Keywords nasolabial fold - aesthetic - dermal filler - facial wrinkles - randomized controlled
trial
Nasolabial folds (NLFs) are defined by facial structures that support the buccal fat
pad, and they separate the cheeks from the upper lip.[1 ]
[2 ] Aging can increase the NLF length and depth.[3 ] Prominent NLFs are caused by the reduction of deep adipose tissues and collagen
and the subsequent reduction of midface muscle contour, resulting in wrinkles and
folds.[3 ] The aging of facial features can be very distressing to many individuals.[4 ]
Even if rhytidectomy is considered a safe procedure, it carries risks of hematoma,
skin necrosis, nerve injury, infection, and scarring,[5 ] and these risks, even if minimal, deter many patients from undergoing surgery to
correct NLFs. Therefore, in the past several decades, dermal filler injection has
been widely applied to facial wrinkles correction.[6 ]
[7 ]
[8 ]
[9 ] In 2018 alone, 2,671,130 dermal injection procedures were performed in the United
States, showing a 39% increase since 2013.[10 ] Although dermal fillers are classified as permanent and nonpermanent,[11 ]
[12 ] they are generally considered safe but delayed reactions can occur.[13 ] Permanent fillers are not recommended in many countries, but nonpermanent fillers
require repeated injections.[11 ]
[12 ] Nevertheless, starting in the 2000s, a new generation of dermal fillers was developed,
known as collagen stimulators, characterized by increased collagen content at the
injection site persisting for some time after the filler has been resorbed.[14 ]
Polycaprolactone is a new dermal filler, which also is a bioresorbable polymer that
possesses collagen-stimulating properties.[15 ]
[16 ] It is a polymer of the aliphatic polyester family, and the degradation of polycaprolactone
is slower than polylactic acid or polyglycolic acid, which are also aliphatic polyesters.[17 ]
[18 ] As a dermal filler, polycaprolactone is formulated as microspheres suspended in
a gel carrier. This gel is an aseptic, latex-free, pyrogen-free, and complete bioabsorbable
nonpermanent dermal filler.[15 ] Polycaprolactone gel has already been safely applied to fill NLFs, crow's feet,
chin, and mandibular lines.[15 ] Previous studies have demonstrated that polycaprolactone-based treatment is a safe
and effective way for NLF correction.[19 ]
[20 ]
[21 ] Recommendations for polycaprolactone-based dermal filler use for the face and hands
have been published.[22 ]
Polycaprolactone has already been fully investigated in patients from many countries
but not China. It is important because satisfaction might differ in different populations
as there are aesthetic differences among populations.[23 ] Therefore, in this study, we explore the efficacy and safety of polycaprolactone
gel in treating Chinese patients with moderate-to-severe NLFs.
Methods
Study Design and Patients
Eligible patients with moderate-to-severe NLF who wished to be treated by dermal fillers
were recruited from three study centers between July 2017 and September 2019. This
study was approved by the Ethics Committee of the hospitals who recruited patients
in the study (Approval No. 2016BJYYEC-090-02). All patients participating in this
study signed informed consent.
The inclusion criteria were (1) 18 to 75 years of age, (2) with severity scores of
3 or 4 for completely visible approximately symmetric bilateral NLF, and (3) wished
to receive correction by intradermal injection described in this study protocol according
to Wrinkle Severity Rating Score (WSRS). The major exclusion criteria were (1) hair,
evident acne scars, active inflammation, infection, tumor, precancerous lesions, or
unhealed wound in the NLF area that could interfere with the visual assessment of
NLF severity and (2) the history of tissue transplantation or tissue filling by silica
gel or other permanent or semipermanent dermal fillers.
Randomization and Blinding
The patients were randomized 1:1 into the two groups. Sealed envelopes were prepared
according to a random number table before the initiation of the study. All the patients
signed the informed consent and wore an eye patch, and the randomization envelope
was opened and read by the third investigators (who were responsible for keeping the
envelopes and preparing the syringes) according to the random number. The therapeutic
investigators were responsible for the injecting polycaprolactone or sodium hyaluronate
gel (as the control group) according to the randomization. Specifically, the patients
in the study group were treated using the polycaprolactone gel (Ellanse TM-S; AQTIS
Medical B.V.), and the patients in the control group were treated using the modified
sodium hyaluronate gel (Restylane 2, Q-med AB). Blinding was applied for both investigators
and patients in this study.
Procedure
The same procedures and equipment were used in the polycaprolactone group and the
control group bilaterally. All patients received surface anesthesia. The filler was
administered into the middeep dermis using a 27-G needle inserted at an approximate
angle of 30 degrees parallel to the length of the fold. The patients were initially
given a suboptimal dose, and the investigators were allowed to provide a touch-up
at the 1-month follow-up visit. According to their willingness, the patients in the
control group received a free compensatory injection of modified sodium hyaluronate
gel (Restylane 2, Q-med AB) for bilateral NLF after unblinding and 1 year following
the control injection.
