Safety and Efficacy of Long-Term Deutetrabenazine Use in Children and Adolescents with Tics Associated with Tourette Syndrome: An Open-Label Extension Study.

Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and phonic tics. Objective: To assess the safety and efficacy of deutetrabenazine (Teva Neuroscience, Inc, Parsippany, NJ), a vesicular monoamine transporter 2 inhibitor, in children and adolescents with TS. Methods: Alternatives for Reducing Tics in TS (ARTISTS) open-label extension (OLE) (NCT03567291) was a 54-week, global, phase 3, open-label extension study of deutetrabenazine (6-48 mg daily) conducted May 28, 2018 to April 3, 2020 with a 2-week randomized withdrawal period. Participants (6-16 years of age) had TS and active tics causing distress or impairment. Safety (primary outcome) was assessed by treatment-emergent adverse events (TEAEs) and clinical laboratory testing. Efficacy was measured by the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS). Results: The intent-to-treat population (228 participants; mean age, 12.0 years; 79.8% male; 86.4% white) had a median (range) duration of exposure of 28.4 (0.3-52.9) weeks. Of 227 participants in the safety analysis, 161 (70.9%) reported ≥1 TEAE (exposure-adjusted incidence rate, 2.77/patient-year), of which 95 (41.9%) were treatment related. The most frequently reported TEAEs were headaches, somnolence, nasopharyngitis, weight increases, and anxiety. No additional safety signals were observed. Worsening of YGTSS-TTS after the 2-week randomized withdrawal was not statistically significant (least squares mean difference, -0.4; P = 0.78). Several exploratory measures showed sustained improvement throughout the treatment periods. Conclusions: In this long-term, open-label trial, deutetrabenazine was well tolerated with low frequency of TEAEs. There was no significant difference in tics between treatment arms during the 2-week randomized withdrawal period, however, descriptive statistics and comparison with baseline showed a numeric improvement in tics, quality of life, and other measures.

Safety and Efficacy of Flexible-Dose Deutetrabenazine in Children and Adolescents With Tourette Syndrome: A Randomized Clinical Trial.

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics; treatments for tics are associated with safety concerns. Deutetrabenazine is a selective vesicular monoamine transporter 2 inhibitor approved for the treatment of chorea associated with Huntington disease and tardive dyskinesia in adults. Objective: To examine whether deutetrabenazine is effective and safe for the treatment of Tourette syndrome in children and adolescents. Design, Setting, and Participants: This phase 2/3, randomized, double-masked, placebo-controlled, parallel-group, dose-titration study included children and adolescents (aged 6-16 years) with Tourette syndrome with active tics causing distress or impairment (ie, Yale Global Tic Severity Scale-Total Tic Score [YGTSS-TTS] ≥20). The trial was conducted over 12 weeks, with 1 week of follow-up from February 2018 to November 2019 at 36 centers in the United States, Canada, Denmark, Russia, Serbia, and Spain. Data analysis was conducted from January 31 to April 22, 2020. Intervention: Patients were randomized (1:1) to receive deutetrabenazine or placebo, titrated during 7 weeks to an optimal level, followed by a 5-week maintenance period. The maximum total daily deutetrabenazine dose was 48 mg/d. Main Outcomes and Measures: The primary efficacy end point was change from baseline to week 12 in YGTSS-TTS. Key secondary end points included changes in Tourette Syndrome-Clinical Global Impression, Tourette Syndrome-Patient Global Impression of Impact, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety was assessed based on treatment-emergent adverse events, vital signs, questionnaires, and laboratory parameters. Results: A total of 119 participants were randomized to deutetrabenazine (59 participants; mean [SD] age, 11.5 [2.5] years; 53 [90%] boys; 49 [83%] White; 3 [5%] Black) and placebo (60 participants; mean [SD] age, 11.5 [2.6] years; 51 [85%] boys; 53 [88%] White; 3 [5%] Black). At week 12, the difference in YGTSS-TTS score was not significant between deutetrabenazine and placebo (least squares mean difference, -0.7; 95% CI, -4.1 to 2.8; P = .69; Cohen d, -0.07). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 38 patients (66%) and 33 patients (56%) receiving deutetrabenazine and placebo, respectively, and were generally mild or moderate. Conclusions and Relevance: In this study of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. These results may be informative for future studies of treatments for tics in Tourette syndrome. Trial Registration: ClinicalTrials.gov Identifier: NCT03452943.

Efficacy and Safety of Fixed-Dose Deutetrabenazine in Children and Adolescents for Tics Associated With Tourette Syndrome: A Randomized Clinical Trial.

