ARTICLE
Auteur(s) : Helmut
Schöfer1, Arndt Van Ophoven2, Ulrike
Henke1, Tamara Lenz3, Angelika
Eul4
1Department of Dermatology and Venerology, University
Hospital, J.W. Goethe University Theodor-Stern-Kai 7, D-60596
Frankfurt/M, Germany
2Department of Urology, University Hospital of Münster,
Germany
3Statistical Consulting, Mannheim, Germany
4Medical Consulting, Velen, Germany
Conventional ablative methods of anogenital warts show high initial
clearance rates, but also unsatisfactorily high recurrence rates of
up to 60% within a few months post-treatment [1-3]. In contrast,
imiquimod, a novel immune response modifier which is able to clear
anogenital warts in more than 50% of subjects, has recurrence rates
as low as 13-19% when applied three times/week until clearance of
all visible anogenital warts [4, 5].Topical imiquimod has been
shown to induce the production of interferons (alpha and gamma) and
other Th1-related cytokines in the skin of papillomavirus-infected
subjects, thus enhancing the cell-mediated immunity against
cutaneous virus infections [6, 7]. Based upon this model of action,
it was assumed that imiquimod cream treatment following ablative
therapy should result in a favourable effect on the sustained
clearance of successfully treated anogenital warts. A first
open-label clinical trial with these combined procedures
demonstrated a remarkably low recurrence rate of 7.3% [8].We now
present the results of the first clinical trial directly comparing
the long-term efficacy of imiquimod 5% cream with that of
conventional ablative procedures. The main goal of the study was to
assess whether imiquimod 5% cream – either alone or in combination
with any ablative method – is able to improve the sustained
clearance of the treatment area during a 6-month follow up period
compared to ablation alone.
Methods
Study design
This was a Phase IIIb, open-label, randomized, 3-armed, multicenter
trial conducted at 60 study sites in Germany over a period of 21
months in 2001/2002. Participant investigators were dermatologists
(n = 45), gynecologists (n = 9), urologists (n = 5), and others (n
= 1). After informed consent, subjects were randomized in a ratio
of 2:3:2, to one of three treatment groups: Group A, ablative
treatment; Group B, imiquimod 5% cream alone, and Group C, ablative
therapy followed by topical imiquimod 5% cream.
The study patients were randomized using the RPAS 3 program,
Version 1.52, a part of the EQUILA software package of Episys Ltd.
UK, which was kept by the study sponsor. The study was conducted in
accordance with the Declaration of Helsinki and Good Clinical
Practice Guidelines (ICH-GCP) and was approved by the local ethics
committees.
Study subjects
Male and female subjects, 18 years of age or older, with external
anogenital warts were eligible for the study. Maximum extension of
the wart area was limited to 2000 mm2 and the
maximum height of single anogenital warts being less than
1 cm. Exclusion criteria were pre-treatment with imiquimod 5%
cream within the previous 6 months or any drug treatment with
interferon, interferon inducers, immunomodulators, oral antiviral
drugs (except for oral acyclovir for suppressive or acute therapy
of herpes simplex virus infections), topical antiviral drugs at the
target site, cytotoxic drugs, investigational drugs or any other
anogenital wart therapy within 4 weeks prior to the initiation
visit. Furthermore, subjects with internal anogenital warts,
bowenoid papulosis, inflammatory skin conditions within the target
area, autoimmune diseases, cancer, HIV infection, a history of
organ transplantation or unstable medical conditions were excluded
as well as pregnant or lactating females.
Study procedures
The study consisted of a treatment phase and a 6-month follow-up
period. Subjects in Group A were treated by one of the following
procedures, depending on which method was usually practiced by the
investigator: electrocautery, liquid nitrogen, laser therapy or
surgical removal of all external anogenital warts. The procedure
could be repeated over a period of 4 weeks until all visible
anogenital warts were removed. Subjects in Group B received
imiquimod 5% cream 3 times/week (8 ± 2 hours) before bedtime to
treat their anogenital warts until complete clearance or for a
maximum of 16 weeks. Subjects in Group C first had an ablative
procedure according to Group A; after complete clearance and wound
healing subjects started an adjuvant treatment with imiquimod 5%
cream 3 times/week for a total of 12 weeks.