Photos of the injection area were taken during follow-up to collect data for evaluating
the WSRS of the patients, the same as other studies.[19 ]
[20 ] The photos were taken before the injection, on the day of injection, 2 weeks, 1
month, 3 months, 6 months, 9 months, and 12 months after injection respectively. The
same photographer took the photos from the same angle and distance, and the area included
the bilateral nasolabial areas. The photos were preserved for evaluation. The photos
had to be symmetric from the view of originating sites of bilateral nasolabial areas,
the chin tip, and the centerline of the lips. Photos were taken repeatedly to achieve
an accurate assessment. The clearest photo was selected and preserved, while the other
photos were archived.
Endpoints
The primary endpoint was the effectiveness rate at 12 months after injection by therapeutic
investigator-reported. It was defined as the percentage of patients whose bilateral
WSRS scores (the worse results of the bilateral sides were recorded for analysis)
improved over ≥1 point during follow-up compared with the baseline.
The secondary endpoints were (1) the comparison of effectiveness rate between 6 months
in the control group and 12 months after injection in the polycaprolactone group;
(2) the comparison of the therapeutic investigator-reported WSRS changes among different
time points of follow-up by 2 weeks,1 months, 3 months, 6 months, 9 months, and 12
months; (3) the comparison of the WSRS changes among different time points of follow-up
by patient-reported; and (4) the comparison of the GAIS changes among different time
points of follow-up by therapeutic investigator-reported.
The safety assessment included the responses of the treatment sites, signs, and symptoms
assessed for 14 days after injection. In addition, the adverse events (AEs) were reported
by therapeutic investigators and used for safety assessment. AE is defined as any
adverse or unintended symptom, sign, or disease associated with the use of a study
device over time, regardless of whether or not the device is associated. Severe adverse
events (SAEs) are defined as AEs severe enough to cause loss of the ability to work
and perform daily activities.
Sample Size Calculation
The patients were randomized 1:1 to the active and the control treatment group. In
light of clinical data, it was assumed that the effective rate was 30% in the control
group after treatment, and the effective rate in the polycaprolactone group could
be at least 25% higher than that of the control group, of 55%. The α-value (two-sided)
was set at 5%, and power was set at 80%. Considering a dropout rate of 20%, we planned
to enroll 80 patients in each group, and 160 patients for the study.
Statistical Analysis
The full analysis set (FAS) included all patients who were randomized and treated
in this study. The per-protocol set (PPS) included all patients who completed all
the study procedures and did not have severe protocol deviations. The safety set (SS)
included all patients randomized and who received the study treatment and with at
least one safety assessment. The primary endpoint analysis was based on the FAS and
PPS. All the baseline demographic data and secondary endpoints were analyzed based
on the FAS. Safety analysis was performed based on the SS. Missing data were imputed
using the last observation carry forward (LOCF) and the worst-case carry forward (WCCF)
methods.
SAS 9.4 (SAS Institute, Cary, NY) was used for statistical analysis. Continuous data
were reported as means ± standard deviations. Categorical data were reported as n
(%). The paired t -test and repeated measures analysis of variance were used to compare the data before
and after treatment. The t -test or Wilcoxon rank-sum test was used to analyze intergroup differences. All statistical
analyses were two-sided. p -Values < 0.05 were considered statistically significant.
Results
Characteristics of the Patients
Of 160 patients enrolled, 80 patients were randomized in each group. [Fig. 1 ] presents the patient flowchart. The FAS and SS had 80 patients in each group, and
the PPS had 77 and 78 patients in the polycaprolactone and control groups, respectively.
They were middle-aged adults, mostly female and of Han ethnicity. According to the
investigators, the left-side NFLs were moderate in 56.3 to 60.0% and severe in 40.0
to 43.8% and the right-side NFLs were moderate in 57.5 to 62.5% and severe in 37.5
to 42.5% ([Table 1 ]).
Table 1
Baseline characteristics (FAS)
Characteristic
Polycaprolactone
n = 80
Control
n = 80
Age (years), mean ± SD
42.9 ± 8.5
44.5 ± 8.7
Sex (female), n (%)
77 (96.3)
78 (97.5)
Ethnicity (Han), n (%)
77 (96.3)
74 (92.5)
Body weight (kg), mean ± SD
57.5 ± 7.8
57.2 ± 8.1
Height (cm), mean ± SD
162.5 ± 5.3
161.9 ± 5.5
BMI (kg/m2 ), mean ± SD
21.8 ± 2.7
21.8 ± 2.7
Pregnancy check (negative), n (%)
66 (82.5)
61 (76.3)
NFL Assessment by investigators
Left face, n (%)
Moderate
48 (60.0)
45 (56.3)
Severe
32 (40.0)
35 (43.8)
Right face, n (%)
Moderate
50 (62.5)
46 (57.5)
Severe
30 (37.5)
34 (42.5)
Assessment by patients
Left face, n (%)
Moderate
53 (66.3)
50 (62.5)
Severe
26 (32.5)
25 (31.3)
Right face, n (%)
Moderate
53 (66.3)
51 (63.8)
Severe
24 (30.0)
25 (31.3)
Abbreviations: BMI, body mass index; FAS, full-analysis set; SD, standard deviations.