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics, often accompanied by behavioral and psychiatric comorbidities. Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved in the US for the treatment of chorea associated with Huntington disease and tardive dyskinesia. Objective: To report results of the ARTISTS 2 (Alternatives for Reducing Tics in Tourette Syndrome 2) study examining deutetrabenazine for treatment of Tourette syndrome. Design, Setting, and Participants: This phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted over 8 weeks with a 1-week follow-up (June 21, 2018, to December 9, 2019). Children and adolescents aged 6 to 16 years with a diagnosis of Tourette syndrome and active tics causing distress or impairment were enrolled in the study. Children were recruited from 52 sites in 10 countries. Data were analyzed from February 4 to April 22, 2020. Interventions: Participants were randomized (1:1:1) to low-dose deutetrabenazine (up to 36 mg/d), high-dose deutetrabenazine (up to 48 mg/d), or a matching placebo, which were titrated over 4 weeks to the target dose followed by a 4-week maintenance period. Main Outcomes and Measures: The primary efficacy end point was change from baseline to week 8 in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) for high-dose deutetrabenazine. Key secondary end points included changes in YGTSS-TTS for low-dose deutetrabenazine, Tourette Syndrome Clinical Global Impression score, Tourette Syndrome Patient Global Impression of Impact score, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety assessments included incidence of treatment-emergent adverse events, laboratory parameters, vital signs, and questionnaires. Results: The study included 158 children and adolescents (mean [SD] age, 11.7 [2.6] years). A total of 119 participants (75%) were boys; 7 (4%), Asian; 1 (1%), Black; 32 (20%), Hispanic; 4 (3%), Native American; 135 (85%), White; 2 (1%), multiracial; 9 (6%), other race; and 1 (0.6%), of unknown ethnic origin. Fifty-two participants were randomized to the high-dose deutetrabenazine group, 54 to the low-dose deutetrabenazine group, and 52 to the placebo group. Baseline characteristics for participants were similar between groups. Of the total 158 participants, 64 (41%) were aged 6 to 11 years, and 94 (59%) were aged 12 to 16 years at baseline. Mean time since Tourette syndrome diagnosis was 3.3 (2.8) years, and mean baseline YGTSS-TTS was 33.8 (6.6) points. At week 8, the difference in YGTSS-TTS was not significant between the high-dose deutetrabenazine and placebo groups (least-squares mean difference, -0.8 points; 95% CI, -3.9 to 2.3 points; P = .60; Cohen d, -0.11). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 34 participants (65%) treated with high-dose deutetrabenazine, 24 (44%) treated with low-dose deutetrabenazine, and 25 (49%) treated with placebo and were generally mild or moderate. Conclusions and Relevance: In this fixed-dose randomized clinical trial of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. Trial Registration: ClinicalTrials.gov Identifier: NCT03571256.

Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures.

PURPOSE: To evaluate pregabalin (PGB), 150 mg/day, and PGB, 600 mg/day, as an add-on treatment for patients with refractory partial seizures concurrently treated with one to three anticonvulsants (AEDs). METHODS: An international (13 countries), multicenter (45 centers), 12-week, double-blind, randomized study in which patients with partial seizures received placebo (n = 96); PGB, 150 mg/day (n = 99); or PGB, 600 mg/day (n = 92); given 3 times a day (t.i.d.). The primary efficacy criterion was reduction in seizure frequency during treatment as compared with baseline, as measured by RRatio, the symmetrical percentage change in seizure rates determined from daily seizure diaries. The RRatio between the 8-week baseline (pretreatment phase) and the 12-week treatment period were compared between each of the PGB groups and the placebo group by using an analysis of variance analysis of the intent-to-treat population. RESULTS: PGB, 150 mg/day and 600 mg/day, were both significantly more effective than placebo in reducing the RRatio [-11.5 (p = 0.0007) and -31.4 (p < or = 0.0001), respectively, vs. 0.9]. These RRatio values correspond to seizure-frequency reductions from baseline of -1.8, 20.6, and 47.8% for placebo, 150 mg/day, and 600 mg/day, respectively. PGB efficacy was significantly dose related (p < or = 0.0001). Secondary efficacy variables corroborated the findings of the primary analysis. Significantly more patients were responders (> or =50% reduction in seizure frequency) in the PGB, 600 mg/day (43.5%), group than in the placebo group (6.2%) (p < or = 0.001). PGB was well tolerated. Dose-related, treatment-emergent adverse events (> or =10%), mostly mild or moderate in intensity, were somnolence, dizziness, ataxia, diplopia, and weight gain. The withdrawal rate due to adverse events was 10% of patients at 150 mg/day and 18.5% of patients at 600 mg/day, compared with 6.2% of patients receiving placebo. CONCLUSIONS: PGB, 150 mg/day and 600 mg/day, is highly effective and well-tolerated add-on therapy in patients with partial seizures.

Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy.

PURPOSE: This randomised, double-blind study compared the newer antiepileptic drugs (AEDs) gabapentin (GBP) and lamotrigine (LTG) as monotherapy in newly diagnosed epilepsy. METHODS: Patients with partial seizures with and/or without secondary generalization or primary generalized tonic-clonic seizures were randomized to either GBP or LTG. During 2- and 6-week titration periods, respectively, GBP dosage reached 1,800 mg/day, and LTG, 150 mg/day. In the subsequent 24-week maintenance phase, the dose could be adjusted based on seizure control or adverse events between 1,200 and 3,600 mg/day for GBP and 100 and 300 mg/day for LTG. The primary end point was time to exit, a composite of efficacy and tolerability. Evaluable patients were used for the primary efficacy analysis, whereas tolerability was examined on an intent-to-treat basis. RESULTS: A total of 309 patients was randomized, and 291 (148 GBP, 143 LTG) were included in the evaluable population. Nineteen patients in each group had an exit event. The median time to exit was 69 days for GBP and 48 days for LTG. The hazard ratio was estimated as 1.043 (90% confidence intervals, 0.602-1.809). Overall, 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study. Of those, 80 (75.5%) patients taking GBP and 73 (76.0%) taking LTG remained seizure free during the final 12 weeks of treatment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients withdrew because of study drug-related adverse events. CONCLUSIONS: GBP and LTG monotherapy were similarly effective and well tolerated in patients with newly diagnosed epilepsy.