Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01524081 |
| Other study ID # |
FNB_ATB |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
January 30, 2012 |
| Last updated |
February 7, 2012 |
| Start date |
July 2008 |
| Est. completion date |
November 2011 |
Study information
| Verified date |
January 2012 |
| Source |
The Faculty Hospital Na Bulovce |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Czech Republic: State Institute for Drug Control |
| Study type |
Interventional
|
Clinical Trial Summary
Aim of prospective randomized a placebo controlled study is to prove that in case of acute
surgical procedure due to appendicitis, ileus of small bowel and perforation of small bowel
and stomach appropriately administered antibiotic prophylaxis is effective with lower
incidence of infection in surgical site and comparable risk of development of other
nosocomial infections versus group without antibiotic prophylaxis. Secondary aim is to
determine risk of developing nosocomial infection in the above mentioned group of patients,
identify group of patients which does not benefit from prophylaxis, and compile financial
costs for antibiotic prophylaxis and treatment of nosocomial infections and thus the
background for the recommended procedure with regards that such prospective study does not
exist in the Czech Republic.
Description:
Introduction Infection related to surgical procedure was always considered the main cause of
mortality end morbidity in surgical patients. ATB prophylaxis has become the breakthrough in
surgical praxis in terms of prevention of surgical postoperative complications (Surgical
Site Infection - SSI) and radical improvement of surgical results. ATB prophylaxis prior to
intervention procedures presents however 1/3 of costs for medicinal products and it is also
potentially hazardous. Even single use of antibiotic agent can be a cause for development of
nosocomial infection with indispensable mortality and costly treatment. Several
recommendation in worldwide literature have been presented during the last 10 years which
concerned indications and route of administration of antibiotics prior to scheduled or acute
surgical procedure; indications for acute procedures broaden and it increases the
consumption of antibiotics. Excessive pre-hospital and hospital exposure to antibiotics is
however related to development of microbial resistance which shows in higher incidence of
nosocomial infections (health care - associated infection - HAI) - urinary infections,
pneumonia, catheter infection and another diseases such as Clostridium colitis caused by
highly virulent type. Moreover some studies suggest bad compliance in dosing and timing of
antibiotic prophylaxis which causes only the negative effect of prophylaxis without positive
affection of SSI. This knowledge and disagreement led us to elaboration of protocol for
prospective randomized placebo controlled study which could be the base for correct surgical
praxis in investigator's conditions.
Aim of the project The aim of this prospective randomized placebo controlled study is to
prove the positive effect of antibiotic prophylaxis on the incidence of SSI in patients with
comparable risk of developing other nosocomial infections in case of acute abdominal
procedures for diagnosis such as appendicitis, ileus of small bowel and stomach or small
bowel perforation and thus with exclusion of tertiary peritonitis. Secondary aim is to
identify the group of patients in which risk of developing nosocomial infection exceeds
benefit of ATB prophylaxis. Tertiary aim is to assess whether preoperative microbial
screening has its significance for reduction of HAI. After comparing the financial cost of
therapy (including SSI and HAI generally) it will be possible to submit background for
proposal of recommended procedure for administration of antibiotic prophylaxis in the most
common acute surgical procedures with regard to risk factors for genesis of nosocomial
infections. Such prospective randomized placebo controlled study has not been conducted in
the Czech Republic; further study with similar target group of patients (very common in
surgical praxis) has not been published in world literature.
Hypothesis Correctly administered antibiotic prophylaxis prior to acute abdominal procedures
reduces frequency of SSI. It can increase the frequency of severe nosocomial infections in
risk group of patients. rational use of antibiotic prophylaxis should however lead to
reduction of incidence of nosocomial infections with clinical and socioeconomic impacts
including prevention of feared severe infections associated with health care (HAI).
Methodology
Method is aimed at:
1. Assessing the effect of risks to development of nosocomial infections on behalf of
patient (ASA, morbidity, relevance of the actual disease, microbial screening targeted
on community infection, BMI, previous hospitalization in health care facility).
2. Assessing perioperative influence on the genesis of nosocomial infections (correct
administration of ATB prophylaxis- protocol control, perioperative influences - blood
loss, body temperature, extend of inflammation, SIRS sings, duration of surgery, ICU
stay, microbial profile, analgesia, physiotherapy, complications assessment).
