Short-term outcomes of cochlear implantation for single-sided deafness compared to bone conduction devices and contralateral routing of sound hearing aids—Results of a Randomised controlled trial (CINGLE-trial)

Jeroen P M Peters; Jan A A van Heteren; Anne W Wendrich; Gijsbert A van Zanten; Wilko Grolman; Robert J Stokroos; Adriana L Smit

doi:10.1371/journal.pone.0257447

. 2021 Oct 13;16(10):e0257447. doi: 10.1371/journal.pone.0257447

Short-term outcomes of cochlear implantation for single-sided deafness compared to bone conduction devices and contralateral routing of sound hearing aids—Results of a Randomised controlled trial (CINGLE-trial)

Jeroen P M Peters ^1,², Jan A A van Heteren ^1,^2,^#, Anne W Wendrich ^1,^2,^#, Gijsbert A van Zanten ^1,², Wilko Grolman ³, Robert J Stokroos ^1,², Adriana L Smit ^1,^2,^*

Editor: Vance Berger⁴

PMCID: PMC8513831 PMID: 34644322

Abstract

Single-sided deafness (SSD) leads to difficulties with speech perception in noise, sound localisation, and sometimes tinnitus. Current treatments (Contralateral Routing of Sound hearing aids (CROS) and Bone Conduction Devices (BCD)) do not sufficiently overcome these problems. Cochlear implants (CIs) may help. Our aim was to evaluate these treatments in a Randomised Controlled Trial (RCT). Adult SSD patients were randomised using a web-based randomisation tool into one of three groups: CI; trial period of ‘first BCD, then CROS’; trial period of ‘first CROS, then BCD’. After these trial periods, patients opted for BCD, CROS, or No treatment. The primary outcome was speech perception in noise (directed from the front (S₀N₀)). Secondary outcomes were speech perception in noise with speech directed to the poor ear and noise to the better ear (S_peN_be) and vice versa (S_beN_pe), sound localisation, tinnitus burden, and disease-specific quality of life (QoL). We described results at baseline (unaided situation) and 3 and 6 months after device activation. 120 patients were randomised. Seven patients did not receive the allocated intervention. The number of patients per group after allocation was: CI (n = 28), BCD (n = 25), CROS (n = 34), and No treatment (n = 26). In S₀N₀, the CI group performed significantly better when compared to baseline, and when compared to the other groups. In S_peN_be, there was an advantage for all treatment groups compared to baseline. However, in S_beN_pe, BCD and CROS groups performed worse compared to baseline, whereas the CI group improved. Only in the CI group sound localisation improved and tinnitus burden decreased. In general, all treatment groups improved on disease-specific QoL compared to baseline. This RCT demonstrates that cochlear implantation for SSD leads to improved speech perception in noise, sound localisation, tinnitus burden, and QoL after 3 and 6 months of follow-up. For most outcome measures, CI outperformed BCD and CROS.

Trial registration: Netherlands Trial Register (www.trialregister.nl): NTR4580, CINGLE-trial.

Introduction

Single-sided deafness

Single-sided deafness (SSD) is defined as severe to profound hearing loss in one ear and near to near-normal hearing in the contralateral ear [1]. Patients with SSD often experience problems with speech perception in noise and sound localisation, because they lack binaural benefits [2]. Specifically, they cannot benefit from the binaural summation effect (redundancy of auditory input) and the squelch effect (the ability of the brain to suppress noise on the side with the best signal-to-noise-ratio using the noise information of the contralateral side) [2,3]. Moreover, the head acts as an acoustic barrier and attenuates signals from the contralateral side (head shadow effect) [2,4]. The head shadow effect can be of benefit for SSD patients when the speaker is on the side of the better hearing ear, but it may deteriorate speech perception when the speaker is on the deaf side. Furthermore, SSD patients frequently suffer from tinnitus in the affected ear [2,5]. Due to these hearing-related difficulties, patients with SSD may experience problems in social interaction and communication, possibly negatively affecting their quality of life (QoL) [6–8].

CROS and BCDs

In most countries, there are currently two reimbursed treatment options for patients with SSD: Contralateral Routing of Sound hearing aids (CROS) and Bone Conduction Devices (BCDs). A CROS transfers signals from the hearing field of the poor ear to an output transducer in the ear canal of the better ear, so that awareness for sound at the poor side is restored. A BCD conducts signals from the hearing field of the poor side to the cochlea of the better ear by vibration of the skull bone via a titanium implant or tight headband. CROS and BCD can alleviate the head shadow effect and restore sound awareness from the impaired side [9,10]. However, neither modality provides auditory input to the deaf ear, and thus binaural hearing cannot be restored [10].

So far, only retrospective case series comparing CROS and BCD for SSD have been published (for a review see Peters et al. [11]). The included studies often had small sample sizes, unclear inclusion criteria and a moderate to high risk of bias. As demonstrated in this review [11], CROS and BCD only led to improved speech perception in noise when speech was presented to the impaired ear. Both treatment modalities and the unaided condition show equal results for sound localization. Quality of life did not differ significantly between conditions, but quality of hearing improved for the speech communication subscales of the Abbreviated Profile for Hearing Aid Benefit (APHAB) questionnaire.

Cochlear implantation

Since a cochlear implant (CI) provides input to the auditory nerve of the deaf ear, binaural input can be partially restored. Consequently, cochlear implantation led to improved speech perception in noise and sound localisation in patients with SSD [12–14].

Tinnitus is frequently believed to be the consequence of (central) auditory deprivation due to hearing loss. Cochlear electrical stimulation of the auditory nerve is assumed to have a beneficial influence on tinnitus burden [15]. Recent studies reported lower tinnitus burden following cochlear implantation in SSD patients [16–18].Moreover, (disease-specific) quality of life of SSD patients was also improved following cochlear implantation [13,17,19].

However, previously published studies on CI for SSD often had retrospective study designs, unclear eligibility criteria and definitions of SSD, small sample sizes with lack of statistical power, or no power calculations (see reviews [9,17,20]). Although recently published studies showed improved methodology with larger sample sizes and prospective trials design, randomised allocation of treatment to ensure equal distribution of known and unknown confounders amongst groups was not performed.

Need for current trial

To provide higher level of evidence about the treatment outcomes of CI, BCD, and CROS for SSD, we designed a Randomised Controlled Trial (RCT). In this paper we publish the short-term results of our RCT comparing CI, BCD, CROS, and No treatment for patients with SSD. The outcomes of interest were speech perception in noise, sound localisation, tinnitus burden, and disease-specific QoL at 3 and 6 months follow-up (out of total follow-up duration of 5 years). Later follow-up moments as well as other secondary outcomes (e.g. generic QoL, cost utility) will be discussed later.

Materials and methods

The research protocol of this study was approved by the Institutional Review Board of the University Medical Center Utrecht (NL45288.041.13) and is registered in the Netherlands Trial Register (www.trialregister.nl, NTR4580). For a detailed description of the CINGLE-trial (Cochlear Implantation for siNGLE-sided deafness), we refer to the study protocol [21] or S1 File. The authors confirm that all ongoing and related trials for this drug/intervention are registered. Details about patient recruitment, sample size calculation, and ethical considerations are described here. All patients provided signed Informed Consent between July 2014 and February 2019, and the last follow-up visit took place in March 2020. After approval of the study protocol, but before the first patient was included in the trial, we amended the trial protocol to also measure at 3 months follow-up. In the current paper we presented a summary of the methods to assess the presented outcomes. This RCT is reported according to the CONSORT guidelines [22], and a separate CONSORT Checklist is uploaded as S2 File.

