Scheduled Prophylactic Antiemetics for Reduction of Emesis With Doxycycline (SPARED) Trial

Scheduled Prophylactic Anti-emetics for Reduction of Emesis with Doxycycline (SPARED) Trial -
Study Protocol

Principal Investigator:

Sarah Betstadt, MD MPH Department of Obstetrics & Gynecology University of Rochester Medical
Center 601 Elmwood Avenue Rochester, NY 14642-8668 Phone: (585) 276-5367

Co-Investigators:

Amy Harrington, MD

1. PURPOSE OF THE STUDY AND BACKGROUND

1.1 Purpose of the study The goal of this study is to determine if administering the
anti-nausea medication ondansetron prior to doxycycline will decrease the rates of
nausea and vomiting in patients taking doxycycline for antibiotic prophylaxis prior to
undergoing surgical pregnancy termination.

1.2 Background The use of prophylactic antibiotics are standard of care to prevent
surgical site infections in gynecologic surgery 1. Doxycycline is the recommended
antibiotic of choice for surgical pregnancy termination and completion of spontaneous
abortion given its effectiveness, low cost, and rare occurrence of allergic reaction 2.
Previous studies have shown that a common side effect of doxycycline is nausea and
vomiting, with reported rates as high as 30-40% 3. Nausea and vomiting may be reduced by
taking the antibiotic with food 4. Doxycycline given on an empty stomach the morning of
a surgical pregnancy termination resulted in nausea and vomiting in 50% of patients and
this rate was decreased to 15% when it was taken with food the night before surgery 5.
It is not known whether the use of scheduled prophylactic anti-emetics prior to
doxycycline use would further reduce the rate of associated nausea and vomiting. The
goal of the investigators' proposed study is to determine this.

The investigators' study will be a double blinded randomized controlled trial that will
examine whether the use of scheduled prophylactic anti-emetics prior to doxycycline use
reduces the incidence of associated nausea and vomiting. Nausea and vomiting is
distressing to patients and it affects their perioperative care. It is well documented
that minor gynecologic procedures, such as uterine evacuations, can be performed safely
with moderate and deep sedation without an endotracheal tube 6. At the investigators'
institution, patients experiencing nausea and vomiting prior to a surgical procedure
receive general anesthesia with endotracheal intubation, due to their symptoms, not
because that would be the preferred route of anesthesia. For minor gynecologic
procedures, the time for general anesthesia induction can be as long as the duration of
the entire surgical procedure would be without general anesthesia. The use of general
anesthesia increases the duration of time in the operating room, which increases the
costs of operating room and anesthesia time, as well as recovery time for the patient 7.
General anesthesia also poses possible risks such as impairment of cardiovascular
function and development of pneumonia 8,9.

In addition to anesthesia risks and patient discomfort, nausea and vomiting many also
affect antibiotic efficacy due to reduced serum levels. Reeves' et al. showed lower
serum doxycycline levels in patients with emesis within one hour of doxycycline
administration. A serum level greater than 0.8 mg/L has been shown to provide adequate
antibiotic prophylaxis. Vomiting after ingestion of doxycycline decreased serum levels
by an average of 0.26 mg/L5.

Reducing the rates of nausea and vomiting in patients undergoing minor gynecologic
procedures may increase the efficacy of antibiotic prophylaxis, and decrease the rates
of general anesthesia, patient risks and hospital costs. Most importantly, decreased
nausea and vomiting will certainly improve patient experience and is clinically relevant
because doxycycline is an antibiotic commonly used for many gynecologic procedures.

