Participation in Medical Decision Making: The Patients' Perspective 2007 27: 533 originally published online 14 September 2007The online version of this article can be found at: can be found at: Medical Decision Making Additional services and information for Participation in Medical Decision Making:Liana Fraenkel, MD, MPH, Sarah McGraw, PhDPurpose. Variability in reports of
Pridopidine for the treatment of motor function in patients with huntington's disease (mermaihd): a phase 3, randomised, double-blind, placebo-controlled trialArticles
Pridopidine for the treatment of motor function in patients
with Huntington’s disease (MermaiHD): a phase 3,
randomised, double-blind, placebo-controlled trial
Justo Garcia de Yebenes, Bernhard Landwehrmeyer, Ferdinando Squitieri, Ralf Reilmann, Anne Rosser, Roger A Barker, Carsten Saft, Markus K Magnet, Alastair Sword, Åsa Rembratt, Joakim Tedroﬀ, for the MermaiHD study investigators Summary
Background Huntington’s disease is a progressive neurodegenerative disorder, characterised by motor, cognitive, and Lancet Neurol 2011; 10: 1049–57
behavioural deﬁcits. Pridopidine belongs to a new class of compounds known as dopaminergic stabilisers, and results Published Online
from a small phase 2 study in patients with Huntington’s disease suggested that this drug might improve voluntary November 8, 2011
motor function. We aimed to assess further the eﬀects of pridopidine in patients with Huntington’s disease.
See Comment page 1036
Methods We undertook a 6 month, randomised, double-blind, placebo-controlled trial to assess the eﬃcacy of pridopidine Department of Neurology,
in the treatment of motor deﬁcits in patients with Huntington’s disease. Our primary endpoint was change in the Hospital Ramón y Cajal,
modiﬁed motor score (mMS; derived from the uniﬁed Huntington’s disease rating scale) at 26 weeks. We recruited CIBERNED, Madrid, Spain
patients with Huntington’s disease from 32 European centres; patients were aged 30 years or older and had an mMS of (J G de Yebenes MD);
10 points or greater at baseline. Patients were randomly assigned (1:1:1) to receive placebo, 45 mg per day pridopidine, Department of Neurology,
University of Ulm, Ulm,
or 90 mg per day pridopidine by use of centralised computer-generated codes. Patients and investigators were masked Germany
to treatment assignment. We also assessed the safety and tolerability proﬁle of pridopidine. For our primary analysis, all (B Landwehrmeyer MD);
patients were eligible for inclusion in our full analysis set, in which we used the last observation carried forward method Neurogenetics and Rare
for missing values. We used an analysis of covariance model and the Bonferroni method to adjust for multiple Disease Centre, IRCCS
Neuromed, Pozzilli, Italy
comparisons. We used a prespeciﬁed per-protocol population as our sensitivity analysis. The α level was 0·025 for our (F Squitieri MD); Department of
primary analysis and 0·05 overall. This trial is registered with ClinicalTrials.gov, number NCT00665223.
Neurology, University of
Münster, Münster, Germany
Findings At 26 weeks, in our full analysis set the diﬀerence in mean mMS was −0∙99 points (97∙5% CI −2∙08 to 0∙10, (R Reilmann MD); Neuroscience
Division, School of Biosciences,
p=0∙042) in patients who received 90 mg per day pridopidine (n=145) versus those who received placebo (n=144), and University of Cardiﬀ, Cardiﬀ,
−0∙36 points (−1∙44 to 0∙72, p=0∙456) in those who received 45 mg per day pridopidine (n=148) versus those who UK (A Rosser MD); Cambridge
received placebo. At the 90 mg per day dose, in our per-protocol population (n=114), the reduction in the mMS was of Centre for Brain Repair,
−1∙29 points (−2∙47 to −0∙12; p=0∙014) compared with placebo (n=120). We did not identify any changes in non-motor Cambridge University,
Cambridge, UK (R A Barker MD);
endpoints at either dose. Pridopidine was well tolerated and had an adverse event proﬁle similar to that of placebo.
