Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT03352115 |
| Other study ID # |
103717MP4F |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
November 20, 2017 |
| Last updated |
November 22, 2017 |
| Start date |
January 2018 |
| Est. completion date |
January 2019 |
Study information
| Verified date |
November 2017 |
| Source |
Wayne State University |
| Contact |
Bianca Siegel, MD |
| Phone |
3137459048 |
| Email |
bsiegel[@]dmc.org |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Tonsillectomy is one of the most common surgical procedures in the United States, and
post-operative pain management is a challenge for otolaryngologists. A 2013 black-box warning
on codeine following tonsillectomy has drawn attention to potential concerns with all
narcotics in these patients, and many surgeons try to avoid narcotics. The use of
intra-operative corticosteroids has been proven to be beneficial in reducing post-operative
morbidity, and some small studies have shown possible benefit to the use of post-operative
oral corticosteroids as well, although the results of these studies are mixed. To date, no
one has looked at whether the use of post-operative oral steroids may reduce or eliminate the
need for narcotics. We aim to determine whether the addition of oral steroids to our
post-operative pain regimen can reduce the need for narcotic pain medications.
Description:
I. Background
Tonsillectomy is one of the most common surgical procedures in the United States with the
predominant indications being obstructive sleep apnea and recurrent tonsillitis1. While it is
usually performed on young and otherwise healthy children, postoperative morbidity is
ubiquitous occurring in nearly 20% of children with the most frequent complaints being throat
pain, otalgia, fever, poor oral intake, nausea and emesis, and secondary hemorrhage2.
Historically, Tylenol with codeine was commonly used for pain control post-operatively in
children. However, in 2013 the FDA issued a black box warning on codeine following
tonsillectomy due to reports of multiple deaths and morbidities in children3. Since that
time, there has been increased awareness of the dangers of opioids in general and many
surgeons are trying to minimize or eliminate the prescription of opioids to children
following tonsillectomy.
It has been found by multiple studies that intra-operative use of steroids during
tonsillectomy has beneficial effects in children. A Cochrane Review updated in 2011 presented
a meta-analysis of 19 randomized, placebo-controlled, double blinded studies and concluded
that routine use of a single intra-operative dose of dexamethasone reduces post-operative
morbidity. The studies found a decrease in post-operative emesis and a higher likelihood of
advancement to a soft or solid diet on the first postoperative day. Eight of the studies used
the Visual Analog Scale (ranging from 0-10), which found a reduction of post-operative pain
of more than one point. No adverse effects related to intra-operative corticosteroid use were
reported and a single dose of steroids is believed to be virtually harmless4. Despite the
utility of corticosteroids intra-operatively, there is currently a paucity of studies
investigating the potential effects of a short post-operative course of oral (PO) steroids on
pain control and other morbidities of tonsillectomy. Of the available literature, a short
course of prednisolone of up to 1 week in patients without specific contraindications was
found to provide a significant benefit in pain relief, return to normal diet, return to
normal activity, and re-epithelialization of the tonsillar fossae, in an assessment of 69
pediatric patients5. Another study by Macassey et al. compared 5 days of oral prednisolone to
placebo by assessing pain, nausea, vomiting, return to normal function, and sleep duration
and quality. This study did not find a difference in any of the study parameters between the
two groups6. To our knowledge, there have been no studies specifically looking at how the
addition of a post-operative course of oral steroids impacts patient's necessity for narcotic
pain medications.
Due to conflicting reports and a general paucity of literature to support or refute routine
postoperative steroid use in children following tonsillectomy, it will be useful to determine
the efficacy of this otherwise ubiquitous and benign medication on pain control, time to
return to normal diet, dehydration, post-operative infections, and post-operative bleeding in
our patient cohort; these are the most common complaints and complications following
tonsillectomy surgery. Therefore, similar to the above-referenced studies5,6 we will be
evaluating all of these endpoints in our patients. However, in addition to these endpoints we
will also look at the need for post-operative narcotics. Given the recent black box warning
on Tylenol with codeine use in children following tonsillectomy3, many surgeons are
understandably hesitant to prescribe any narcotics to children following tonsillectomy. Our
study will evaluate the potential role of steroids to reduce or possibly even eliminate the
need to prescribe these children narcotics.
