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Efficacy and tolerability of pregabalin in essential tremor: A randomized, double-blind, placebo-controlled, crossover trial
Journal of the Neurological Sciences 285 (2009) 195–197
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Efficacy and tolerability of pregabalin in essential tremor: A randomized, double-blind, placebo-controlled, crossover trial Joseph M. Ferrara, Christopher Kenney, Anthony L. Davidson, Lina Shinawi, Abigail M. Kissel, Joseph Jankovic ⁎ Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, Texas 77030, USA
a r t i c l e
i n f o
Article history: Received 5 June 2009 Received in revised form 22 June 2009 Accepted 30 June 2009 Available online 25 July 2009 Keywords: Essential tremor Pregabalin Fahn–Tolosa–Marin Tremor Rating Scale (TRS) Quality of Life in Essential Tremor Questionnaire (QUEST)
a b s t r a c t We performed a double-blind, crossover-design study to assess the tolerability and efficacy of pregabalin (PGB) in patients with essential tremor (ET). Twenty patients (11 women; mean age of 62.2± 12.7 years, mean ET duration of 25.5± 14.9 years) with ET were randomized for treatment with PGB (150–600 mg/day) or placebo, titrated over 6 weeks. Identical assessments of the Fahn–Tolosa–Marin Tremor Rating Scale (TRS) (primary endpoint), Clinical Global Impression of Change (CGI-C), Quality of Life in Essential Tremor Questionnaire (QUEST), Hamilton Anxiety Scale (HAM-A), and a sleep hygiene questionnaire (HD-16) were made at the baseline, at the end of treatment periods for both drug and placebo, and following the 2-week washout period preceding crossover. We found no improvement in any of the TRS measures and a statistically significant worsening of QUEST scores while patients were taking PGB. Adverse events were similar in frequency to previously published studies of PGB, the most common being drowsiness and dizziness. © 2009 Elsevier B.V. All rights reserved.
1. Introduction
2. Methods
Essential tremor (ET) is a common, often heritable, neurological disorder characterized by bilateral, progressive action tremor predominantly affecting the hands, arms, head and voice. Several medications, including propranolol, primidone, topiramate and gabapentin, have shown moderate tremorlytic effects in placebo-controlled trials [1]. Current drug therapies, however, are ineffective in approximately 25–55% of ET patients [2], and treatment is often limited by adverse effects. Accordingly, additional safe and well-tolerated medical therapies for ET are needed. Pregabalin (PGB) is an amino acid derivative of gamma-amino butyric acid with antiepileptic, analgesic, and anxiolytic properties. PGB binds to the alpha-2-delta subunit of neuronal voltage-gated calcium channels, resulting in reduced depolarization-induced calcium influx at nerve terminals and diminished release of excitatory neurotransmitters [3]. Preliminary studies suggest that PGB has tremorlytic effects [4], and the drug has been proven to be reasonably well-tolerated in elderly patients [3]. Accordingly, we assessed the tolerability and efficacy of PGB in patients with ET in this pilot, placebo-controlled, crossover-design trial.
2.1. Participants
⁎ Corresponding author. Tel.: +1 713 798 5998; fax: +1 713 798 6808. E-mail address: [email protected] (J. Jankovic). URL: http://www.jankovic.org (J. Jankovic). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.06.044
Twenty patients with definite or probable ET, defined according to Tremor Investigational Group criteria [5], were recruited from the Baylor College of Medicine Parkinson's Disease Center and Movement Disorders Clinic in Houston, Texas. Exclusion criteria were as follows: age b18 or N80 years; pregnancy, lactation or lack of a safe contraceptive method in females; known renal insufficiency; past hypersensitivity or intolerance to PGB; any ongoing cause of enhanced physiologic tremor; recent exposure to tremorgenic drugs; direct or indirect trauma to the nervous system within 3 months preceding the onset of tremor; historical or clinical evidence of psychogenic tremor; prior surgical treatment for tremor; and use of other tremorlytic drugs, apart from beta-blockers and an evening dose of a benzodiazepine hypnotic. Patients using a beta-blocker were required to be on a stable dose for 4 weeks prior to entry into the study and were not allowed to change the dose of that medication throughout the duration of the study. Medications that were discontinued during screening in order to comply with these criteria were stopped for N5 half-lives prior to study initiation. All patients signed an informed consent before entering the study, and the study protocol was approved by the Baylor College of Medicine Internal Review Board for Human Research. The trial has been registered at ClinicalTrials.gov (NCT00646451).