During topical imiquimod treatment in Groups B and C, subjects
were assessed for clearance at 4-week intervals. Only subjects who
completely cleared their anogenital warts entered the follow-up
phase and were assessed for sustained clearance at 1 month (Group A
only), 3 months and 6 months of follow-up (all treatment
groups).
Assessment of efficacy and safety parameters
The primary efficacy parameter was the observed sustained clearance
at month three of the treatment-free follow-up period.
Additionally, subjects were assessed after 4 weeks (Group A only)
and at 6 months post-treatment for sustained clearance/recurrences.
The target areas were determined at the initiation visit by
measuring the width and length of each anogenital wart or cluster
of warts and taking the product of the two largest perpendicular
extensions. The sum of the individual anogenital warts or wart
areas presented the target area which was not to exceed
2000 mm2. The initial wart areas were diagrammed
and numbered and any new anogenital warts outside the target area
appearing during the course of the study were added to the diagram
at the control visits. Subjects with recurrent anogenital warts
within the target area(s) were excluded from further study
participation.
The investigators assessed the safety of the imiquimod
treatments at each control visit by documenting the presence and
severity of local skin reactions (erythema, edema, induration,
vesicles, erosion, ulceration, flaking or scabbing) on a scale from
0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe). Subjects
reported any symptoms like itching, burning or pain using the same
severity scale. For both imiquimod groups, vital signs (blood
pressure, heart rate) were recorded during the treatment period and
for all treatment groups throughout the follow-up period. Adverse
events were documented for all treatment groups. No laboratory
analyses were performed except for a HIV test for all subjects and
a pregnancy test for the female subjects randomized to the
imiquimod groups at study start.
Statistical analysis
The determination of sample size was based upon the published
recurrence rates for the different treatment modalities used in
this trial. For the conventional ablative treatments, a recurrence
rate of 25% was assumed [3]. Results from previous trials showed a
recurrence rate of 13% for imiquimod 5% cream alone [4] and 7% for
a combined laser and imiquimod therapy [8]. Thus, at least 223
evaluable subjects were considered sufficient to determine safety
and efficacy. Subjects were randomized in a ratio of 2:3:2 because
a lower primary clearance rate was projected for the treatment with
imiquimod 5% cream alone (Group B).
The primary efficacy parameter, observed sustained clearance,
was evaluated in all subjects who successfully cleared their
anogenital warts and were not lost to follow-up, in accordance with
the protocol. Evaluation of safety included all randomized subjects
who received treatment at least once (Intent-to-treat population,
ITT). All analyses were performed using the SAS Version 8.1
statistical software.
Results
Baseline characteristics
A total of 377 subjects were screened and n = 19 of them were
withdrawn prior to study initiation, mainly because they had
withdrawn their consent to participate (n = 14) or were excluded
due to various exclusion criteria. The remaining 358 subjects
represent the ITT study population (flowchart, ( figure 1 )). Subject
characteristics and demographic data at baseline are shown in table
1( Table 1 ). About 71% of subjects were
male, and the mean age of all subjects was 33.1 years (range 18 –
73). Of 254 males, 28.7% were circumcised, and 49% of 104 female
subjects used oral contraceptives. About 50% of all subjects were
current tobacco smokers.
The median duration of the current outbreak was 2 months (25%
percentile: 1 month; 75% percentile: 6 months), and the most common
location of genital warts was the foreskin/glans penis and the
penis shaft in males and the vulva in females. About 43% of all
subjects had undergone previous anogenital wart treatments, most
often with an ablative method or a combination of ablation and
chemical treatment. There were no statistical differences between
the treatment groups except for the wart area (p = 0.0328,
Kruskal-Wallis test); the smallest area was found in Group B
(105.4 mm2), the largest in Group C
(180.3 mm2). The wart area was significantly larger
in females (p = 0.0022, Wilcoxon two sample test, t
approximation).
At the beginning of the study, all 358 subjects completed a
questionnaire regarding their anogenital wart history. Among those
subjects reporting previous anogenital wart treatments (43%), about
45% (n = 65) had been successfully treated within the last 6
months, but only 19.7% declared they were satisfied with the
previous treatment.
