Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02334878 |
| Other study ID # |
FMASU 3098/2014 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
December 21, 2014 |
| Last updated |
September 7, 2017 |
| Start date |
October 1, 2015 |
| Est. completion date |
December 1, 2016 |
Study information
| Verified date |
September 2017 |
| Source |
Ain Shams Maternity Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This study evaluates the effectiveness of mesenchymal stem cells in treatment of stress
urinary incontinence due to intrinsic sphincter deficiency; in which the problem is weakness
or damage of the sphincter muscle responsible for continence. Mesenchymal stem cells are
undifferentiated cells which can undergo self-renewal & differentiation into other cell types
like muscle cells; thus can be used to regenerate the damaged sphincter muscles. In this
study mesenchymal stem cells will be obtained from bone marrow from the patient, processed, &
then re-injected periurethrally. Effectiveness will be compared to that of the surgical
treatment (tension-free vaginal tape).
Description:
** Study settings : The study is to be held at Ain-Shams University Maternity Hospital -
urogynecolgy unit; recruiting the patients from the urogynecology outpatient clinic
** Sample size:
Fifty female patients with stress urinary incontinence due to intrinsic sphincter deficiency
will be recruited into two groups; group A including 25 patients will be injected with stem
cells, & these will be the patients refusing surgery as a primary line of treatment, or unfit
for surgery. Group B; including 25 patients, will undergo the tension-free vaginal tape
operation. The sample size is determined according to the following equation:
[ P1( 100-P1) + P2( 100-P2) ] / (P2 - P1)2 where; Power of the test = 80% Confidence level =
95% Alpha error = 5% Assuming success rate for the preferably used intervention "tension-free
vaginal tape" in patients with intrinsic sphincter deficiency P1=80% ( Schierlitz et al,
2008).
Assuming success rate for stem cell therapy P2= 90% ( Smaldone et al, 2009).
** Intervention:
1. Consent Informed consent will be taken according to World Medical Association (WMA)
Declaration of Helsinki; the Ethical Principles for Medical Research Involving Human
Subjects.
2. History Full medical history will be taken from each patient, together with detailed
history as regards voiding habits, incontinence, voiding dysfunction, urinary infection.
Questionnaire about incontinence, & questionnaire about quality of life will be
obtained.
3. Examination Complete physical and pelvic examination to evaluate the presence of stress
urinary incontinence, & to exclude patients with marked hypermobility of the urethra, or
severe cystocele or rectocele.
4. Urodynamic study A multi-channel urodynamic study using Euet Sensik ® will be performed
including cystometry, urethral pressure measurement, abdominal leak point pressure
(ALPP) measurement, & residual urine measurement. Patients with stress urinary
incontinence due to intrinsic sphincter deficiency will be selected. Criteria for
selection are: absence of involuntary contractions during leakage caused by a stress
maneuver; low ALPP (<60 cmH2O); & maximum urethral closure pressure (MUCP) <20-30 cmH2O.
Patients with voiding dysfunction will be excluded (residual urine volume >100ml).
5. Cells retrieval, culture, & processing:
* Bone marrow aspiration:
-Site: posterior superior iliac crest.
-Procedure: The patient is placed in the lateral decubitus position, with the top leg
flexed and the lower leg straight. The iliac crest is palpated, and the preferred
sampling site is marked with a pen. Aseptic technique is employed, including sterile
gloves and gown. The site is prepared with an antiseptic (povidone-iodine), scrubbed,
and draped, exposing only the site to be sampled. The skin and the underlying tissue to
the periosteum are infiltrated with a local anaesthetic (approximately 10 mL of 1%
Xylocaine [lidocaine]). A 10-mL syringe with a 25-gauge needle is used to inject an
initial 0.5 mL directly under the skin, raising a wheal. A 22-gauge needle is used to
penetrate deeper into the subcutaneous tissue and the underlying periosteum, an area
roughly 1 cm in diameter. A skin incision is made with a small surgical blade, through
which the bone marrow aspiration needle, with a stylet locked in place, is inserted.
Once the needle contacts the bone, it is advanced by slowly rotating clockwise and
counter clockwise until the cortical bone is penetrated and the marrow cavity is
entered. The depth of the penetration should not extend beyond an initial 1cm. Once
within the marrow cavity, the stylet is removed. Using a 20 mL syringe, approximately 5
mL of bone marrow are aspirated. Subsequent specimens are obtained by attaching a
separate syringe, collecting 5 mL at a time. The samples are then transferred into an
ethylenediaminetetraacetic acid (EDTA) -containing tube. The marrow needle is removed,
and pressure is applied to the aspiration site with gauze until any bleeding stops.
* Cells processing & culture:
- Mononuclear cells (MNCs) will be isolated by density gradient centrifugation using
Ficol/Hypaque.
- Mesenchymal stem cells (MSCs) will be isolated through plastic adherence by the
seeding of MNCs in T25 tissue culture flasks in complete culture media (DMEM, 1%
antibiotics/antifungal, 20% autologous serum). Flasks will be incubated at 37ºC in CO2
incubator for 3-5 days.
