The ConVenTu study is a multicenter randomized non-inferiority study conducted in clinical settings of seven hospitals located in all four Regional Health Authorities in Norway. The postoperative care is assessed by either an otolaryngologist at the hospital where VT surgery was performed, or by the patients’ regular GP. A flowchart of design and timeline in the study is presented in figure 1, and a SPIRIT schedule of enrolment, interventions, and assessments in figure 2.
Eligible participants are children, age 3-10 years, where VTs are placed in one or two ears. Exclusion criteria are conditions that need closer postoperative care by otolaryngologists: medical syndromes (e.g. Downs syndrome), other coexisting severe diseases, or severe neurogenic hearing loss in at least one ear (children with > 50 dB hearing threshold in at least one frequency 0.25 - 4.0 KHz are excluded). Also, children with cognitive impairment or no comprehension of Norwegian language are excluded.
Random allocation of level of expertise for postoperative control of VTs
After discharge from the hospital, each patient who agreed to participate, is randomly allocated to receive postoperative care by either an otolaryngologist or by their regular GP (Figure 1). The randomization procedure is computerized and carried out by means of the ‘WebCRF’ software developed at Unit for Applied Clinical Research at The Faculty of Medicine and Health Sciences, NTNU (16). The design is block randomization with varying size of blocks, with an allocation ratio of 1:1, stratified on study center.
Procedures for postoperative controls
Children randomized to postoperative care by otolaryngologists will receive an appointment at 6, 12 and 18 months after surgery, to reflect the existing management of these patients in Norway. Postoperative care by GPs will not be planned appointments, but on the initiative of the parents as this reflects existing management in general practice. Parents of children randomized to the GP group will receive written information on when they need to contact their GP; for instance, if the child is suffering from otorrhea, persistent reduced hearing, or otitis media. The GPs receive information regarding the study and a procedure for postoperative care on how to treat the most common complications. In addition, a procedure for handling complications are enclosed in the hospital discharge letter after surgery, therefore it is available for the GPs at point-of-care. If needed, the GP can refer the children to an otolaryngologist. If the VTs have not been spontaneously expelled within 18 months, the GP is requested to refer the patient to an otolaryngologist. Accordingly, the parents are told to contact the GP latest 18 months after surgery (Figure 1).
Audiological tests and assessment of sociodemographic factors
All participants will be evaluated with audiological tests prior to surgery and two years following surgery. Audiological tests are performed with audiometry and tympanometry at the hospital where the surgery takes place. Hearing thresholds are measured by pure tone audiometry. In the youngest children equipment for play audiometry is used if needed (17). Results from at least three of the pure tone thresholds in dB at 0.5-1-2-4 kHz form the pure tone average (PTA), the main clinical outcome in this study. Two years after surgery an otolaryngologist will examine all participants. Complications during the postoperative period will be registered by carefully examining the patient record.
Sociodemographic information is assessed through questionnaires at enrollment. Both before and two years after surgery the parents are asked to complete questionnaires regarding their perception of the child’s HRQoL. The parents’ evaluation of the postoperative controls is assessed through questionnaires at the end of the follow-up period. Each study center has a local coordinator responsible for a Case Report Form to ensure complete recording of individual data.
Primary and secondary endpoints
Hearing thresholds two years after surgery, measured as PTA, is the main clinical outcome and defined as primary endpoint.
The following clinical and sociodemographic factors are considered as secondary endpoints:
- Middle ear function assessed with tympanometry and otomicroscopy (18)
- Complication rates
- Disease specific HRQoL by the otitis media questionnaire for children (‘OM8-30’) (19)
- Generic HRQoL by ‘PedsQL’, based on proxy-report (participants aged 3-8 years) or by adolescent self-report (8-12 years) and ‘SDQ-Nor’ (20, 21)
- Parents evaluation of the postoperative care
The secondary endpoints measures no. 1-2 act as surrogate markers for possible reduced hearing thresholds in the future. The secondary endpoints measures no. 3-5 is assessing the risks and benefits of postoperative care and important for patient-centered care.
The Department of Otolaryngology, Head and Neck Surgery at St. Olavs Hospital is the main investigator center and is responsible for coordination with the other participating hospitals. The study is organized in collaboration with the Norwegian University of Science and Technology (NTNU).
The steering committee is responsible for the implementation and progress of the study, applications, and data-management. The principal investigator, the study director and the main project coordinator are members of the steering committee and have regularly communication. The reference group supports the decision making and governance processes of the study. We have regular internal trial audits from the trial sponsor at the main investigator center. Study visits have been performed at all study sites to identify and overcome reasons which could hinder recruitment. In addition, meetings with all participating hospitals and user representatives are held bi-annually.
All handling of personal data will be in accordance with the EU General Data Protection Regulation (GDPR), as implemented at NTNU and St. Olavs hospital. All personal information will be anonymized. The anonymized data is only available for the steering committee. Processing of personal study audiological data will be done according to procedures approved by the data protection official at each study center. The nurses at the outpatient clinics are responsible for taking informed consent. The main project coordinator does the final check-up that all informed consents are taken and that they are stored in a secured place.
Figure 1. Flowchart
Figure 2. Schedule of enrolment, interventions, and assessments.
*PTA=Pure Tone Average, dB=decibel, HRQoL=Health Related Quality of Life, OM8-30, PedsQL, SDQ-Nor: see manuscript
Sample size and power
In this non-inferiority study, we defined equality in PTA two years after surgery (primary endpoint) as < 5dB (5dB as equivalence margin). Hearing thresholds are determined in 5dB steps and we also consider 5dB as the minimum difference of clinical importance (22). To avoid an incorrect conclusion of no difference between the groups (Type II error), the power of the tests for detecting a difference of ≥ 5 dB must be high (≥ 95 %, error margin <5 %). Thus, with a power of 95% and a significance level of 5% (two-sided test), 105 participants is needed in each group to be able to detect an absolute difference in mean PTA between the groups of ≥5 dB (standard deviation of 10 dB in each group). With additional 15% for dealing with a potential skew distribution of hearing level, and a 20% further increase to account for potential dropouts during the follow-up period, we are left with a sample size of 145 participants in each group. To maintain power in an analysis stratified for seven study centers (six additional parameters in model), the total sample size must be increased by at least 60 participants, applying general rules of thumb of at least 10 cases per parameter. If we assume that the 60 participants are evenly distributed in the two randomization groups, this leaves us with a sample size of at least 175 participants in each group. We chose to truncate upwards to 200 participants in each group (Figure 1) to maintain power in case of a higher dropout rate or a need for inclusion of additional adjustment factors.
The analyses will be performed according to intention-to-treat. Unadjusted two-sample T-tests, and a general linear model and/or a linear mixed model (LMM), with study center as fixed or random factor, respectively, will be applied to compare mean PTA two years after surgery. To quantify the effect of the treatment, and to validate results in case of potential inequalities between the two randomization groups. Furthermore, we will also compare the mean change in PTA after two years (change from baseline). Similar analytic methods will be applied for other relevant variables that are measured on a continuous scale (HRQoL). Log-transformation, or non-parametric methods, may need to be considered. Generalized linear mixed model, and/or McNemar’s test is relevant for analyzing changes in categorical, dichotomous outcome variables. A Chi-square test, or Fischer exact test, is relevant for comparing the two study groups with respect to number of complications during postoperative care. Equality between the two treatment groups will be evaluated in terms of the magnitude of observed differences (point and interval estimate).