Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01837914 |
| Other study ID # |
H12-02721 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 2013 |
| Est. completion date |
December 2018 |
Study information
| Verified date |
November 2022 |
| Source |
University of British Columbia |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Obstructive Sleep Apnea is a serious medical condition affecting an estimated 1-5% of
children. The disease is believed to have several overlapping causes including large tonsils
and small or narrow jaws. This prospective, randomized cross-over study will evaluate the
effectiveness of orthodontic treatment of narrow upper teeth and jaws compared to the current
standard of care which is surgical removal of the adenoids and tonsils.
Patients will be evaluated by both an orthodontist and ENT physician, complete a series of
questionnaires and undergo an overnight sleep study, both initially and after undergoing the
randomized treatment. Patients who on reassessment have residual symptoms of sleep apnea will
then be crossed over and receive the other form of treatment. The levels of improvement to
both subjective (questionnaire) and objective (overnight sleep study) measures of sleep apnea
will then be compared.
The null hypothesis is there is no significant difference in improvement between maxillary
expansion and adenotonsillectomy in the objective and subjective outcome measures in children
with mild to moderate obstructive sleep apnea.
Description:
Background Literature Review Obstructive sleep apnea syndrome (OSAS) is a sleep disorder
characterized by recurrent, partial or complete episodes of upper airway obstruction,
commonly associated with intermittent hypoxemia and sleep fragmentation.1 The best data
available from international studies reports a prevalence rate of 1.2-5.7% in children.2-4
The potential consequences of OSAS in children are serious and include failure to thrive5,
attention deficit and hyperactivity disorder6, excessive daytime sleepiness7, and poor
learning6. There is also significant concern about long-term cardio-pulmonary risks in these
patients8. Not surprisingly, along with higher morbidity, children with OSAS also have higher
use of health care services starting from the first year of life9.
OSAS is a multifactorial disease, with the primary cause in children thought to be
hypertrophic tonsils and adenoids. However the persistence of OSAS following surgery to
remove the tonsils and adenoids is not uncommon. Recent studies using a moderate cut-off
apnoea-hyponea index (AHI) of greater than 5 events per hour in relatively low-risk
populations, have demonstrated that 13%10 to 29%11 of children have residual OSAS following
adenotonsillectomy (AT). Craniofacial form also clearly plays a role in pediatric OSAS as
skeletal discrepancies such as transverse maxillary deficiency have been strongly associated
with the disease12,13, and skeletal malocclusion has been found to be predictive of a higher
AT failure rate14. While the precise nature of the contribution of craniofacial proportions
to OSAS remains to be characterized, there is early evidence in the literature to support
maxillary expansion (ME) as an alternative treatment to surgery. Results of OSAS treatment
with ME have suggested that it may be effective in reducing sleep respiratory disturbances in
patients with15 and without16 tonsillar hypertrophy. However, limitations existing in the
study designs have left unanswered questions as to the role of ME in the treatment of
children suffering from OSAS. Furthermore the studies have been limited to patient
populations in Rome, Italy, and while anatomical factors are key determinants of the
predisposition to airway collapse, their relative importance for OSAS risk likely varies
between ethnicities.17 For this reason, further studies examining these effects on a diverse
multicultural population such as that found in North America and in particular urban centers
such as Vancouver, Canada are warranted to realize the potential of this novel form of OSAS
treatment.
Study Purpose The purpose of this study is to explore the efficacy of maxillary expansion in
the treatment of OSAS in children with tonsil and adenoid hypertrophy.
3. Hypothesis The null hypothesis is there is no significant difference in improvement
between maxillary expansion and adenotonsillectomy in the objective and subjective outcome
measures in children with mild to moderate obstructive sleep apnea.
4. Objectives 4.1: Aim 1- To validate the methodology. The methodology will be validated
through conducting this pilot study and analyzing the preliminary data that are generated -
if required, improvements in methodology design can be identified during this pilot study to
assist in design modification before a larger multi-site study.
4.2: Aim 2- To obtain preliminary data to provide the basis for a larger scale multi-centre
randomized controlled trial The results of this study will be analyzed, and if it is
under-powered to avoid type II error as predicted from the sample size calculations, the data
will used to leverage further funding for a multi-site study.
5. Methods and Statistics 5.1: Research Design Pilot, randomized, controlled single-blinded
crossover study. (see Figure 1 - Study Design).
5.2: Study Patient Selection The study patients will be recruited from the Pediatric
Otolaryngology Outpatients Clinic and the Pediatric Sleep Disorders Clinic at BC Children's
Hospital, with fully informed consent from parents/caregivers and assent from study patients.
