Crohn Disease Clinical Trial
Official title:
Autologous Adipose-derived Stem Cells (ASCs) for the Treatment of Perianal Fistula in Crohn Disease: A Pilot Study
Crohn's disease is an immunologically mediated inflammatory bowel disease with a reported
incidence of 4.0-7.0, 7.1, and 1.34 per 100,000 persons in Europe, the U.S., and Korea,
respectively. Uncontrolled chronic inflammation finally causes various complications in
intestine such as bowel obstruction, fistulas, abscesses, and anal fissures.
The incidence of perianal fistula was reported in 13%- 39% of patients with Crohn's disease.
Medical treatment for Crohn's fistulae initially focused on surgical intervention
accompanied by symptomatic treatment with antibiotics and immunosuppressants. The most
serious problem after surgical intervention is the relatively high incidence of
postoperative anal incontinence caused by sphincter injury during the procedure. Conversely,
available pharmacological therapies for Crohn's fistulae based on biologic agents such as
infliximab do not generally reach ideal goal of treatment (e.g., complete closure of the
fistula). A high recurrence rate after treatment with infliximab has also been reported,
even after long-term maintenance therapy, which suggests that infliximab monotherapy does
not provide adequate healing.
The ACCENT II study demonstraded a complete fistula healing in 25% of patients. To reach a
better clinical outcome, combination treatment with infliximab and surgical intervention is
highly recommended for management of Crohn's fistulae. Nonetheless, even this strategy does
not result in a satisfactory healing for many patients.
The ideal therapeutic goal of treatment is not only complete closure of the fistula without
recurrence but also preservation of anal sphincter function. Unfortunately, currently
available medical or surgical treatment is not likely to offer a cure for perianal fistulae
and, as noted above, recurrence is frequently reported.
Together with active research in the field of bone marrow-derived mesenchymal stem cells
(BM-MSCs) and hematopoietic stem cells, autologous or allogenic adipose tissue-derived stem
cells (ASCs) have been studied for management of Crohn's disease and other disorders.
Of particular relevance to this study, ASCs could be considered to be safe and efficacious
therapeutic tools for the treatment of Crohn's fistulae. Importantly, ASCs do not cause
fecal incontinence after injection into the lesion site in Crohn's disease patients. A phase
I dose-escalation clinical study with ASCs manufactured by Anterogen Co., Ltd. (Seoul,
Korea) demonstrated the safety and therapeutic potential of these cells for the treatment of
Crohn's fistulae. A phase II study demonstrated a good rate of cronh's related fistula
closure using a ASCS injection.
Actually the best accepted treatment of Crohn related perianal fistula, is the surgical
procedure in association whit medical therapy.
Basic information:
Lipogems: Lipogems® system is a disposable device for liposuction, processing and adipose
tissue reinjection. Procedure takes place in a single surgical time. It's a disposable
device that progressively reduces adipose tissue clusters size, washing completely
pro-inflammatory oil and blood debrides through a minimal manipulation "free enzyme" in a
aseptic closed system completely prefilled by room temperature physiological solution.
Lipogems product is a non-expanded and microfractured fat tissue ready for autologous
settings.
SalveColl-E: Salvecoll® is sterile bioplastic, equine derived, type I collagen material with
a fully preserved fibrous structure (non-reconstructed) that ensures the regeneration of
affected tissues. Type I collagen has zero risk of transmitting viral or microbial
infections.
Rationale for the trial: To evaluate the efficacy of the use of ACSS in crohn related
perianal fistulas. The aim of the study is to improve fistula healing at 1 year from 25% to
65%.
Treatment of subjects At the time of fistula diagnosis the patients will be screened for
eligibility and a informed consent will be administered . All patients will be underwent a
loose seton placement after antibiotics prophylaxis administration with Ciprofloxacin and
Metronidazole to obtain a pelvis sepsis resolution at time 0.