Study population

Patients were eligible for inclusion if they fulfilled the following criteria:

age 18 years or older;
Pure Tone Average threshold at 0.5, 1, 2, 4 kHz: of the best ear (PTA_be) maximum 30 dB HL, and of the poor ear minimum 70 dB HL;
duration of SSD minimum 3 months and maximum 10 years;
health status allows general anaesthesia and surgery for the potential implantation of BCD or CI
Dutch language proficiency
coverage of Dutch health insurance
willingness and ability to participate in all scheduled procedures outlined in the protocol

Patients were not eligible for inclusion if they had retrocochlear pathology or abnormal cochlear anatomy (e.g. ossification) or an implanted BCD. Patients were referred to our tertiary clinic by otolaryngologists or audiologists who were informed of our trial at national meetings. Patients were also informed of our trial via announcements on the websites of SSD patient associations, and could contact the research team directly.

Study design

Patients were randomised in one of three groups by a web-based randomisation tool (ratio 2:3:3, block randomisation):

CI (type: Cochlear™);
trial period of first BCD on headband, then CROS;
trial period of first CROS, then BCD on headband (see also Fig 1).

Fig 1 — See S3 File for an explanation of the numbers per group at different moments.

In the latter two groups (BCD-CROS, CROS-BCD), each device was tested for six weeks. The reversed order of the trial periods in the BCD-CROS and CROS-BCD groups was implemented to correct for the order effect: patients may judge their second hearing aid based on experiences with the first hearing aid. After the trial period, patients were asked which of both treatments they preferred: when they opted for BCD, the abutment was surgically implanted and after six weeks fitted with a BCD (Cochlear™). Patients who opted for a CROS were referred to a local audiologist to purchase a CROS, and later device settings were optimized by an experienced audiologist from our audiological center. Patients could also opt for ‘No treatment’ if neither BCD nor CROS was preferred. This trial period and the possible options resemble the current clinical practice in The Netherlands for single-sided deaf patients. Following the trial period, four groups were assessed:

CI;
BCD;
CROS;
No treatment.

In this paper, we report on data obtained at baseline (i.e. unaided situation), at 3, and at 6 months follow-up (i.e. after activation of CI, fitting of CROS or BCD, or unaided after the end of the trial period for patients that opted for no treatment, respectively).

Outcomes

Speech perception in noise and sound localisation were measured in the Crescent of Sound test set-up [23] following the same protocol. Patients were instructed not to move their head.

Speech perception in noise

The primary outcome was speech perception in noise, with speech and noise coming front the front (S₀N₀) with the Utrecht Sentence Test with Adaptive Randomized Roving Levels (U-STARR) [24]. The U-STARR is designed to determine a patient’s ability to understand speech in a noisy environment. Five key words were selected in long sentences and 3 key words in shorter sentences. A sentence was considered to be understood correctly when a subject repeated at least 3 out of 5 or 2 out of 3 key words correctly. Sentences were presented at 65, 70, or 75 dB SPL (randomly selected) with an initial signal-to-noise-ratio (SNR) of +20 dB (sentence 20 dB louder than noise). When the sentence was repeated correctly, the SNR of the next sentence was decreased. If repeated incorrectly the SNR for the next sentence was increased. The SNR step size was adaptively decreasing from initially 10 to 5, and to 2.5 dB. At the latter size at least 10 sentences were presented, the mean of which was the measurement outcome. Noise was presented 500 ms before the start of the sentence and ended 500 ms after the sentence. Additionally, speech perception in noise was measured with speech directed to the poor ear (pe) and noise directed to the better ear (be) and with speech directed to the better ear (be) and noise directed to the poor ear (pe) (S_peN_be and S_beN_pe, respectively), with the stimuli coming from -60° and +60°. The outcome was a speech reception threshold in noise (SRTn) in dB at which patients were able to repeat 50% of the sentences correctly [24].

Sound localisation

The stimulus (sentence “hello, what’s this?”, spoken by various female English speakers) for the sound localisation task was presented in quiet (roving level of 55–65 dB SPL) in three configurations: 5 loudspeakers separated by an angle of 15° (-30°, -15°, 0°, +15°, and +30°); 5 loudspeakers separated by an angle of 30° (-60°, -30°, 0°, +30°, and +60°); 3 loudspeakers separated by an angle of 60° (-60°, 0°, and +60°). The patient had to indicate from which loudspeaker the stimulus came. The outcome was a percentage correct score (30 sentences per configuration were presented).

Tinnitus

At baseline and at 3 and 6 months follow-up, patients indicated whether they had tinnitus or not. If yes, tinnitus questionnaires were completed. In this paper we report outcomes of the validated Dutch versions of the Tinnitus Questionnaire (TQ) as a self-report measure of tinnitus-related distress [25,26] and of the Tinnitus Handicap Inventory (THI) that quantifies the impact of tinnitus on daily life [27].

Disease-specific QoL

Patients completed three disease-specific QoL questionnaires:

The Speech, Spatial and Qualities of hearing (SSQ) scale [28] assesses three domains of hearing in everyday life.
The APHAB questionnaire [29] has four subdomains: ease of communication (EC), listening under reverberant conditions (RV), listening in background noise (BN), and aversiveness of sounds (AS).
The Glasgow Benefit Inventory (GBI) is validated to measure outcomes on health status after otorhinolaryngological procedures [30]. The GBI is scored on three subscales (general, social support, and physical health).

Statistical analysis

None of the outcome variables were normally distributed, so we used non-parametric tests. We used a generalized estimating equation (mixed model) to compare values within groups over time and between groups at follow-up moments. Due to the nature of our interventions, subject data were analysed ‘as treated’. All figures show boxplots with medians, 1^st and 3^rd quartiles, and minimum/maximum values to show the distribution of data.

Because there was a low percentage of missing data for all outcomes, we chose not to use multiple imputation as was stated in the study protocol. Instead, we performed a complete case analysis (missing data: speech perception in noise 0.9%, sound localisation 0.9%, TQ 3.5%, THI 3.5%, SSQ 1.2%, APHAB 3.8%, and GBI 1.9%). A statistically significant result was defined as a p-value <0.05. Statistical package SPSS version 25.0 (IBM Corp., Armonk, NY, USA) was used.

Results

Patient characteristics

We assessed 633 patients for eligibility. Of these, 513 patients were excluded due to various reasons (see Flow diagram in Fig 1). In total, 120 patients were randomised into three groups: 29 patients to the CI group, 45 patients to the ‘first BCD, then CROS’ group, and 46 patients to the ‘first CROS, then BCD’ group. Not all patients received the allocated intervention; for an explanation of the numbers per group, see S3 File.

Table 1 shows the patient characteristics of our study population per group after randomisation. The mean age at inclusion of the complete study sample was 53.0 ± 12.1 (standard deviation, SD) years, the median PTA_be was 15.0 dB (range 2.5–30.0 dB) and the median duration of deafness was 1.8 years (range 3 months– 10 years).

Table 1. Patient characteristics per group after randomisation.

