A review of medications for chorea in Huntington’s Disease and related current quality of life measures (2016)
Timothy J. Zablocki
Running Title: “Medications for chorea in HD and QoL measures”
Author Affiliation (at the time of original research):
University at Buffalo
School of Pharmacy and Pharmaceutical Sciences
285 Kapoor Hall
Buffalo, NY 14214-8033
Abstract:
Currently, the only FDA-approved drug for the treatment of chorea associated with Huntington’s disease is tetrabenazine. It has been granted orphan drug status by the FDA for this indication and so is relatively expensive. A literature review was performed to find information on all available and potential treatments and on quality of life (QoL) measures associated with Huntington’s disease. Different QoL instruments exist, but there is no universally accepted one. Estimation of Quality Adjusted Life Years associated with the disease and various states of the disease may be a potentially unexplored and needed area of research and could help guide future economic studies.
Keywords: chorea, Huntington’s Disease, tetrabenazine, QALYs, quality of life
Introduction:
Huntington’s disease is a neurodegenerative disorder with symptoms that typically begin to manifest in individuals in the third or fourth decade of their life.[1] It is characterized by motor dysfunction, psychiatric impairment and a decline in cognitive abilities. Dystonia, bradykinesia, depression, anxiety, obsessive-compulsive behavior and even suicidality are just some of the symptoms that are observed in individuals with the disease. The hallmark symptom, however, and an example of the motor dysfunction is chorea, which is present in approximately 90% of individuals with HD. Chorea is characterized by irregular and uncontrolled movements affecting the face, the extremities and other parts of the body that can jump from one region to another in a seemingly spontaneous fashion. Individuals diagnosed with the disease have trouble performing tasks of daily living and frequently need to be cared for by others. The estimated prevalence of the disease in the western world is 4 to 10 individuals per 100,000 and there are approximately 25,000 to 30,000 individuals living with HD in the United States.
The primary tool used in most studies related to Huntington’s disease in the past 15 years has been the Unified Huntington’s Disease Rating Scale (UHDRS). The clinical rating scale was developed to assess different aspects of motor, behavioral and cognitive functions of individuals with HD, as well as their functional capacity.[2] The “Motor Assessment” section, also frequently referred to in studies as “Total Motor Score” (TMS), consists of 15 items, including “maximal chorea,” “maximal dystonia,” “tongue protrusion,” “bradykinesia-body” and “gait.” Each item is rated on a scale of 0 to 4 based on the individual’s performance, with a score of 0 indicating normal performance or an absence of signs/symptoms and a score of 4 indicating an inability to perform a task or a marked presence of signs/symptoms. Consequently, higher scores on each item and in the section overall are associated with poorer motor performance. Individual items may have different maximum scores depending on how many body parts are utilized in the assessment. The “maximal chorea” item, which is frequently singled out in studies, is assessed in the face, mouth, trunk and all 4 extremities for a total of 7 body parts and a maximum possible score of 28 on the item alone.
The “Motor Assessment” or TMS section has a maximum possible score of 124. Additionally, some studies have grouped particular items into subsections.[3, 4] In one, a “Parkinsonism” sub score was defined as a sum of the “rigidity-arms” (left and right) and “bradykinesia-body” items for a total of 12 points.[3] In another, a “Parkinsonism item” was not clearly defined nor did the scoring appear to be consistent with that found in the previous study.[4] While the “Motor Assessment” section and “maximal chorea” item appear to be the most frequently utilized or highlighted scores in studies assessing the efficacy of medications, the UHDRS also contains a “Behavioral Assessment” section that contains items such as “anxiety,” “sad/mood,” “suicidal thoughts,” “obsessions,” “compulsions” and “hallucinations” that are each scored using a similar 0 to 4 point system as well as some questions with simple yes/no answers.[2] The “Functional Assessment” also utilizes questions with yes/no answers. The “Independence Scale” rates the subject’s level of independence with 100 being complete independence and 0 being complete dependence on outside care. The “Functional Capacity” section assesses items such as the ability to perform daily chores or activities of daily living using scores that range from 0 to 2 or 0 to 3. “Cognitive Assessment,” “Verbal Fluency Test,” “Symbol Digit Modalities Test” and “Stroop Interference Test” are the 4 other sections that make up the UHDRS.