II. Objectives
We propose a double-blind, randomized placebo-controlled study comparing the
post-tonsillectomy morbidity and analgesic/narcotic use in children 4 to 18 years old
receiving a 5 day-course of oral prednisolone versus those receiving placebo. We plan to
approach patients and parents preoperatively to assess their willingness to participate in
the study. Following tonsillectomy, parents will be asked to complete a patient log,
detailing the child's post-operative course. This log will document the quantity of narcotics
and other pain medications used, daily pain assessments using the validated Wong-Baker facies
tool, return to regular oral diet, and return to regular activities. Complications such as
dehydration, post-operative infection, and post-operative bleeding requiring an emergency
room visit will also be assessed in a post-operative survey, which will be completed at the
post-operative office visit.
Because the use of a single dose of intraoperative steroids is a widely accepted practice, we
believe there is a value in investigating whether a short postoperative course of steroids
adds further benefit to a child's post-tonsillectomy course, especially because it is a safe
and inexpensive intervention, and may reduce the need for post-operative narcotics. Given the
significant concerns with narcotics in this cohort of patients and the recent black-box
warning, there is great interest among pediatric otolaryngologists in minimizing narcotic
use. This study has significant potential to change the paradigm of post-operative pain
management after tonsillectomy to minimize or even avoid the use of narcotics.
The primary endpoints for this study include frequency and total amount of narcotic and
non-narcotic pain medication required, time to return to normal diet, and time to return to
normal activity. Secondary endpoints will include the rates of post-operative emergency
department visits, dehydration, and post-operative tonsillar hemorrhage.
III. Methods
We propose a prospective double-blinded randomized placebo-controlled control trial to assess
the effects of oral prednisolone on the post-operative course following tonsillectomy.
Recruitment At the pre-operative visit, a member of the patient care team (resident, nurse
practitioner, or attending physician within the Pediatric Otolaryngology department) will
assess the willingness of the patient and parents to hear more about the study. Study details
will be made available to the parents and child, with the understanding that their child will
be randomized into a group receiving post-operative steroids or a group who receives placebo.
It will be emphasized that study participation is voluntary and without participation
children will receive our current standard of care, which is a single intra-operative dose of
dexamethasone but no post-operative oral steroids. It will be made clear that the parents are
able to withdraw from the study at any time. If they agree to take part in the study, parents
will be asked to record all pain medications taken by their child in the five days following
surgery as well as keep a record of diet and activity. Informed consent will be obtained for
participation in the study at the first visit. Parents will also be asked to bring the study
medication bottle and the pain medication bottle to the follow-up visit to ensure compliance.
A survey assessing secondary endpoints will be completed at the post-operative follow-up
visit. Study details and patient logs will be available in English only.
Subjects Pediatric patients aged 4-18 undergoing tonsillectomy at the Children's Hospital of
Michigan by Dr. Bianca Siegel, Dr. Nathan Gonik, or Dr. Mallory O'Niel will be eligible to
participate in this study.
