Trial Information

Antiseptic Preparation of the Rectum Prior to Transrectal Prostate Biopsy

1. Purpose This research aims to determine the efficacy and safety of cleaning the rectal
mucosa with antiseptic solution (Povidone-iodine) prior to transrectal prostate biopsy.

2. Hypothesis We hypothesize that prophylactic cleaning of the rectal mucosa with
antiseptic solution prior to transrectal prostate biopsy will decrease the rate of
infectious complications after biopsy. We believe that this can be achieved without any
significant complications related to the antiseptic solution.

3. Justification Prostate cancer is the most common cancer in men. Since the diagnosis of
prostate cancer requires a transrectal prostate biopsy, this procedure is performed
frequently. More than 6000 biopsies are performed in British Columbia each year, and
more than 1000 are performed at Vancouver General and UBC Hospitals (combined numbers).
In these hospitals, the biopsy is performed by the radiologists using transrectal
guidance. Subjects receive antibiotic prophylaxis in the form of ciprofloxacin for
three days starting one day before the biopsy. They also instill an enema into the
rectum a few hours before the biopsy to empty the rectum. Local anesthetic is injected
through the rectal mucosa into the periprostatic space prior to the biopsy. Depending
on the size of the prostate, between 8 and 12 cores of tissue are remove from the
prostate by repetitive passes of the 18 gauge biopsy needle through the anterior rectal
wall. Cleaning the rectum with an antiseptic solution prior to biopsy is not routinely
practiced and is not considered a current standard of care.

Despite routine antibiotic prophylaxis, prostate biopsies are associated with a
considerable rate of infectious complications. Sepsis after biopsy is described in the
literature with an incidence 0.1 to 2.0 %.

Rate of sepsis has been determined in a retrospective but contemporary study of
approximately 4500 biopsies at VGH/UBC to occur with a rate of 0.55% (Lange et al.,
submitted to Journal of Urology). Less severe but more common adverse events include
urinary tract infection and fever, which both occur in approximately 10% of men
undergoing biopsy.

Cleaning the rectum prior to biopsy offers a potential method to decrease the risk of
these infectious complications, and we propose the use of Povidone-iodine for this
purpose. Surgical site disinfection is standard in most surgical procedures, and
Povidone-iodine is a safe antiseptic utilized routinely for the surgical preparation
of the body surface as well as mucosal surfaces, including the vagina, mouth and bowel.
Park et al. reported that the mean number of colony-forming units decreased 99.9% after
Povidone-iodine cleansing of the rectum. Hay et al. reported similar results with
Povidone-Iodine enema administration when combined with metronidazole. Povidone-iodine
has been shown to significantly reduce bacterial concentrations in the mucosa of the
colon and rectum. Brown et al. reported that a Povidone-iodine enema provided a safe
and effective means for preventing bacteremia and bacteruria after transrectal prostate
biopsy. Furthermore, severe allergic reaction to Povidone-iodine is rare.

4. Objectives

The objectives of this study are:

1. To determine whether cleaning the lining of the rectum with an antiseptic solution
before prostate biopsy is effective in decreasing the rate of three outcome variables:

- Urinary Tract Infection

- Fever

- Sepsis

2. To determine at what rate bacteria are found in the rectum prior to biopsy that are
resistant to ciprofloxacin.

3. To determine at what rate bacteria are found in the urine after biopsy, with or without
rectal cleaning.

4. To determine any adverse reactions to antiseptic solution in the rectum.

5. Research Method All subjects undergoing transrectal prostate biopsy as clinically
indicated and determined by the treating Urologist at Vancouver General Hospital and
University of British Columbia Hospital will be considered for entry into this trial.
If the subject consents to participation, he will be randomized to undergo prostate
biopsy with rectal cleaning with antiseptic solution ("treatment" group) or without
rectal cleaning ("control" group). A urine sample will be collected before and after
biopsy and sent for routine culturing. A rectal swab will be taken before the biopsy
(and before rectal cleaning in treatment group) and will be cultured in
ciprofloxacin-enriched medium.

In the treatment group, the radiologist performing the biopsy will wipe the rectal
lining overlying the prostate with gauze soaked with Povidone-iodine. Otherwise the
biopsy is performed in standard fashion in both groups. After the procedure, the
subjects are instructed to measure and record their temperature every 6 hours for 48
hours. A telephone interview is conducted seven days after biopsy to ascertain any
adverse events from the biopsy, including whether a temperature ≥38.0˚C was measured.

