Autologous Muscle Derived Cells for Treatment of Stress

Urinary Incontinence in Women

Kenneth M. Peters,* Roger R. Dmochowski, Lesley K. Carr, Magali Robert,
Melissa R. Kaufman, Larry T. Sirls,k Sender Herschorn,{ Colin Birch,
Patricia L. Kultgen and Michael B. Chancellor**
From Beaumont Health System, Royal Oak, Michigan (KMP, LTS, MBC); Vanderbilt Medical Center, Nashville, Tennessee
(RRD, MRK); Sunnybrook Health Sciences Centre, Toronto, Ontario (LKC, SH), and Foothills Medical Centre, Calgary,
Alberta (MR, CB), Canada; and MED Institute, Inc., West Lafayette, Indiana (PLK)

Purpose: We assess the 12-month safety and potential efficacy of autologous

muscle derived cells for urinary sphincter repair (Cook MyoSite Incorporated,
Pittsburgh, Pennsylvania) in women with stress urinary incontinence.
Materials and Methods: Pooled data from 2 phase I/II studies with identical
patient selection criteria and outcome measures were analyzed. Enrolled patients
had stress urinary incontinence refractory to prior treatment and no symptom
improvement during the last 6 months. Patients received intrasphincter injection
of 10 (16), 50 (16), 100 (24) or 200  106 (24) autologous muscle derived cells for
urinary sphincter repair, derived from biopsies of each patients quadriceps
femoris. The primary outcome measure was safety, determined by incidence and
severity of adverse events. Potential efficacy was measured by changes in 3-day
voiding diaries, 24-hour pad tests, and UDI-6 and IIQ-7 scores.
Results: A total of 80 patients underwent injection of autologous muscle derived
cells for urinary sphincter repair, and 72 completed diaries and pad tests at
12-month followup. No adverse events attributed to autologous muscle derived
cells for urinary sphincter repair were reported. Higher dose groups tended to
have greater percentages of patients with at least a 50% reduction in stress leaks
and pad weight at 12-month followup. All dose groups had statistically significant improvement in UDI-6 and IIQ-7 scores at 12-month followup compared to
baseline.
Conclusions: Autologous muscle derived cells for urinary sphincter repair
at doses of 10, 50, 100 and 200  106 cells appears safe. Efficacy data suggest
a potential dose response with a greater percentage of patients responsive to
higher doses.
Key Words: transplantation, autologous; urinary incontinence,
stress; myoblasts, skeletal; muscle cells

STRESS urinary incontinence, the

involuntary leakage of urine during
activities that increase abdominal
pressure (eg coughing, sneezing,
physical exercise), affects up to 35%
of adult women.1 This condition is
caused by pelvic floor weakness,

Abbreviations
and Acronyms
AMDC-USR autologous muscle
derived cells for urinary sphincter
repair
IIQ-7 Incontinence Impact
Questionnaire short form
SUI stress urinary incontinence
UDI-6 Urogenital Distress
Inventory short form
Accepted for publication February 17, 2014.
Study received ethics board approval.
Supported by Cook MyoSite Incorporated,
Pittsburgh, Pennsylvania.
* Financial interest and/or other relationship
with Taris Biomedical, Medtronic Inc., Trillium
Therapeutics and Uroplasty.
Financial interest and/or other relationship
with Allergan and Medtronic.
Financial interest and/or other relationship
with Cook MyoSite.
Financial interest and/or other relationship
with Cook MyoSite, Astellas and Allergan.
k Financial interest and/or other relationship
with J & J and AMS.
{ Financial interest and/or other relationship
with Cook, Allergan, Astellas, Lilly and Pfizer.
** Financial interest and/or other relationship
with Cook.

See Editorial on page 301.

urethral
hypermobility
and/or
sphincter deficiency. Interventional
therapies may be necessary when
first line conservative management
such as pelvic floor muscle training
fails to provide adequate symptom
relief. Sling procedures and bladder

0022-5347/14/1922-0469/0
THE JOURNAL OF UROLOGY
2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.

http://dx.doi.org/10.1016/j.juro.2014.02.047
Vol. 192, 469-476, August 2014
Printed in U.S.A.