	CI	BCD, CROS	CROS, BCD	Statistics
Gender
Male:Female	14:15	24:21	20:26	ns^a
Age at inclusion (years)
Mean (SD)	53.2 (13.1)	53.6 (12.6)	52.3 (11.2)	ns^b
PTA_be (0.5–4 kHz) (dB)
Mean (SD)	15.6 (7.1)	15.6 (6.9)	15.1 (6.8)	ns^c
Median [range]	15.0 [5.0–30.0]	15.0 [6.3–30.0]	15.6 [2.5–28.8]
Duration of deafness (years)
Mean (SD)	3.1 (2.8)	3.1 (3.3)	2.7 (2.7)	ns^c
Median [range]	1.9 [0.3–10.0]	1.3 [0.3–10.0]	1.8 [0.3–10.0]
Etiology
Unknown	6	10	13	ns^a
Iatrogenic	1	1	0
Sudden deafness	15	21	23
Labyrinthitis	4	4	4
Infection (not otherwise specified)	0	3	1
Ménière’s disease	3	4	3
Traumatic	0	2	2

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Abbreviations:

CI = Cochlear Implant, BCD = Bone Conduction Device, CROS = Contralateral Routing of Sound hearing aid, SD = standard deviation, PTA_be = Pure Tone Average threshold of the best ear at 0.5, 1, 2, 4 kHz (dB), ns = not significant.

^a Fisher’s Exact test.

^b One-way ANOVA.

^c Kruskal Wallis test.

The patient characteristics of the groups after allocation of treatment (i.e. CI activation, BCD implantation and CROS fitting) and for the No treatment group are displayed in S1 Table. There were no significant differences in patient characteristics between these groups (p > 0.05).

Device characteristics

Due to the long inclusion period of the study, newer versions of the CI and BCD became available during the study. The first 12 CI patients were implanted with a Nucleus^® CI422 with a Slim Straight electrode array, the other 16 patients were implanted with a Nucleus^® CI512 with a Contour Advance electrode array. The median duration of CI use per day during the first 6 months after fitting was 12.7 hours (range 2.0–16.3 hours), based on the electronic data logging of the speech processor. There were no non-users in the CI group.

In the trial period, the first 52 patients tested the Baha^® BP110 on a headband from 2014 until 2016. From 2017 on, 33 patients tested the Baha^® 5 Power on a headband. There was a remarkable difference in satisfaction after the trial period with these two devices: 10 of 52 patients (19.2%) chose to proceed with BCD after the Baha^® BP110 trial, whereas 15 of 33 patients (45.5%) opted for BCD after the Baha^® 5 Power trial (Fisher’s exact test, p = 0.014). Thus, in total 25 of 85 patients (29.4%) opted to be implanted with a BCD after the trial period. After implantation, three patients were fitted with the Baha^® BP110 and all other patients were fitted with the Baha^® 5 Power.

Speech perception in noise

The results on speech perception in noise are shown in Figs 2–4. Lower values (SRTn in dB) reflect better performance. See S2 Table for exact data.

Fig 2 — Speech reception threshold in noise (SRTn) in decibels (dB), configuration S₀N₀. Statistical difference compared to baseline. ▲▲▲ = p < 0.001; ▲▲ = p < 0.01; ▲ = p < 0.05. Statistical difference compared to 3 months follow-up. ■■■ = p < 0.001; ■■ = p < 0.01; ■ = p < 0.05. Statistical difference between groups at same follow-up moment. *** = p < 0.001; ** = p < 0.01; * = p < 0.05.

Fig 4 — Speech reception threshold in noise (SRTn) in decibels (dB), configuration S_beN_pe. Statistical difference compared to baseline. ▲▲▲ = p < 0.001; ▲▲ = p < 0.01; ▲ = p < 0.05. Statistical difference compared to 3 months follow-up. ■■■ = p < 0.001; ■■ = p < 0.01; ■ = p < 0.05. Statistical difference between groups at same follow-up moment. *** = p < 0.001; ** = p < 0.01; * = p < 0.05.

S₀N₀

For the CI group, there was a statistically significant improvement in speech perception in noise (with speech and noise coming from the front) at 3 and 6 months follow-up compared to baseline (Fig 2). Also the BCD group had a significant improvement compared to baseline, but only at 6 months follow-up. Even when one outlier was not included in the analysis, these results remained statistically significant. There were no significant changes for the CROS and No treatment groups.

At 3 months follow-up, the CI group performed better than all other groups. At 6 months, the CI group performed significantly better than the BCD and No treatment groups. The difference between the CI group and the CROS group was not statistically significant.

S_peN_be

With speech directed to the poor ear, all treatment groups (CI, BCD, CROS) showed statistically significantly improved speech perception at 3 and 6 months follow-up compared to baseline (Fig 3). There was no significant change for the No treatment group during follow-up.

Fig 3 — Speech reception threshold in noise (SRTn) in decibels (dB), configuration S_peN_be, Statistical difference compared to baseline. ▲▲▲ = p < 0.001; ▲▲ = p < 0.01; ▲ = p < 0.05. Statistical difference compared to 3 months follow-up. ■■■ = p < 0.001; ■■ = p < 0.01; ■ = p < 0.05. Statistical difference between groups at same follow-up moment. *** = p < 0.001; ** = p < 0.01; * = p < 0.05.

At 3 and 6 months follow-up, the patients in all treatment groups had better speech perception in noise than the patients in the No treatment group. The CI group also performed statistically significantly better than the BCD group.

S_beN_pe

With speech directed to the better ear, the CI group showed a significant improvement in speech perception at 3 and 6 months follow-up compared to baseline, whereas both the BCD and CROS group deteriorated significantly (Fig 4). The No treatment group showed no significant changes over time.

At 3 and 6 months follow-up, the BCD and CROS group had a significantly worse speech perception than the CI and No treatment groups.

Sound localisation

See Figs 5–7 for the results on sound localisation. See S2 Table for exact data. In all configurations and in all groups, a wide range in performance was observed.

Fig 5 — Sound localisation as a percentage correct score (%) for configuration 15° angle between 5 loudspeakers (chance level: 20%). Statistical difference compared to baseline. ▲▲▲ = p < 0.001; ▲▲ = p < 0.01; ▲ = p < 0.05. Statistical difference compared to 3 months follow-up. ■■■ = p < 0.001; ■■ = p < 0.01; ■ = p < 0.05. Statistical difference between groups at same follow-up moment. *** = p < 0.001; ** = p < 0.01; * = p < 0.05.

Fig 7 — Sound localisation as a percentage correct score (%) for configuration 60° angle between 3 loudspeakers (chance level: 33.3%). Statistical difference compared to baseline. ▲▲▲ = p < 0.001; ▲▲ = p < 0.01; ▲ = p < 0.05. Statistical difference compared to 3 months follow-up. ■■■ = p < 0.001; ■■ = p < 0.01; ■ = p < 0.05. Statistical difference between groups at same follow-up moment. *** = p < 0.001; ** = p < 0.01; * = p < 0.05.

Fig 6 — Sound localisation as a percentage correct score (%) for configuration 30° angle between 5 loudspeakers (chance level: 20%), Statistical difference compared to baseline. ▲▲▲ = p < 0.001; ▲▲ = p < 0.01; ▲ = p < 0.05. Statistical difference compared to 3 months follow-up. ■■■ = p < 0.001; ■■ = p < 0.01; ■ = p < 0.05. Statistical difference between groups at same follow-up moment. *** = p < 0.001; ** = p < 0.01; * = p < 0.05.

The sound localisation of the CI group significantly improved between baseline and 3 and 6 months follow-up in all configurations. For the 15° and 60° configurations, there was also a statistically significant improvement between 3 and 6 months follow-up. There was no difference compared to baseline for the other groups.