3. Assessing the influence of ATB if those are correctly administered on the genesis of
SSI in acute procedures (length of hospitalization, length of treatment and
complications).
4. Long term and socioeconomic impacts of SSI (60 days follow up, life quality
assessment), standard proposal. After completion of patient monitoring the analysis of
cost for hospitalization including medication, surgery and postoperative outpatient
control will be conducted using the hospital information system.
Appropriate patients to be enrolled in the study are all patients with following diagnosis
operated at the site: Acute appendicitis (classical or laparoscopy appendectomy), ileus of
the small bowel (adhesiolysis, enterotomy with suction or resection of small bowel),
perforated stomach or duodenal ulcer (classical excision of the ulcer and suture of the GIT
wall), i.e. patients without stercoral peritonitis. Patient will be definitely included if
they signed the preoperative informed consent form which they were able to understand well
and whose diagnosis was confirmed during surgery. Patients will be excluded if they are
younger than 18 years of age, pregnant females, and patients with known allergy to
administered ATB and also if their mental state does not allow appropriate instruction and
signing of the informed consent and further patients who used ATB in the course of last 2
weeks.
Preoperative care, actual surgical procedure and subsequent postoperative care are not the
direct subject of study and will be conducted according to so far known procedures.
Patient will be administered therapeutic agent (antibiotic) or placebo in form of
intravenous infusion 60 minutes prior the surgical procedure due to suspicion of the above
mentioned diagnosis. If the surgery lasts for more than 3 hours, the infusion will be
repeated. After analysis of the most common pathogens in individual clinical diagnosis,
microbiologist chose following preparations: Acute appendicitis - Cefuroxim (Zinacef 1.5 g)
+ Ornidazol (Avrazor 1g), perforated ulcer - Aminopenicillin + inhibitor (Amoksiklav 2.4 g)
+ Fluconazole 800mg i.v., ileus of small bowel - Cefuroxim (Zinacef 1.5 g) + Metronidazol
(Avrazor 1g). Surgeon will confirm the definite diagnosis during surgery which will confirm
the definite inclusion in the study. Surgeon will not be present dilution or administration
of the agent. Nobody from patient's attending study personnel will not be able to
distinguish whether the patient was administered antibiotic or saline solution. The
prophylaxis will be extended for 24 hours in common half-dosage according to publication
sources.
Randomization will be conducted using generator of random numbers. This sequence will be
incorporated in simple digital patient database internet access to which will be password
protected. One educated ICU nurse will enter only basic patients´ data and system itself
will determine whether to prepare placebo or diluted antibiotic. Since that moment this
information will be confidential and software will be accessible only for entering other
monitored parameters. Dividing into individual groups will be conducted in interim controls
after six months intervals and final division after completion of study. Totally there will
be 2 major groups and 6 subgroups and those 3 subgroups according to individual diagnosis
each one with 1 control group. If severe complication (allergy reaction) occurs, the
principle investigator can uncover the blinding using specific password; system entry will
automatically mean exclusion of the patient from study.
Patients will be discharge from the hospital based on criteria (agreement of the patient,
without signs of severe infection (SIRS), sufficient oral intake, sufficient analgesia with
oral analgesics, would treatable in the outpatient department); patient will be treated as
outpatients in case of complications; patients will be questioned on the phone in case of
uncomplicated course and they will be ask to fill out life quality questionnaire (SF36) on
the day 30 and 60.
Demographic data on included patient and monitored data will be recorded into special cards
and transmitted in the specifically created software to further processing.
Investigators assume to include total of 500 patients during 3 years.
Time schedule:
1. year of the project: creation of the randomization program, personnel education,
software creation, inclusion of 130 patients with appendicitis diagnosis, 18 patients
with ileus of small bowel and 35 patients with perforation of ulcerous disease. Data
processing. Results will be evaluated at the end of the year.
2. year of the project: Inclusion of 130 patients with appendicitis diagnosis, 18 patients
with ileus of small bowel and 35 patients with perforation of ulcerous disease. Data
analysis will be performed and subgroup analysis and partial results will be processed
and presented.