Inclusion criteria:
- Ages 5.0 to 10.0 years at the time of screening;
- Diagnosed with obstructive sleep apnea defined as AHI>2, confirmed on overnight,
laboratory-based PSG;
- Parental report of witnessed apneas or habitual snoring (on average more than 3 nights
per week);
- Deemed to be a candidate for ME by orthodontic evaluation;
- Deemed to be a candidate for tonsillectomy and adenoidectomy by otolaryngologic
evaluation.
Exclusion criteria:
- Severe OSA or significant hypoxemia in the presence of tonsillar or adenoid hypertrophy
requiring surgical intervention defined as AHI>25 or SpO2 <90% for >2% sleep time.
- An associated craniofacial syndrome or anomaly, including cleft lip and/or palate, or
any anatomic or systemic condition that would otherwise exclude the patient from
orthodontic treatment.
- Recurrent tonsillitis that meets American Academy of Otolaryngology - Head and Neck
Surgery clinical practice guidelines for surgery.
- Extremely overweight defined as a body mass index z-score > 2.99 for age group and sex.
- Severe health problems that could be exacerbated by delayed treatment for OSA,
including: severe cardiopulmonary disorders (e.g., cystic fibrosis, congenital heart
disease); sickle cell disease; poorly controlled asthma (with > 1 hospitalization in
last year); epilepsy requiring medication; diabetes (type 1 or type 2) requiring
medication; doctor-diagnosed heart disease or cor pulmonale; or a history of stage II
hypertension (HTN) defined as > 99% percentile and/or requiring medication.
- Psychiatric or behavioral disorders that would otherwise exclude the patient from
receiving orthodontic treatment
5.3: Intervention Before initiating the intervention the child will undergo overnight
polysomnography (PSG), clinical examination by a Pediatric Otolaryngologist and an
Orthodontist, as well as a series of validated parental questionnaires relating to sleep
habits and quality of life of their child. The intervention period is 4 months with equal
numbers of patients being randomized to treatment with either ME or AT.
At the end of the 4-month intervention period all children will be recalled to the Pediatric
Obstructive Sleep Apnea Clinic at BC Children's Hospital. Again patients will be examined by
the PI Pediatric Otolaryngologist and Orthodontist and undergo a repeat series of
examinations, sleep studies and questionnaires in the same fashion as their initial
appointment. Patients who present with residual OSAS, defined as an AHI>2, on their follow-up
sleep study will be crossed over to the other treatment arm of the study. Treatment protocols
will be identical to those described and used in the first phase of the study.
Patients requiring the second intervention will be recalled for a follow-up assessment,
repeating the series of data collected at their initial appointment. This will again include
overnight polysomnography (PSG), clinical examination by a Pediatric Otolaryngologist and an
Orthodontist, as well the parental questionnaires relating to sleep habits and quality of
life of their child. (see Figure 1 - Study Design)
Children who still have an abnormal AHI after the second intervention (treatment failures)
will be referred to the Sleep Clinic at BC Children's Hospital for further assessment and
reviewed by the Pediatric Respirologist for consideration of other levels of obstruction that
may require either further surgical intervention or prescribed continuous positive airway
pressure (CPAP).
5.4: Primary and Secondary Outcomes
Primary outcome:
Primary outcome measure will be change in AHI between initial and post-intervention overnight
PSG. All children will undergo an attended overnight polysomnography (sleep study) at B.C.
Children's Hospital Pediatric Sleep Laboratory. The data recorded will include the typical
montage monitoring of electroencephalography (EEG), electrooculography (EOG), chin and leg
electromyography (EMG), and one electrocardiography (ECG) lead. Respiration is monitored with
nasal cannula, mouth thermistor or thermo-couple, thoracic and abdominal bands, finger pulse
oxymetry, and neck microphone. Scoring of sleep stages and of respiratory events will follow
previously-accepted published guidelines.
The American Academy of Sleep Medicine, the American Academy of Pediatrics, and the American
Academy of Otolaryngology all define obstructive sleep apnea as an AHI >1, as calculated by
overnight polysomnography. The articles cited in our rationale use a moderate cutoff point of
AHI>5 out of convenience in order to highlight their outcome data.
The use of an AHI>2 for the present study is based on a large body of literature, including a
recently published outline of an ongoing multi-centered clinical trial (Redline et al. Sleep
2011;34(11):1509) examining the outcomes of surgical treatment of OSA, which also used an
AHI>2 as inclusion criteria for the study. A cutoff of 2 is used as a conservative measure to
ensure ample justification for treatment. Furthermore, as maxillary expansion treatment is
considered less invasive than the standard surgical AT intervention, the inclusion of
patients with mild OSAS who might most benefit from non-surgical treatment is justified.