At both 3 and 6 months follow-up, the CI group performed significantly better than all other groups. There were no statistically significant differences between the other groups.

Tinnitus

At all follow-up moments and in all groups, there were some patients who indicated that they did not suffer from tinnitus (anymore) (Table 2). Since these patients had no tinnitus, they did not complete the TQ and THI at that moment. Patients with no tinnitus at baseline did not develop tinnitus after any intervention. See S2 Table for exact data on the TQ and THI.

Table 2. Number of patients with and without tinnitus per group per follow-up moment.

	CI			BCD			CROS			No treatment
Tinnitus?	Baseline	3 months	6 months	Baseline	3 months	6 months	Baseline	3 months	6 months	Baseline	3 months	6 months
Yes	26	20	21	22	18	21	33	31	28	24	21	24
No	2	5	5	3	3	2	1	1	2	2	3	3
Missings	0	2	1	0	2	0	0	2	1	0	2	0
Total number	28	27	27	25	23	23	34	34	31	26	26	27

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In the row ‘total number’, the total number of patients per group and per follow-up moment is mentioned, which corresponds to the numbers shown in the Flow Diagram, Fig 1.

In the CI group, two patients did not suffer from tinnitus at baseline and they remained tinnitus-free after 3 and 6 months follow-up. Three patients reported to have no tinnitus anymore after cochlear implantation at 3 and 6 months follow-up.

In the BCD group, there were three patients who did not suffer from tinnitus at baseline. One of them was a patient who switched to the No treatment group after 3 and 6 months follow-up. The two other patients also did not suffer from tinnitus at 3 and 6 months follow-up. One other patient who suffered from tinnitus at baseline reported not to have tinnitus at 3 months follow-up, but the tinnitus had returned at 6 months follow-up.

In the CROS group, one patient had no tinnitus at baseline, 3 and 6 months follow-up. One other patient reported to have no tinnitus anymore at 6 months follow-up, whereas tinnitus was present at baseline and 3 months follow-up.

In the No treatment group, two patients were tinnitus-free at baseline, 3 and 6 months follow-up. The aforementioned patient with no tinnitus who switched from the BCD group was analysed in the No treatment group at 3 and 6 months follow-up.

Abbreviations: CI = Cochlear Implant, BCD = Bone Conduction Device, CROS = Contralateral Routing of Sound hearing aid, SD = standard deviation.

TQ

There was a significant decrease in tinnitus-related distress for the CI group and the BCD group at 3 and 6 months follow-up compared to baseline (Fig 8).

Fig 8 — Statistical difference compared to baseline. ▲▲▲ = p < 0.001; ▲▲ = p < 0.01; ▲ = p < 0.05. Statistical difference compared to 3 months follow-up. ■■■ = p < 0.001; ■■ = p < 0.01; ■ = p < 0.05. Statistical difference between groups at same follow-up moment. *** = p < 0.001; ** = p < 0.01; * = p < 0.05.

At 3 and 6 months follow-up, the CI group had significantly lower TQ scores than the No treatment group.

THI

We measured a significant decrease in impact of tinnitus on daily life for the CI group at 3 and 6 months follow-up compared to baseline (Fig 9).

Again, at 3 and 6 months follow-up, the CI group had significantly lower THI scores than the No treatment group.

Disease-specific QoL

See S2 Table for exact data on the disease-specific QoL questionnaires.

SSQ

Speech-hearing. There was a significant improvement (higher score) for all treatment groups at 3 and 6 months follow-up compared to baseline (Fig 10). There was no significant change compared to baseline for the No treatment group.

At 3 and 6 months follow-up, the CI group had significantly higher median values compared to all other groups, and both the BCD and CROS groups scored better than the No treatment group.

Spatial hearing. We observed a significant improvement for all treatment groups at 3 months follow-up, and for CI and BCD groups also at 6 months follow-up (Fig 11). The score for the CROS group slightly decreased at 6 months follow-up and was therefore not significantly improved compared to baseline. There was no significant change for the No treatment group.

Fig 11 — Spatial hearing subscale. Statistical difference compared to baseline. ▲▲▲ = p < 0.001; ▲▲ = p < 0.01; ▲ = p < 0.05. Statistical difference compared to 3 months follow-up. ■■■ = p < 0.001; ■■ = p < 0.01; ■ = p < 0.05. Statistical difference between groups at same follow-up moment. *** = p < 0.001; ** = p < 0.01; * = p < 0.05.

At 3 and 6 months follow-up, the scores for the CI group were significantly higher compared to all other groups. Also, at 6 months follow-up, the BCD group reached higher scores than the No treatment group.

Qualities of hearing. For all treatment groups, the scores at 3 months follow-up were significantly better than the baseline scores (Fig 12). At 6 months follow-up, this improvement remained for only the CI group. For the BCD group, there was a significant deterioration between 3 and 6 months follow-up. There was no significant change for the No treatment group.

At 3 months follow-up, the scores of all treatment groups were significantly better than the scores of the No treatment group. At 6 months follow-up, the scores of only the CI and CROS groups were significantly better than the scores of the No treatment group.

APHAB

Ease of Communication (EC). At 3 and 6 months follow-up, all treatment groups had an improvement (i.e. a decrease in APHAB score) on this subscale (Fig 13).

At 3 and 6 months, all treatment groups had better scores than the No treatment group. The CI group had significantly better scores than the CROS group.

Background noise (BN). All treatment groups had significantly improved scores at 3 and 6 months follow-up (Fig 14).

All treatment groups scored significantly better than the No treatment group at 3 and 6 months follow-up. The CI group had significantly better scores than the CROS group at 3 and 6 months follow-up, and also significantly better scores than the BCD group at 6 months follow-up.

Reverberant conditions (RV). The scores of all treatment groups had significantly improved at 3 and 6 months follow-up (Fig 15). However, the scores for the CROS group significantly deteriorated between 3 and 6 months follow-up.

At 3 months follow-up, the CI group and the CROS group scored significantly better than the No treatment group. The CROS group also scored better than the BCD group. At 6 months follow-up, the CI group outperformed all other groups. All treatment groups scored better than the No treatment group.

Aversiveness of sounds (AS). At 3 months follow-up, the scores of all treatment groups were better than the score of the No treatment group (Fig 16). This benefit remained for the BCD and CI groups, whereas this benefit decreased for the CROS group, leading to a non-significant difference between baseline and 6 months follow-up for the CROS group.

At 3 months of follow-up, all treatment groups scored better than the No treatment group. At 6 months follow-up, the CI group scored significantly better than the CROS and No treatment groups. The scores of the BCD group were significantly better than the scores of the No treatment group.

GBI

On the general subscale, the scores improved (i.e. >0) in all treatment groups. The CI group had a significantly better score than the CROS group at 3 months follow-up. Since the social support subscale and the physical health subscale of the GBI are calculated by adding the responses of three questions each, there was hardly any variability in the data (quartile 1, the median, and quartile 3 had exactly the same values; see S2 Table).

Serious Adverse Events (SAEs)

There were two related SAEs in the BCD group: two implant extrusions occurred; one patient was re-implanted, in the other case no re-implantation was performed at the patient’s request.

There were also unrelated SAEs: in the CI group one patient suffered from a transient ischemic attack several months after implantation; in the CROS group, one patient had a myocardial infarction for which he underwent percutaneous coronary intervention, and one patient had nasal polyps for which he underwent sinus surgery; in the No treatment group one patient had an arm fracture requiring surgery.

