fluid or 
tape on the CRF. If corrections are necessary, an authorized member of the investigator’s 
staff will enter them in the following manner: the wrong entry will be crossed out with a 
single line (although it must remain legible) and the correct entry will be placed next to it. 
Corrections will be initialed, dated, and (if necessary) explained (e.g., corrections 
concerning AEs or the primary variable). Corrections that become necessary after 
collection of original CRF data sheets have to be documented on Data Clarification 
Forms (DCFs) and signed by the principal investigator (PI). 
All data required by this clinical study protocol are to be entered into an EDC system if 
applicable, and a validated database, which applies to both paper-based and EDC 
systems. 
If corrections in the subject diary or subject MHQ are necessary, the subject should be 
instructed to make a correction by drawing only a single line through the error, leaving 
the incorrect entry legible. The subject should date and initial the correction. The 
investigator should not make any changes to these documents. 
Essential documents at the investigational site include but are not limited to: 
(1)
Subject files
(2)
Subject identification code list
(3)
A copy of the study protocol and any amendments
(4)
Investigator’s copies of the CRFs, DCFs forms, and any associated subject-related
source data
(5)
Signed ICFs
(6)
Copies  of  all  direct  correspondence  with  the  IRB  and  with  the  regulatory
authority(ies), and with the Sponsor
(7)
Copies of hand photographs
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(8)
Copies of IP disposition records
Essential documents should be retained per applicable regulations and as instructed by 
the study Sponsor. Study documents may not be destroyed by study site personnel prior 
to the end of the required retention period of 25 years. The PI or the institution must 
inform the Sponsor in due time if the PI leaves the institution during the retention period. 
This rule also applies when the institution closes within the retention period. 
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14 
PUBLICATION POLICY 
The publication policy will be in accordance with the investigator agreement with the PI 
as executed prior to initiation of the investigational site. 
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15 
REFERENCES 
1. Carruthers, et al., “A Validated Hand Grading Scale,” Dermatol Surg  2008, 34:S179-
S183.
2. Narins R, 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.
3. Aaron DH and Jansen CWS, “Development of the Functional Dexterity Test (FDT):
Construction, Validity, Reliability, and Normative Data,” J Hand Ther 2003; 16: 12-21.
4. Mathiowetz V, et al., “Reliability and Validity of grip and pinch strength evaluations,”
J Hand Surg 1984; 9A: 222-6.
5. Mathiowetz V, et al., “Grip and pinch strength: Normative data for adults,” Arch Phys
Med Rehabil 1985; 66: 69-72.
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