www.jurology.com

469

470

AUTOLOGOUS CELL THERAPY FOR STRESS URINARY INCONTINENCE

neck suspensions can be effective. However, complications of urinary retention, worsening urgency
symptoms and erosion/extrusion of mesh have been
reported.2 Injection of urethral bulking agents is
less invasive, but lacks durability and has been
associated with degradation/reabsorption, migration, bladder outlet obstruction and hypersensitivity
reactions.3
A potential alternate therapy is the use of autologous muscle progenitor cells, which are isolated
from skeletal muscle biopsies and expanded ex vivo
before injection into the urethral sphincter. This
approach may benefit patients with SUI by augmenting sphincter function. Two previous studies
assessed AMDC-USR in women with SUI.4,5 A pilot
study tested 18 to 22  106 AMDC-USR in 8 patients and another assessed doses ranging from 1
to 128  106 AMDC-USR in 38 patients. In both
studies the patients could opt to receive a second
treatment of AMDC-USR and the use of AMDCUSR appeared safe. Additionally, the dose ranging
study results suggested greater efficacy for patients
who received 2 AMDC-USR treatments of at least
32  106 cells.5 In this report we describe pooled
data from 2 open label studies conducted concurrently that were designed to collectively assess the
12-month safety and potential efficacy of 4 doses of
AMDC-USR for the treatment of SUI in 80 women.

METHODS
Two phase I/II studies were conducted to assess the
12-month safety and potential efficacy of AMDC-USR for
the treatment of SUI in women. Both studies were performed in accordance with the Declaration of Helsinki.
Study protocols were approved by the ethics board at
each site before study initiation and written informed
consent was obtained from all patients. Both studies were
conducted concurrently and intended to be evaluated
together. Each protocol specified the same patient selection criteria and outcome measures.
Study 1 was a dose escalation study conducted between
October 2008 and November 2011 at 3 investigative
sites in the United States and Canada (ClinicalTrials.gov
Identifier: NCT00847535). The study protocol, designed
to test 10, 50 and 100  106 AMDC-USR in 48 patients
(16 patients per group), was approved by the FDA (Food
and Drug Administration) and Health Canada. In an
amendment approved by the FDA, study 1 was expanded
to include 16 additional patients to receive 100 or
200  106 AMDC-USR (8 patients per group) at 2 U.S.
investigative sites. A separate protocol to test 200  106
AMDC-USR in 16 patients was approved by Health
Canada and was conducted at 2 Canadian investigative
sites from June 2010 to September 2012 (study 2,
ClinicalTrials.gov Identifier: NCT01008943).
Inclusion criteria were women age 18 years or older with
SUI refractory to prior treatment with no improvement
of SUI symptoms for at least 6 months before enrollment

(see Appendix). Each patient underwent a needle biopsy

of the quadriceps femoris under local anesthesia during
an outpatient office procedure. The biopsy tissue was
placed in a hypothermic solution and shipped at 2 to 8C
to a central cell processing facility at Cook MyoSite
Incorporated.
Manufacturing and testing were conducted using proprietary procedures based on global standards for aseptic
biological product manufacturing. A subpopulation of
muscle derived cells was expanded in culture. Products
were formulated to the cell number dose in a total volume
of 2 ml with biopreservation media and cryopreserved
at 80C.
Before release all products underwent complete
quality control testing and inspection. The percentage of
myogenic cells in the product, as identified through skeletal muscle marker expression, was 86%  14%. The other
cells were primarily fibroblasts.
Frozen AMDC-USR product was supplied to the investigator. The product was thawed and diluted to a total
volume of 4 ml with 2 ml of 0.9% saline. Each patient
received a single treatment of AMDC-USR during an
outpatient office procedure. Local anesthetics were
generally used. Intrasphincter injections (at least 8 injections of about 0.5 ml each) were made into the mid
urethral complex, with needle lengths allowing cell injection into the region of the external striated sphincter.
Techniques used included cystoscope guided transurethral
injection (modified Williams Cystoscopic Injection Needle,
Cook Medical, Bloomington, Indiana), cystoscope guided
periurethral injection (22 gauge needle, brand not specified) and transurethral injection with the SUI Injection
Needle (Cook Medical), a device containing 3 simultaneously deployed needles.
The primary objective of the studies was to assess
safety by the incidence and severity of adverse events.
Secondary objectives were to assess efficacy via 3-day
voiding diaries, 24-hour pad tests, and the validated patient questionnaires UDI-6 and IIQ-7.6 Diaries and pad
tests were completed at baseline and at 1, 3, 6 and 12
months after treatment. UDI-6 and IIQ-7 were completed
at baseline and at 6 and 12 months after treatment.
The percentage of patients with at least a 50% reduction from baseline stress leaks as measured by 3-day
diary, the percentage with at least a 50% reduction from
baseline pad weight, the percentage reporting no stress
leaks over 3 days and the percentage with negative pad
tests (less than 1.3 gm pad weight) were determined from
12-month data. If no outcome data were available for a
patient at a given point, the patient was excluded from the
calculation for that particular outcome measure and
point. Patients reporting no stress leaks during 3 days at
baseline were excluded from the analysis of stress leak
data since no improvement could be detected by diary
reported stress leaks. Stress leak and pad test data were
also assessed for the subset of patients with at least 3
diary reported stress leaks during 3 days and at least a
3 gm 24-hour pad weight at baseline.
Data were analyzed using SAS version 9.3. Continuous variables were summarized as mean  standard
error (range), ordinal variables were summarized as median (range) and categorical variables were summarized