- After 5 days, flasks will be evaluated under inverted microscope for the number and
morphology of MSCs. Non-adherent cells will be discarded and medium replenished.
- Half of the medium will be changed every 3 days.
- Flasks will be evaluated until cells reach about 80-90% confluence.
- MSCs will be harvested using Trypsin-EDTA (0.25%) for 5 minutes. Afterwards,
trypsin action will be stopped by the addition of autologous serum.
- MSCs will be washed using phosphate buffered saline (PBS), counted, tested for
viability using trypan blue exclusion test.
- MSC will be identified using immunophenotypic markers (positive for CD44 and
negative for CD34).
- Cells will be suspended in sterile saline, a minimum of 20 X 106 MSCs cells in a 10
cc syringe, ready for injection.
Quality control check for the sterility by the performance of bacterial aerobic and
anaerobic cultures will be done to ensure the complete aseptic conditions during the
specimen retrieval, preparation, storage, and injection. (Gunetti et al., 2012)
6. Injection of cells:
The patient will be placed in lithotomy position. A Foley's catheter (size 18) will be
inserted in the urethra, then under local anaesthesia; retrieved cells (total 20- 30
million cells per patient in 10cc syringe) (Sebe et al., 2011) will be injected into the
submucosal tissue at the level of the proximal urethra just distal to the bladder neck
(guided by stretch on the Foley's catheter), at 3,9,12 o'clock, injecting around 3.5 cc
in each site.
7. Tension-free vaginal tape (TVT):
Another 25 patients will undergo surgical intervention, which is the "tension-free
vaginal tape" operation at the obstetrics & gynecology department - Ain Shams Maternity
Hospital - urogynecology unit. In this technique, a small midurethral incision will be
made in the vaginal mucosa, then a polypropylene 40*1cm mesh tape attached to two curved
trocars will be passed lateral to the urethra & through the endopelvic fascia into the
retropubic space. The trocar will then be passed along the back of the pubic bone,
through the rectus fascia, in two small suprapubic skin incisions, then the tension on
the tape adjusted & the remaining tape cut off at the level of the skin.
8. Follow up:
Follow up visits will be conducted at 3months, 6months, 9months, and 12months after therapy.
Clinical examination, incontinence questionnaire, quality of life questionnaire, & urodynamic
study will be done.
** Data collection & recording:
Each patient will have a case record form (CRF) in which the following data will be recorded:
- Age, parity
- Body mass index (BMI).
- Type of intervention (stem cell therapy or TVT)
- International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form
(ICIQ-UI SF) on admission & 3m, 6m, 9m, 12m post-injection.
- Incontinence Quality of Life (I-QOL) Instrument Score on admission & 3m, 6m, 9m, 12m
post-injection.
- Cough test on admission & 3m, 6m, 9m, 12m post-injection.
- Urodynamic study on admission & 3m, 6m, 9m, 12m post-injection.
- Statistical analysis:
Descriptive statistics for measured variables will be expressed as range, mean and standard
deviation (for metric data); range, median and interquartile range (for discrete data); and
number and proportions (for categorical data). Pre-injection & post-injection findings will
be compared using the t-test or the Wilcoxon test depending on whether the measured
parameters were Gaussian variables. A P-value of 0.05 or less will be considered
statistically significant.
** Ethical considerations:
1. Delegation of investigator responsibilities:
The investigator will ensure that all persons assisting with the trial are adequately
informed about the protocol, & their trial-related duties and functions. The
investigator will maintain a list of sub-investigators and other appropriately qualified
person to whom he or she has delegated significant trial-related duties.
2. Patient information and informed consent Before being admitted to the clinical study,
the patient must consent to participate after the nature, scope, and possible
consequences of the clinical study have been explained in a form understandable to her.
An informed consent document, in Arabic language, contains all locally required elements
and specifies who informed the patient. After reading the informed consent document, the
patient must give consent in writing. The patient's consent must be confirmed at the
time of consent by the personally dated signature of the patient and by the personally
dated signature of the person conducting the informed consent discussions. If the
patient is unable to read, oral presentation and explanation of the written informed
consent form and information to be supplied to patients must take place in the presence
of an impartial witness. Consent must be confirmed at the time of consent orally and by
the personally dated signature of the patient or by a local legally recognized
alternative (e.g., the patient's thumbprint or mark). The witness and the person
conducting the informed consent discussions must also sign and personally date the
consent document. The original signed consent document will be retained by the
investigator. The investigator will not undertake any measures specifically required
only for the clinical study until valid consent has been obtained.
3. Confidentiality Only the patient number and patient initials will be recorded in the
CRF, and if the patients name appears on any other document, it must be kept in privacy
by the investigators. The investigator will maintain a personal patient identification
list (patient numbers with the corresponding patient names) to enable records to be
identified.
4. Protocol approval Before the beginning of the study and in accordance with the local
regulation followed, the protocol and all corresponding documents will be declared for
ethical and research approval by the council of ob/gyn department, Ain Shams University;
according to the WMA Declaration of Helsinki.