Table 1 Baseline characteristics (intent-to-treat
population)
|
Group A
|
Group B
|
Group C
|
|
Ablation
|
Imiquimod
|
Ablation + Imiquimod
|
|
No. of subjects
|
100
|
155
|
103
|
|
Gender:
|
|
|
|
|
male: no. (%)
|
71 (71.0)
|
114 (73.5)
|
69 (67.0)
|
|
female: no. (%)
|
29 (29.0)
|
41 (26.5)
|
34 (33.0)
|
|
Mean age (yr)
|
32.0
|
32.8
|
34.4
|
|
Wart area: mean mm2 (range)
|
142.2 (4-1960)
|
105.5 (1-1912)*
|
180.3 (2-1354)
|
|
Mean duration of current outbreak: months (range)
|
4.7 (0-39)
|
4.2 (0-74)
|
7.2 (0-121)**
|
|
Previous wart treatment: no. pts. (%)
|
36 (36.0)
|
68 (43.9)
|
49 (47.6)
|
Treatment phase: efficacy of treatments and reasons for
withdrawal
Subjects in Group A and Group C were treated most frequently by
electrocautery (69% and 63%), followed by treatment with different
types of lasers, liquid nitrogen and surgical excision. Most of
these subjects (70%) needed one treatment session only; the others
had to be ablated for up to four times. Out of all 358 ITT
subjects, complete clearance was achieved in 92% (92/100) in Group
A, 65% (100/155) in Group B, and 73% (75/103) in Group C (( figure 1 ), Subject
Disposition).
Overall, 91 subjects (25.4%) (Group A, n = 8; Group B, n = 55;
Group C, n = 28, table 2( Table 2 ))
either withdrew prematurely during the treatment phase of the study
or were not clear of their baseline anogenital warts at the
end-of-treatment, with the proportion of males being significantly
higher than females (p < 0.001, Fisher’s exact test). Lack of
clearance was the most frequent reason for discontinuation in
groups A (n = 7/8) and B (n = 24/55), while in Group C most
subjects were lost for other reasons (n = 23/28; lost during the
treatment phase, non-compliance etc.). Of the 5 subjects in Group C
who completed the treatment phase without clearance, 2 subjects did
not clear anogenital warts after ablation and 3 had experienced
recurrences during the 12-week imiquimod 5% cream application and
were excluded from follow-up in accordance with the protocol.
Sixteen subjects (8 each in groups B and C) terminated the study
prematurely due to local skin reactions to imiquimod 5% cream. In
total, 267 subjects completed the treatment phase clear of baseline
anogenital warts and therefore entered the follow-up phase (n = 92,
100, 75 for groups A, B,C) to evaluate observed sustained
clearance.
Table 2 Reasons for withdrawal (multiple reasons could
be reported)
|
Group A
|
Group B
|
Group C
|
|
Total number of subjects enrolled, n =
|
100
|
155
|
103
|
|
Incomplete anogenital wart clearance during treatment
|
7
|
24
|
2
|
|
Recurrent anogenital warts during treatment
|
–
|
–
|
3
|
|
Adverse events: Local skin reactions to study medication
|
–
|
8
|
8
|
|
Other adverse events related to study procedures
|
0
|
2
|
1
|
|
Non-compliance
|
5
|
15
|
13
|
|
- with visit schedule
|
–
|
2
|
0
|
- - with medication
- - other
|
1
|
3
|
0
|
|
Others (personal, unknown, etc.)
|
4
|
19
|
11
|
|
Total no. of subjects withdrawn/lost to follow-up
|
|
|
|
|
- before end-of-treatment evaluation
|
1
|
31
|
23
|
|
- treatment failures
|
7
|
24
|
5
|
|
- during follow-up (recurrences excluded)
|
5
|
5*
|
4
|
|
|
|
|
Sustained clearance at month 3 and month 6 of follow-up
Twelve subjects were lost to follow-up before the primary, 3-month
evaluation and were excluded from analysis (n = 5,4,3 for groups
A,B,C) in accordance with the protocol. Sustained clearance at 3
months follow-up was observed in 89.8% of all subjects. This was
distributed across treatment groups as follows: Group A, 83.9%;
Group B, 93.8%; Group C, 91.7%. The differences between Group A and
Groups B and C at 3 months approached statistical significance
(overall Chi-Square test for any difference between treatments, p =
0.074; Chi-Square test for Group A vs. B, p = 0.033; test for Group
A vs. C, p = 0.142).