Discussion

We presented the first results of this RCT with 120 included SSD patients evaluating CI, BCD, CROS, and No treatment at 3 and 6 months follow-up. The randomised allocation ensured equal distribution of known and unknown confounders amongst groups.

Speech perception in noise

On our primary outcome (S₀N₀), the CI group demonstrated a significant improvement compared to baseline, which can be attributed to the summation effect. Other studies did not measure an advantage in this configuration after 6 months CI use in SSD patients [14,31]. In the S_peN_be configuration, all treatment options led to an improved speech perception in noise, since the sound from the side of the poor ear is delivered to the better ear. However, in the S_beN_pe configuration the opposite happened: the BCD and CROS negated the positive effect of the head shadow as the noise on the poor side was sent to the better ear and thus impeded speech intelligibility. In this S_beN_pe configuration, the BCD and CROS patients performed worse than at baseline, and worse than patients in the No treatment group at 3 and 6 months follow-up. In contrast to the BCD and CROS groups, there was no disadvantage for the CI patients, proving that the squelch effect is present, as was objectified before after cochlear implantation in patients with asymmetrical hearing loss [12,32].

The speech perception in noise may have been influenced by the hearing thresholds in the better ear. However, there were no significant differences in PTA_be between groups after treatment allocation (see S1 Table). Noticeably, the speech perception in noise of the CI group was not as good as the speech perception in noise of normal-hearing subjects [24].

Sound localisation

Cochlear implantation led to a significant improvement in sound localisation in multiple configurations, which is in line with literature [9,12–14,17,20]. The benefit of binaural input is present very early after CI activation, as was described by others [33]. We found that the sound localisation ability of the CI patients further improved from 3 to 6 months follow-up for two configurations (15° and 60°), which is also in line with what other researchers have described [13,14,34]. Nevertheless, sound localisation is still harder for SSD patients with a CI than for normal-hearing subjects [24,35].

In line with previous articles, we did not find improvement of sound localisation ability with BCD or CROS [11,36,37].

Tinnitus

For the first time in 2008, Van de Heyning et al. [5] reported a significant decrease in tinnitus distress (TQ) and tinnitus loudness (Visual Analogue Scale (VAS) score) following cochlear implantation in unilaterally deaf patients suffering from incapacitating tinnitus. Later, others reported beneficial results of electrical stimulation by cochlear implantation on tinnitus as well [17,20,31,38,39]. An important issue to be mentioned is the absence of a minimum level of tinnitus distress to be eligible for inclusion in our study. Other study groups often required a minimum level of tinnitus distress, such as a minimum VAS score on tinnitus loudness of 6 out of 10 [5,12,32] or a minimum THI score of 58 [40,41]. This requirement explains their higher baseline values for tinnitus distress. Despite our lower baseline values, we also objectified a significant decrease in tinnitus distress after 3 and 6 months for the CI patients.

Interestingly, we identified a significant reduction on tinnitus distress after BCD implantation with the TQ, without a significant change in tinnitus-related effects on daily life as measured by the THI. One other study found a reduction of the impact of tinnitus on daily life after BCD [42]. The mechanism is unclear, but stimulation of the contralateral auditory pathway may play an important role in the experienced tinnitus suppression [42].

Some CI patients reported reduction of tinnitus as the most important advantage of their CI, rather than improved speech perception in noise or sound localisation. This finding could be an important advantage that should be mentioned when counselling SSD patients on expected outcomes of CI.

Disease-specific QoL

For most subscales on the disease-specific QoL questionnaires, there was an improvement for all treatment groups compared to baseline, and compared to the No treatment group at 3 and 6 months follow-up. Our SSQ results are in line with the results of studies that also used the SSQ questionnaire in SSD patients after cochlear implantation [31,38].

Although the APHAB questionnaire has not been widely used in reports on cochlear implantation for SSD, we implemented this questionnaire because it has been extensively used to evaluate BCD and CROS [11]. Also on the APHAB questionnaire we found an improvement for all treatment groups on most subscales, which equals findings by others [11,43].

Trial period

The proportion of patients opting for a BCD after the trial period in our study (29.4%) was on the low end of the range described in literature for patients opting for a BCD after a BCD trial period (32.0–69.6%) [44]. Patients in our study were offered a cross-over design which enabled them to test two devices, which may explain the lower proportion of patients opting for a BCD after the trial period. Moreover, the proportion of patients opting for a BCD could have been influenced by the type of BCD offered during the trial period; we noticed that the satisfaction with the newer Baha^® 5 Power was significantly higher than with the older Baha^® BP110 (45.5% versus 19.2% opted for BCD after the trial period, respectively). Noticeably, 40.0% of patients opted for CROS. This high proportion may be attributed to recent advances in (directional) microphone technology and signal processing algorithms. Importantly, a considerable proportion of patients was satisfied with either modality and preferred these treatments over no treatment.

Other studies have also provided a trial with BCD or CROS to SSD patients. Though, due to lack of reported outcomes in these studies, comparison with our results is hindered. For example, Arndt et al. [31] provided a CI to 11 SSD patients that were not satisfied with the effects of BCD or CROS in a trial period. However, the proportion of patients that opted for BCD or CROS after the trial period was not mentioned, and no objective outcomes of hearing performance were published from these satisfied patients. Likewise, SSD patients were offered a CI in a Swiss study if they had unsatisfactory benefit from a trial with CROS or BCD: forty-four of 54 study patients did not proceed to cochlear implantation [39]. Unfortunately, there were no results available from those patients who opted for BCD or CROS. Of the ten patients that were implanted, only results with CI were published and not from the trial period with CROS or BCD [39]. Kurz et al. [14] implemented the study design that was proposed at an international consensus meeting [1], and found that 16 of 34 patients decided not to opt for cochlear implantation after a trial period with BCD and CROS (3 weeks each).

As an advantage over studies with a trial period of BCD and CROS before the option to choose for CI, we were able to make a longitudinal between-group comparison comparing CI, BCD, CROS, and no treatment. With our study design we diminished the influence of the opinion of patients on CI outcome by previous BCD or CROS treatments, and also diminished the influence on patients’ opinions on BCD and CROS. With a more extended analysis of the trial period in the future, we hope to identify prognostic factors that may predict if BCD or CROS are successful in specific categories of patients. Additionally, we will also analyse the disease-specific QoL questionnaires that were completed after each 6-week phase of the trial period (SSQ, APHAB, and GBI).

Strengths

There are several strengths that characterize our trial. Firstly, we randomly allocated patients to intervention groups. Our random allocation ensured equal distribution of patient characteristics across groups, thereby eliminating the influence of differences in these characteristics on the outcomes [45,46]. Secondly, we compared CI to the treatment options for patients with SSD currently available in many countries. Thirdly, our design provided not only a within-subject comparison, but also allowed a between-group comparison. It also enabled us to evaluate the performance following SSD in the No treatment group. Finally, we had very few missing data permitting a complete case-analysis.