Inclusion criteria -
1. Subject is male or female age 4-18 years of age
2. Patients undergoing total tonsillectomy with or without adenoidectomy or tympanostomy
tubes
3. Patients with obstructive sleep apnea or recurrent tonsillitis requiring tonsillectomy.
4. The patient or caregiver is able to provide written informed consent.
5. Patients with American Society of Anesthesiologist (ASA) physical status 1 or 2.
Exclusion criteria -
1. Subjects with complex medical conditions or craniofacial abnormalities
2. Subjects with known personal or family history of bleeding disorder
3. Subjects with cognitive or developmental disorders
4. Subjects currently taking corticosteroids for other medical conditions, or who have
taken corticosteroids within 2 weeks of surgery
5. Subjects who are wards of the state
6. Subjects who have had an organ transplant
7. Subjects who are on other immunosuppressant medications
8. Subjects with diabetes mellitus
9. Non-English Speakers or English as a second language
10. Subjects undergoing intracapsular tonsillectomy
11. Subjects with American Society of Anesthesiologist (ASA) physical status greater than 2.
12. Pregnancy
Pre-operative Visit (Visit 1) If the patient and family agree to participate after an
explanation of the project (see Recruitment above), and meets all criteria for participation,
they will be enrolled in the study. An informed consent document, oral assent document (if
applicable), and written assent document (if applicable) will then be obtained and a copy
will be given to the patient and/or parent. Only one parent will be required to provide
consent for the surgery and for participation in the study as typically only one parent
accompanies children to our clinic. A physical examination will be performed to note the
patient's tonsil size. Pre-operative sleep study findings in patients with suspected
obstructive sleep apnea will be recorded as well. Any concurrent medications will be
recorded. The patient's information will be sent to the participating pharmacist for
randomization into an experimental arm (5 day course of post-operative oral steroids -
prednisolone) and a control arm (5 day course of post-operative ORA-Sweet © placebo)
Randomization will be performed in a 1:1 ratio at Visit 1 by the participating pharmacist,
using www.randomization.com. The patients as well as the surgeons and the remainder of the
research team will be blinded to the randomization. Prescription documents for the study
medication and placebo will be created by the participating pharmacist prior to the start of
the study. Once a patient is enrolled, a prescription will be sent to the participating
pharmacist who will then randomize the patient to receive either prednisolone or the
equivalent volume of OraSweet © solution to serve as a placebo. Details of randomization as
well as which patients received the study medication will be kept by the participating
pharmacist and can be available for review by the institutional review board or any governing
agencies at their request.
Day of Surgery (Visit 2) On the day of surgery all patients will receive a single
intravenous, weight-based dose of dexamethasone intra-operatively, as this is the current
standard of care. Tonsil size will, once again be noted at this visit and updates to
concurrent medications will be recorded. Any adverse events intraoperatively or immediately
post-operatively will be recorded. In female patients over age 9, it is hospital policy that
the patient undergoes a urine pregnancy test prior to undergoing surgery. This will be
recorded and, if positive, the patient will not undergo surgery and will be disqualified from
the study. After surgery, the participating pharmacist will then deliver the appropriate
volume of study medication (1mg/kg/day prednisolone divided BID (twice per day)) or for 5
days post-operatively to start on post-operative day 1. The control group will receive the
same volume of OraSweet© placebo also to start on post-operative day 1. Each group will
receive an additional quantity of 3 doses in the event of emesis and a need to redose.
Parents will then be asked to monitor their child's post-operative pain, oral intake,
activity, and quantity of pain medication given for 5 days using patient logs created for
this research endeavor (attached). The patient will then be discharged home or admitted for
overnight observation if pre-operative sleep study scores indicate a severe obstructive sleep
apnea (AHI >10) based on recommendations by the American Academy of Otolaryngology - Head and
Neck Surgery Foundation or at the surgeon's discretion.
Post-operative visit (Visit 3) The first follow up visit will occur 2 weeks after surgery. At
this visit, we will collect the patient logs used by the parents as well as the study
medication bottles to ensure compliance or to determine continued eligibility in the study.
At this visit, we will perform a physical examination to ensure healing of the wounds as well
as record any adverse events and other, concurrent medications. Parents will also be asked to
complete a brief survey, asking about the post-operative course and any complications
(attached). We will then transfer the paper patient log recordings into an electronic format
kept securely on the secure DMC server. Once statistical power has been reached, we will use
these data to evaluate whether a 5-day course of post-operative steroids improves
post-operative pain and decreases time to normal activity and oral intake. If patients
develop any postoperative complications, the standard of care for that complication will be
undertaken.