At this time, tetrabenazine (Xenazine) is the only medication approved by the FDA for the treatment of Huntington’s disease.[5] It is specifically indicated for the treatment of chorea associated with HD and has been granted orphan drug status by the FDA for this indication. Other, off-label uses for tetrabenazine include Gilles de la Tourette’s syndrome and tardive dyskinesia.[6] Amantadine, nabilone and riluzole have an off-label indication for the treatment of Huntington’s chorea.[5] According to the American Academy of Neurology (AAN) guideline, the recommended treatment for chorea associated with HD is tetrabenazine (up to 100mg/day), amantadine (300mg to 400mg/day) or riluzole (200mg/day).[7] Based on their literature assessment, tetrabenazine is stated to have “very important antichoreic benefits,” riluzole “likely has moderate benefits” and “the degree of benefit for amantadine is unknown.” The guideline by the AAN also addresses a few other medications in the recommendations. Nabilone is listed as possibly having modest antichoreic benefits, but according to the guideline, information is lacking to support long-term use. Ethyl-EPA, minocycline, creatine and coenzyme Q10 are not recommended as first-line choices, but their modest to moderate anti-chorea benefits have not been excluded based on studies that have been conducted. According to the guideline, data is lacking on the use of clozapine, other neuroleptics and donepezil.
Major Drugs and Clinical Trials:
In a randomized, double-blind, placebo-controlled trial by the Huntington Study Group, tetrabenazine was studied for efficacy and tolerability in a combined pool of 84 patients with HD that were experiencing chorea.[8] Fifty-four patients received tetrabenazine, while 30 received placebo for a total study duration of 12 weeks. Tetrabenazine significantly reduced the total maximal chorea score by 5.0 UHDRS units compared to a reduction of 1.5 UHDRS units in patients on placebo. The UHDRS total motor score also decreased in patients taking tetrabenazine (-6.8 units) compared to placebo (-3.5 units), but that difference was not found to be significant. There was a significantly higher number of all adverse events experienced in the tetrabenazine group compared to the placebo group (90.7% vs. 70.0%) and non-mild adverse events (68.5% vs. 33.3%). Five subjects from the tetrabenazine group withdrew from the study compared to just one from the placebo group and four subjects in the tetrabenazine group experienced at least one serious adverse event compared to none in the placebo group. Serious adverse events included depression and suicidal ideation in one subject. Another individual was lost to suicide. Two subjects in the tetrabenazine group reported dose-limiting symptoms of depression.
Subjects from the previous trial were given the option to participate in an open-label extension study designed to test for long-term safety and efficacy of tetrabenazine over a maximum of 80 weeks.[9] Of the 84 patients from the double-blind trial, 75 were enrolled to take part in this long-term study. Over the first 12 weeks, tetrabenazine doses were titrated up to 200 mg/day or the maximum tolerated dose and were decreased to the previous well-tolerated dose if any moderate to severe adverse events occurred. A total of 45 subjects completed the full 80 weeks. Maximal chorea score was significantly decreased by 5.8 UHDRS units at week 24, 5.6 units at week 48 and 4.6 units at week 80. The total motor score was significantly decreased by 7.4 and 5.6 UHDRS units at weeks 24 and 48, respectively, but there was no significant decrease in the score at week 80. Most frequently observed adverse events were sedation/somnolence (in 18 subjects), depressed mood (17 subjects) and anxiety (13 subjects). Of the 17 subjects that reported depressed mood at some point during the study, 15 had a history of prior depression. Three individuals withdrew due to adverse events that included depression and delusions and one attempted suicide.