Secondary outcome:
Secondary outcome measures include changes in the Children's Sleep Habits Questionnaire18
(CSHQ), and the OSAS Quality of Life Survey19 (OSA-18) between the initial and
post-intervention (4 months) timepoints. The CSHQ is a retrospective 45-item parent reported
sleep-screening instrument to delineate sleep habits and identify problematic sleep domains
in school-aged children. The CSHQ includes items relating to a number of key sleep domains
that encompass the major presenting clinical sleep complaints in this pediatric age group:
bedtime behavior and sleep onset; sleep duration; anxiety around sleep; behavior occurring
during sleep and night wakings; sleep-disordered breathing; parasomnias; and morning
waking/daytime sleepiness. Parents are asked to recall sleep behaviors occurring over a
"typical" recent week.39 The OSA-18 is an 18-item questionnaire that uses a Likert-type
scoring system to collect information about 5 subscales that are considered to be elements in
quality of life: sleep disturbance, physical symptoms, emotional symptoms, daytime function,
and caregiver concerns.40 This is also completed by the parent. The Glasgow Children's
Benefit Inventory: a new instrument for assessing health-related benefit after an
intervention. Ann Otol Rhinol Laryngol. 2004;113(12):980-6). This is a validated instrument
specifically designed to measure caregiver satisfaction with a procedural intervention and is
ideal for our purpose. This is completed by the parent.
5.5: Randomization The parent or guardian will receive verbal and written detail of the
study, and be given the opportunity to consider this information before providing informed
consent to participate. If a decision to participate is made, the child will be allocated a
study reference number by the study coordinator. Randomization will be based on a
pre-established randomization table. To ensure an even distribution of study patient numbers
between the groups, patients will be randomized in blocks with blocks sizes randomized
between 2 and 4 to prevent identification bias. It is also pre-established that if a child
(or their caregiver) decides to opt-out of the study after randomization but before beginning
any treatment, the next identified child would be a replacement for the drop-out child with
same treatment schedule. If a child dropped out once the any treatment is initiated, there
would be no replacement and the subject would be included in the analysis on an
intention-to-treat basis.
For children randomized to ME, treatment will begin either at the private dental office of
the Principal Investigator or in the Dental Department of BC Children's Hospital. Expansion
treatment will be performed by the PI Orthodontist. Additional treatment or referral for
comorbidities and education regarding general sleep hygiene and healthy behaviors, and use of
nasal saline spray as needed for nasal mucosal crusting or dryness will also be initiated.
Costs for orthodontic treatment are not typically covered by the provincial heath insurance
plan and therefore will be paid through the operating costs of the study. The ME protocol
will follow the standard of care for orthodontic treatment of maxillary constriction. Pre and
post-treatment records including lateral and posterior-anterior cephalometric and panoramic
radiographs, dental study casts, and intra and extra-oral photos will be collected. An
expansion appliance will be bonded to the molar teeth of the upper arch, with a rate of
expansion set at 0.25mm each day. A minimum of 7mm of total expansion will be performed. An
expansion appliance may be also attached to the lower arch at the discretion of the treating
orthodontist should it be indicated by the clinical conditions of the patient. ME patients
will have follow up appointments to access the progress of expansion at 2 week intervals for
the first month, then monthly until appliance removal 4 months later. Upon removal of the
expansion appliance, patients will be provided with a removable dental retainer and then
recalled 6 months later for observation as for non-study patients undergoing this form of
orthodontic treatment.
For those patients randomized to AT, the procedure will follow the standard of care for this
procedure. The AT will be performed by the co-investigator Pediatric Otolaryngologist at the
BC Children's Hospital. A standardized technique for tonsillectomy (using bipolar
extracapsular dissection) and adenoidectomy (using monopolar suction cautery) will be used.
Patients will have the standard peri-operative care, post-operative monitoring, and
post-operative follow-up as for non-study patients undergoing this procedure for this
indication. Additional treatment or referral for comorbidities and education regarding
general sleep hygiene and healthy behaviors, and use of nasal saline spray as needed for
nasal mucosal crusting or dryness will also be initiated.
5.6: Blinding Assessment and scoring of the primary (overnight sleep studies) outcome
variable will be performed by Dr. David Wensley, director of the BCCH Sleep Lab. Dr. Wensley
will be blinded to the treatment received by each patient.
