Trial results

Participant flow

In total, 445 individuals registered their interest in taking part in the trial between 8 May 2018 and 30 September 2019. Figure 2 presents the recruitment and screening flow diagram for the trial, summarising information for exclusion at both the initial telephone screen and the baseline appointment through to randomisation. Phase 1 of the trial was considered complete on 30 April 2020 when the last participant completed the 6-month follow-up. Phase 2 and the trial overall were considered complete on 12 April 2021 when the last participant completed the 18-month follow-up. Retention to follow-up data during phase 1 (3-month primary end point and 6-month follow-up) and phase 2 (12- and 18-month follow-ups) are shown in the CONSORT flow diagram in Figure 3.

FIGURE 2 Recruitment and screening flow. (Figure not reproduced here; see the original article.)

FIGURE 3 CONSORT flow diagram. Note: Figure in Hollis et al.79 (Figure not reproduced here; see the original article.)

Internal pilot

The TSC met on 28 January 2019 to judge the success of the internal pilot against the three targets. The TSC judged that all three targets had been met; a summary is provided in Table 3. As a result, the trial was recommended to continue.

Baseline characteristics

Baseline characteristics of the sample are presented in Table 4 and show that characteristics and scores on the primary outcome and secondary outcomes were similar between the two arms. Participants had a mean age of 12 years, were predominately male (177/224; 79%) and defined their ethnicity as white (195/224; 87%). It is interesting to note that very few participants (30/224; 13%) were receiving medication for tics at baseline. Given that the phase 1 and phase 2 results were analysed at separate time points, the findings are reported separately for each phase.

Instances of unblinding

Four occasions of unblinding occurred throughout the entire trial. Each instance was reported to the trial manager and reviewed by the independent TSC and DMC for monitoring. For all occasions, the young person disclosed information about their treatment to the outcome assessor at the end of the follow-up assessment. When this occurred, all remaining follow-ups were conducted by an alternative, blinded assessor.

Phase 1 results

The phase 1 results were published in Hollis et al.78

Losses to follow-up

The sample size calculation allowed for 20% missing data; however, data from the primary outcome measure (YGTSS-TTSS) at the primary end point (3 months) were collected from 99/112 participants (88.4%) in the intervention group and 105/112 participants (93.7%) in the psychoeducation group. Thus, retention to follow-up was better than anticipated. Data from the primary measure at 6 months were obtained from 93/112 participants (84.5%) for each group. The only predictor of missingness was site, which was included as a covariate in the statistical models.

Primary outcome

The mean scores for the primary outcome – the YGTSS-TTSS at 3 months – were lower in the ERP group (23.9, SD 8.2) than in the psychoeducation group (26.8, SD 7.3). When comparing to baseline scores, the mean total decrease in the YGTSS-TTSS was greater in the ERP group (4.5; 16%) than the psychoeducation group (1.6; 6%). Table 5 shows the results of the adjusted (for baseline and site) difference in mean scores when comparing the ERP group with the psychoeducation group. The results showed that the ERP intervention reduced the YGTSS-TTSS by −2.29 points (95% CI −3.86 to −0.71) in comparison to psychoeducation, with an effect size of −0.31 (95% CI −0.52 to −0.10).

At 6 months, this adjusted effect on tics (YGTSS-TTSS) was slightly increased (estimated difference −2.64, 95% CI −4.56 to −0.73), with an effect size of −0.36 (95% CI −0.62 to −0.10).

Effect sizes for the primary and secondary outcomes are presented in Figure 4.

FIGURE 4 Effect sizes for primary and secondary outcomes up to the 6-month follow-up. Note: Figure published in Hollis et al.78 (Figure not reproduced here; see the original article.)

Secondary outcomes

Figure 4 shows the forest plot of effect sizes for secondary outcomes.

Secondary tic measures

An additional measure of tic symptoms was recorded through the PTQ. The findings supported that of the primary outcome: that is, participants in the ERP group showed greater tic reduction than those in the psychoeducation group at 3 months (−9.44, 95% CI −15.37 to −3.51) and 6 months (−8.60, 95% CI −14.43 to −2.77). However, the findings from the YGTSS impairment scale did not show any statistically significant difference in tic-related impairment at either time point (see Table 5).