Medication Details On the day of surgery, medication will be prepared for the patients by the
participating pharmacist, which the parents will receive in the recovery room. The medication
bottle will either contain 15 mg/5 mL prednisolone elixir (Prednisolone group) or ORA-Sweet ©
Syrup (Placebo group). The medication will be provided in a marked bottle by the pharmacy.
The medication will be supplied specifically for this study and will be stored at room
temperature in the investigational drug room in the inpatient pharmacy until needed.
Medications will be ordered specifically for this study and will have its own medication lot
independent from the regular hospital supply. A weight-based dose of 1 mg/kg/day of
prednisolone elixir rounded to the nearest whole number and divided BID (twice per day ) for
5 days will be given with a maximal dose of 60 mg per day for the intervention group. This
dosing schedule is similar to other common pediatric uses of prednisolone including acute
asthma attacks. The placebo group will take the equivalent volume of OraSweet © Syrup
placebo. An additional volume of 3 doses will be provided to ensure proper redosing in the
event of emesis. Marked oral syringes will be provided by the pharmacy for ease of dosing.
The study medication or placebo is to begin on post-operative day 1 and will continue twice
daily through post-operative day 5. It will be suggested that all medications be taken with
food to minimize gastrointestinal side effects. Other post-operative medications will be
standardized and all will receive oxycodone elixir (0.05 mg/kg every 4 hours (Q4hr) as
needed), acetaminophen (15 mg/kg every 4 hours (q4hr) with a maximum dose of 500mg per dose)
and ibuprofen (10 mg/kg every 6 hours (Q6hr with a maximum of 400mg per dose) to be used
regularly. No post-operative antibiotics will be given as this is currently recommended
against by the American Academy of Otolaryngology - Head and Neck Surgery Foundation. Parents
will be advised to use acetaminophen and ibuprofen as primary medications for pain control,
and to use oxycodone only if inadequate pain relief with alternating acetaminophen and
ibuprofen.
Sample Size Determination Statistical analysis will be performed to evaluate for any
differences between the control and experimental groups using an analysis of covariance
design. For a 2 group design with 2 covariates and a medium-to-large effect size (alpha
0.05), a sample of about 80-180 participants would be needed to achieve a power of 0.80 or
above. Therefore in order to allow for some drop-out, our goal is to achieve a sample size of
200 participants.
Patient logs Attached are the patient logs that are to be used for this research study. Aside
from the Wong-Baker Faces scale, the remainder of the items in the patient logs to be used
are non-validated as no such tool currently exists for use of this purpose. Parents will be
asked to fill out a daily log for 5 days post-operatively focusing on aspects of pain
control, medication administration, activity level, and oral intake. Parents will be asked to
evaluate the child's pain on each post-operative day. Pain will be assessed in all patients
using the validated Wong-Baker FACES scale, which has been incorporated into our study
patient logs. Parents will be given a packet with written instructions and space to record
the child's pain level on each post-operative day, as well as space to record their pain
medication administration. They will also be given an activity and diet diary to monitor the
child's activity and diet.
Post-operative Survey Parents will be given a survey to complete at the post-operative visit
(Visit 3). The survey will be completed while they are at the office, so that we can clarify
or ask any further questions as needed. The survey will assess general compliance with the
study, as well as ask about any complications, including bleeding, ED visits, or hospital
admissions. This will allow us to capture any potential visits to outside emergency rooms
which we would not otherwise be aware of. If the parents indicates "yes" to the question
about whether they visited an emergency room, further details will be elucidated.