In a double-blind, placebo-controlled and randomized crossover study with two 2-week long study arms, amantadine efficacy was assessed using the UHDRS maximal chorea score.[10] Both video and live assessments of patients were utilized. Based on video ratings, amantadine significantly reduced maximal chorea from the baseline value of 15 by 18% compared to a 5% reduction in patients taking placebo. Video ratings of chorea at rest and extremity chorea at rest also showed significant improvements in patients taking amantadine. Based on the live rating, amantadine significantly reduced maximal chorea by 22% compared to placebo (0%), but the baseline UHDRS score was not provided. Patients were also evaluated for parkinsonian signs using a combined value of UHDRS items 6, 7, 9 and 10 (maximum score = 28). Neither amantadine or placebo was found to significantly reduce parkinsonian signs as defined by the researchers. No serious adverse events were observed. Some of the side effects observed in the amantadine group included forgetfullness (2 subjects) and insomnia (2). Hallucinations and confusion, exacerbation of preexisting morbid thoughts, dry mouth, hives, nausea and diarrhea were each observed once. Dry mouth, hives and insomnia were also each observed once in the placebo group.
In a similarly randomized crossover trial that did not appear to have a wash out period, amantadine was once again compared to placebo over two 2-week study periods.[11] Maximal chorea was once again assessed using a scale very similar to the UHDRS, but out of a maximum of 24 points. Neither amantadine nor placebo significantly reduced the chorea score, however 19 patients reported a subjective improvement following the amantadine phase compared to 6 patients following the placebo phase. The amantadine phase was also associated with a statistically significant improvement in quality of life (qol) as compared to placebo, but the authors did not explain how this was measured. Most common adverse events observed during amantadine treatment were insomnia, agitation or anxiety, confusion, diarrhea and sleepiness.
Another double-blind, randomized placebo-controlled trial by the Huntington Study Group evaluated riluzole at doses of either 100mg/day or 200mg/day.[12] Sixty-three patients were randomized into three study groups and results were assessed after 8 weeks. Compared to placebo (TMS: +1.6; chorea: +0.7), both 100mg/day (TMS: -1.6; chorea: -0.2) and 200mg/day (TMS: -4.0; chorea: -2.2) riluzole treatments were associated with greater reductions in total motor score and total chorea score using the UHDRS scale, but only the reductions in the 200mg/day treatment arm were statistically significant. Additionally, both riluzole treatments were associated with reductions in the UHDRS behavior score, but the reductions were just outside the range of significance. Adverse events were significantly more common in the 100mg/day riluzole treatment arm (83.3%) and the 200mg/day treatment arm (78.3%) than in the placebo group (54.5%), but differences were no longer statistically significant when mild adverse events were excluded. Of particular note, however, was an elevated ALT value greater than two times the normal upper limit which was found in 3 subjects in the 100mg/day riluzole group and in 5 subjects in the 200mg/day riluzole group, but was not observed in any individuals taking placebo.
A larger randomized trial comparing riluzole 50mg twice daily treatment to placebo over the course of 3 years showed that riluzole had no beneficial symptomatic effects in patients with HD.[13] Five hudred thirty-seven patients were enrolled and grouped in a 2 to 1 ratio to receive either riluzole or placebo. No significant differences were found in the UHDRS total motor scores or total functional capacity scores between the two groups. Additionally, UHDRS scores on the maximal chorea, cognitive, behavioral, functional and independence items/sections were not statistically significantly different between individuals treated with riluzole and with placebo. Adverse events were similar between the two groups, however depression and insomnia rates were actually significantly lower in the riluzole group. Five patients (3 taking riluzole) committed suicide during the study and 6 patients (4 taking riluzole) attempted suicide.