196
J.M. Ferrara et al. / Journal of the Neurological Sciences 285 (2009) 195–197
Fig. 1. Study design. Patients were randomized for treatment with PGB or placebo, titrated over 6 weeks. Identical assessments of the TRS (primary endpoint), CGI-C, QUEST, HAM-A, and HD-16 were made by a consistent rater at the baseline, at the end of treatment periods for both drug and placebo, and following the 2-week washout period preceding crossover. Patients were asked to avoid caffeine on study visit days and refrain from alcohol consumption for at least 24 h prior to evaluations.
carryover effect was excluded. Analyses were performed using Stata IC version 10.0 for Windows.
2.2. Evaluation procedures A randomized, double-blind, placebo-controlled, crossover-design study was used with Fahn–Tolosa–Marin Tremor Rating Scale (TRS) scaled total score serving as the primary endpoint [6]. Secondary endpoints were the Clinical Global Impression of Change (CGI-C), Quality of Life in Essential Tremor Questionnaire (QUEST) [7], Hamilton Anxiety Rating Scale (HAM-A) [8], and a health status questionnaire on sleep hygiene (HD-16) [9] (Fig. 1). Indistinguishable capsules and an identical titration protocol were used for PGB and placebo. Patients received the study drug at an initial dose of 75 mg twice daily, with upward titration to a target dose of 150 mg twice daily. Patients were given the option to increase the study drug to as high as 300 mg twice daily if inadequate benefit was perceived after 3 weeks of treatment. The study drug was increased at a rate of 150 mg/day/week. All patients in both periods were contacted by phone after two weeks of treatment to facilitate drug titration and address any adverse events. Patients were permitted to return to a lower dose if side effects occurred during drug titration. After assessment protocols were completed, patients were titrated off the study drug at a rate of 150 mg every 2 days until discontinuation. 2.3. Data analysis TRS raw scores were normalized prior to analysis using previously described methods [10]. The QUEST, HAM-A and HD-16 were scored as per published guidelines [7–9]. Outcome on study completers was assessed via ANOVA models using a 2 × 2 Latin-square crossover design including sequence, period, and treatment effects. A significant Table 1 Clinical characteristics of patients at baseline. Sex, F/M Age, mean years ± SD ET duration, mean years ± SD Family history of ET, N (%) Adjunct beta-blocker use, N (%) Number of failed tremorlytic treatments preceding enrollment, mean ± SD Normalized TRS, mean ± SDa Part A Part B Part C Total b QUEST summary index, mean ± SD HAM-A, mean ± SDc HD-16, mean ± SDd
11/9 62.2 ± 12.7 25.5 ± 14.9 13 (65) 13 (65) 2.9 ± 1.8 18.3 ± 6.0 50.8 ± 16.4 43.1 ± 15.3 37.1 ± 11.6 37.5 ± 19.0 11.7 ± 7.5 87.8 ± 160.7
3. Results Demographics and clinical characteristics of participants at study initiation are listed in Table 1. Sixteen of 20 patients completed the study and were included in the analysis of drug efficacy (Table 2). Analysis of variance revealed no treatment effect (P=0.16), period effect (P=0.67), or treatment-period interaction (P=0.07). Although TRS measures were worse when patients were taking PGB, this difference did not reach statistical significance. There was a statistically significant difference in QUEST scores between PGB and placebo, favoring placebo (P=0.03). Two patients noted an improvement while enrolled in the trial and elected to remain on PGB following completion of the study. One patient withdrew from the PGB period of the study due to postural instability and died of a malignant arrhythmia 6 days later. This patient had a history of chronic pulmonary hypertension, and the death was judged unrelated to PGB. Of the remaining 3 patients who discontinued the study prematurely, 1 patient withdrew due to nausea which began during the washout period, and 2 patients withdrew due to dizziness and personal reasons following their PGB period efficacy evaluation and preceding crossover. Other adverse effects were mild to moderate in severity (Table 3). PGB could not be titrated beyond 75 mg twice daily in 3 (15%) patients due to poor tolerability (drowsiness and instability); the mean dose of PGB at the time of efficacy assessments was 443±172 mg. 4. Discussion In this randomized, double-blind, placebo-controlled, crossover study, PGB failed to significantly reduce ET severity, as assessed by TRS, the primary end point. The TRS has good intra-rater reliability, making it well-suited for a crossover study where patients serve as their own controls [11]. The TRS, however, is based upon an ordinal scale of tremor amplitude and may be insensitive to modest changes in tremor severity. Accordingly, it is possible that our study did not identify a change in tremor severity, which might have been apparent using accelerometry, a digitizing tablet or other kinematic techniques. Indeed, in a prior study of PGB for ET, there was a significant reduction in tremor amplitude as measured by accelerometry without a corresponding Table 2 Change in TRS and secondary measures of efficacy compared with baseline.