5.7: Sample Size For this pilot study we anticipate recruiting 30 patients, with 15 entering
into each initial treatment arm of the study. An informal audit of the referral pattern to
the Pediatric Otolaryngology Clinic at BC Children's Hospital has revealed that approximately
15-25 potentially eligible subjects are seen per month. Therefore assuming a very
conservative recruitment rate of 5 subjects per month, investigators estimate it may take
approximately 6 months to complete subject enrollment,
Drop-out/non-compliance rate:
We estimate a low drop-out rate from the study, based on other studies of this age-group and
pathology, and we expect drop-outs to be unrelated to treatment effectiveness, therefore
would be randomly distributed between the groups. Assuming a drop-out rate of around 30%, we
will require recruitment of 39 study patients to have complete data on 30 study patients.
Study Patient compliance:
To reinforce general study participation, after two months a research assistant will contact
via telephone all patients' families to provide advice as well as for safety and adverse
event monitoring. At the end of the 4-month intervention period all children will be recalled
to BCCH for follow-up examinations and testing.
However due to the invasive nature and inconvenience for children and their family to attend
an overnight sleep study at a hospital, recruitment into the study and the possibly required
three PSGs may become an issue. To overcome this concern, a patient incentive of $50 per
sleep study, to compensate the family for their time and inconvenience as been budgeted.
5.8: Data
Data handling and record keeping:
A study coordinator will be responsible for data collection and storage of randomization
codes. The numeric data will be stored electronically using REDCap. All electronic files will
be password protected. Information about study patients and study materials will be kept in a
locked file cabinet in the Ear, Nose and Throat Clinic at BCCH. The study records will
continue to be stored in these lockers 5 years after the study has completed.
Data analysis:
A two-sample t-test will be used to compare groups after randomization into the two treatment
arms. Repeated measures ANOVA will be used to evaluate overall treatment effect between
initial and follow up data for the primary and secondary outcome measures.
A logistic regression model will be used to relate AHI to combined dental and craniofacial
variables. Pearson correlation will measure initial intermolar width, mandibular plane angle
and tonsillar score to changes in the PSG parameters, OSA-18 and CSHQ score before and after
treatment. Receiver operating characteristic (ROC) curves will be constructed to determine
the sensitivity and specificity associated with any given cutoff of the dentofacial variables
in predicting PSG diagnosed OSA. For all statistical analyses P < .05 will be considered
statistically significant. The results of this pilot study will be underpowered to provide
any statistically significant conclusions, however the initial data will be invaluable in
future grant applications necessary for larger scale clinical trials, as well as for
streamlining patient flow and participation within the Pediatric Obstructive Sleep Apnea
Clinic at BCCH. Analysis of this preliminary data will also guide future work to focus on
specific measures and outcomes of potential significance.
6. Risk
This study carries no significant safety risk to the participants, beyond the recognized
risks of the two interventions:
ME: Minor risks include those associated with undergoing routine and well-established
orthodontic treatment for maxillary constriction. As with any intra-oral procedure, there is
a risk of aspirating or ingesting materials or instruments, as well as irritation of the soft
and hard tissues of the oral cavity. These risks are well understood and generally accepted
by patients and parents in the routine delivery of any form of dental or orthodontic care.
AT: Adenoidectomy and tonsillectomy can be associated with post-operative infection or
post-operative hemorrhage, sometimes requiring antibiotic administration (<10%), readmission
to hospital (<2%), and/or a return to the operating room for hemostatic control (<2%). These
risks have low incidence, and are inherent to the surgical procedure, but are not specific to
this research study. As adenotonsillectomy is the current standard of care for these
subjects, no additional risk is being undertaken to participate in this study if this
intervention is included.
The risk of undergoing ME as the first intervention, subsequently failing to improve, and
therefore being subject to a minimum 4 month delay before receiving of the current standard
of care intervention (AT) - is recognized to have minimal clinical significance in this
population of children with non-severe OSA.
7. After the study Study patients will be followed by the Pediatric Otolaryngology Clinic at
BC Children's Hospital on an as needed basis, but as a minimum patients will be recalled at 6
months following their completion of the study, or normalization of their symptoms, to assess
the long-term improvement to their sleep disordered breathing. This appointment will consist
of a clinical exam and general questions to both the patient and parents, as would be
standard for any post-treatment follow-up appointment in the Otolaryngology department
8. Difficulties and Limitations The main weakness of the study stems from the fact that it is
a pilot project for the interdisciplinary management of children with OSA. Patient flow
through the study will require careful monitoring and coordination between three different
departments within BCCH.
To maximize efficiency and convenience for participating patients, the PI, Co-Investigator,
and study coordinator will meet at least twice monthly to review any adverse events in
patient flow through the study or timely delivery of study interventions.