AMDC-USR Dose
10  10

Overall
Demographics:
Mean  SE pt age (range)
% Caucasian (No.)
% Black (No.)
% Asian (No.)
Mean kg/m2  SE body mass index (range)
% Postmenopausal (No.)
Urinary signs symptoms:
% Urgency (No.)
% Urge incontinence (No.)
Median stress leaks over 3 days (range)
Mean gm 24-hour pad wt  SE (range)
Mean  SE UDI-6 (range)
Mean  SE IIQ-7 (range)
% Prior incontinence therapies (No.):
Pelvic floor muscle exercises
Medication
Urethral suspension or other surgery
Urethral inserts/incontinence pessaries
Bladder training
Bulking injections
Biofeedback

55  1
(35e80)
96
(77)
1
(1)
3
(2)
27.8  0.6 (20.6e43.9)
56
(45)

100  106

e
e
27.4  1.3 (22.1e38.8)
56
(9)

e
e
27.6  1.3 (21.8e38.6)
31
(5)

65
(52)
50
(40)
7
(0e65)
51.1  12.9 (1.8e710.0)
51.8  2.1 (20.8e91.7)
40.3  2.5 (9.5e100.0)

75
(12)
63
(10)
8.5
(1e29)
24.2  4.9 (3.5e69.2)
60.4  4.1 (29.2e91.7)
39.6  5.0 (9.5e76.2)

75
(12)
50
(8)
5
(0e40)
33.5  18.1 (2.2e289.8)
55.7  4.8 (25.0e91.7)
38.7  5.0 (9.5e85.7)

84
31
29
11
10
8
6

88
38
31
6
13
0
0

(67)
(25)
(23)
(9)
(8)
(6)
(5)

(35e73)
(16)

(14)
(6)
(5)
(1)
(2)
(0)
(0)

52
100

 2

200  106

54  2
(38e80)
88
(21)
4
(1)
8
(2)
27.8  0.9 (20.6e35.7)
46
(11)

56
100

3

50  10

100
38
13
6
0
0
13

Comparisons among dose groups were made by Fishers exact test, nonparametric Wilcoxon rank sum or F-test, as appropriate.
* Statistically significant difference among dose groups.

(44e72)
(16)

(16)
(6)
(2)
(1)
(0)
(0)
(2)

58  2
100

p Value

(42e78)
(24)

0.18
0.32

e
e
28.1  1.1 (20.7e43.9)
83
(20)

0.98
<0.01*

58
(14)
38
(9)
6.5
(0e33)
45.3  20.6 (1.8e501.8)
47.1  3.5 (20.8e75.0)
37.7  4.6 (9.5e90.5)

58
(14)
54
(13)
10
(2e65)
86.4  35.3 (2.6e710.0)
48.1  4.3 (20.8e91.7)
44.3  5.5 (9.5e100.0)

0.54
0.48
0.31
0.32
0.09
0.77

83
29
21
13
13
13
8

71
25
46
17
13
13
4

0.09
0.77
0.11
0.77
0.63
0.36
0.67

(20)
(7)
(5)
(3)
(3)
(3)
(2)

(17)
(6)
(11)
(4)
(3)
(3)
(1)

AUTOLOGOUS CELL THERAPY FOR STRESS URINARY INCONTINENCE

Table 1. Baseline patient demographics and characteristics

471

472

AUTOLOGOUS CELL THERAPY FOR STRESS URINARY INCONTINENCE

as percentage (count). Comparisons across dose groups

were made by Fishers exact test, the Wilcoxon rank sum
test or F-test. Comparisons between baseline and followup
points were made by the Wilcoxon rank sum test or paired
t-test.