a
TRS part A rates the severity of resting, postural and action tremor in upper and lower extremities, face, tongue, voice, head and trunk. Part B rates the severity of upper extremity tremor while writing, drawing, and pouring liquid. Part C rates functional disability of tremor while speaking, eating, drinking, maintaining hygiene, dressing, and working. b The QUEST rates patient perception of health status as influenced by tremor across 5 domains: physical, psychosocial, communication, hobbies/leisure, and work/finance. c The HAM-A rates the severity of anxiety symptomatology across 14 parameters. Scores of 14–17 correspond to mild anxiety, scores of 18–24, moderate anxiety, and scores of 25–30 severe anxiety. d The HD-16 rates insomnia-related quality of life across five domains: physical symptoms, energy and motivation, concentration, interpersonal relations, and psychological symptoms.
Change in normalized TRS
Part A Part B Part C Total
CGI-C Change in QUEST summary index Change in HAM-A Change in HD-16
Pregabalin
Placebo
P-value
2.4 ± 4.7 6.7 ± 12.3 4.5 ± 13.9 5.1 ± 9.7 3.9 ± 1.3 8.0 ± 20.3 1.1 ± 5.2 32.2 ± 146.8
− 0.2 ± 4.1 3.6 ± 6.6 − 1.5 ± 12.8 0.3 ± 4.6 3.8 ± 0.5 − 9.7 ± 14.5 4.1 ± 5.4 − 38.6 ± 99.3
0.242 0.237 0.129 0.162 0.162 0.031 0.257 0.143
For the TRS, HAM-A, QUEST and HD-16, higher scores represent increased symptom severity or diminished quality of life. CGI-C was scored as follows: 1 = very much improved, 2 = much improved, 3 = mildly improved, 4 = no change, 5 = mildly worse, 6 = much worse, and 7 = very much worse.
J.M. Ferrara et al. / Journal of the Neurological Sciences 285 (2009) 195–197 Table 3 Adverse events. Symptom Drowsiness Dizziness Fatigue Instability Insomnia Headache Confusion Vivid dreams Upper respiratory tract infection Blurred vision Burning tongue Fatal arrhythmia Possible jaw dislocation Nausea Night sweats Weight gain
Frequency, N (%) PGB (N = 20)
Placebo (N = 18)
5 (25) 4 (20) 3 (15) 3 (15) 0 0 1 (5) 1 (5) 2 (10) 1 (5) 1 (5) 1 (5) 1 (5) 0 0 0
3 1 0 1 2 2 1 1 1 0 0 0 0 1 1 1
(17) (6) (6) (11) (11) (6) (6) (6)
(6) (6) (6)
197
efficacy analysis finished the PGB period of the study, and their response to the drug was not superior to those of the patients who completed both periods of the study. This study was conducted at a tertiary referral center for movement disorders, and the study population consisted largely of patients with long-standing, pharmacoresistant tremor. Whether PGB would provide clinical benefit in patients with less severe, previously untreated ET is not known. The most common adverse effects of PGB were drowsiness, dizziness and fatigue, which were mild to moderate in severity. Overall, adverse events of PGB in our ET population were comparable to those previously reported in patients with epilepsy, anxiety and chronic pain conditions [3,12]. In conclusion, we found PGB to be well-tolerated in patients with moderately severe ET, but without a clinically meaningful tremorlytic effect. Acknowledgment This investigator-initiated study was supported by a grant from Pfizer, Inc.