Other secondary measures

There was no statistically significant difference in young person-reported anxiety (SCAS) at 3 months; however, at 6 months there was a greater reduction in SCAS scores in the ERP group than in the psychoeducation group (−5.10, 95% CI −9.70 to −0.50). Conversely, the young person-reported tic-specific QoL (CandA-GTS-QoL) and the outcome assessor-completed perception of global improvement (CGI-I) showed greater improvement in the ERP group than in the psychoeducation group at 3 months (CGI-I −0.41, 95% CI −0.71 to −0.11; CandA GTS-QoL −4.81, 95% CI −8.79 to −0.83) but no statistically significant difference at 6 months.

FIGURE 5 Forest plot of standardised effect sizes for primary and secondary outcomes at 12- and 18-month follow-ups. Note: Figure in Hollis et al.79 (Figure not reproduced here; see the original article.)

There was no statistically significant difference at either 3 or 6 months in the other secondary outcomes of parent-reported general emotional and behavioural functioning (SDQ), young person-reported low mood (MFQ) and outcome assessor-reported overall functioning (CGAS).

Effect of the intervention at the intervention mid-point

Table 6 shows there was no statistical difference in scores on the MFQ or the PTQ at the mid-point of the intervention.

Unplanned analysis

An unplanned post hoc analysis investigated whether the interventions had a differential effect on participants with or without comorbid anxiety or ADHD. Table 7 shows that there was no evidence to support this.

Treatment responders

An additional unplanned analysis was also conducted to compare treatment responders between the two groups. A positive treatment response was defined by a rating of 1 or 2 (very much/much improved) on the CGI-I. Table 8 shows that there were more people classified as treatment responders at both 3 and 6 months in the ERP group than the psychoeducation group. The analysis demonstrated significantly greater treatment response with ERP at 3 months [36% (95% CI 26 to 45); N = 101] than for psychoeducation [20% (95% CI 12 to 28); N = 100], odds ratio (OR) 2.22 (95% CI 1.17 to 4.20). This superior treatment response was sustained at 6 months for ERP [47% (95% CI 37 to 57); N = 93] compared to psychoeducation [29% (95% CI 20 to 39); N = 93], OR 2.20 (95% CI 1.20 to 4.04).

Treatment adherence

The minimum treatment was specified as completion of the first four chapters for both groups. This minimum treatment was selected as the first four chapters contained the main principles of the intervention, with the subsequent chapters used to reinforce the theory and strategies. This was achieved for 88% (99/112) in the ERP group and 94% (105/112) in the psychoeducation group, indicating high engagement rate for both treatments. The results of engagement are shown in Table 9.

The numbers of times participants logged in to the intervention were similar across both groups, although there was a slightly higher number of logins for the participants in the ERP group.

There was slightly more therapist time required to support the ERP intervention compared to the psychoeducation intervention by approximately 15 minutes. However, it is noteworthy that the overall therapist contact time per family (combined parent/carer and young person) was 2.5 hours, which equates to 15 minutes a week; this is much lower than that of face-to-face therapy. Parent/carer and young person perceptions of treatment suitability and credibility are explored in Chapter 6, but Table 9 demonstrates that they were high across both groups.

Adverse events

Adverse events were recorded up until 6 months (phase 1). Table 10 shows the number of AEs recorded throughout the trial. There were slightly fewer AEs in the ERP group compared to psychoeducation (359 vs. 431), and fewer participants in the ERP group experienced one or more AEs (n = 88/112; 79%) than in the psychoeducation group (n = 94/112; 84%). The most commonly occurring AEs were low mood, increased tics and anger/irritability.

There were two SAEs throughout the trial, which affected two participants who were both in the psychoeducation group. The SAEs were judged as unrelated to the trial by the TSC and DMC. One of the SAEs was a male participant collapsing and being admitted to hospital as a result of a functional movement disorder. The other SAE involved a female participant attending accident and emergency as a result of a ‘tic attack’. The independent clinicians on the TSC and DMC agreed with the chief investigator that waxing and waning of tics is part of the natural course of the disorder and should not be considered related to the intervention. Both participants were discharged from hospital with no further action. The parents informed the trial team that they had not recently been engaging with ORBIT at the time of the event and they did not consider the events to be related to their participation.

Phase 2 results

The findings from phase 2 are currently under review.

On 12 April 2021, the final 18-month follow-up was completed (see Figure 3).