Limitations

Our study also has limitations. First, following the stringent in- and exclusion criteria, we included only a subset of patients with SSD, which may limit the generalisability of our results. Moreover, our study patients were highly motivated to return for follow-up visits, whereas in real-life compliance may not be as high. Possibly, non-use of initially started treatment may occur when follow-up time is longer [19,34,47]. We therefore implemented a follow-up period of five years. Second, neither patients nor personnel were blinded for the allocated intervention. Given the nature of the interventions, blinding was impossible to achieve, which may have influenced outcomes; this is a well-known problem in non-pharmacological studies [48]. Moreover, the magnitude of the placebo effect in surgical trials is unknown [49]. Third, we used fixed block sizes (n = 8, 2:3:3) in our block randomisation, which may result in a predictable allocation of participants based on previous randomisations. This lack of allocation concealment may lead to selection bias [50]. However, the baseline characteristics showed no statistically significant differences between allocation groups. Fourth, due to the long inclusion period of our trial, we implemented newly developed devices in the trial. Consequently, not all patients tested the same BCD in the trial period, or had the same type of CROS or CI fitted. We feel this is part of conducting a multi-annual trial and reflects technological advancements similar to clinical care settings. Because of standardised fitting strategies for all devices, we think the groups are still comparable. Fifth, the TQ and THI are not designed to measure treatment effects [51]. To measure treatment-related changes in tinnitus intrusiveness and severity, the more recently developed Tinnitus Functional Index [52] is recommended nowadays. Nevertheless, the commonly used THI makes comparisons with other studies possible [18]. Furthermore, both the TQ and the THI have high internal consistency, high convergence and discriminant validity and good change sensitivity [53]. Thus, both questionnaires appear appropriate to evaluate the effects of tinnitus treatments [53]. Finally, we only measured the median duration of CI use per day, and not the median duration of BCD and CROS use per day. Data of device use from the BCD and CROS devices would have given us insight in the satisfaction with the devices as mirrored from duration of use per day; unfortunately, this data was unavailable.

Future perspectives

In this paper we presented the first results of the CINGLE-trial [21]. Long-term results will follow. Aside from the reported outcome measures, which show the individual benefits, analysis of the costs of the treatment options is necessary to reveal societal benefits. This information will allow health care committees to perform a cost utility analysis, which will help in the consideration whether or not to reimburse cochlear implantation for patients with SSD. Interestingly, a recent modelling study on patients with SSD found that cochlear implantation may be cost-effective compared with no intervention, but bone-conduction implants were unlikely to be cost-effective [54]. Studies comparing CI to other treatment options for SSD and conducting a cost utility analysis are expected in the near future [55,56]. Finally, others work on developing a minimum set of core outcomes for use in future trials of SSD interventions [57].

Conclusion

In this RCT, we compared CI, BCD, CROS, and No treatment for patients with SSD. Speech perception in noise improved in all configurations for the CI group, whereas speech perception in noise improved or deteriorated for the BCD and CROS groups depending on the configuration. Sound localisation improved in the CI group only. Patients with no tinnitus at baseline did not develop tinnitus after any intervention. After cochlear implantation, three patients reported that their tinnitus had completely disappeared. On both the TQ and THI, a decrease in tinnitus burden was detected for the CI group. In general, all treatment options improved disease-specific QoL on most subscales of the used questionnaires.

Results from long-term follow-up moments will be presented in the future, as well as an analysis of the BCD/CROS trial period and a more detailed analysis of the tinnitus burden. Finally, cost utility analyses on treatment options for SSD are needed to evaluate if cochlear implantation should be reimbursed.

Supporting information

S1 File. Original study protocol CINGLE-trial: Cochlear Implantation for siNGLE-sided deafness, a Randomised controlled trial and economic evaluation.

(PDF)

Click here for additional data file.^{(1.4MB, pdf)}

S2 File. CONSORT checklist.

(PDF)

Click here for additional data file.^{(138.5KB, pdf)}

S3 File. Explanation of numbers per group at different follow-up moments.

(PDF)

Click here for additional data file.^{(66.9KB, pdf)}

S1 Table. Patient characteristics after allocation of treatment.

(PDF)

Click here for additional data file.^{(119.9KB, pdf)}

S2 Table. Data tables.

(PDF)

Click here for additional data file.^{(342.5KB, pdf)}

Acknowledgments

The authors would like to thank D. Ramekers PhD for his help with the statistical analysis.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study is partly funded by Cochlear Ltd. as an unrestricted research grant. By research contract, Cochlear Ltd. did not have influence on the study design, data collection, analysis, data interpretation, and publication. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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57.Katiri R, Hall DA, Buggy N, Hogan N, Horobin A, van de Heyning P, et al. Core Rehabilitation Outcome Set for Single Sided Deafness (CROSSSD) study: protocol for an international consensus on outcome measures for single sided deafness interventions using a modified Delphi survey. Trials 2020;21(1):238. doi: 10.1186/s13063-020-4094-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0257447.r001

Decision Letter 0

Vance Berger

21 Dec 2020

PONE-D-20-34585

Short-term Outcomes of Cochlear Implantation for Single-Sided Deafness compared to Bone Conduction Devices and Contralateral Routing of Sound hearing aids – Results of a Randomised Controlled Trial (CINGLE-trial)

PLOS ONE

Dear Dr. Peters,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Please pay careful attention to the review comments, and also please address the following issues.

Why would you use blocked randomization, given its well known fatal flaws?

Clearly the data are not normally distributed. That could have been determined by appeal to the fact that no data are normally distributed. Why would you feel the need to test to arrive at this conclusion?

Where are the p-values in Table 1?

==============================

Please submit your revised manuscript by Feb 04 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Vance Berger

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please ensure that all deviations from the original approved protocol are discussed and justified in the manuscript text. In particular, please provide a justification why some questionnaire used to assess quality of life as a secondary outcome are not detailed in the Methodology.

Furthermore, please provide additional details to the inclusion criteria within the Manuscript text. And finally please provide clarification regarding the discrepancy in the start date between the manuscript and the clinical trial registry.

3. Thank you for submitting your clinical trial to PLOS ONE and for providing the name of the registry and the registration number. The information in the registry entry suggests that your trial was registered after patient recruitment began. PLOS ONE strongly encourages authors to register all trials before recruiting the first participant in a study.

As per the journal’s editorial policy, please include in the Methods section of your paper:

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4. Thank you for stating the following in the Financial Disclosure section:

'This study is partly funded by Cochlear Ltd. as an unrestricted research grant. By research contract, Cochlear Ltd. did not have influence on the study design, data collection, analysis, data interpretation, and publication. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.'

We note that you received funding from a commercial source: Cochlear Ltd

a. Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors aimed to compare different treatments (CI, BCD, CROS and no treatment) to support patients with single-side deafness. The trial is described as randomized controlled trial where the description suggests that it is a patient preference design.

From a methodological point of view, I have some difficulties with the analysis and subsequent conclusion.

First, patients were randomised to CI or to one of the treatment sequences BCF followed by CROS or CROS followed by BCF as in a cross-over design. After this “randomized” run-in period, patients from the cross-over groups were treated based on their preference with BCD, CROS or no treatment. Patients treated initially with CI were further treated with CI without having a choice. These options lead to seven different groups, namely CI; BCF based on BCF/CROS; CROS based on BCF/CROS; No treatment based on BCF/CROS; BCF based on CROS/BCF; CROS based on CROS/BCF and No treatment based on CROS/BCF but were analysed as four (CI, BCF, CROS and no treatment). This approach ignores the effects from the pre-treatment, causes confounding and thus implies bias in the analysis. Comparisons using the non-randomised and confounded groups are unreliable because of the presence of uncontrolled confounders.

One possible option would be to use the randomisation status as a covariate. In general, a patient preference trial should be treated as an observational study with known confounding factors adjusted for in the analysis. This also means that the STROBE checklist is more suitable than CONSORT.