improvement in TRS subsection scores [4]. Our results may also differ from the previous trial because of differences in the study populations. On average, our patients were older and had longer disease duration. Also, a higher percentage of our patients were on a beta-blocker. Unfortunately the small sample size of our study limits the possibility of a meaningful post-hoc analysis targeted to these variables. We included the QUEST as a secondary endpoint in this study, as our interest was in demonstrating a reduction in tremor that improved quality of life and motor function. Unexpectedly, we found a statistically significant deterioration in QUEST scores during the PGB period versus placebo. The basis for this change is not clear, as TRS scores were similar for PGB and placebo, and patient-rated CGI-C was essentially unchanged from the baseline in both groups. Differences in the work/finance domain of the QUEST appear to underlie the decline in health status, and economic factors external to the study may be relevant. Although the QUEST does not specifically address medication tolerability, adverse drug effects may also have contributed to the observed difference in this patient-based outcome measure. There were several limitations in our study, including its small sample size and the relatively high (20%) dropout rate. Given its size, this trial cannot exclude the possibility that PGB had tremorlytic effects, but any effect is likely to be modest, and our results suggest that a larger study is unlikely to yield more favorable results. We performed a study completer analysis, rather than an imputed intentto-treat analysis, which potentially introduces bias to the statistical methods. However, all four patients who were excluded from our
References [1] Zesiewicz TA, Elble R, Louis ED, Hauser RA, Sullivan KL, Dewey JR, et al. Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005;64: 2008–20. [2] Louis ED. Clinical practice. Essential tremor. N Engl J Med 2001;345:887–91. [3] Montgomery S, Chatamra K, Pauer L, Whalen E, Baldinetti F. Efficacy and safety of pregabalin in elderly people with generalised anxiety disorder. Br J Psychiatry 2008;193:389–94. [4] Zesiewicz TA, Ward CL, Hauser RA, Salemi JL, Siraj S, Wilson MC, et al. A pilot, double-blind, placebo-controlled trial of pregabalin (Lyrica) in the treatment of essential tremor. Mov Disord 2007;22:1660–3. [5] Findley LJ, Koller WC. Definitions and behavioural classification. In: Findley LJ, Koller WC, editors. Handbook of tremor disorders. New York: Marcel Dekker; 1995. p. 1–5. [6] Fahn S, Tolosa E, Marin C. Clinical rating scale for tremor. In: Jankovic J, Tolosa E, editors. Parkinson's disease and movement disorders. Baltimore: Urban and Schwarzenberg; 1988. p. 225–34. [7] Tröster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of Life in Essential Tremor Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord 2005;11:367–73. [8] Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:50–5. [9] Leger D, Scheuermaier K, Raffray T, Metlaine A, Choudat D, Guilleminault C. HD-16: a new quality of life instrument specifically designed for insomnia. Sleep Med 2005;6:191–8. [10] Ondo WG, Jankovic J, Connor GS, Pahwa R, Elble R, Stacy MA, et al, Topiramate Essential Tremor Study Investigators. Topiramate in essential tremor: a doubleblind, placebo-controlled trial. Neurology 2006;66:672–7. [11] Stacy MA, Elble RJ, Ondo WG, Wu SC, Hulihan J, TRS study group. Assessment of interrater and intrarater reliability of the Fahn–Tolosa–Marin Tremor Rating Scale in essential tremor. Mov Disord 2007;22:833–8. [12] Lyrica [package insert]. New York, NY: Pfizer Inc.; Revised 6/2007.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Efficacy and tolerability of pregabalin in essential tremor: A randomized, double-blind, placebo-controlled, crossover trial Joseph M. Ferrara, Christopher Kenney, Anthony L. Davidson, Lina Shinawi, Abigail M. Kissel, Joseph Jankovic ⁎ Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, Texas 77030, USA
a r t i c l e
i n f o
Article history: Received 5 June 2009 Received in revised form 22 June 2009 Accepted 30 June 2009 Available online 25 July 2009 Keywords: Essential tremor Pregabalin Fahn–Tolosa–Marin Tremor Rating Scale (TRS) Quality of Life in Essential Tremor Questionnaire (QUEST)
a b s t r a c t We performed a double-blind, crossover-design study to assess the tolerability and efficacy of pregabalin (PGB) in patients with essential tremor (ET). Twenty patients (11 women; mean age of 62.2± 12.7 years, mean ET duration of 25.5± 14.9 years) with ET were randomized for treatment with PGB (150–600 mg/day) or placebo, titrated over 6 weeks. Identical assessments of the Fahn–Tolosa–Marin Tremor Rating Scale (TRS) (primary endpoint), Clinical Global Impression of Change (CGI-C), Quality of Life in Essential Tremor Questionnaire (QUEST), Hamilton Anxiety Scale (HAM-A), and a sleep hygiene questionnaire (HD-16) were made at the baseline, at the end of treatment periods for both drug and placebo, and following the 2-week washout period preceding crossover. We found no improvement in any of the TRS measures and a statistically significant worsening of QUEST scores while patients were taking PGB. Adverse events were similar in frequency to previously published studies of PGB, the most common being drowsiness and dizziness. © 2009 Elsevier B.V. All rights reserved.