The effects of nabilone on UHDRS total motor, chorea, cognitive assessment and behavioral assessment were studied in a randomized, double-blind, placebo-controlled crossover trial.[14] Forty-four patients were randomized and split evenly between the nabilone group and the placebo group. No significant differences were found between the two groups in the TMS (0.86 point reduction of nabilone relative to placebo) and cognitive assessment. There was some improvement in the behavioral assessment in the nabilone treatment arm as compared to the placebo arm, although the results fell just outside of the range of significance. Finally, the chorea score significantly improved by 1.68 units with nabilone relative to placebo. Adverse events included drowsiness and forgetfullness, but rates were similar between the two groups. All other adverse events were considered minor by the authors.
Other Drugs and Studies:
In a crossover study that compared tetrabenazine to aripiprazole, both drugs significantly lowered the UHDRS chorea item score as compared to an off-drug condition.[4] Mean reduction was 5.2 units in patients treated with aripiprazole and 5.4 units in patients treated with tetrabenazine. Tetrabenazine was associated with an increase in sleepiness compared to “no treatment” and aripiprazole based on the Epworth Sleepiness scale. Depression, as assessed with the Hamilton Depression scale, was also singificantly higher in association with tetrabenazine treatment. This study was admittedly very small as only 6 patients were enrolled.
One randomized, double-bind study showed no benefit to using ethyl-EPA over placebo in the intent-to-treat analysis.[15] However, further analysis of patients treated per protocol showed significant improvement in the UHDRS TMS of those treated with ethyl-EPA as compared to those that were given placebo. The improvement was attributed to a decreased maximal chorea score, but actual relevant values were not provided by the authors. Another randomized controlled trial showed no improvement in UHDRS TMS or chorea score in patients taking Ethyl-EPA as compared to placebo after 6 months, but a significant decrease in both scores was present at 12 months (TMS: 0.6 vs. 3.4; Chorea: -1.7 vs. -0.5).[17]
A small open-label study assessed the usefulness of olanzapine in nine patients with HD.[3] Subjects were evaluated at baseline and after 14 days of treatment using the UHDRS motor scale. Mean chorea score significantly decreased from 13.4 at baseline to 6.9 following 14 days of treatment. Total motor scores decreased significantly from a mean of 54.6 to an average of 38.6. Significant decreases in scores on onther subsections of the UHDRS motor scale were also seen. This was a promising, but small trial that lacked controls and significant study duration.
Huntington’s Disease and Quality of Life Instruments:
In a study by Helder et al., an assessment of the impact HD has on health-related quality of life (HRQoL) was made using the Sickness Impact Profile (SIP), the Mini Mental State (MMS) and the UHDRS TMS.[17] Seventy-seven dutch HD patients were enrolled and evaluated with the three different instruments. The MMS evaluated cognitive performance while the TMS was used to assess motor performance. The SIP is a broader HRQoL instrument composed of physical and psychosocial dimensions (with each composed of several other subscales) that is used to help determine the impact of an illness from the patient’s perspective. A measure of depression was not utilized in the study. HD patients showed highest impairment in the “work” and “alertness behavior” subscales of the SIP. Nearly all of the subscales, as well as the two main dimensions and the total SIP score were found to be highly correlated with the TMS and with the MMS.
Ho et al., compared the SIP and another generic HRQoL instrument, the SF-36, to determine their usefulness in assessing the quality of life in HD patients.[18] Subjects were evaluated initially using the UHDRS TMS and Independence score. The SIP, SF-36, as well as the Beck Depression Inventory (BDI) were sent out to patients that were enrolled for the initial evaluation. A retest with the SIP and SF-36 being sent a second time was conducted approximately 6 weeks after the initial SIP/SF-36 assessment. Data from 65 patients was collected from the initial evaluation and 44 patients responded the second time around. General cognitive performance of subjects was evaluated between the two testing periods using the Telephone Interview of Cognitive Status (TICS). Analysis of the data showed that both tests demonstrated a high degree of internal consistency. The SF-36 showed a superior test-retest stability and a higher construct validity based on separate analysis of the SIP and the SF-36 and their correlations to the other clinical measures (TMS, independence, BDI, TICS). Multiple regression analysis showed the BDI to be the most important predictor of aggregate scores for either the SIP or the SF-36. Spearman’s correlation coefficients were calculated between the clinical measures and each one of the subscales of the SF-36 and the SIP. Particularly noteworthy and statistically significant coefficients were found between the physical functioning and mental health subscales of the SF-36 and the TMS (-0.54 and 0.27, respectively).
