Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Jankovic J

PROVIDER: S-EPMC10525047 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Jankovic Joseph J Coffey Barbara B Claassen Daniel O DO Jimenez-Shahed Joohi J Gertz Barry J BJ Garofalo Elizabeth A EA Stamler David A DA Wieman Maria M Savola Juha-Matti JM Harary Eran E Alexander Jessica J Barkay Hadas H Gordon Mark Forrest MF

Movement disorders clinical practice 20230824 9

<h4>Background</h4>Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and phonic tics.<h4>Objective</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 37772282

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Project description:ImportanceTourette 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.ObjectiveTo 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 participantsThis 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.InterventionsParticipants 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 measuresThe 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.ResultsThe 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 relevanceIn 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 registrationClinicalTrials.gov Identifier: NCT03571256.

Project description:BackgroundDeutetrabenazine is approved in the USA, China, Australia, Israel, Brazil, and South Korea for the treatment of chorea associated with Huntington disease.ObjectiveWe aimed to evaluate the long-term safety and tolerability of deutetrabenazine for the treatment of Huntington disease.MethodsThis open-label, single-arm, multi-center study included patients who completed a double-blind study (Rollover) and patients who converted overnight from a stable tetrabenazine dose (Switch). Exposure-adjusted incidence rates (adverse events per person-year) were calculated. Efficacy was analyzed using a stable post-titration timepoint (8 weeks). Changes in the Unified Huntington's Disease Rating Scale total motor score and total maximal chorea score from baseline to week 8, as well as those from week 8 to week 145 (or the last visit on the study drug if that occurred earlier), were evaluated as both efficacy and safety endpoints during the study.ResultsOf 119 patients (Rollover, n = 82; Switch, n = 37), 100 (84%) completed ≥ 1 year of treatment. End-of-study exposure-adjusted incidence rates for adverse events in Rollover and Switch, respectively, were: any, 2.57 and 4.02; serious, 0.11 and 0.14; leading to dose suspension, 0.05 and 0.04. Common adverse events (≥ 4% either cohort) included somnolence (Rollover, 20%; Switch, 30%), depression (32%; 22%), anxiety (27%; 35%), insomnia (23%; 16%), and akathisia (6%; 11%). Adverse events of interest included suicidality (9%; 5%) and parkinsonism (4%; 8%). Mean dose at week 8 was 38.1 mg (Rollover) and 36.5 mg (Switch). Mean dose across cohorts after titration was 37.6 mg; at the final visit, mean dose across cohorts was 45.7 mg. Patients showed minimal change in the Unified Huntington's Disease Rating Scale total maximal chorea scores with stable dosing from weeks 8-145 or at the end of treatment, but total motor score increased versus week 8 (mean change [standard deviation]: 8.2 [11.9]). There were no unexpected adverse events upon drug withdrawal, and mean (standard deviation) total maximal chorea scores increased 4.7 (4.6) units from week 8 to 1-week follow-up.ConclusionsAdverse events observed with long-term deutetrabenazine exposure were consistent with previous studies. Reductions in chorea persisted over time. Upon treatment cessation, there was no unexpected worsening of chorea.Clinical trial registrationClinicalTrials.gov identifier: NCT01897896.

Project description:ImportanceTourette 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.ObjectiveTo examine whether deutetrabenazine is effective and safe for the treatment of Tourette syndrome in children and adolescents.Design, setting, and participantsThis 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.InterventionPatients 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 measuresThe 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.ResultsA 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 relevanceIn 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 registrationClinicalTrials.gov Identifier: NCT03452943.