The analysis performed by the authors includes comparison between to measurements moments within one group or between two groups at the same follow-up moment. But what is in fact of interest is the comparison of changes between groups. I would suggest to adapt the analysis accordingly to the above mentioned aspects.

Moreover, in the protocol is stated, that missing values will be imputed using a multiple imputation approach and all analyses will be performed on an intention-to-treat basis. Since a protocol is a binding document, the analysis should follow the agreed details.

For the same reason, a justification for the evaluation of the 3 months measurements should be provided, because in the protocol planned evaluation starts at 6 months after randomisation.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Oct 13;16(10):e0257447. doi: 10.1371/journal.pone.0257447.r002

Author response to Decision Letter 0

21 Jan 2021

PLEASE ALSO SEE THE UPLOADED WORD FILE REPLY TO REVIEWERS

Reply to Reviewers letter PONE-D-20-34585

Original comments

>>Reply to Reviewers by authors

>>First of all, we would like to thank the editor and reviewer for their detailed feedback and review of our manuscript. In this letter we respond (in blue) to each point raised by the editor and reviewer and made changes in the manuscript accordingly.

Editor

Please pay careful attention to the review comments, and also please address the following issues.

Why would you use blocked randomization, given its well known fatal flaws?

>>The main reason to use block randomisation was to achieve balanced allocation of participants to the three groups over time. We agree that a well-known disadvantage of block randomization is that the allocation of participants may be predictable and result in selection bias when the study groups are unmasked. However, in this trial we did not (could not) blind researchers or patients given for the intervention. Therefore, this disadvantage of block randomization was not applicable to our trial.

>>Our statistical analysis plan was designed to first check if data were normally distributed, so we could know which type of tests to use (parametric or non-parametric). We agree that our data are clearly not normally distributed; however, there is no harm to check this statistically. For clarity for the readers, we removed the first sentence of the section ‘statistical analysis’ for easier reading and more clarity.

Where are the p-values in Table 1?

>>Since patients were randomly distributed across groups, statistical comparison between baseline characteristics is not advocated. In short, if there would be a statistically significant difference, it would be based on chance by definition (since randomised allocation occurred). See for example the Editorial: Statistical testing for baseline differences between randomised groups is not meaningful via https://www.nature.com/articles/s41393-018-0203-y)

==============================

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

>>We changed the layout of the manuscript, (figure) legends and supporting information according to the PLOS One style requirements.

>>We explained deviations from the original protocol in the Introduction (lines 131-132), where we specified that some secondary outcomes will be discussed in a separate manuscript that will follow. Moreover, in the Materials and Methods (line 142-144) we detailed the addition of the extra follow-up moment 3 months after device activation.

Furthermore, please provide additional details to the inclusion criteria within the Manuscript text.

>>We added information on the inclusion criteria, so it now equals the exact text from the original research protocol and published study protocol manuscript (lines 154-159).

And finally please provide clarification regarding the discrepancy in the start date between the manuscript and the clinical trial registry.

>>Thank you for this remark. The start date in the clinical trial register was incorrect. We updated the info in the clinical trial register (see https://www.trialregister.nl/trial/4457), and now the start date is the same in the clinical trial register and in the manuscript (start date/first inclusion July 15th, 2014).

>>Please see the info online (https://www.trialregister.nl/trial/4457). We registered our trial online (May 6th, 2014) which was before inclusion of the first patient (July 14th, 2014).

4. Thank you for stating the following in the Financial Disclosure section:

We note that you received funding from a commercial source: Cochlear Ltd

>>We amended the Competing Interests Statement in the manuscript (page 2).

b. Please include your amended Competing Interests Statement within your cover letter. We will change the online submission form on your behalf.

>>We amended the Competing Interests Statement also in the new cover letter.

5. Review Comments to the Author

>>We aimed to compare CI to the current clinical practice in The Netherlands (lines 186-188), which consists of a trial period with BCD and CROS. Patients were randomly assigned to CI or to the ‘clinical practice’ groups. We agree with the reviewer that the order in which the ‘current clinical practice’ devices are tested by participants may be of influence on their decision which they prefer. To correct for this ‘order effect’ (line 179), we designed two groups: ‘first BCD, then CROS’, and ‘first CROS, then BCD’, and both then lead to the final groups: BCD, CROS or No treatment (like in current clinical practice).

It may indeed be interesting, as the reviewer suggests, to analyse differences between patients opting for BCD after having tested the BCD first compared to having the BCD tested second. As detailed in the study protocol (S1_File), a detailed analysis will follow in a later manuscript. For clarity of the reader, we also added this information to the Discussion section (lines 629-631).

>>Thank you for your comment. Since we used a randomized study design, we used the CONSORT Statement, which is suitable to assess the randomization (e.g. sequence generation) and allocation process. None of the study types that the STROBE checklist was designed for contains this information. Nevertheless, it would be interesting to use the randomisation status as a covariate in the detailed analysis of the trial period.

>>Thank you for this suggestion. For all outcomes, the test/questionnaire median results from baseline and the 3 and 6 months follow-up moments are displayed in Figures 3-6. These results were statistically compared between groups, as was detailed in the data analysis plan. In these figures, readers can also see the changes between groups. All exact medians, interquartile ranges and minimum/maximum values are provided in S5_Tables. In this manuscript, we did not statistically compare the differences/changes in follow-up moments between groups.

>>We thank the reviewer for this remark. Given the very low proportion of missing data in our study, we chose not to use multiple imputation. When designing the study, we took a larger proportion of missing data into account, for which we aimed to use multiple imputation. Due to the nature of our interventions, subject data were analysed ‘as treated’. To make it clear that we deviated from the original protocol, we added this information to the ‘Statistical analysis’ section.

For the same reason, a justification for the evaluation of the 3 months measurements should be provided, because in the protocol planned evaluation starts at 6 months after randomisation.

>>It is correct that we added the 3 month follow-up moment after first approval of the study protocol. However, we added this follow-up moment before inclusion of the first patient. In lines 142-145 we detailed this deviation from the original protocol.

Attachment

Submitted filename: Reply to Reviewers_Jan 21.docx

Click here for additional data file.^{(21.6KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0257447.r003

Decision Letter 1

Vance Berger

8 Feb 2021

PONE-D-20-34585R1

PLOS ONE

Dear Dr. Peters,

Please submit your revised manuscript by Mar 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Vance Berger

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

I am repeating the earlier comments, and your replies to them, for ease of reference.

Please pay careful attention to the review comments, and also please address the following issues.

Why would you use blocked randomization, given its well known fatal flaws?

You have that completely wrong. The problem with permuted blocks is especially acute in unmasked trials. How would you possibly think that unmasking would somehow mitigate or eliminate this problem? Obviously, you cannot go back now and correct your mistake, but you can admit that you made a rather serious mistake, you can agree to randomize better in the future, and you can test for the extent to which your mistake resulted in selection bias. This is done with baseline p-values and also with the Berger-Exner test. See:

Berger, VW, Exner, DV (1999). “Detecting Selection Bias in Randomized Clinical Trials”, Controlled Clinical Trials 20, 319-327.

Berger, VW (2005). “Selection Bias and Covariate Imbalances in Randomized Clinical Trials”, John Wiley & Sons, Chichester, Section 6.5.

There certainly is harm in allowing the folly of normality to hold sway. The data could not have possibly been normally distributed, and pretending that they could be has implications for the preservation of the Type I error rate.

Where are the p-values in Table 1?