Fig. 1 Patient flowchart.
Primary Endpoints
As shown in [Table 2 ], the investigator-reported effectiveness rate by 12 months in the polycaprolactone
group was 88.8, 86.3, and 88.3% in the FAS (LOCF), FAS (WCCF), and PPS respectively,
compared with 23.8, 22.5, and 23.1% in the control group respectively. The difference
(95% CI) between the two groups was 28.7% (13.6%, 50.0%), 28.2% (12.7%, 50.6) and
29.8% (14.1, 52.3) respectively in the 3 analysis sets/methods. The difference between
the 2 groups were very significant statistically at all the 3 analyses (P <0.001).
Table 2
Comparison of effectiveness rate at 12 months after injection – Analyses with and
without adjustment of center effects
Analysis Set
Before adjustment
After adjustment
Polycaprolactone
Control
Difference (95%CI)
Difference (95%CI)
FAS[# ]
71/80 (88.8%)
19/80 (23.8%)
28.7% (13.6; 50.0)
65.0% (53.4; 76.6)
FAS[* ]
69/80 (86.3%)
18/80 (22.5%)
28.2% (12.7; 50.6)
63.8% (51.9; 75.6)
PPS
68/77 (88.3%)
18/78 (23.1%)
29.8% (14.1; 52.3)
65.2% (53.4:77.0)
Abbreviations: CI, confidence interval; FAS, full-analysis set; PP, per-protocol.
Note: P -value <0.0001 for comparisons between groups in all the analyses.
# Missing data imputed by LOCF (last observation carry over).
* Missing data imputed by WCCF (worst case carried-over).
Secondary Endpoints
The effectiveness rate was 88.5% at 12 months in the polycaprolactone group, compared
with 67.1% at 6 months in the control group (p = 0.001; [Table 3 ]).
Table 3
Effectiveness of polycaprolactone at 12 months versus the control group at 6 months
Polycaprolactone
Control
p- Value
Effectiveness rate
69/78 (88.5%)
53/79 (67.1%)
0.0011
In the investigator-reported outcomes, as shown in [Fig. 2 ], the improvement in WSRS remained relatively stable over 12 months in the polycaprolactone
group, while the improvement in WSRS was gradually lost in the control group, starting
at 3 months (p < 0.05 at 3, 6, 9, and 12 months). As shown in [Fig. 3 ], the GAIS assessment was improved, much improved, or very much improved in all patients
during follow-up, while the proportion of patients with a “no change” assessment gradually
increased during follow-up. Based on the patient-reported outcomes, the differences
in the improvements in WSRS became significant between the two groups at 9 months
([Fig. 4 ]). The patient-reported GAIS scores gradually declined with time in both groups but
more severely in the control group ([Fig. 5 ]).
Fig. 2 Comparison of the wrinkle severity rating scale (WSRS) scores by investigator-reported
during follow-up, *p < 0.05, ***p < 0.001.
Fig. 3 Comparison of the global aesthetic improvement scale (GAIS) scores by investigator-reported
during follow-up, ***p < 0.001.
Fig. 4 Comparison of the wrinkle severity rating scale (WSRS) scores by patient-reported
during follow-up, *p < 0.05.
Fig. 5 Comparison of the global aesthetic improvement scale (GAIS) scores by patient-reported
during follow-up, *p < 0.05.
Safety
The rates of AEs and SAEs were 45.0 versus 43.8% and 6.3 versus 3.8% in the polycaprolactone
and control groups, respectively ([Table 4 ]). The incidence of injection-related AEs and SAEs was 8.8 versus 11.3% and 0 versus
1.3% in the polycaprolactone and control groups, respectively. The most occurred injection-related
AE was injection site swelling (22.2%) in the polycaprolactone group, and swelling
(22.2%) and discoloration (22.2%) were the most occurred injection-related AEs in
the control group (data not shown). All injection-related AE recovered, and no sequelae
were observed. No patients dropped out due to the AEs or SAEs.