At the 6-month, study endpoint evaluation fourteen subjects were
lost to follow-up and were excluded from analysis (n = 5,5,4 for
groups A,B,C). One additional subject was lost to follow-up between
month 3 and 6 in Group C and for one subject from Group B the
efficacy data were not recorded at the 6-month visit (table 2).
Observed sustained clearance rates were distributed across
treatment groups as follows: Group A, 73.6%; Group B, 93.7%; Group
C, 91.5%. The differences between Group A and Groups B and C at 6
months were highly significant (overall Chi-Square test for any
difference between treatments, p-value < 0.001; Chi-Square test
for Group A vs. B, p < 0.001; test for Group A vs. C, p <
0.004).
Additional efficacy endpoints
With regard to the 253 subjects clear of baseline anogenital warts
after treatment and evaluated at 6-months follow-up 86.2% (n = 218)
were clinically assessed without recurrence within the treatment
area. End-of-follow-up clearance rate comparisons across all ITT
subjects enrolled in the study are also of interest. Of all 358 ITT
subjects 218 (60.9%) were successfully treated and returned free
from any anogenital warts at the 6 month post-treatment follow-up
period. This result was distributed across treatment groups as
follows: Group A, 64.0% (64/100); Group B, 57.4% (89/155); Group C,
63.1% (65/103). The differences between Group A and Groups B and C
for this outcome were not significant (overall Chi-Square test for
any difference between treatments, p-value > 0.49; Chi-Square
test for Group A vs. B, p = 0.295; test for Group A vs. C, p =
0.895).
Recurrences were observed in 23 subjects in Group A and 6
subjects in Groups B and C, respectively. However, recurrences
occurred at different time points during follow-up: at one month
(assessed in Group A only), eight subjects presented with recurrent
anogenital warts. At the 3-month visit, six subjects in each of the
three treatment groups presented with recurrent anogenital warts,
while 3-6 month recurrences were observed only in Group A (n = 9).
All subjects in groups B and C (100%) were free of recurrences
between 3-6 months, while this was the case for 87.7% in Group A
(64/73) only. This difference was statistically significant between
treatments in favour of the imiquimod groups (overall p-value <
0.001, Fisher’s exact test). Sustained clearance and recurrences
are displayed graphically in ( figure 2 ).
Simple logistic regression analyses were performed to find
possible relationships between the response variable “recurrence of
successfully cleared anogenital warts within the treatment area”
and various independent variables (gender, age, total wart area at
baseline, wart location, previous treatments, duration of current
outbreak, circumcision, smoking habits, concomitant diseases or
medications). At the 3-month follow-up visit, females and
circumcised males seem to have a marginally improved sustained
clearance. For any other parameter at any time of the study, no
significant relationship could be detected. In particular, baseline
wart area was not statistically significantly associated with
observed sustained clearance. Additionally, due to the small
numbers of subjects with recurrences in each ablative treatment
group, differences between the ablative procedures could not be
evaluated.
Safety evaluation
In total, 185 adverse events were recorded, seven of which were
classified as serious, but in no case drug-related. No deaths
occurred during the course of the study. Eighteen of the
non-serious adverse events in groups B and C were considered to be
drug-related, mainly local eczemas and burning. Four adverse events
led to study discontinuation: three were possibly drug-related
(severe pruritus, eczema in the treatment area, and fever, headache
and myalgia in one subject) and one was not related to study drug
(car accident). No other systemic adverse reactions were reported
and there were no substantial changes with regard to vital signs
during treatment and follow-up. The most frequently reported local
skin reactions to imiquimod 5% cream were erythema and erosions,
occurring in 56.7% and 18.5% of those subjects evaluated at week 4
and in 44% and 12% of those subjects evaluated at week 16.
Imiquimod-treated subjects reported incidence rates for itching
(38%), burning (37%), and pain (18%) at the application site at
week 4 of treatment. In subjects evaluated at week 16, the
incidence of these symptoms was 24%, 26% and 16%, respectively. The
incidence of all local skin reactions and symptoms at week 4 is
shown in ( figure
3 ). The degree of pain perceived during treatment,
directly compared in Group C receiving ablative and imiquimod
therapy, showed no differences between treatments or between sexes,
(p > 0.05, Kruskall-Wallis test and Wilcoxon two sample signed
rank test). Local skin reactions were commonly found to be mild to
moderate in intensity, only 10% of all cases were classified
severe. Sixteen subjects (6.2% of 258 subjects), eight in each
imiquimod treated group, discontinued the study due to local skin
reactions (table 2). This represents 11.5% of all 139 subject
withdrawals during the course of the study. No relevant statistical
differences were found between the two imiquimod treatment groups.