Missing data

There was no primary outcome for the phase 2 results; however, the YGTSS-TTSS (the primary outcome for phase 1) was a key outcome of interest. Completion of this YGTSS-TTSS was good throughout the trial. At 12 months, data were collected from 91/112 participants (81%) in both the ERP group and the psychoeducation group, and at 18 months data were collected from 89/112 participants (80%) from the ERP group and from 90/112 participants (80%) from the psychoeducation group. The only predictor of missingness was site, which was included as a covariate in the statistical models. Other measures that were completed by the outcome assessor, including the CGI-I and the CGAS, also sustained good completion rates (see Table 11).

However, data from measures that the parent/carer or young person completed online into the database, which were not directly collected or supported by the outcome assessors (e.g. PTQ, MFQ, SCAS, SDQ, CandA-GTS-QoL), were less well completed, with a large amount of missing data (ranging from 41% to 61% missing). Thus, the results from these measures should be interpreted with caution. In all cases, the quantities of missing data were similar for each randomised group.

Key outcome of interest

At 12 months, the mean YGTSS-TTSS in the ERP group was 21.7 (SD 8.8) compared to 24.9 (SD 7.3) in the psychoeducation group. The analysis, which adjusted for tic severity at baseline and site, demonstrated that the ERP intervention reduced TTSS by −2.64 points (95% CI −4.48 to −0.79), with an effect size of −0.36 (95% CI −0.61 to −0.11), compared to the psychoeducation group.

At 18 months, the mean YGTSS-TTSS in the ERP group was 21.5 (SD 9.0) and 23.9 (SD 8.4) in the psychoeducation group. The analysis indicated that the ERP intervention reduced the TTSS by −2.01 points (95% CI −3.86 to −0.15), with an effect size of −0.27 (95% CI −0.52 to −0.02), in comparison to the psychoeducation group (see Table 12).

The standardised effect sizes for all outcomes in phase 2 are presented in Figure 5.

Other measures

The parent-reported measure of tics (PTQ) also showed that the ERP group had less tic severity than the psychoeducation group at 12 months (−9.89, 95% CI −16.01 to −3.77), but this was not found at 18 months (see Figure 5 and Table 12). There was no statistically significant difference between the two groups on the YGTSS impairment scale at either time point.

The young person-reported MFQ (mood) and SCAS (anxiety) showed larger reductions in symptoms at 12 months (MFQ −2.93, 95% CI −5.77 to −0.09; SCAS −6.11, 95% CI −10.41 to −1.81) and 18 months (MFQ −4.87, 95% CI −8.00 to −1.75; SCAS −9.41, 95% CI −14.11 to −4.70) in the ERP group compared to the psychoeducation group.

At both time points, young person-reported tic-specific QoL showed greater improvement in the ERP group compared to the psychoeducation group (12 months −5.79, 95% CI −10.28 to −1.30; 18 months −9.00, 95% CI −13.98 to −4.01).

The same was also true for the outcome assessor-completed CGAS (12 months 2.85, 95% CI 0.15 to −5.56; 18 months 3.18, 95% CI 0.47 to −5.90) and CGI-I (12 months −0.43, 95% CI −0.75 to −0.10; 18 months 0.38, 95% CI −0.71 to −0.05). However, there was no statistically significant difference in parent-reported general emotional and behavioural functioning (SDQ) at either time point (see Table 12).

Unplanned analysis

After 6 months (phase 2), participants were allowed to start other tic treatments (behavioural or pharmacological) outside the trial interventions. However, between 6 and 12 months only 11 (6%) started a new tic medication and only 6 (3%) started a new tic therapy. Between 6 and 18 months only 7 (4%) started a new tic medication and only 2 (1%) started a new tic therapy (see Table 13).

Most participants were not using tic medication (90% at 12 months, 92% at 18 months) or other tic therapy (94% at 12 months, 96% at 18 months) during phase 2. The number of participants who changed their medication or therapy status was too small to conduct a sensitivity analysis on the YGTSS-TTSS.

We conducted the same unplanned post hoc analysis conducted in phase 1 that compared treatment response on the CGI-I. Comparable to phase 1, the analysis revealed greater treatment responses with ERP at 12 months (2.27, 95% CI 1.23 to 4.22) and 18 months (1.80, 95% CI 0.99 to 3.27). Furthermore, we demonstrated that participants who responded at 6 months were more likely to continue to respond at later follow-up and less likely to relapse if they were in the ERP group than the psychoeducation group (see Table 14).