Department of Neurology,
St Josef-Hospital, Ruhr
Interpretation This study did not provide evidence of eﬃcacy as measured by the mMS, but a potential eﬀect of University Bochum, Bochum,
pridopidine on the motor phenotype of Huntington’s disease merits further investigation. Pridopidine up to 90 mg Germany (C Saft MD);
Department of Psychiatry,
per day was well tolerated in patients with Huntington’s disease.
University of Graz, Graz,
Austria (M K Magnet MD);
Funding NeuroSearch A/S.
Centum, Stirling, UK
(A Sword MSc); NeuroSearch
A/S, Ballerup, Denmark
ﬁrm conclusions about best medical practice for the (Å Rembratt PhD); and
Huntington’s disease is an autosomal dominant, pro- control of motor and non-motor symptoms of the disease, NeuroSearch Sweden AB,
gressive, neurodegenerative disease caused by a cytosine– although some compounds are thought to be somewhat Gothenburg, Sweden
adenine–guanine (CAG) trinucleotide repeat expansion in eﬀective. For example, tetrabenazine, the only drug (J Tedroﬀ MD) the huntingtin gene.1,2 Pathologically, Huntington’s disease licensed in North America and some European countries Correspondence to: leads to widespread neuronal degeneration, especially in for Huntington’s disease, is eﬀective for the control of Department of Neurology, the striatum.1,3–8 The disease produces a range of cognitive, chorea, but is associated with risk of serious adverse Hospital Ramón y Cajal, behavioural, and motor deﬁcits, including involuntary events.12 Furthermore, antipsychotic drugs are used E-28034 Madrid, Spain movements, motor impersistence, parkinsonism, apraxia, widely oﬀ label for the treatment of chorea13 and some email@example.com
and abnormal gait, posture, and eye movements.1,9 The behavioural symptoms.
progressive deﬁcits of Huntington’s disease substantially Previous research suggests that glutamate and dopamine aﬀect patients’ daily functioning, ultimately leading to loss neurotransmission are aﬀected in Hun tington’s disease; of independence and premature death.
hence, the mechanism by which dopamine modulates The prevalence of Huntington’s disease has been glutamate-induced excitation in the basal ganglia and the estimated at about 5–7 per 100 000 people,1 but recent cortex might be disrupted.14 Pridopidine belongs to a new reports suggest that it might be at least double this class of drugs called dopaminergic stabilisers. These number.10,11 A Cochrane review12 was unable to draw any compounds act primarily at dopamine type 2 (D2) www.thelancet.com/neurology Vol 10 December 2011
receptors and cause state-dependent behavioural eﬀects. isation codes were computer-generated by Catalent Pharma In vivo, pridopidine normalises dysregulated psychomotor Solutions, Bolton, UK). Patients were stratiﬁed across functions, while having only subtle eﬀects on normal groups according to antipsychotic drug use and were not psychomotor activity.15–17 An important pharma cological identiﬁed by name on trial documents, but by their property of pridopidine might be explained by its ability to screening or randomisation number. To ensure equal strengthen corticostriatal glutamate functions in various distribution of patients receiving antipsychotic drugs in settings of perturbed neuro transmission. Pridopidine is the diﬀerent treatment groups, we used diﬀerent eﬀective in animals that have signs relevant to Huntington’s randomisation sequences for patients either receiving or disease, including depression, anxiety, and motor not receiving antipsychotic drugs. A separate log of patient dysfunction. Preliminary clinical ﬁndings also suggest codes, names, and addresses was maintained conﬁdentially that pridopidine might improve motor function without by the investi gators at their sites. Treatment packs and worsening chorea.18 To assess further the potential of tablets were identical in appearance to guarantee masking pridopidine as a symptomatic treatment for Huntington’s from the patient and the investigator. Placebo was matched disease, we undertook a phase 3 study: the Multinational to the study drug for taste, colour, and size. Only the European Multicentre ACR16 study in Huntington’s independent safety committee were permitted to unmask data before the listings were compiled and locked, at which point the data were unmasked for statistical analysis. The statistical analysis plan and any exclusions from the per Participants
protocol set were ﬁnalised before unmasking. Between April, 2008, and November, 2009, we undertook
a randomised, double-blind, placebo-controlled trial to Procedures
assess the eﬃcacy of pridopidine in treating motor deﬁcits