At week 4 a surgical procedure will be performed. In general anesthesia a antibiotics
prophylaxis will be administrated and subcutaneous abdominal adipose tissue will be
collected by LIPOGEMS system to prepare ASCS.
In the infiltration step, adrenalin in a saline solution (2 μg/ml final concentration) is
infiltrated using a 19-cm specially designed disposable blunt cannula.
The vasoconstriction together with the blunt point of the cannula avoids any accidental
intravascular injection and facilitates the subsequent lipoaspiration. Three hundred to 500
ml are usually injected in the chosen area for fat harvesting (usually the lower abdomen),
making the tissue really "filled" with the injecting solution. The aspiration step
(lipoaspirate) is performed by a luer lock syringe connected to a disposable 19-cm blunt
cannula (3 mm OD), with 5 oval holes (1 ´ 2 mm). A few strokes using a standard liposuction
technique are enough to harvest 6-10 ml of fat tissue. Vacuum while aspirating can be
obtained manually or by clamping the syringe plunger with a clamp instrument. Up to 1,000 ml
can be harvested in less than 15 min, and 1-2 min are enough. The harvested lipoaspirate can
be progressively put into the device using multiple 10-cc syringes.
Subsequently, in lithotomy position, a seton will be removed and a fistula tract will be
thoroughly curetted and irrigated. After a mucosal flap preparing round the internal
opening, cells will be injected in the perianal adipose tissue.
Between 40 and 130 ml of lipoaspirate (ideally 100 ml) are processed at each time in the
standard 225-ml device. To avoid cell damage, no air should be in the device during all
procedural steps and the device should be prefilled with saline before beginning the
processing. The aspirated fat should be always surrounded by a liquid environment: this is
essential to obtain healthy smaller fat clusters instead of oil and adipose tissue debris.
The first cluster reduction was obtained by pushing the aspirated fat from the syringe into
the device and through the first size reduction filter while allowing the corresponding
quantity of saline to exit towards the waste bag. The final Lipogems product is then
collected into 10-ml syringes connected to the upper opening of the device. The final
Lipogems product is now ready for the injection in the perianal fistula.
After a SALVECOLL-E paste injection into the fistula tract the mucosal flap will may be
closed with an absorbable interrupted sutures. A external opening will be sealed with
Dermabond Mini.
The patients will receive a intravenous infusion of Infliximab (Remicade) at a dose of 5 mg
per kilogram of body weight at weeks 8, 10, 14 and every 8 week for a total of nine doses.
Rationale for treatment The ASCS injection in the perianal adipose tissue in association
with Infliximab therapy, would improve a crohn related perianal fistula healing.
This association could be reduce a recurrence and reintervention rate with an improvement of
quality of life.
Trial population Number of subjects to be studied Planned number of subjects to be screened:
10 Anticipated number of trial sites: 1
Withdrawal criteria The subject may withdraw at will at any time. The patient may be
withdrawn from the trial at the discretion of the investigator for safety concerns. If the
patient withdraws or is withdrawn at any time after receiving trial product, final safety
information will be obtained.
Patients who are deemed during surgery not suitable included in this protocol will be
withdrawn from the study. In case a subject is being prematurely withdrawn from the trial
the Investigator will ensure that the procedures for the last visit are undertaken, if
possible. The primary reason (adverse event, non-compliance with protocol or other) for
discontinuation must be specified in the CRF.
A patient withdrawn from the study will be analyzed according to evaluability of Subjects
for Analysis.
Methods and assessments Visit procedures
The study comprises of the following visits:
- Visit 1: Diagnosis, baseline visit and first surgery procedure: Screening of patient,
Baseline examination, Pre-surgery and surgery assessment, Informed consent.
- Visit 2: Treatment visit: Surgery
- Visit 3: Medical treatment: start Infliximab administration
- Visit 4, 5, 6, 7,8,9: Medical treatment follow-up
- Visit 10: end of study: last infliximab dose
In case of any premature discontinuation of the trial, the patient will, if possible, be
called in for a last visit. Even if the patient is not able to attend, the End of Trial Form
must be completed.