3. year of the project: Inclusion of 90 patients with appendicitis diagnosis, 14 patients
with ileus of small bowel and 30 patients with perforation of ulcerous disease. Follow
up termination. Definite data collection, analysis, results evaluation including
financial analysis. Standard proposal. Presentation in national and international
forums, publications.
Principle investigator will apply the created protocol and will continuously control its
compliance including schedule, will process interim data, will evaluate data compliance with
literature and will prepare their presentation and publication and will process final
results. 2nd co-worker is guarantees the microbiological part of the project; 3rd and 4th
co-workers will collect rather large amount of data and will enter them in created system.
5th and 6th co-workers will control including appropriate patients in study (it means acute
procedure), % of included patients out of number of suitable patients is an important
criterion for significance of gathered data. They also cooperate in presentation data
processing. 7th co-worker controls correctness of data collection. 5 specifically educated
independent nurses who do not attend the patient (24 hour service) will prepare infusions
for patients according to acquired randomization data - placebo or monitored group.
Administrative worker will select data from the information system and patients´ files, file
and selects study cards and supervises their correct completion.
Means of data collection Data collection will be conducted in terms of preoperative
examination: Demographic data (age, diagnosis, co-morbidity expressed by score - ASA, BMI,
blood count, CRP), microbiology samples for detection of influence of community pathogens,
especially presence of multiresistant pathogens - Clostridium difficile will be sought.
In course of surgery: evaluation of perioperative finding, SSI risk 0-3 point; contamination
scoring I-IV, body temperature monitoring (BT), blood loss (including weighing of screens),
length of surgery.
In postoperative period will be recorded: number of transfusion preparations, number of days
on UPV, days at ICU, oral intake, physiotherapy, invasive inlets (peripheral venous
catheter, permanent urinary catheter, nasogastric tube, drains) and quality of analgesia
(Visual Analog Scale - VAS).
On discharge: samples collection for microbiological examination, record of SSI incidence
and other HAI defined according to criteria of National Healthcare Safety Network (NHSN),
completion of assessment of life quality questionnaire (SF36).
After discharge: complications will be recorded till day 30 and 60 (SSI and HAI), life
quality assessment. After completion of patient monitoring the analysis of cost for
hospitalization including medication, surgery and postoperative outpatient control will be
conducted using the hospital information system.
Statistics:
Morbidity which ranges from 15 to 20%, investigators consider 10% as clinically significant
reduction. Minimal extent of each collection is 118 when considering 5% level of
significance for single sided test and test power 70%; minimal extent of each collection for
portion of nosocomial infection 6-10% is 234 in case of clinically significant decrease by
5%. Estimates of numbers required for detection of clinical difference of two days (standard
deviation estimate 2.6 for appendicitis respectively 3.2 for perforation and 2.3 for ileus
of small bowel) lead to values 36, 47 a 25 people in each group. Total number for each set
is 250 people and it fulfills the above mention criteria and ranges 175, 50 and 25 in each
subgroup are sufficient. Group homogeneity will be compared based on descriptive statistical
methods; risk factors will be evaluated using regression analysis and multivariant analysis.
When comparing basic factors p<0.05 will be considered as clinically significant in case of
above given test power.