We randomly assigned patients (1:1:1) to receive placebo, in patients with Huntington’s disease. We recruited 45 mg per day pridopidine, or 90 mg per day pridopidine patients from 32 clinics in eight European countries (45 mg twice daily) orally for 26 weeks. Our choice of doses (Austria, Belgium, France, Germany, Italy, Portugal, Spain, was based on eﬃcacy data from a smaller, short-term study and the UK). We included patients with Huntington’s assessing the eﬀects of pridopidine in patients with disease (on the basis of clinical features and the presence Huntington’s disease18 and on safety data generated from of ≥36 CAG repeats) who were aged 30 years or older (to other studies (NeuroSearch, data on ﬁle). During the ﬁrst avoid recruitment of patients with juvenile disease), were 4 weeks, all patients received once-daily treatment with ambulatory, and had a modiﬁed motor score (mMS; 45 mg pridopidine or placebo. Thereafter, the pridopidine derived from the uniﬁed Huntington’s disease rating scale dose was increased to 45 mg twice daily (morning and [UHDRS]) of 10 points or greater. We included participants afternoon) in the 90 mg per day group while the 45 mg per treated with allowed antipsychotics (amisulpride, halo- day and placebo groups received placebo for their second piride, or tiapride, daily dose. In cases of poor tolerability the afternoon which are the most commonly prescribed antipsychotics capsule was stopped, resulting in a dose decrease in the in the parti cipating countries), antidepressants, or other 90 mg per day pridopidine group, but not in the other two psychotropic drugs if they had received a stable dose for groups. Compliance was assessed by capsule count at each 6 weeks or longer before randomisation. We excluded visit. We judged as compliant all patients who took 70% or patients who were pregnant, lactating, or fertile women more of their capsules. Compliance greater than 100% was not using con traception, patients who received disallowed classiﬁed as 100% (since extra drug was provided in case a antipsychotics or tetrabenazine in the 12 weeks before visit was delayed, some patients could have taken more randomisation, and patients who used ﬂuoxetine, than the intended amount of drug; also, some patients on paroxetine, tricyclic anti the 90 mg per day dose who were de-escalated to 45mg per thmics, or strong CYP2D6 inhibitors in the 6 weeks before day could have mistakenly continued to take the second daily dose). All concomitant drug use was recorded.
Written, informed consent was obtained from patients Our primary outcome measure was change in the mMS before any study-related procedure was undertaken. Our from baseline to week 26. The mMS is a shortened version study was done in accordance with the ethical principles of the UHDRS total motor score (TMS)19 that comprises of the Declaration of Helsinki. All study protocol and trial items 4–10 (dysarthria, tongue protrusion, ﬁnger taps, documentation was reviewed by the appropriate ethics pronate and supinate hands, ﬁst–hand–palm sequencing, committees and institutional review boards before our arm rigidity, and body bradykinesia) and 13–15 (gait, study began.
tandem walking, and retropulsion pull test), and excludes eye movements, dystonia, and chorea. This subscale has Randomisation and masking
been tested on the Coenzyme Q and Remacemide After eligibility assessment, patients were randomly Evaluation Huntington’s Disease (CARE-HD) dataset,20 and assigned by the investigator in each site by allocation of a shows good internal consistency and test–retest reliability.21,22 prenumbered treatment pack (block-balanced random- The rationale for our choice of the mMS as primary www.thelancet.com/neurology Vol 10 December 2011
endpoint was also based on results from a small, 4 week We assessed our primary endpoint in our full analysis study in Scandinavian patients with Huntington’s disease set with an ANCOVA model, with treatment as the receiving 45 mg per day pridopidine, which suggested that classiﬁcation variable. Baseline mMS, sex, and use of the primary eﬀects of the drug were on voluntary motor antipsychotic drugs were covariates. We used the last function.18 We assessed the mMS at screening (week −2), observation carried forward method to account for baseline (week 0), and weeks 4, 8, 12, and 26. All investigators missing data. We assessed the two pridopidine groups who administered the UHDRS–TMS were certiﬁed by the independently versus placebo and we used the Bonferroni European Huntington’s Disease Network. method to adjust for multiple comparisons. The overall α For more on the European
Huntington’s Disease Network
Our prespeciﬁed secondary outcome measures were level was 0·05 (0·025 for the Bonferroni adjustment). We see http:// www.euro-hd.net/ the clinical global impression improvement (CGI-I) also assessed our secondary and tertiary endpoints with assessment,23 the Stroop word reading test, the UHDRS the ANCOVA model with suitable baseline covariates. We behavioural assessment, and the hospital anxiety and report comparisons between active treatment and placebo depression scale; secondary outcome measures were as ANCOVA estimates unless we state otherwise.