The Investigator must keep a subject screening log and a subject enrolment log. These can be
combined in one document.
Subjects enrolled in the trial will be provided with a documents stating that he/she is in a
trial, contact address and telephone numbers.
In case a subject is being prematurely withdrawn from the trial the Investigator will ensure
that the procedures for the last visit are undertaken, if possible. The primary reason
(adverse event, non-compliance with protocol or other) for discontinuation must be specified
in the CRF.
All patients will be classified according to the American Society of Anesthesiology Physical
Status Classification as described below. No restriction regarding to ASA status will be
applied in this trial.
Patient Compliance The investigator will reinforce compliance with the protocol by ensuring
that only patients willing to follow the trial procedures are enrolled in the trial.
Definitions adverse events
Adverse event (AE):
Any untoward medical occurrence in a subject or clinical investigation subject administered
a pharmaceutical product and which does not necessarily have to have a causal relationship
with this treatment.
An adverse event can therefore be any unfavourable and unintended sign (e.g., including an
abnormal laboratory finding), symptom, or disease temporally associated with the use of a
medicinal product, whether or not considered related to the medicinal product.
Note: This includes events from the first trial related activity after the subject has
signed the informed consent and until post treatment follow-up period as defined in the
protocol.
The following should not be recorded as AEs:
- Pre-planned procedures unless the condition for which the procedure was planned has
worsened from the first trial related activity after the subject has signed the
informed consent.
- Pre-existing conditions found as a result of screening procedures. These should be
recorded as medical history/concomitant illness.
An AE can also be a clinical laboratory abnormality regarded as clinically significant i.e.
an abnormality that suggests a disease and/or organ toxicity and is of a severity which
requires active management (i.e. discontinuation of trial product, more frequent follow-up
or diagnostic investigation).
The following events will not be recorded as adverse events, as such discomforts are
expected to be related to the surgical procedure:
- Post operative nausea/vomit
- Post operative sore throat due to intubation
- Post operative pain due to surgical intervention within 3 months from the operation.
Serious adverse event (SAE):
A SAE is an experience that at any dose results in any of the following:
- Death
- A life-threatening* experience
- In-subject hospitalization or prolongation of existing hospitalization
- A persistent or significant disability/incapacity
- Important medical events that may not result in death, be life-threatening*, or require
hospitalization may be considered a SAE when, based upon appropriate medical judgment,
they may jeopardize the subject and may require medical or surgical intervention to
prevent one of the outcomes listed in this definition.
- The term "life-threatening" in the definition of SAE refers to an event in which
the subject was at risk of death at the time of the event. It does not refer to an
event which hypothetically might have caused death if it was more severe.
Non-serious adverse event:
A non-serious AE is any AE which does not fulfil the definition of a serious AE.
Severity assessment definitions:
- Mild - No or transient symptoms, no interference with the subject's daily activities.
- Moderate - Marked symptoms, moderate interference with the subject's daily activities.
- Severe - Considerable interference with the subject's daily activities, unacceptable.
Relationship to trial product assessment definitions:
- Probable: good reasons and sufficient documentation to assume a causal relationship
- Possible: a causal relationship is conceivable and cannot be dismissed
- Unlikely: the event is most likely related to an aetiology other than the trial product
Outcome categories and definitions:
- Recovered - Fully recovered, or by medical or surgical treatment the condition has
returned to the level observed at the first trial related activity after the subject
signed the informed consent.
- Recovering - The condition is improving and the subject is expected to recover from the
event. This term should only be used when the subject has completed the trial.
- Recovered with sequelae - As a result of the AE the subject suffered persistent and
significant disability/incapacity (e.g. became blind, deaf, paralyzed). Any AE
recovered with sequelae should be rated as an SAE.
- Not recovered.
- Fatal.
- Unknown - This term should only be used in cases where the subject i
;
Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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