Ho et al. also attempted to establish which aspects of HD were most important to consider when assessing HRQoL.[19] Seventy participants with HD were evaluated using the UHDRS TMS and its subsections. The UHDRS TFC, verbal fluency and symbol digit scores were also obtained. The BDI was used to determine the level of depressed mood. HRQoL was assessed using the SF-36. TMS and chorea scores were found to be highly correlated with the physical summary scores of the SF-36 based on pearson correlation coefficients of -0.407 and -0.322, respectively. However, neither was found to correlate well with the mental summary score of the SF-36. The BDI and the UHDRS TFC were found to be highly correlated with both the physical and mental summary scores of the SF-36. The authors concluded that depressive mood and functional ability were the key factors in assessing HRQoL in patients with HD.
Two disease-specific HRQoL instruments have been developed more recently.[20, 21] The Huntington’s Disease Quality of Life (HDQoL) questionaire was the first patient-derived and disease specific HRQoL instrument developed specifically to more accurately assess the impact HD has on patients’ daily life.[20] It is divided into three primary scales (physical and cognitive, emotions and self, and services), 6 specific scales (cognitive, hopes and worries, services, physical and functional, mood state, and self and vitality) and a summary scale. Each scale showed good test-retest reliability. Construct validity was established by comparing the test to two generic instruments, the SF-12v2 and the EQ-5D.
The Huntington Quality of Life Instrument (H-QoL-I) was developed around the same time for similar reasons.[21] It consists of 4 items that assess motor functioning, 4 items that make up the psychology dimension and 3 items related to socializing. The test was shown to have a high internal consistency and external validity. The overall test and each one of its 3 dimensions were found to be highly correlated to the EQ-5D and the SF-36. Test-retest validity had not been confirmed at the time of the publication. Either the HDQoL or the H-QoL-I or both may become more relevant in the future in helping assess the quality of life in HD patients though neither one has been universally accepted as a standard.
Huntington’s Disease and Quality Adjusted Life Years:
What appears to be lacking is studies that assess utility associated with HD or across different HD severities. There appear to be no studies available that discuss quality adjusted life years (QALYs) associated with HD or any of the treatments. There is no literature available that describes any correlations between the BDI or SIP and calculations of QALYs. Two studies, however, provide algorithms and describe the procedures that could be followed in order to derive QALYs for any disease or condition based on SF-36 scores. The methods described in the two studies are briefly touched upon here.
The first study by Brazier, Roberts and Deverill discusses the method for deriving SF-6D scores from individual SF-36 survey results, which can then in turn be used to estimate QALYs.[22] Physical functioning items 1, 2 and 10, role limitation due to physical problems item 3, role limitation due to emotional problems item 2, social functioning item 2, both bodily pain items, mental health items 1 and 4 and vitality item 2 from the original SF-36 survey would be needed. The 11 items could then be used to derive a health state based on the original SF-6D form. Depending on the ratings obtained for each one of the 6 dimensions (physical functioning, role limitations, social functioning, pain, mental health and vitality) from the SF-6D, values would be substracted incrementally from the starting perfect health value of 1.0 based on the models generated and provided by the authors. A preference-based health state in the range between 0 and 1.0 would be obtained. Using this procedure, changes in health states could be converted to QALYs gained or lost.