1. Introduction
2. Methods
Essential tremor (ET) is a common, often heritable, neurological disorder characterized by bilateral, progressive action tremor predominantly affecting the hands, arms, head and voice. Several medications, including propranolol, primidone, topiramate and gabapentin, have shown moderate tremorlytic effects in placebo-controlled trials [1]. Current drug therapies, however, are ineffective in approximately 25–55% of ET patients [2], and treatment is often limited by adverse effects. Accordingly, additional safe and well-tolerated medical therapies for ET are needed. Pregabalin (PGB) is an amino acid derivative of gamma-amino butyric acid with antiepileptic, analgesic, and anxiolytic properties. PGB binds to the alpha-2-delta subunit of neuronal voltage-gated calcium channels, resulting in reduced depolarization-induced calcium influx at nerve terminals and diminished release of excitatory neurotransmitters [3]. Preliminary studies suggest that PGB has tremorlytic effects [4], and the drug has been proven to be reasonably well-tolerated in elderly patients [3]. Accordingly, we assessed the tolerability and efficacy of PGB in patients with ET in this pilot, placebo-controlled, crossover-design trial.
2.1. Participants
⁎ Corresponding author. Tel.: +1 713 798 5998; fax: +1 713 798 6808. E-mail address: [email protected] (J. Jankovic). URL: http://www.jankovic.org (J. Jankovic). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.06.044
Twenty patients with definite or probable ET, defined according to Tremor Investigational Group criteria [5], were recruited from the Baylor College of Medicine Parkinson's Disease Center and Movement Disorders Clinic in Houston, Texas. Exclusion criteria were as follows: age b18 or N80 years; pregnancy, lactation or lack of a safe contraceptive method in females; known renal insufficiency; past hypersensitivity or intolerance to PGB; any ongoing cause of enhanced physiologic tremor; recent exposure to tremorgenic drugs; direct or indirect trauma to the nervous system within 3 months preceding the onset of tremor; historical or clinical evidence of psychogenic tremor; prior surgical treatment for tremor; and use of other tremorlytic drugs, apart from beta-blockers and an evening dose of a benzodiazepine hypnotic. Patients using a beta-blocker were required to be on a stable dose for 4 weeks prior to entry into the study and were not allowed to change the dose of that medication throughout the duration of the study. Medications that were discontinued during screening in order to comply with these criteria were stopped for N5 half-lives prior to study initiation. All patients signed an informed consent before entering the study, and the study protocol was approved by the Baylor College of Medicine Internal Review Board for Human Research. The trial has been registered at ClinicalTrials.gov (NCT00646451).
196
J.M. Ferrara et al. / Journal of the Neurological Sciences 285 (2009) 195–197
Fig. 1. Study design. Patients were randomized for treatment with PGB or placebo, titrated over 6 weeks. Identical assessments of the TRS (primary endpoint), CGI-C, QUEST, HAM-A, and HD-16 were made by a consistent rater at the baseline, at the end of treatment periods for both drug and placebo, and following the 2-week washout period preceding crossover. Patients were asked to avoid caffeine on study visit days and refrain from alcohol consumption for at least 24 h prior to evaluations.
carryover effect was excluded. Analyses were performed using Stata IC version 10.0 for Windows.