2. STUDY DESIGN

2.1 Overview This will be a randomized controlled trial. Data will be collected by
asking patients to fill out a demographic questionnaire and a baseline visual analog
scale rating their nausea, pain and anxiety at their clinic appointment 1-2 days prior
to their procedure. Patients will then take either ondansetron or a placebo 30 minutes
prior to taking doxycycline the night before their procedure. They will then fill out a
symptom/medication log recording their symptoms from the time that they take the study
medication to the time that they present for their procedure. When they present for
their procedure, patients will fill out a second identical visual analog scale rating
nausea, pain and anxiety. The primary outcome is nausea and vomiting after taking the
study drug and doxycycline the night prior to surgery. Doxycycline prophylaxis the night
prior to surgery is the current standard of care. Eligible patients will be enrolled
over the course of two years. Patients will also have a tube of blood drawn at the time
of the procedure so that doxycycline serum levels can be measured.

2.2 Rationale for Study Design A randomized controlled trial was selected in order to
study ondansetron's effect on the rates of nausea and vomiting in the investigators'
particular population, so that patient's will not know if they are being given
ondansetron or placebo before taking doxycycline. Some potential barriers that are
expected in the study include that the patients may not fill out their
symptom/medication log as this will be done at home. There are approximately 450
patients undergoing surgical termination of pregnancy at the University of Rochester
each year. In order to attain the investigators' goal sample size of 300 patients, the
investigators would have to enroll a large portion of the total patients. The primary
hypothesis is that the rate of nausea and vomiting in patients undergoing surgical
pregnancy termination will be decreased in the group receiving ondansetron versus the
group receiving placebo.

3. CHARACERISTICS OF THE RESEARCH POPULATION

3.1 Subject Characteristics

3.1.1 Number of Subjects: 300 total subjects are expected to participate in the study.
150 total subjects will be randomized to receive ondansetron, while 150 total subjects
will be randomized to receive placebo.

3.1.2 Gender and Age of Subjects: Patients included in the study will be pregnant
females that are ages 18-45 years old.

3.1.3 Racial and Ethnic Origin: There will be no racial or ethnic restrictions to
participation.

3.1.4 Vulnerable Subjects: The women included in this study will be pregnant, although
the study interventions are surveys and the administration of a medication that is both
safe in pregnancy and commonly used in pregnancy, ondansetron.

3.2 Inclusion and Exclusion Criteria

3.2.1 Inclusion Criteria:

- Pregnant women seeking care at the University of Rochester's Women's Health
Practice Family Planning Clinic

- Ages 18-45 years old

- Undergoing second trimester surgical termination of pregnancy

- Proficient in reading, writing, and comprehending English

- Able to give informed consent 3.2.2 Exclusion Criteria:

- Less than 18 years old or older than 45 years old

- Not proficient in reading, writing, or comprehending English

- Not able to give informed consent

- Already taking antiemetics

- Doxycycline allergy

- Hyperemesis gravidarum

- History of gastroparesis or cyclical vomiting

- Unable to swallow pills

3.3 Discussion of Subject Population Pregnant women ages 18-45 years old were selected
for this study, as they will already be taking doxycycline as the standard of care when
they present for abortion care.

4. SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT

4.1 Method of Subject Identification and Recruitment Patients presenting for a surgical
termination of pregnancy at Women's Health Practice will be offered the opportunity to
participate in the study, after they have consented for a pregnancy termination. The
investigators offering participation to patients would otherwise have routine contact
with these patients, as they will be caring for them regardless of whether or not they
participate in the study. If a subject is interested in participating, they will then be
screened to determine if they are eligible. Patients will be assigned a random number
for the study that will link together their demographic questionnaire, the two visual
analog scales, their study drug, and their symptom/medication log.

4.2 Process of Consent Patients will be consented by either Dr. Sarah Betstadt, Dr. Amy
Harrington, research assistant Keelin Abbott, Allison Carletta, NP. The patients will be
given a written consent form to sign that will be extensively reviewed with the
individual consenting them. The written consents will be stored in a locked filing
cabinet, and only Keelin Abbott or Dr. Sarah Betstadt, or Dr. Amy Harrington will be
able to access them.