Table 2. Followup status of treated patients

RESULTS

* Of 74 patients 72 completed diaries and pad tests at 12-month followup.

Overall 80 patients received intrasphincter injection of AMDC-USR. Injections were delivered by a

transurethral (70%, 56 of 80) or periurethral (30%,
24 of 80) approach. In study 1, 66 patients underwent biopsy and 64 patients were treated with
AMDC-USR. One patient who underwent biopsy
elected to not receive treatment and for 1 patient
the product could not be produced. In study 2, 16
patients underwent biopsy and were treated with
AMDC-USR. Overall 16 patients received 10  106
AMDC-USR, 16 received 50  106 AMDC-USR,
24 received 100  106 AMDC-USR and 24 received
200  106 AMDC-USR.
A total of 100 biopsy procedures were conducted
in 82 patients (67 underwent a single procedure,
12 underwent 2 procedures and 3 underwent 3
procedures). Mean biopsy mass was 86  33 mg.
Products that met all specifications were produced
for 96% (79 of 82) of patients who underwent biopsy.
AMDC-USR could not be produced for 1 patient
who underwent 2 separate biopsies. Additionally,
2 patients in the 100  106 AMDC-USR group
received product that contained a lower percentage
of myogenic cells than stipulated in product
specifications.
Treated patients had a mean age of 55  1 years
(table 1). Demographics were similar among dose
groups except for postmenopausal status, which
ranged from 31% to 83% (p <0.01). No significant
differences in baseline urinary incontinence measures of severity were observed among the dose
groups. Sixty-six (83%) patients had at least 3 stress
leaks over 3 days and at least 3 gm 24-hour pad tests
at baseline. Three patients had no diary reported
stress leaks over 3 days at baseline (2 patients in the
50  106 dose group and 1 in the 100  106 dose
group). However, each of these patients did have a
positive provocative stress test during screening. In
addition, 65% (52 of 80) of patients reported urgency
and 50% (40 of 80) reported urge incontinence
(table 1).
A total of 74 (93%) patients completed 12-month
followup (table 2). Two patients completed validated patient questionnaires at 12-month followup
but did not complete diaries or pad tests. One patient
was lost to followup and 5 withdrew from the study
after treatment (2 were unwilling to travel to office
visits, 2 did not report improvement in symptoms
and 1 had surgical treatment for incontinence).

Study 1
Study 2
AMDC-USR
Total
6
6
6
6
Dose
10  10 50  10 100  10 200  10 200  106 No.
No. baseline
No. 6 mos
No. 12 mos

16
15
15

16
15
15

24
22
21

8
8
8

16
16
15

80
76
74*

No adverse events attributed to AMDC-USR

product were reported. Biopsy related adverse
events occurred in 4 patients, and included wound
hematoma (2 cases), procedural dizziness and associated responses (2 cases), postoperative bleeding
requiring sutures (1 case) and joint swelling (1 case)
(table 3). Injection procedure related adverse events
occurred in 18% (14 of 80), and included dysuria
(7 cases), pelvic or abdominal pain (4 cases), vulvovaginal pruritus (3 cases), urinary urgency (2 cases)
and transient hematuria (2 cases). All injection
procedure related events occurred after transurethral injection (25%, 14 of 56). All biopsy and injection
procedure related events were easily treated or
self-resolved.
All dose groups had significantly fewer diary reported stress leaks at 12 months (p <0.05, table 4).
This reduction was detected within 1 to 3 months of
AMDC-USR treatment. Only patients who received
200  106 AMDC-USR had a statistically significant
reduction in mean pad weight. Similar stress leak
and pad test results were observed with periurethral and transurethral injection (data not shown).
Higher dose groups tended to have greater percentages of patients with at least a 50% reduction in
stress leaks and pad weight at 12-month followup
(fig. 1, A). While only 53% of the 10  106 dose group
had at least a 50% reduction in stress leaks, 69% of
Table 3. Biopsy and injection procedure related adverse events
Rate/Procedure
Biopsy procedure*:
Wound hematoma
Procedural dizziness associated responses
Postop bleeding
Joint swelling
Injection procedure:
Dysuria
Pelvic/abdominal pain
Vulvovaginal pruritus
Urinary urgency
Hematuria
Vulvovaginal burning sensation
Sensation of foreign body within urethra
Urinary frequency
Urinary tract infection

2.0
2.0
1.0
1.0
8.8
5.0
3.8
2.5
2.5
1.3
1.3
1.3
1.3

* Events related to the biopsy procedure were defined as systemic responses to

the biopsy procedure or injury at the biopsy site.
Events related to the injection procedure were defined as systemic responses to
the injection procedure and genitourinary events occurring within 30 days of the
injection that could be attributed to cystoscopy or catheterization.