More recently, Ara and Brazier derived an algorithm for predicting SF-6D values from mean SF-36 scores when patient-level data is not available.[23] One model presented by the authors assigns weighted values to mean scores from each one of the 8 dimensions of the SF-36. Using the algorithm provided, the scores can be converted to a corresponding SF-6D value between 0 and 1.0. A second model given by the authors can be utilized to derive an SF-6D value in a similar fashion, but includes additional parameters that account for interactions between the 8 SF-36 dimensions. QALYs gained or lost can then be estimated accordingly. Although the individual patient-level raw item score conversion method is the prefferred strategy, this method allows one to derive SF-6D values from published studies that only report cohort means for the 8 SF-36 dimensions.
It is possible that a model could be derived for estimating SF-6D values and consequently QALYs based on the TMS. This model could then in turn be used with TMS or maximal chorea scores from the clinical trials of interest that evaluated specific treatments based only on those values. A development of such a model would depend on a number of factors including the assumption that there is correlation between TMS and overall well-being. In their analysis, Ho et al., did show that the physical functioning and mental health subscales of the SF-36 correlated with TMS.[18] Additionally, significant intercorrelations between UHDRS domains have also been found.[2] Although the UHDRS behavioral subscale did not correlate well with the TMS or other subscales, higher mood subscale scores did correlate with better motor performance. Since depressive mood and functional ability might be the key factors in assessing HRQoL in patients with HD[19], TMS may at least partially account for those factors. The assumption that there is a relationship between TMS, mood and well-being is at least supported in part by some of the studies. The development of any model for deriving QALYs from TMS based on such assumptions and correlations would likely introduce error and would serve as an estimate at best. At least one other study has used the model provided by Brazier, Roberts and Deverill to estimate QALYs for the purposes of a pharmacoeconomic analysis.[24]
In their guideline recommendations for future research, the AAN has stated that “quality of life data across chorea severities should be sought to guide research and clinical decisions regarding treatment.”[4] Because there is no consistent use of any single QoL instrument for assessing the impact Hunington’s Disease has on patients, consideration should be given to obtaining QALYs associated with HD, chorea and different disease severity states in individuals with HD. Since calculating QALYs based on prior research would likely not yield the best estimates, a study geared specifically toward obtaining QALYs associated with HD, chorea and different HD severity states could potentially adress an area of research that has not been explored and that could be of major importance for conducting any economic studies.
Conclusion:
Tetrabenazine is the only drug approved by the FDA for the treatment of chorea associated with Huntington’s disease. Other alternatives exist, but clinical data supporting the use of other medications does not appear to be as strong. The UHDRS has been shown to be an excellent tool for assessing clinical outcomes in studies dealing with patients with HD, but a widely accepted instrument that assesses the increasingly important measure of patients’ QoL is currently lacking. Future research that would derive QALYs associated with HD and various states as determined by UHDRS scores could be of great importance in assessing the impact that medications have on patients’ quality of life.
Disclosure:
The author has nothing to disclose.
REFERENCES
[1] Scott LJ. Tetrabenazine: for chorea associated with Huntington's disease. CNS Drugs. 2011 Dec 1;25(12):1073-1085.
[2] Huntington Study Group. Unified Huntington's disease rating scale: reliability and consistency. Movement Disorders. 1996 Mar;11(2):136-42.
[3] Bonelli RM, Mahnert FA, Niederwieser G. Olanzapine for Huntington's disease: an open label study. Clinical Neuropharmacology. 2002 Sep-Oct;25(5):263-5.
[4] Brusa L, Orlacchio A, Moschella V, Iani C, Bernardi G, Mercuri NB. Treatment of the symptoms of Huntington's disease: preliminary results comparing aripiprazole and tetrabenazine. Movement Disorders. 2009 Jan 15;24(1):126-9.
[5] Clinical Pharmacology. Elsevier/Gold Standard. Available at: http://www.clinicalpharmacology-ip.com/default.aspx. Accessed June 22, 2016.
[6] Micromedex 2.0. Truven Health Analytics Inc. Available at: http://www.micromedexsolutions.com/. Accessed June 23, 2016.
[7] Armstrong MJ, Miyasaki JM, American Academy of Neurology. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2012 Aug 7;79(6):597-603.
[8] Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006 Feb 14;66(3):366-72.