5. METHODS AND STUDY PROCEDURES During their clinic visit 1-2 days before the procedure,
patients will fill out a demographic questionnaire regarding their age, race,
relationship status, income and education level, pregnancy history, gestational age, and
symptoms of nausea and vomiting thus far in the pregnancy. This questionnaire will also
include questions regarding cigarette and THC use, as well as any diagnoses of
gastroesophageal reflux disease or hyperemesis gravidarum. They will then fill out a
baseline visual analog scale rating their nausea, pain and anxiety.

The patients will then be given a symptom/medication log to take home. The patients will
use the log to record symptoms they experience from the time they take the ondansetron
or placebo to the time that they present for their procedure. The log will include the
timing of the study medication, doxycycline, whether the doxycycline was taken with food
(and the time of/type of food if applicable), pain medications, and misoprostol. The log
will also include the time of nausea and vomiting, and the severity of the nausea and
pain (if applicable).

When patients present to the hospital for their procedure, research assistant Keelin
Abbott, Dr. Amy Harrington, or Dr. Sarah Betstadt will give them a second visual analog
scale to fill out which asks them to rate their nausea, pain and anxiety. This scale
will be identical to the one they filled out at their clinic visit. This scale will be
filled out prior to their procedure.

Patients will have a tube of blood drawn for a doxycycline serum level upon arrival to
the hospital on the day of the procedure.

5.1 Safety Assessments A comprehensive medical history will be obtained at the patient's
clinic visit, and a physical exam will be performed as well to ensure that patients are
not only fit and able to undergo their procedure, but also to participate in the study.

5.2 Assessment of Subject Compliance Compliance with the demographic questionnaire and
baseline visual analog scale will be assessed by nature of them both being filled out
and turned in in clinic. Compliance with taking the study medication will be assessed by
asking the patient if and when they took either the ondansetron or placebo when they
present for their procedure. Compliance with completing the symptom/medication log will
be assessed by asking the patient to turn in their log when they present for their
procedure. Compliance with the second visual analog scale will be ensured by asking the
patient to complete it in the hospital before their procedure.

5.3 Costs to the Subject Subjects will not incur any additional costs by participating
in this study.

5.4 Payment for Participation Patients will not be reimbursed to participate in this
study.

6. CONCOMITANT AND DISALLOWED MEDICATIONS As per standard of care (and irrespective of the
research study), in addition to doxycycline, patients will take 400 mcg of misoprostol
buccally 3 hours before their procedure. It is also standard of care that patients are
able to take either Ibuprofen or Tylenol #3 as needed for pain before their procedure.
They will also be permitted to take any other medications that they take on a daily
basis. None of these medications are part of the research protocol. They will be
instructed not to take any antiemetics. The investigators will record any medications
that are used.

7. SUBJECT WITHDRAWALS Patients will be withdrawn from the study if they themselves request
to do so, or if they fail to take the study medication or the doxycycline. They will not
be withdrawn if they fail to complete the demographic questionnaire, the baseline visual
analog scale, the symptom/medication log, or the second visual analog scale. In the
event that a patient does not complete one of these forms, the investigators' research
assistant Keelin Abbott will help her complete them. No additional study activities will
be completed prior to subject withdrawal.

8. SAFETY AND REPORTABLE EVENTS 8.1 Adverse Event Definition An adverse event is any
symptom, sign, illness, or experience which develops or worsens during the course of the
study, whether or not the event is considered related to the study survey.

8.2 Serious Adverse Event

A serious adverse event is defined as any adverse medical experience that results in any
of the following outcomes:

- death;

- is life-threatening;

- requires inpatient hospitalization or prolongation of existing hospitalization;

- results in persistent or significant disability/incapacity;

- is a congenital anomaly/birth defect; or

- requires medical or surgical intervention to prevent permanent impairment or
damage.

8.3 Recording Adverse Events At each subject visit the site study staff will assess
adverse events by recording all voluntary complaints of the subject and by assessment of
clinical and laboratory features. At each study visit, the subject should be questioned
directly regarding the occurrence of any adverse experience since her last visit.