Discussion
External anogenital warts are primarily treated by
physician-applied ablative methods which may require local or even
systemic anesthesia to avoid excessive pain, and sometimes may
result in wound healing disorders, bacterial infection, hypo- or
hyperpigmentation and scars. Often more than one ablation is
required to remove all anogenital warts. The major drawback is
regarded to be the relatively high recurrence rate. Rates reported
from clinical trials were 24% for electrocautery, 0-39% for liquid
nitrogen, < 7-45% for laser treatment, and 0-29% for surgical
excision [3, 9]. The reason hypothesized is that any
cytodestructive method just removes the visible anogenital warts
without affecting the underlying infection with human
papillomavirus (HPV). Therefore, attempts have been made to improve
the sustained clearance by enhancing the cutaneous immune response
by adjuvant interferon, however, with inconsistent study results
[10].
Imiquimod is a small imidazochinoline molecule which is assumed
to have stimulatory effects on both the innate and the adaptive
immune system by activating the Toll-like receptor-7 (TLR-7), an
important part of the innate immune system located mainly upon
dendritic cells and macrophages. As a consequence, large amounts of
interferon and interleukin-12 enhance the immune response against
viral and bacterial infections [11]. Furthermore, this stimulation
also improves the adaptive cell-mediated immune system by enhancing
the migration and the antigen presentation of Langerhans cells
[12].
Imiquimod 5% cream 3 times/week not only shows good efficacy in
the primary treatment of external anogenital warts but also in
terms of recurrences [4, 5]. In a first, open-label trial on
sustained clearance with a combined therapy, laser treatment of the
anogenital warts was followed by a 3-month adjuvant course of
treatment with imiquimod 5% cream to prevent recurrences. The
recurrence rate at 3 months post-treatment was 7.3%, and between 3
and 6 months post-treatment no further recurrences were observed.
Imiquimod 5% cream, was well tolerated after laser ablation
[8].
This 3-armed, randomized, group-parallel study was designed to
support the safety and long-term efficacy of imiquimod 5% cream.
Sustained clearance of external anogenital warts was analyzed after
treatment with imiquimod 5% cream when used either alone or in
combination with ablation and directly compared to ablation of
external anogenital warts alone. Only those subjects in each group
whose anogenital warts were completely cleared after the treatment
period entered the follow-up period. To achieve equivalent patient
numbers between the three treatment groups starting the follow-up
phase, subjects were randomized to the different treatment groups
in a ratio of 2:3:2 because a lower clearance rate was projected
for the treatment with imiquimod 5% cream alone. This assumption,
based upon the results from a pivotal placebo-controlled clinical
trial [4], was confirmed by a primary clearance rate of 92% in
Group A (only ablation) and 65% in Group B (imiquimod monotherapy).
For the combined treatment, it seems sensible to wait until
sufficient wound healing has taken place after ablation. No
experience is available to date from clinical trials in subjects
with external anogenital warts applying the cream immediately after
conventional ablative therapy.
Sustained clearance rates 6 months post-treatment in the three
groups were rather high and varied between 73.6% (A), 93.7% (B) and
91.5% (C). Thus, successfully cleared subjects who administered
imiquimod 5% cream alone or as adjuvant therapy presented a
significantly improved sustained clearance rate. Interestingly,
recurrences in the ablation group seem to occur over a longer time
period than in the imiquimod treated subjects. Recurrence rates at
month 3 were 16.1% (A), 6.3% (B) and 8.3% (C). Similar to the
previously cited post-laser study [8], no further recurrences (3-6
months) were reported in either treatment group receiving imiquimod
5% cream, and the difference between Group A and the other groups
during this time interval was statistically significant. These
results may be blurred by some bias resulting from different
clinical assessment time points during follow-up. However, the
additional visit in Group A after 4 weeks post-treatment appeared
clinically advisable because most recurrences after simple ablative
therapy seem to occur within a short time frame and subjects should
have access to subsequent therapy without excessive delay. In
effect, this assumption was confirmed by a relatively high
short-term recurrence rate in Group A.