2.2. Evaluation procedures A randomized, double-blind, placebo-controlled, crossover-design study was used with Fahn–Tolosa–Marin Tremor Rating Scale (TRS) scaled total score serving as the primary endpoint [6]. Secondary endpoints were the Clinical Global Impression of Change (CGI-C), Quality of Life in Essential Tremor Questionnaire (QUEST) [7], Hamilton Anxiety Rating Scale (HAM-A) [8], and a health status questionnaire on sleep hygiene (HD-16) [9] (Fig. 1). Indistinguishable capsules and an identical titration protocol were used for PGB and placebo. Patients received the study drug at an initial dose of 75 mg twice daily, with upward titration to a target dose of 150 mg twice daily. Patients were given the option to increase the study drug to as high as 300 mg twice daily if inadequate benefit was perceived after 3 weeks of treatment. The study drug was increased at a rate of 150 mg/day/week. All patients in both periods were contacted by phone after two weeks of treatment to facilitate drug titration and address any adverse events. Patients were permitted to return to a lower dose if side effects occurred during drug titration. After assessment protocols were completed, patients were titrated off the study drug at a rate of 150 mg every 2 days until discontinuation. 2.3. Data analysis TRS raw scores were normalized prior to analysis using previously described methods [10]. The QUEST, HAM-A and HD-16 were scored as per published guidelines [7–9]. Outcome on study completers was assessed via ANOVA models using a 2 × 2 Latin-square crossover design including sequence, period, and treatment effects. A significant Table 1 Clinical characteristics of patients at baseline. Sex, F/M Age, mean years ± SD ET duration, mean years ± SD Family history of ET, N (%) Adjunct beta-blocker use, N (%) Number of failed tremorlytic treatments preceding enrollment, mean ± SD Normalized TRS, mean ± SDa Part A Part B Part C Total b QUEST summary index, mean ± SD HAM-A, mean ± SDc HD-16, mean ± SDd
11/9 62.2 ± 12.7 25.5 ± 14.9 13 (65) 13 (65) 2.9 ± 1.8 18.3 ± 6.0 50.8 ± 16.4 43.1 ± 15.3 37.1 ± 11.6 37.5 ± 19.0 11.7 ± 7.5 87.8 ± 160.7
3. Results Demographics and clinical characteristics of participants at study initiation are listed in Table 1. Sixteen of 20 patients completed the study and were included in the analysis of drug efficacy (Table 2). Analysis of variance revealed no treatment effect (P=0.16), period effect (P=0.67), or treatment-period interaction (P=0.07). Although TRS measures were worse when patients were taking PGB, this difference did not reach statistical significance. There was a statistically significant difference in QUEST scores between PGB and placebo, favoring placebo (P=0.03). Two patients noted an improvement while enrolled in the trial and elected to remain on PGB following completion of the study. One patient withdrew from the PGB period of the study due to postural instability and died of a malignant arrhythmia 6 days later. This patient had a history of chronic pulmonary hypertension, and the death was judged unrelated to PGB. Of the remaining 3 patients who discontinued the study prematurely, 1 patient withdrew due to nausea which began during the washout period, and 2 patients withdrew due to dizziness and personal reasons following their PGB period efficacy evaluation and preceding crossover. Other adverse effects were mild to moderate in severity (Table 3). PGB could not be titrated beyond 75 mg twice daily in 3 (15%) patients due to poor tolerability (drowsiness and instability); the mean dose of PGB at the time of efficacy assessments was 443±172 mg. 4. Discussion In this randomized, double-blind, placebo-controlled, crossover study, PGB failed to significantly reduce ET severity, as assessed by TRS, the primary end point. The TRS has good intra-rater reliability, making it well-suited for a crossover study where patients serve as their own controls [11]. The TRS, however, is based upon an ordinal scale of tremor amplitude and may be insensitive to modest changes in tremor severity. Accordingly, it is possible that our study did not identify a change in tremor severity, which might have been apparent using accelerometry, a digitizing tablet or other kinematic techniques. Indeed, in a prior study of PGB for ET, there was a significant reduction in tremor amplitude as measured by accelerometry without a corresponding Table 2 Change in TRS and secondary measures of efficacy compared with baseline.
a
TRS part A rates the severity of resting, postural and action tremor in upper and lower extremities, face, tongue, voice, head and trunk. Part B rates the severity of upper extremity tremor while writing, drawing, and pouring liquid. Part C rates functional disability of tremor while speaking, eating, drinking, maintaining hygiene, dressing, and working. b The QUEST rates patient perception of health status as influenced by tremor across 5 domains: physical, psychosocial, communication, hobbies/leisure, and work/finance. c The HAM-A rates the severity of anxiety symptomatology across 14 parameters. Scores of 14–17 correspond to mild anxiety, scores of 18–24, moderate anxiety, and scores of 25–30 severe anxiety. d The HD-16 rates insomnia-related quality of life across five domains: physical symptoms, energy and motivation, concentration, interpersonal relations, and psychological symptoms.