Table 4
Safety analysis
Polycaprolactone (n = 80)
Control (n = 80)
Any AEs
36/80 (45.0%)
35/80 (43.8%)
SAEs
5/80 (6.3%)
3/80 (3.8%)
Injection-related AEs
7/80 (8.8%)
9/80 (11.3%)
Injection-related AEs
0/80 (0%)
1/80(1.3%)
Abbreviations: AEs, adverse events; SAE, serious adverse event.
Discussion
To our knowledge, this was the first study that compared the efficacy and safety of
polycaprolactone and sodium hyaluronate gel in treating Chinese patients with moderate-to-severe
NLFs. In the FAS, the effectiveness rate at 12 months in the polycaprolactone group
was 88.8% compared with 23.8% in the control. Furthermore, the improvement in WSRS
remained relatively stable over 12 months in the polycaprolactone group, while the
improvement in WSRS was gradually lost in the control group, starting at 3 months.
No new safety signal was identified. The results suggest that polycaprolactone gel
injection is effective and safe in moderate to severe NLFs in Chinese patients.
The WSRS and GAIS were used to assess the treatment efficacies of the fillers. In
this trial, the effectiveness rate (based on a WRSR score improved by ≥1 point) was
significantly higher in the polycaprolactone group than that in controls at 12 months,
and the effectiveness rate at 12 months in the polycaprolactone group was higher than
that in the control group at 6 months (−1.08 vs. −0.48). These results are supported
by trials from Western populations.[19 ]
[20 ]
[21 ] In a split-face trial, the polycaprolactone-based dermal filler showed better WSRS
scores at 6 (2.0 vs. 2.3), 9 (2.2 vs. 2.9), and 12 (2.6 vs. 3.1) months than a hyaluronic
acid-based filler.[19 ] The results suggest the long-term stability of the volumize effect of polycaprolactone-based
dermal filler. Indeed, the results suggested that the improvement in WSRS was stable
over the 12 months of follow-up, while the improvements in WSRS in the control group
were gradually lost. It is also supported by European studies with follow-ups of 18
and 24 months; one showed an improvement of ≥1 point of WSRS in 92% at 6 months and
64% at 18 months,[21 ] while another study showed improvements of ≥1 point of WSRS at 24 months in at least
50% of patients who received two different formulations of polycaprolactone (Ellanse-S
and Ellanse-M).[20 ]
In the present trial, the investigator's GAIS assessment showed improvements in nearly
all patients of the polycaprolactone group over the 12-month follow-up, while the
improvement rate decreased rapidly in the control group. In a split-face trial, the
GAIS assessment showed that the total proportions of patients with improvements were
higher at 6 (85 vs. 64%), 9 (41 vs. 0%), and 12 (20 vs. 0%) months in the polycaprolactone
group compared with a hyaluronic acid-based filler.[19 ] At 12 months, the improvement rate on GAIS showed improvements in 90 and 91.4% of
patients who received Ellanse-S and Ellanse-M, respectively,[20 ] which were similar in the present trial (>90% in the polycaprolactone group). Moers-Carpi
and Sherwood reported an investigator-evaluated GAIS improvement rate at 24 months
of 77.8 and 100% using Ellanse-S and Ellanse-M, respectively.[20 ] Another multicenter clinical study by Moers-Carpi et al[21 ] that included 90 patients with moderate-to-severe NLFs followed for 18 months after
a single injection and no touch-up showed that significant improvement of GAIS was
observed similarly by the physicians and the subjects in more than 90% of subjects
up to 12 months and 81% of subjects at 18 months.
Therefore, the long-term efficacy based on the WSRS and GAIS observed in Chinese patients
appears to be similar to the long-term efficacy observed in Western patients. Future
studies will be conducted to determine the long-term effect of polycaprolactone-based
dermal filler in Chinese. Still, a study in Koreans showed that the GAIS was maintained
for 24 months in patients who underwent forehead augmentation using a polycaprolactone-based
gel.[24 ]
Compared with other studies,[15 ]
[19 ]
[20 ]
[21 ] no new safety signals were found. A study of 1,111 patients performed in France
and Taiwan showed that the complication rate of polycaprolactone-based gel was low,
with edema lasting >2 weeks observed in 4.5% of the 1111 patients, bruising in 2.7%,
malar edema in 0.7%, temporary lump in 0.5%, and discoloration in 0.2%; in addition,
no nodules or granuloma were observed over 3 years of follow-up.[25 ] In the present study, the AEs were all responses at the injection site, such as
swelling and reddening, which all disappeared without sequelae.
This trial has limitations. The follow-up was relatively short. More studies are needed
to investigate the long-term effects further. More safety data should be collected
in the future.
In conclusion, polycaprolactone gel injection is effective and safe to treat moderate-to-severe
NLFs in Chinese patients. Furthermore, this trial confirms the outcomes of the polycaprolactone
dermal filler in Chinese patients.