6. Statistical Analysis The primary outcome in this study will be the rate of urinary
tract infection and the rate of fever after biopsy (see definitions below). The rate of
sepsis will be measured, but the study will not be powered to detect a difference in
the rate of sepsis.

The rate of UTI and fever is estimated from the literature data at 10% each. A relative
reduction of 50% (absolute reduction from 10% to 5%)would be considered clinically
significant. With type I & II errors set at 0.05 and 0.2, respectively, and a two-sided
test of significance, the necessary sample size is estimated at 435 in each group.
Assuming 20% inability to enroll and loss to follow up, the total sample size is 1044.

Descriptive statistics of baseline parameters will be provided in each group. The mean,
median, standard deviation or range of the variables will be computed as applicable.
The association between exposure and the defined outcomes will be assessed in
univariate analysis. The proportion of each outcome in each group will be compared
using the chi square test. Multivariate analysis using logistic regression will be
performed to assess effect of variables such as age, number of biopsy cores, individual
performing the biopsy and other co-morbidities. A test of interaction will be
performed.

7. Definition of Endpoints

- Urinary tract infection: > 100 million colony forming units per liter in the
urine culture obtained48 hours after biopsy.

- Fever: oral temperature ≥38.0˚C within 48 hours after biopsy.

- Sepsis(19),(20): positive urine or blood culture plus two or more of the
following within 1week of biopsy:

1. temperature ≥38.0˚C or < 36.0˚C,

2. heart rate >90 beats/minute,

3. respiratory rate > 20 breaths/min,

4. WBC count >12.0 or <4.0 x 10 9/L, or > 0.10 immature forms (bands).

8. Summary of Procedures:

Eligible subjects will be counseled in the office regarding the prostate biopsy as per each
physician's routine. This includes instructions for ciprofloxacin prophylaxis (1000 mg of
extended release ciprofloxacin daily for three days starting the day before the biopsy) and
the use of a fleet enema at home approximately 2 hours before biopsy. The Urologist will
also discuss this study with the subject at the same time as he/she orders the biopsy.
He/she will ensure that the subject meets the eligibility criteria using a pre-biopsy
questionnaire. The subject will be able to take the consent home for further consideration
and discussion. It must be signed before the biopsy for the subject to participate in the
study.

Each subject will be assigned a study code. At the time of biopsy, subjects will be
randomized 1:1 by computer generated random numbers into two groups. The first group
("controls") will undergo biopsy according to the current standard of care, which does not
include antiseptic cleaning. The second group ("treatment") will undergo biopsy in the same
fashion, but after cleaning the rectal lining with 10% Povidone-iodine.

Before the biopsy is started, the subject is asked to give a midstream urine sample for
routine culture. A culture swab is also inserted into the rectum and then cultured in
ciprofloxacin-enriched media in order to isolate ciprofloxacin-resistant rectal flora prior
to the biopsy.

The control group will undergo the routine biopsy while in the treatment group, the
radiologist performing the biopsy will have a gauze soaked with Povidone-iodine over his/her
index finger, and will insert this into the rectum. Before this, the Radiologist asks the
subject again if he has allergy to Povidone-iodine, shellfish or IVP dye. The gauze will be
wiped back and forth across the prostate with the finger at least five times from one
lateral margin to the other. The radiologist will allow at least 2 minutes to pass between
prep and the insertion of the first needle into the prostate in order to allow the
Povidone-iodine to dry. The radiologist will ask the subject to inform the Radiologist if
the subject does experience any symptoms of allergic reaction (rash; hives; itching;
difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue
). The 2 minutes will be spent measuring the prostate size using the rectal ultrasound
probe. After those two minutes the routine biopsy is done. A second rectal swab for culture
will not be taken, as this will likely be negative due to the Povidone-iodine contamination
of the swab, and due to the added cost.

All subjects will be discharged from the recovery according to standard care. During the
recovery period, a watchful eye is kept on the subjects in the treatment group for
developing severe allergic reaction. A crash-cart will be available all the time during the
procedure and in the recovery room. Should the subject develop an allergic reaction, the
radiologist will take the necessary measures as per the Radiology Department standard of
care protocol. The subjects will be asked to provide another midstream urine sample for
routine culturing 2 days after the biopsy. This will be grown in conventional media.
Subjects will be asked to measure and record their oral temperature once they wake up and
just before going to sleep and every 6 hours in between, for 2 days after the procedure. A
telephone interview using a post-biopsy questionnaire will be performed with the subject
seven days after the biopsy to ascertain any side effects from the biopsy, including whether
a temperature ≥38.0˚C was measured.