Project description:ObjectiveThe purpose of this study was to evaluate the long-term safety and efficacy of risperidone in treating irritability and related behaviors in children and adolescents with autistic disorders.MethodsIn this 6 month (26 week) open-label extension (OLE) study, patients (5-17 years of age, who completed the previous fixed-dose, 6 week, double-blind [DB] phase) were flexibly dosed with risperidone based on body weight. The maximum allowed dose was 1.25 mg/day for those weighing 20 to <45 kg, and 1.75 mg/day for those weighing ≥ 45 kg. The study primarily assessed risperidone's safety; efficacy was assessed as a secondary end-point.ResultsFifty-six (71%) out of 79 enrolled patients completed the OLE; the most common discontinuations were for insufficient response (7 [9%]) or adverse events (AE) (5 [6%]). The most common (≥ 5% frequency in the total group) AEs were increased appetite (11% [n=9]); increased weight and vomiting (9% [n=7] each); sedation, pyrexia, and upper respiratory tract infection (8% [n=6] each); nasopharyngitis (6% [n=5]); and somnolence and fatigue (5% [n=4] each). Extrapyramidal AEs were reported in 6 (8%) patients. Increase in mean weight (11-15%) and body mass index (5-10%) occurred; one patient discontinued because of weight increase. One potentially prolactin-related AE (irregular menstruation) was reported. The risperidone high-dose group had the greatest mean improvement in sleep visual analog scale (24.6). All groups showed additional improvement in efficacy scale scores during the OLE.ConclusionsDuring this OLE, safety findings with risperidone treatment (maximum weight-based dose of 1.25 mg/day or 1.75 mg/day) were consistent with those observed in the DB phase, and with the current safety information for risperidone in autistic, psychiatric, and behavioral disorders. Patients experienced some additional improvement in irritability and related behaviors.Clinical trials registryThis phase-4 study is registered at ClinicalTrials.gov (NCT00576732).

Project description:ObjectiveEvaluate long-term efficacy (percent seizure frequency reduction and responder rates), safety, and tolerability of adjunctive cenobamate in an open-label extension (OLE) of the randomized, double-blind, placebo-controlled study.MethodsPatients (aged 18-70 years) with uncontrolled focal seizures despite treatment with 1-3 antiseizure medications who completed the 18-week double-blind study (n=360) could enter the OLE, where they underwent a 2-week blinded conversion to cenobamate (target dose, 300 mg/day; min/max, 50/400 mg/day).ResultsThree hundred fifty-five patients were included in the OLE safety population (265 originally randomized to cenobamate, 90 originally randomized to placebo), and 354 were included in the OLE modified intent-to-treat population. As of July 2019, 58.9% (209/355) of patients were continuing cenobamate treatment and 141 had discontinued, including 16.6% (59/355) due to lack of efficacy, 8.7% (31/355) due to withdrawal by patient, and 7.6% (27/355) due to adverse events. Median (range) duration of OLE exposure was 53.9 (1.1-68.7) months. Retention rates at 12, 24, 36, and 48 months were 83%, 71%, 65%, and 62%, respectively. Median percent seizure frequency reduction over baseline increased with each 6-month OLE interval, up to 76.1% at months 43-48. Among observed patients, 16.4% (36/220) achieved 100% and 39.1% (86/220) achieved ≥90% seizure reduction during >36-48 months. Among the initial OLE mITT population, 10.2% (36/354) of patients achieved 100% and 24.3% (86/354) achieved ≥90% seizure reduction during >36-48 months. Similar to the double-blind study, adverse events (AEs) included dizziness, somnolence, fatigue, and headache. Serious AEs occurred in 20.3% (72/355) of patients.ConclusionLong-term efficacy, including 100% and ≥90% seizure reduction, was sustained during 48 months of cenobamate treatment, with 71% retention at 24 months. No new safety issues were identified. These results confirm the findings of the double-blind study and support the potential long-term clinical benefit of cenobamate.RegistrationClinicalTrials.gov NCT01866111.Classification of evidenceThis study provides Class IV evidence that oral Cenobamate 50-400 mg/day is effective as an adjunctive treatment for the long-term management of patients with uncontrolled focal seizures previously treated with 1 to 3 ASMs.

Project description:BackgroundHereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years.MethodsPatients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004.ResultsIn the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen-inotersen) and 39 switched from placebo to inotersen (placebo-inotersen). The placebo-inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen-inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo-inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study.ConclusionInotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.

Dataset Information

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

Background

Objective

Methods

Results

Conclusions

Publications

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

Similar Datasets

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