Patient informed consent (short version, complete version was approved by ethics committee
and is enclosed in appendix): Study description: Each surgical procedure has its own risk so
called postoperative infectious complications. One possibility how to prevent those
complications is the preventive administration of antibiotics just prior the procedure - so
called antibiotic (ATB) prophylaxis. There is no clear evidence for positive effect of ATB
prophylactic use in some acute surgical procedures. On the other hand introduction of ATB
prophylaxis has its complications. Aim of study: Aim of the study is the recommendation
whether in given cases administration of ATB prophylaxis has positive effect on reduction of
incidence of postoperative infectious complications and whether this benefit is higher than
risks related to ATB administration. Inclusion in study and conductance: Single inclusion is
only based on the decision of patient (approximately 500 patients). Study participation will
be offered to patients who will be operated on due to acute appendicitis, perforated stomach
or duodenal ulcer or due to ileus of small bowel. Pregnant and lactating females are
excluded from the study. After patient's consent with study participation the intravenous
preparation will be administered which contains active substance (antibiotic) or placebo
(only saline solution). Both administered substances are registered preparations
administered for given purpose in general praxis. The chance of application of either active
preparation and or placebo is 50:50. Patient will be telephonically inquired about concrete
postoperative complications on day 30 and 60 after surgery. If there is suspicion on
complication, patient will be examined and treated using standard procedure. He will be
further asked for completion of questionnaire about life quality. Health risks: This study
is not related to practically any excessive risk. ATB and placebo administration does not in
any way influence the surgical procedure or postoperative care. Non-invasive sample
collection for cultivation (urine collection, sputum collection -secretion from respiratory
tract mucosa, smear from throat and stool). Compensation for bodily harm: If patient obliges
to study physician's instructions and her/his team and health damage of patient occurs as a
result of administration of any preparation, the study sponsor will cover all cost for
treatment of this damage which is not covered by patient's health insurance. Patient's
declaration: I, undersigned, agree with my participation in study. I am older than 18 years
of age. I was informed in detail about the aim of study, its procedures and what it is
expected from me. Study physician explained me the expected benefits and possible health
risks. I acknowledge that conducted study is an investigation activity. Study is randomized
and therefore I acknowledge possibility of random assignment into individual groups which
differ in therapy. I fully understood and I have the opportunity to ask additional questions
which were satisfactory answered to me. I informed study conducting physician about all my
diseases and medications which I have been taking over the last 28 days and also about
medication which I currently take. I declare that I do know that I am pregnant at time of
inclusion in the study. I understood that I can discontinue or withdraw my participation in
the study at any time without affecting course of my further treatment. My personal data
will be kept in full confidentiality after study enrollment according to applicable laws in
the Czech Republic. Based on my given consent my original medical information could be
accessed to authorized acquired data by sponsor representatives, independent ethics
committees and international or local competent authorities (The State Institute for Drug
Control in the Czech Republic). Confidentiality protection of personal data is guaranteed
for those cases. There will not be any cost to me for my participation in study and
concomitantly study enrollment is not related to any financial reward. I understood that my
name will never be present in reports about this study. (date, name, signature) Cooperation
Working site of co-worker participates in postgraduate education; co-worker is recognized
surgical expert and therefore he is guarantee for correct study conductance and results
applications in praxis; the cooperation will be confirmed by agreement.
Discussion Investigator's working site will conduct internal retrospective study dealing
with SSI in patients with appendicitis and stomach ulcer perforation. 180-200 acute
appendectomies will be performed every year with SSI frequency 2.5 - 18.5% according to
contamination. Group of patient with stomach ulcer perforation will be evaluated similarly
(n=42) with SSI 14.3%, total morbidity 35% and mortality 11.9%. All of those data correlate
with results from the world literature however it is possible that after retrospective
assessment correct monitoring of ATB prophylaxis (40% compliance) and patient stratification
will reduce the frequency of complications.
Information Working site of designer performs hundreds of the above given operations which a
presumption for completion of the study aims. Especially young surgeon will participate in
this study who will manage methodology of hospital care as well as surgery under supervision
of experienced physician and will educated for patients´ monitoring. Statistical evaluation
will be performed by professional statistician. Principle investigator has numerous
experiences with clinical studies and she/she published his/her results in journals. Other
specific equipment is not necessary for study procedure.
Conclusion Proposed prospective randomized double blinded study will provide clear results
assessing effect of administration of ATB prophylaxis on the incidence of SSI and other HAI
in case of the most common acutely performed surgical procedures. Risk factor analysis and
costs for treatment will aid to determine group of patients who will benefit from
prophylaxis and vice versa.
Expected results and significance of the project Project results will be used as background
for establishing recommended procedure of antibiotic prophylaxis administration in surgery.
Standardized protocol will be introduced for patients monitoring including monitorzation of
nosocomial infections which is can be applied in general surgical praxis. Simple universal
software will be created in terms of study which manages patient database and thus enables
rapid concurrent assessment of health care quality. Respective reduction of nosocomial
infections frequency should result in significant economic benefit for surgical praxis. With
regard that similar complex prospective study has not been published in national and
international magazines, publication in impact journal; socioeconomic analysis will be
published especially in national medical journals so it would be easily accessible.
Project should aid the prevention of nosocomial infections (HAI) and reduction of their
genesis and thus to increase surgical care, shorten hospitalization and should have impact
on the whole society.