AUTOLOGOUS CELL THERAPY FOR STRESS URINARY INCONTINENCE

473

Table 4. Improvement in diary reported stress leaks and 24-hour pad tests over time
AMDC-USR Dose
10  10
Median stress leaks over 3 days
(No., range):
Baseline
1 Mo
3 Mos
6 Mos
12 Mos
Mean gm  SE pad wt
(No., range):
Baseline
1 Mo
3 Mos
6 Mos
12 Mos

8.5
2
3
2
3
24.2
15.9
15.9
13.7
21.5

(16,
(16,
(15,
(15,
(15,






4.9
5.5
5.9
5.6
6.2

(16,
(16,
(15,
(14,
(15,

50  10

1e29)
0e32)*
0e13)
0e22)*
0e17)*

3.5e69.2)
0.0e89.6)
0.3e84.6)
0.0e81.9)
0.6e79.6)

5
3
2.5
1.5
1
33.5
31.9
18.6
23.4
19.2

100  106

(14,
(12,
(14,
(14,
(13,






18.1
24.4
12.2
16.1
13.0

1e40)
0e51)
0e29)*
0e50)
0e55)

(16, 2.2e289.8)
(14, 0.0e347.2)
(14, 0.0e174.8)
(14, 0.60e227.8)
(14, 0.0e183.7)

7
4
3
3
1.5
45.3
32.9
29.9
15.3
22.2

200  106

(23,
(23,
(22,
(21,
(20,






20.6
11.9
14.2
5.5
10.9

1e33)
0e29)*
0e24)
0e19)
0e14)

(24, 1.8e501.8)
(23, 0.0e201.7)
(23, 0.0e312.3)
(22, 0.0e95.0)
(21, 0.0e230.0)

10
2.5
2.5
5
1
86.4
45.0
52.9
49.6
37.2

(24,
(24,
(24,
(23,
(22,






35.3
21.6
25.2
22.0
24.4

(24,
(24,
(24,
(24,
(22,

2e65)
0e30)
0e27)*
0e30)*
0e27)

2.6e710.0)
0.0e475.0)
0.0e505.0)*
0.0e400.0)*
0.0e545.0)*

Three patients who reported no stress leaks over 3 days at baseline were excluded from the stress leak analysis.
Comparisons of stress leaks at baseline and followup points were made by nonparametric Wilcoxon rank sum test.
Comparison of pad weight at baseline and followup points made by paired t-test.
Statistically significant changes from baseline are indicated as *dp <0.05, dp <0.01 and dp <0.001.

the 50  106 dose group, 85% of the 100  106 dose

group and 77% of the 200  106 dose group met this
end point. Similarly the percentage of patients
with at least a 50% improvement in 24-hour pad
test increased with increasing AMDC-USR dose
at 12-month followup, and ranged from 20% (3 of 15)
in the 10  106 dose group to 64% (14 of 22) in the
200  106 dose group. Similar results were observed
for the subgroup of patients with at least 3 diary
reported stress leaks during 3 days and at least a
3 gm 24-hour pad weight at baseline (fig. 1, B).

Intrasphincter injection of AMDC-USR at doses of

10, 50, 100 and 200  106 cells appears safe with
no serious procedure or treatment related adverse
events reported. No adverse events were attributed

100%

90%

Percentage of patients at 12 months

Percentage of patients at 12 months

DISCUSSION

100%

80%
70%
60%
50%
40%
30%
20%
10%
0%

Compared to baseline, all dose groups had statistically significant improvement in UDI-6 scores
at 6 and 12-month followup, and in IIQ-7 scores at
12-month followup (fig. 2).