This is absolutely incorrect. The randomization is very much in question. Selection bias is very much a possibility. It is this selection bias, enabled by the combination of permuted blocks and unmasking, that we are testing with the baseline p-values. See:

Berger, VW (2004). “Selection Bias and Baseline Imbalances in Randomized Trials”, Drug Information Journal 38, 1-2.

Berger, VW (2005). “Selection Bias and Covariate Imbalances in Randomized Clinical Trials”, John Wiley & Sons, Chichester.

Berger, VW (2009). “Do Not Test for Baseline Imbalances Unless They Are Known To Be Present?”, Quality of Life Research 18, 399.

Berger, VW (2010). “Testing for Baseline Balance: Can We Finally Get It Right?”, Journal of Clinical Epidemiology 63, 8, 939-940.

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PLoS One. 2021 Oct 13;16(10):e0257447. doi: 10.1371/journal.pone.0257447.r004

Author response to Decision Letter 1

12 Mar 2021

Please see our Reply to Reviewers that was uploaded separately.

Attachment

Submitted filename: Reply to Reviewers_Mar 12.docx

Click here for additional data file.^{(17.8KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0257447.r005

Decision Letter 2

Vance Berger

23 Jul 2021

PONE-D-20-34585R2

PLOS ONE

Dear Dr. Peters,

==============================

You stated, and I quote, "The randomised 526 allocation ensured equal distribution of known and unknown confounders amongst 527 groups". This is simply not true. It might have been true, had a better randomization method been used. But as it stands, we cannot know this, and that is why the CONSORT guidance against baseline testing is misguided. We do not know that all baseline imbalances are of a random nature, because they may represent selection bias. That is what the baseline p-values would be testing. With that, I am again asking for baseline p-values, even though CONSORY explicitly, and incorrectly, states that they are illogical.

==============================

Please submit your revised manuscript by Sep 06 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Vance Berger

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: I have asked my statistician to comment on the concerns regarding randomization. We have had a large NIH P50 grant evaluating cochlear implant outcomes for over 30 years. Jacob Oleson has been the statistician on this grant for the last 15 years. Here is is comment on randomization in this research trial.

My opinion is that this is a reviewer who is too hung up on one particular method. It is true that the type of randomization can lead to bias. However, it is really hard (impossible) to truly randomize cochlear implants. The statistical clinical trials population (which I am not one of) spends A LOT of time discussing all of the ins and outs of the randomization process. My take is that there is always some amount of bias in studies no matter what you do. You control what can control and accept that the results are not undeniable fact. That’s what followup studies are for! A truly correctly randomized clinical trial is designed to get you close to undeniable fact. I would say accept that there could be bias (probably isn’t much) and report the p-values as requested.

The remainder of the manuscript is very well done. This is an important clinical trial and could only be done in a country that would provide hearing aids or implants to all patients. The results are dramatic and demonstrate the effectiveness of cochlear implants for single sided deafness on all variables tested. Single sided deafness is one of the most common forms of deafness that we see. The ability to treat with a cochlear implant is extremely important to this population. I suggest that this manuscript be published as soon as possible with a very high priority score.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

PLoS One. 2021 Oct 13;16(10):e0257447. doi: 10.1371/journal.pone.0257447.r006

Author response to Decision Letter 2

9 Aug 2021

Dear Academic Editor

In your reply dated July 23rd, you asked us to add baseline p-values. However, these values were already added to Table 1 in our most recently uploaded version dated March 12th. Based on the comments of the extra reviewer, there were no other points to improve. In the currently uploaded version, I deleted the old reply to reviewers, since no new comments needed to be addressed.

I did include the previous ‘tracked changes’-version of the manuscript, so you can clearly see the addition of the p-values in Table 1.

We hope you consider the current version of our manuscript for publication. Thanks again for your careful consideration.

Jeroen P.M. Peters, MD PhD

Corresponding author

Attachment

Submitted filename: Reply to editor_R2.docx

Click here for additional data file.^{(12.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0257447.r007

Decision Letter 3

Vance Berger

2 Sep 2021

PONE-D-20-34585R3

Dear Dr. Peters,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Vance Berger

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0257447.r008

Acceptance letter

Vance Berger

5 Oct 2021

PONE-D-20-34585R3

Dear Dr. Peters:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Vance Berger

%CORR_ED_EDITOR_ROLE%

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 File. Original study protocol CINGLE-trial: Cochlear Implantation for siNGLE-sided deafness, a Randomised controlled trial and economic evaluation.

(PDF)

Click here for additional data file.^{(1.4MB, pdf)}

S2 File. CONSORT checklist.

(PDF)

Click here for additional data file.^{(138.5KB, pdf)}

S3 File. Explanation of numbers per group at different follow-up moments.

(PDF)

Click here for additional data file.^{(66.9KB, pdf)}

S1 Table. Patient characteristics after allocation of treatment.

(PDF)

Click here for additional data file.^{(119.9KB, pdf)}

S2 Table. Data tables.

(PDF)

Click here for additional data file.^{(342.5KB, pdf)}

Attachment

Submitted filename: Reply to Reviewers_Jan 21.docx

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PERMALINK

Short-term outcomes of cochlear implantation for single-sided deafness compared to bone conduction devices and contralateral routing of sound hearing aids—Results of a Randomised controlled trial (CINGLE-trial)

Jeroen P M Peters

Jan A A van Heteren

Anne W Wendrich

Gijsbert A van Zanten

Wilko Grolman

Robert J Stokroos

Adriana L Smit

Roles

Abstract

Introduction

Single-sided deafness

CROS and BCDs

Cochlear implantation

Need for current trial

Materials and methods

Study population

Study design

Fig 1. CONSORT flow diagram of the study.

Outcomes

Speech perception in noise

Sound localisation

Tinnitus

Disease-specific QoL

Statistical analysis

Results

Patient characteristics

Table 1. Patient characteristics per group after randomisation.

Device characteristics

Speech perception in noise

Fig 2. Speech perception in noise.

Fig 4. Speech perception in noise.

S0N0

SpeNbe

Fig 3. Speech perception in noise.

SbeNpe

Sound localisation

Fig 5. Sound localisation.

Fig 7. Sound localisation.

Fig 6. Sound localisation.

Tinnitus

Table 2. Number of patients with and without tinnitus per group per follow-up moment.

TQ

Fig 8. Tinnitus Questionnaire (TQ).

THI

Fig 9. Tinnitus Handicap Inventory (THI).

Disease-specific QoL

SSQ

Fig 10. Speech, Spatial and Qualities of hearing questionnaire (SSQ).

Fig 11. Speech, Spatial and Qualities of hearing questionnaire (SSQ).

Fig 12. Speech, Spatial and Qualities of hearing questionnaire (SSQ).

APHAB

Fig 13. Abbreviated Profile for Hearing Aid Benefit questionnaire (APHAB).

Fig 14. Abbreviated Profile for Hearing Aid Benefit questionnaire (APHAB).

Fig 15. Abbreviated Profile for Hearing Aid Benefit questionnaire (APHAB).

Fig 16. Abbreviated Profile for Hearing Aid Benefit questionnaire (APHAB).

GBI

Serious Adverse Events (SAEs)

Discussion

Speech perception in noise

Sound localisation

Tinnitus

Disease-specific QoL

Trial period

Strengths

Limitations

Future perspectives

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Vance Berger

Roles

Author response to Decision Letter 0

Decision Letter 1

Vance Berger

S₀N₀

S_peN_be

S_beN_pe