Limitations of this clinical comparative trial clearly are given
by the open label design which however was unavoidable. It is not
possible to blind a direct comparison of ablative and medical
treatment modalities. As this study did not aim at a primary
efficacy assessment of the therapeutic methods used, which is well
documented in the literature, a placebo arm was not introduced. To
overcome any possible bias, patients were allocated randomly to the
different treatment groups through an investigator blinded
procedure. Nevertheless, an imbalance turned up with respect to a
single baseline characteristic. The mean anogenital wart area in
Group B was signifcantly smaller than in the other treatment
groups, which could have caused a bias in favour of the primary
clearance rate of the imiquimod monotherapy. However, as the major
goal of this study was to compare sustained clearance rates until
the end of a 6 month follow up period in successfully cleared
patients, this difference appears to be negligible.
The results of this study indicate that for successfully treated
subjects, the recurrence rate for anogenital warts was lower in the
groups administered imiquimod than in the group receiving ablation
alone. This lends credence to the hypothesis that while immediate
clearance rates are higher in subjects receiving ablation over
those applying imiquimod 5% cream, a higher post-ablation
recurrence rate results in comparable overall clearance outcomes by
6 months post-treatment. Therefore, in clinical practice a combined
procedure using imiquimod cream after ablation of anogenital warts
might be favourable compared to any of the monotherapies.
Acknowledgements
The authors would like to gratefully acknowledge the contribution
of the investigators participating in the study: Dr. U. Ammann,
Lingen; Dr. O. Barsom, Baden-Baden; Dr. T.-H. Bauer, Fellbach;
H.-C. Braun, Hamburg; Dr. H. Brüning, Kiel; Dr. R. Drunkenmölle,
Halle; Dr. H. Engelke, Husum; Dipl.med. T.-M. Ernst, Berlin; Dr. K.
Fritz, Landau; Dr. A. Frommer, Günzburg; Dr. G.G. Gerhardt,
Neumünster; Dr. H. Grenz, Friedberg; Dr. W. Halbig, Kaarst; Dr. A.
Heinzelmann, Verl; P. Hoch, Quickborn, Prof. Dr. H. Hofmann,
München; Dr. H. Jessen, Berlin; Dr. U. Karsten, Geesthacht; Dr. J.
Kirsch, Mannheim; Dr. M. Klosok-Romanowski, Hamburg; Dr. K.-O.
Knaust, Bad Oeynhausen; Dr. D. Konietzko, Bamberg; P. Krolak,
Wuppertal; Dr. G. Kurzhls, Wangen, Dr. Ch. Kühler-Obarius, Hamburg;
Dr. B. Laux, Augsburg; Dipl. med. F. Leistner, Erfurt; Dr. R.
Leitz, Stuttgart; Dr. D. Lucka, Bremen; PD Dr. G.-A. Lutz,
Wesseling; Dr. K.-G. Meyer, Berlin; Dr. C.-P. Möller, Hamburg; Dr.
T. Neudeck, Ansbach; Dr. K.T. Nimri, Goch; Dr. C. Nüchel,
Mönchengladbach; Dr. D. Peiler, Essen; Dr. A. Petry, Gelsenkirchen;
Dr. G. Popp, Augsburg, Dr. D. Prause, München; Dr. H. Reupke,
Berlin; Dr. H. Richter, Düsseldorf; Dr. A. Rothaar, Berlin; Dr.
T.H. Rüther, Kiel; Dr. T. Schaefer, Köln; Dr. H.-E. Schlaak,
Schleswig; Dr. F. Schumann, Wertheim; Dr. T. Stuhlert, Frankfurt;
Prof. Dr. T. Tüting, Bonn; Dr. P. Uhl, Berlin; Dr. J. Weihe,
Berlin; Dr. E. Welker, Berlin; Dr. A. Weller, Schwäbisch-Gmünd;
Prof. Dr. J. Weiß, Hannover; OMR Dr. H.-J. Wolf, Markkleeberg. We
also want to thank Drs. T. Greis and E. Will (3M Medica) for the
effort in monitoring the study sites.
The study was supported by 3M Medica, Neuss, Germany.
Disclosure: Prof. Schöfer has served as principal investigator and
a speaker for 3M Medica. Dr Eul was an employee of 3M Medica. Dr.
van Ophoven and Dr. Henke were investigators in the study and Dr.
Lenz performed the statistical analyses as a freelance
biostatistician
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