All adverse events, whether observed by the Investigator, elicited from or volunteered
by the subject, should be documented. Each adverse event will include a brief
description of the experience, the time of onset, the time of resolution, the duration
and type of experience, the severity, the relationship to the study, contributing
factors, and any action taken with respect to the study.

The recording of adverse events will take place from the time that the subject signs the
consent until the subject completes the study (1-2 days after signing the consent) or
withdraws from participation.

8.4 Responsibilities for Reporting Serious Adverse Events All serious adverse
experiences that occur during the study period will be recorded. The recording of
experiences will occur from the time of signing of the consent until the subject
completes the study or withdraws from participation.

9. RISK/BENEFIT ASSESSMENT

9.1 Risk Category: Greater than minimal risk.

9.2 Potential Risks Potential risks to subjects include the possibility of an adverse
reaction to either ondansetron or placebo, and the potential risk of a patient's greater
realization of the nausea and vomiting they are experiencing due to doxycycline. The use
of doxycycline is already standard of care.

9.3 Protection Against Risks The only additional risk may be loss of confidentiality.
Study materials will be kept in a locked file cabinet.

9.4 Potential Benefits to Subjects A potential benefit to subjects participating in this
study is a decrease in their nausea and vomiting.

9.5 Alternatives to Participation Patients who decline to participate in the study will
receive the standard of care at the investigators' clinic for termination of pregnancy,
which involves the use of doxycycline as a prophylactic antibiotic the night before the
procedure, as well as misoprostol the morning of the procedure. They will also be able
to take Ibuprofen or Tylenol #3 for pain. They will not fill out any surveys or logs or
take the study drug.

10. CONFIDENTIALITY OF DATA AND INFORMATION STORAGE 10.1 Subject data will be identified in
the research data set by random unique identifiable code. Research assistant Keelin
Abbott will maintain the code to that information and it will be used to re-identify
patients when they present for their procedure, in order to link together their
demographic questionnaire, the two visual analog scales, their study medication, and the
symptom/medication log. The research data will be secured in a locked filing cabinet
during the study. No identifying information will be included in the research database
except for the subject's ID number, any identifying information will be kept separately
from the research database. Research files will be locked up when they are unsupervised,
and only Keelin Abbott, Dr. Sarah Betsadt, or Dr. Amy Harrington will be able to access
the files.

11. RESEARCH INFORMATION IN MEDICAL RECORDS No research data will be included in the
subject's medical record.

12. DATA ANALYSIS AND MONITORING 12.1 Sample Size Determination Based on Reeves' study as
well as anecdotal data from the investigators' clinic population, the investigators
expect vomiting to occur in approximately 30% of the investigators' patients who take
their doxycycline the night before their procedure. To have 80% power to detect a 50%
decrease in nausea and vomiting, the investigators will need 122 patients in each arm of
the study. In order to account for subject withdrawal or non-compliance, the
investigators intend to enroll 150 patients in each arm of the study.

12.2 Planned Statistical Analysis Our primary outcome of vomiting, will be analyzed using
chi-square analysis. All dichotomous outcomes will be analyzed using chi-square analysis.
Continuous variables will be examined using t-tests. If demographic variables are found to be
confounders with significance, they will be placed into a logistic regression model. SPSS
software will be used for statistical analysis.

Inclusion Criteria:

- Pregnant women seeking care at the University of Rochester's Women's Health Practice
Family Planning Clinic

- Undergoing second trimester surgical termination of pregnancy

- Proficient in reading, writing, and comprehending English

- Able to give informed consent

Exclusion Criteria:

- Not proficient in reading, writing, or comprehending English

- Not able to give informed consent

- Already taking antiemetics

- Doxycycline allergy

- Hyperemesis gravidarum

- History of gastroparesis or cyclical vomiting

- Unable to swallow pills