OBJECTIVE: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD.
METHODS: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach.
RESULTS: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study.
CONCLUSIONS: These data do not justify use of CoQ as a treatment to slow functional decline in HD.
CLINICALTRIALSGOV IDENTIFIER: NCT00608881.
CLASSIFICATION OF EVIDENCE: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.
OBJECTIVE: To investigate whether creatine administration could slow progressive functional decline in adults with early symptoms of Huntington disease.
METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled study of up to 40 g daily of creatine monohydrate in participants with stage I and II HD treated for up to 48 months. The primary outcome measure was the rate of change in total functional capacity (TFC) between baseline and end of follow-up. Secondary outcome measures included changes in additional clinical scores, tolerability, and quality of life. Safety was assessed by adverse events and laboratory studies.
RESULTS: At 46 sites in North America, Australia, and New Zealand, 553 participants were randomized to creatine (275) or placebo (278). The trial was designed to enroll 650 patients, but was halted for futility after the first interim analysis. The estimated rates of decline in the primary outcome measure (TFC) were 0.82 points per year for participants on creatine, 0.70 points per year for participants on placebo, favoring placebo (nominal 95% confidence limits -0.11 to 0.35). Adverse events, mainly gastrointestinal, were significantly more common in participants on creatine. Serious adverse events, including deaths, were more frequent in the placebo group. Subgroup analysis suggested that men and women may respond differently to creatine treatment.
CONCLUSIONS: Our data do not support the use of creatine treatment for delaying functional decline in early manifest HD.
CLINICALTRIALSGOV IDENTIFIER: NCT00712426.
CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with early symptomatic HD, creatine monohydrate is not beneficial for slowing functional decline.
IMPORTANCE: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.
OBJECTIVE: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.
DESIGN, SETTING, AND PARTICIPANTS: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.
INTERVENTIONS: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.
MAIN OUTCOMES AND MEASURES: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test.
RESULTS: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia.
CONCLUSIONS AND RELEVANCE: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01795859.
BACKGROUND: It has been suggested that treatment with ethyl-eicosapentaenoic acid (EPA) may improve motor function in patients with Huntington's disease (HD) with cytosine-adenine-guanine repeat numbers of <45.
METHODS: This multicenter, randomized, double-blind, placebo-controlled 6-month trial compared the effects of ethyl-EPA versus placebo on 290 subjects with mild-to-moderate HD. The primary endpoint was the change from baseline to 6 months in the Total Motor Score 4 (TMS-4) component of the Unified Huntington's Disease Rating Scale (UHDRS). Secondary endpoints included change from baseline in UHDRS subscores and Clinical Global Impression (CGI).
RESULTS: No significant differences in TMS-4 scores were noted between treatment groups. Similarly, there were no significant differences between groups on any of the UHDRS subscores or CGI scores.
CONCLUSION: Ethyl-EPA was not beneficial in patients with HD during 6 months of placebo-controlled evaluation.
BACKGROUND: The objective of this study was to evaluate citalopram for executive functioning in Huntington's disease (HD).
METHODS: The study was randomized, double-blind, and placebo-controlled. Thirty-three adults with HD, cognitive complaints, and no depression (Hamilton Depression [HAM-D] rating scale ≤ 12) were administered citalopram 20 mg or placebo (7 visits, 20 weeks), with practice and placebo run-ins. The primary outcome was change in executive functioning.
RESULTS: The intent to treat analysis was controlled for practice effects, comparing visits 1 and 2 to visits 5 and 6 for citalopram versus placebo. There were no significant benefits on the executive function composite (treatment-placebo mean difference -0.167; 95% confidence interval [CI], -0.361 to 0.028; P = .092). Citalopram participants showed improved clinician-rated depression symptoms on the HAM-D (t = -2.02; P = 0.05). There were no group differences on motor ratings, self-reported executive functions, psychiatric symptoms, or functional status.
CONCLUSIONS: There was no evidence that short-term treatment with citalopram improved executive functions in HD. Despite excluding patients with active depression, participants on citalopram showed improved mood, raising the possibility of efficacy for subsyndromal depression in HD.
The primary objective of this study is to assess the efficacy of laquinimod as treatment in participants with HD after 52 weeks using the Unified Huntington\'s Disease Rating Scale Total Motor Score (UHDRS-TMS or TMS).