1/15 3/15 3/15 8/15

4/14 5/13 6/14 9/13

10 x 10^6

50 x 10^6

90%
80%
70%
60%
50%
40%
30%
20%
10%

5/21 6/20 11/21 17/20 7/22 7/22 14/2217/22

100 x 10^6

200 x 10^6

0%

0/13 3/13 2/13 7/13

3/10 2/10 4/10 6/10

5/18 4/18 11/1815/18

6/18 5/18 12/1814/18

10 x 10^6

50 x 10^6

100 x 10^6

200 x 10^6

AMDC-USR dose

AMDC-USR dose
Negative pad test
Zero stress leaks over 3 days
50% improvement in pad test
50% reduction in stress leaks

Figure 1. Improvement in stress leak frequency and amount of urine leakage at 12-month followup as gauged by percentages of
patients with negative pad tests, zero stress leaks during 3 days, at least 50% improvement in pad tests and at least 50% reduction
in stress leaks. Ratio at base of each bar is number of patients meeting specified outcome/total number of patients with available
data. A, all patients. Patients who reported no stress leaks during 3 days at baseline were excluded from stress leak analyses since
no improvement could be detected by diary reported stress leaks. B, patients with at least 3 stress leaks during 3 days and at least
3 gm 24-hour pad weight at baseline.

AUTOLOGOUS CELL THERAPY FOR STRESS URINARY INCONTINENCE

474

B
70
Baseline

6 Months

Baseline

6 Months

50

*
*
*

30

40

* *

30

*
20

*
*

20

10

10
0

12 Months

50

Mean IIQ-7 score

Mean UDI-6 score

60

40

60

12 Months

16 14 15

16 14 14

24 21 20

24 24 23

10 x 10^6

50 x 10^6 100 x 10^6 200 x 10^6

AMDC-USR dose

16 15 15

16 15 15

24 21 21

24 24 23

10 x 10^6

50 x 10^6 100 x 10^6 200 x 10^6

AMDC-USR dose

Figure 2. Patient reported incontinence symptom distress and life impact. A, mean UDI-6 scores. B, mean IIQ-7 scores. UDI-6 and IIQ-7
are scored 0 to 100 with lower scores indicating higher quality of life. Error bars represent standard error of mean. Asterisk indicates
statistically significant change from baseline as determined by paired t-test. Number of patients who completed questionnaire at each
point is indicated at base of each bar.

to AMDC-USR, and reported biopsy and injection

procedure related events were consistent with the
known risks of skeletal muscle biopsy and intrasphincter injection. A higher percentage of patients
experienced injection procedure related events with
the transurethral approach than the periurethral
approach (25% [14 of 56] vs 0% [0 of 24]), but these
events were minor and self-resolved or were easily
treated. These safety data are consistent with other
clinical studies of autologous muscle progenitor cells
for the treatment of SUI and provide further support for the safety of this potential therapy.4,5,7e13
The efficacy data suggest that a single treatment
of AMDC-USR improves SUI and patient quality of
life. All dose groups experienced a statistically
significant reduction in stress leaks within 1 to
3 months of treatment that was maintained through
the 12-month followup. Although the studies were
not statistically powered to assess differences in
efficacy across dose groups, data trends for the
percentage of patients with at least a 50% reduction
in diary reported stress leaks and at least 50%
improvement in 24-hour pad tests suggest a potential dose response. In the range of tested doses a
greater percentage of patients appear to be responsive to higher doses of AMDC-USR than lower
doses. Similar results were observed for the subgroup of patients with at least 3 diary reported
stress leaks over 3 days and at least a 3 gm 24-hour
pad weight at baseline. Only patients receiving
200  106 AMDC-USR had a statistically significant
reduction in pad weight. Unlike the diary, which

was designed to distinguish between stress leaks

and urge leaks, the 24-hour pad test results may be
confounded by the presence of urge incontinence,
which was reported by 50% of patients. Injection
approach did not appear to affect efficacy outcomes.
Improvements in UDI-6 and IIQ-7 scores did not
appear to be dose related.
Previous results of an AMDC-USR dose ranging
study in 38 women also suggested that the efficacy
of AMDC-USR may be related to cell dose.5 Patients
who received 2 treatments of 32, 62 or 128  106
AMDC-USR appeared to have better efficacy outcomes than those who received 2 treatments of
lower doses. Other clinical studies of autologous
muscle progenitor cells for SUI treatment have not
examined or have not identified an effect of cell dose
on safety or efficacy outcomes.7e11,13
Self-repair mediated by autologous cell therapies
is an attractive treatment modality. However,
due to the individualized nature of the products,
there are challenges to commercialization. AMDCUSR are produced under tightly controlled
manufacturing processes that include product specifications for safety, cell dose, cell composition and
myodifferentiation potential. Due to the inherent
variability in cell growth across patient samples, it
may not be possible to generate products for all patients or meet all nonsafety specifications for each
individualized product. Furthermore, product specifications set at the start of clinical development
for an autologous cell therapy are determined based
on nonclinical data and may not reflect product