[9] Frank S. Tetrabenazine as anti-chorea therapy in Huntington Disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators. BMC Neurology. 2009 Dec 18;9:62.
[10] Verhagen Metman L, Morris MJ, Farmer C, Gillespie M, Mosby K, Wuu J, Chase TN. Huntington's disease: a randomized, controlled trial using the NMDA-antagonist amantadine. Neurology. 2002 Sep 10;59(5):694-9.
[11] O'Suilleabhain P, Dewey RB Jr. A randomized trial of amantadine in Huntington disease. Archives of Neurology. 2003 Jul;60(7):996-8.
[12] Huntington Study Group. Dosage effects of riluzole in Huntington's disease: a multicenter placebo-controlled study. Neurology. 2003 Dec 9;61(11):1551-6.
[13] Landwehrmeyer GB, Dubois B, de Yébenes JG, Kremer B, Gaus W, Kraus PH, Przuntek H, Dib M, Doble A, Fischer W, Ludolph AC, European Huntington's Disease Initiative Study Group. Riluzole in Huntington's disease: a 3-year, randomized controlled study. Annals of Neurology. 2007 Sep;62(3):262-72.
[14] Curtis A, Mitchell I, Patel S, Ives N, Rickards H. A pilot study using nabilone for symptomatic treatment in Huntington's disease. Movement Disorders. 2009 Nov 15;24(15):2254-9.
[15] Puri BK, Leavitt BR, Hayden MR, Ross CA, Rosenblatt A, Greenamyre JT, Hersch S, Vaddadi KS, Sword A, Horrobin DF, Manku M, Murck H. Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial. Neurology. 2005 Jul 26;65(2):286-92.
[16] Huntington Study Group TREND-HD Investigators. Randomized controlled trial of ethyl-eicosapentaenoic acid in Huntington disease: the TREND-HD study. Archives of Neurology. 2008 Dec;65(12):1582-9.
[17] Helder DI, Kaptein AA, van Kempen GM, van Houwelingen JC, Roos RA. Impact of Huntington's disease on quality of life. Movement Disorders. 2001 Mar;16(2):325-30.
[18] Ho AK, Robbins AO, Walters SJ, Kaptoge S, Sahakian BJ, Barker RA. Health-related quality of life in Huntington's disease: a comparison of two generic instruments, SF-36 and SIP. Movement Disorders. 2004 Nov;19(11):1341-8.
[19] Ho AK, Gilbert AS, Mason SL, Goodman AO, Barker RA. Health-related quality of life in Huntington's disease: Which factors matter most? Movement Disorders. 2009 Mar 15;24(4):574-8.
[20] Hocaoglu MB, Gaffan EA, Ho AK. The Huntington's Disease health-related Quality of Life questionnaire (HDQoL): a disease-specific measure of health-related quality of life. Clinical Genetics. 2012 Feb;81(2):117-22.
[21] Clay E, De Nicola A, Dorey J, Squitieri F, Aballéa S, Martino T, Tedroff J, Zielonka D, Auquier P, Verny C, Toumi M. Validation of the first quality-of-life measurement for patients with Huntington's disease: the Huntington Quality of Life Instrument. International Clinical Psychopharmacology. 2012 Jul;27(4):208-14.
[22] Brazier J, Roberts J, Deverill M. The estimation of a preference-based measure of health from the SF-36. Journal of Health Economics. 2002 Mar;21(2):271-92.
[23] Ara R, Brazier J. Predicting the short form-6D preference-based index using the eight mean short form-36 health dimension scores: estimating preference-based health-related utilities when patient level data are not available. Value in Health. 2009 Mar-Apr;12(2):346-53.
[24] Kauf TL, Roskell N, Shearer A, Gazzard B, Mauskopf J, Davis EA, Nimsch C. A predictive model of health state utilities for HIV patients in the modern era of highly active antiretroviral therapy. Value in Health. 2008 Dec;11(7):1144-53.