Change in normalized TRS
Part A Part B Part C Total
CGI-C Change in QUEST summary index Change in HAM-A Change in HD-16
Pregabalin
Placebo
P-value
2.4 ± 4.7 6.7 ± 12.3 4.5 ± 13.9 5.1 ± 9.7 3.9 ± 1.3 8.0 ± 20.3 1.1 ± 5.2 32.2 ± 146.8
− 0.2 ± 4.1 3.6 ± 6.6 − 1.5 ± 12.8 0.3 ± 4.6 3.8 ± 0.5 − 9.7 ± 14.5 4.1 ± 5.4 − 38.6 ± 99.3
0.242 0.237 0.129 0.162 0.162 0.031 0.257 0.143
For the TRS, HAM-A, QUEST and HD-16, higher scores represent increased symptom severity or diminished quality of life. CGI-C was scored as follows: 1 = very much improved, 2 = much improved, 3 = mildly improved, 4 = no change, 5 = mildly worse, 6 = much worse, and 7 = very much worse.
J.M. Ferrara et al. / Journal of the Neurological Sciences 285 (2009) 195–197 Table 3 Adverse events. Symptom Drowsiness Dizziness Fatigue Instability Insomnia Headache Confusion Vivid dreams Upper respiratory tract infection Blurred vision Burning tongue Fatal arrhythmia Possible jaw dislocation Nausea Night sweats Weight gain
Frequency, N (%) PGB (N = 20)
Placebo (N = 18)
5 (25) 4 (20) 3 (15) 3 (15) 0 0 1 (5) 1 (5) 2 (10) 1 (5) 1 (5) 1 (5) 1 (5) 0 0 0
3 1 0 1 2 2 1 1 1 0 0 0 0 1 1 1
(17) (6) (6) (11) (11) (6) (6) (6)
(6) (6) (6)
197
efficacy analysis finished the PGB period of the study, and their response to the drug was not superior to those of the patients who completed both periods of the study. This study was conducted at a tertiary referral center for movement disorders, and the study population consisted largely of patients with long-standing, pharmacoresistant tremor. Whether PGB would provide clinical benefit in patients with less severe, previously untreated ET is not known. The most common adverse effects of PGB were drowsiness, dizziness and fatigue, which were mild to moderate in severity. Overall, adverse events of PGB in our ET population were comparable to those previously reported in patients with epilepsy, anxiety and chronic pain conditions [3,12]. In conclusion, we found PGB to be well-tolerated in patients with moderately severe ET, but without a clinically meaningful tremorlytic effect. Acknowledgment This investigator-initiated study was supported by a grant from Pfizer, Inc.
improvement in TRS subsection scores [4]. Our results may also differ from the previous trial because of differences in the study populations. On average, our patients were older and had longer disease duration. Also, a higher percentage of our patients were on a beta-blocker. Unfortunately the small sample size of our study limits the possibility of a meaningful post-hoc analysis targeted to these variables. We included the QUEST as a secondary endpoint in this study, as our interest was in demonstrating a reduction in tremor that improved quality of life and motor function. Unexpectedly, we found a statistically significant deterioration in QUEST scores during the PGB period versus placebo. The basis for this change is not clear, as TRS scores were similar for PGB and placebo, and patient-rated CGI-C was essentially unchanged from the baseline in both groups. Differences in the work/finance domain of the QUEST appear to underlie the decline in health status, and economic factors external to the study may be relevant. Although the QUEST does not specifically address medication tolerability, adverse drug effects may also have contributed to the observed difference in this patient-based outcome measure. There were several limitations in our study, including its small sample size and the relatively high (20%) dropout rate. Given its size, this trial cannot exclude the possibility that PGB had tremorlytic effects, but any effect is likely to be modest, and our results suggest that a larger study is unlikely to yield more favorable results. We performed a study completer analysis, rather than an imputed intentto-treat analysis, which potentially introduces bias to the statistical methods. However, all four patients who were excluded from our
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