Data analysis Outcome measures will include: the amount of post-operative narcotics required
in the 5 day post-operative period, amount of other non-narcotic analgesic medications
(acetaminophen or ibuprofen) required in the 5 day post-operative period, time to return to
normal activity, and time to return to normal diet. Complications such as post-operative
bleeding, dehydration that requires an emergency department visit, and post-operative
infection requiring antibiotics will be monitored as well. As study subjects with
complications return to the Children's Hospital of Michigan Emergency Department, the study
team will be notified by the on call otolaryngology resident and appropriate measures can be
undertaken. Complication rates will be compared between the two study groups.
Drug Safety Monitoring Plan Adverse effects associated with post-operative oral steroids or
complications from tonsillectomy will be monitored via the research team using the data
collection sheets. During the period that the study is ongoing, Dr. Bianca Siegel will
compile all information on adverse events every three months beginning after the first 20
patients. The pharmacy will reveal the randomization groups and statistical analysis will be
performed to determine any significant difference in adverse events between the two groups.
Statistical analysis will be performed by a Wayne State University biostatistician. We will
monitor specifically for serious adverse events such as dehydration or post-operative
tonsillar hemorrhage. If a statistically significant increase in serious adverse events is
found between the study group and the placebo group, the study will be aborted. We will also
abort the study if there is a non-statistically significant difference, but a noticeable
trend of increased adverse events in the study group. Early in the study, our small sample
size may result in a lack of statistical significance despite a large increase in relative
risk of serious adverse events.
IV. Benefits
The potential physical benefits to a subject participating in this study include:
- Decreased narcotic use
- A faster return to normal activity
- A faster return to normal diet
- Decreased post-tonsillectomy complication rates
- Improvement in severity or resolution of obstructive sleep apnea
- Improvement in rates or resolution of recurrent tonsillitis/pharyngitis
The potential benefits to society include:
- Data-based information on the improvement of a normally very painful post-operative
tonsillectomy course following administration of prednisolone, with decreased necessity
for narcotic prescriptions
- The potential for a new standard of care for improving tonsillectomy surgical outcomes.
- Decreased costs to society from readmissions following tonsillectomy
V. Risks Short-term corticosteroid use is general considered safe. The most common adverse
reactions to steroids in the pediatric population include gastrointestinal upset,
hyperactivity, agitation, mood swings, and insomnia (up to 10%). Other, more infrequent risks
include adrenal suppression, delayed wound healing, glucose intolerance, myopathy, neuritis,
and weight gain (1-5%). These adverse events typically resolve with the discontinuation of
the corticosteroid. There are some reports of avascular necrosis of the hip, although these
are exceedingly rare. Corticosteroids, including prednisolone, are used for a variety of
pulmonary, rheumatological, and musculoskeletal pathologies in children and have stood the
test of time for safety and efficacy. These risks are mitigated by the short duration of use
of the medication, the encouragement to take the medication with food, the recommended dosing
schedule, and proper preoperative counseling and education regarding administration of
prednisolone.
As a part of this study and the current standard of care following tonsillectomy at DMC
Children's Hospital of Michigan, subjects will be prescribed acetaminophen (Tylenol ®) and
ibuprofen (Motrin ® or Advil ®) if acetaminophen is not tolerated. Oxycodone will also be
prescribed for additional pain coverage as needed as a normal part of the post-operative
course. A list of the more common and serious risks of each of the medications is as follows:
- Acetaminophen: swelling, itching, liver failure (very uncommon)
- Ibuprofen: nausea, vomiting, swelling, ringing in the ears (3-9%)
- Oxycodone: dizziness, nausea, vomiting, fatigue, sedation
There are risks associated with undergoing tonsillectomy including, but not limited to,
dehydration, bleeding, infection, trouble swallowing, painful swallowing, sore throat,
temporary voice changes, difficulty breathing, and, very rarely, death. These risks can be
lessened by good oral hydration and adequate pain management after surgery.
Social risks are unlikely to occur during the course of this study, but there is a small risk
of breach of confidentiality. In order to maintain your child's confidentiality, all of their
identifiable information will be kept separate from study documents.