OBJETIVO: Determinar si el ácido etil-eicosapentaenoico (AEP de etilo), un ácido graso omega-3, mejora las funciones motoras de la enfermedad de Huntington.
DISEÑO: Seis meses multicéntrico, aleatorizado, doble ciego, controlado con placebo, seguido de una fase abierta de 6 meses sin dar a conocer las asignaciones iniciales de tratamiento.
AJUSTE: Cuarenta y un centros de investigación en los Estados Unidos y Canadá.
Pacientes: Trescientos dieciséis adultos con la enfermedad de Huntington, enriquecidos por una población con trinucleótidos más corto (citosina-adenina-guanina) expansiones longitud de repetición.
Intervenciones: La asignación al azar a placebo o etil-EPA, 1 g dos veces al día, seguido de tratamiento abierto con etil-EPA.
Medición de resultados principales: el cambio de seis meses en el motor de puntuación total de 4 componentes de Valoración de la Enfermedad de Huntington Escala Unificada analizados para todos los participantes en la investigación y los que tienen expansiones longitud de repetición de citosina-adenina-guanina más cortos (<45).
RESULTADOS: A los 6 meses, el total del motor puntuación de cambio de 4 puntos para los pacientes que reciben etil-EPA no fue diferente de la de los que recibieron placebo. No se encontraron diferencias en las medidas de función, la cognición, o la impresión global. Antes de la divulgación pública de los resultados controlados con placebo de 6 meses, 192 individuos completaron la fase abierta. El motor Puntaje total de 4 cambios no empeoró para los que recibieron tratamiento activo durante 12 meses continuos en comparación con los que recibieron tratamiento activo durante sólo 6 meses (2,0 puntos empeoramiento; P = 0,02).
CONCLUSIÓN: Etil-EPA no era beneficiosa en pacientes con la enfermedad de Huntington durante los 6 meses de evaluación controlado con placebo. Ensayo Clínico Identificador clinicaltrials.gov registro: NCT00146211.
OBJETIVO: Se realizó un estudio aleatorizado, doble ciego, de riluzol en la enfermedad de Huntington para investigar la eficacia de este fármaco antiexcitotoxic en el retraso de progresión de la enfermedad.
MÉTODOS: El estudio incluyó a 537 pacientes adultos con un diagnóstico clínico de la enfermedad de Huntington confirmada por genotipificación. Los pacientes fueron aleatorizados (2:1) al tratamiento con riluzol (50 mg dos veces al día) o placebo durante 3 años. El uso concomitante de medicamentos antichoreic estaba prohibido, y la introducción de esos medicamentos fue un punto final predefinido. La medida de resultado primaria fue el cambio en el puntaje combinado derivado del motor y el total de resultados parciales de la capacidad funcional de la Escala Unificada de la Enfermedad de Huntington Clasificación. La seguridad se evaluó también.
RESULTADOS: Un total de 379 pacientes completaron el estudio (edad media, de 47 años [desviación estándar, 9,5 años; 50% de pacientes de sexo femenino). La principal razón para la suspensión fue la introducción de medicamentos antichoreic. La mediana del cambio desde la basal en la puntuación combinada (resultado primario) para el "por protocolo" de la población fue de 13,7 (intervalo de confianza 95%, 11,1-17,2) en el grupo placebo y el 14,3 (intervalo de confianza 95%, 11,7 a 16,6) en el riluzol grupo. No se encontraron diferencias entre los grupos en el resultado por lo tanto se ha podido demostrar (p = 0,93, Mann-Whitney U). No hubo diferencias en las variables secundarias de resultados de eficacia se observó con excepción de recurso más frecuente a los medicamentos antichoreic en el grupo placebo. No hay eventos adversos inesperados fueron reportados, y la tolerabilidad fue aceptable.
INTERPRETACIÓN: No tiene efectos neuroprotectores sintomáticos o beneficioso de riluzol en la enfermedad de Huntington se ha demostrado.
To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD.
METHODS:
We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach.
RESULTS:
An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study.
CONCLUSIONS:
These data do not justify use of CoQ as a treatment to slow functional decline in HD.
CLINICALTRIALSGOV IDENTIFIER:
NCT00608881.
CLASSIFICATION OF EVIDENCE:
This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.