AUTOLOGOUS CELL THERAPY FOR STRESS URINARY INCONTINENCE

characteristics for optimal clinical efficacy. In this

report, products that met all specifications were
produced for 96% (79 of 82) of patients who underwent biopsy.
Other studies of autologous muscle progenitor
cells for SUI treatment have required that patients
undergo open muscle biopsies.8,9,11,12 In our studies
the patients underwent less invasive needle muscle
biopsies. However, repeat biopsy was necessary in
15 patients due to inadequate biopsy samples or
manufacturing failures. Ongoing studies of AMDCUSR include modifications to improve biopsy procedures and stricter controls to ensure the integrity
of future biopsy samples.
A number of study limitations exist. The pooled
sample size was not powered to demonstrate safety
or efficacy by individual dose, and blinding of physicians or patients to dose was not part of the study
design. Without a placebo control group the efficacy
data should be interpreted with caution. These
limitations are addressed by 2 double-blind, placebo
controlled studies of 150  106 AMDC-USR in
women with moderate to severe SUI that are
currently under way in North America, Europe and
Asia (ClinicalTrials.gov Identifiers: NCT01382602
and NCT01893138).

475

CONCLUSIONS
Intrasphincter injection of AMDC-USR at doses of
10, 50, 100 and 200  106 cells appears safe for
the treatment of women with SUI. Efficacy data
suggest that AMDC-USR treatment reduces stress
leak frequency and the amount of urine leakage.
In addition, efficacy data suggest a potential dose
response, providing critical information for phase
III trials.

ACKNOWLEDGMENTS
Magnus Murphy (Foothills Medical Centre),
Melissa Fischer (Beaumont Health System), Pradeep Nagaraju (Beaumont Health System), Daniel
Biller (Vanderbilt Medical Center), Harriette Miles
Scarpero (Vanderbilt Medical Center), Ren
ee Ward
(Vanderbilt Medical Center) and Priya Padmanabhan (Vanderbilt Medical Center) served as study
investigators. Alan Saunders (MED Institute, Inc.,
a contract research organization and Cook Group
Company) served as study statistician, Jennifer
Rodenberg (MED Institute, Inc.) served as clinical
project manager, and Sean Werner (Cook Incorporated), Ryan Pruchnic (Cook MyoSite Incorporated)
and Ron Jankowski (Cook MyoSite Incorporated)
provided review of the manuscript.

APPENDIX
Selected inclusion and exclusion criteria
Inclusion criteria

Exclusion criteria

 Patient has provided written informed consent.

 Patient is at least 18 years of age.
 Patient has SUI with normal detrusor activity
confirmed with urodynamics.
 Patient has bladder capacity greater than 200 ml.
 Patients incontinence has not shown any improvement
for at least 6 months.
 Patient has failed prior treatments (eg behavior
modification, bladder exercises, biofeedback,
electrical stimulation, bulking injections, urethral
suspensions, and/or drug therapy).
 Patient has a viable mucosal lining along the urinary
tract and in the bladder.

 Patient has known vesicoureteral reflux, vaginal prolapse beyond the introitus, or other
significant pelvic floor abnormalities with high pressure instability.
 Patient cannot be maintained on a stable dose of any medication known to affect lower
urinary tract function, including but not limited to anticholinergics, tricyclic antidepressants,
or alpha-adrenergic blockers, throughout the treatment and followup period.
 Patient has urinary incontinence of neurogenic etiology.
 Patient has fibrosis of the tissue at the likely injection sites.
 Patient has any condition which could lead to significant postoperative complications, including
current infection, or elevated residual urine from bladder outlet obstruction (ie repeated post-void
residual volume greater than 150 ml).
 Patient is morbidly obese (defined as 100 pounds over their ideal body weight, or body mass
index 40 or greater) and not expected to benefit from treatment.
 Patient has current or acute conditions involving cystitis or urethritis.
 Patient is actively immunosuppressed or has known allergy or hypersensitivity to bovine proteins
or allergens, gentamicin sulfate, or ampicillin.

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