assessed at baseline (week 0) and at week 26. Our We did predeﬁned sensitivity analyses on our primary prespeciﬁed tertiary outcomes included changes in endpoint: to assess eﬀects in our per-protocol population motor function, as measured by the UHDRS–TMS, and with the same ANCOVA model as for the full analysis set individual items within the mMS (gait and dysarthria). on observed cases; to assess interactions between Our other prespeciﬁed tertiary outcomes included treatment and study centre, use of antipsychotic drugs, measures of cognitive function with the Stroop and CAG repeat length; and a mixed-eﬀects model for interference tests, the anxiety and depression subscales repeated measures without imputation for missing within the hospital anxiety and depression scale and the values, including terms for baseline mMS, sex, use of UHDRS behavioural assessment sub scores, the UHDRS antipsychotic drugs, study week, and the interaction functional assessment, the UHDRS independence between study week and treatment.
assessment, and the UHDRS functional capacity assess- We undertook exploratory post-hoc analyses to ment. We also undertook standard safety and tolerability identify drivers of improvements in the mMS and the UHDRS–TMS, and to assess the eﬀect of treatment on the mMS and the UHDRS–TMS when the CAG repeat Statistical analysis
length and age terms were included in our main eﬀects To detect a between-group diﬀerence of 2·0 points ANCOVA model.
(SD 3·6–4·4) in our primary outcome, with a two-sided An independent safety committee reviewed masked signiﬁcance level of 0·025, a power of 90%, and an data encompassing any protocol violations; numbers of assumed dropout rate of 10%, 82–122 patients would be patient withdrawals and the reason for withdrawal; needed per treatment group. Since we planned to adverse events and serious adverse events; and laboratory undertake the statistical analysis with stratiﬁcation of the data. The committee was allowed to request unmasking sample according to use of antipsychotic drugs, it was of individual patients, the entire trial, or both, at any necessary to increase the sample size to 420 patients time, and reported its ﬁndings on a quarterly basis. This (140 per group) to allow for the possibility of separate trial is registered with ClinicalTrials.gov, number analyses of each stratum, should a signiﬁcant interaction between strata and treatment be recorded.
Our full analysis set included all patients randomly Role of the funding source
assigned to study groups who received study drug and had This study was funded by NeuroSearch A/S. Employees a postrandomisation clinical assessment. Our per-protocol of the company were involved in the study design, the population included all patients who had 70% or greater collection, analysis, and interpretation of data, the writing compliance with treatment and completed the study in of the report, and the decision to submit for publication. accordance with our protocol or with only minor violations. The corresponding author had full access to all the data Events that led to exclusion from our per-protocol in the study, received no payment for writing or revision population were those thought to aﬀect the validity of a of the report, and had ﬁnal responsibility for the decision patient’s primary endpoint. These events included to submit for publication.
stopping the study drug more than 1 week before assessment of the primary outcome at week 26, an invalid mMS assessment at week 26 or made more than 28 days The ﬁrst visit of the ﬁrst patient took place in April, 2008, before the intended date of assessment, taking disallowed and the ﬁrst and last visits of the last patient took place concomitant drugs, and inclusion and exclusion criteria in April and November, 2009, respectively. Figure 1 violations and major protocol violations identiﬁed by shows the trial proﬁle. In total, 437 patients were clinical monitoring staﬀ. The inclusion and exclusion of randomly assigned and included in the full analysis set each patient in our per-protocol population was established (144, 148, and 145 individuals in the placebo, 45 mg per day pridopidine, and 90 mg per day pridopidine groups, www.thelancet.com/neurology Vol 10 December 2011
148 assigned to 45 mg per day pridopidine 145 assigned to 90 mg per day pridopidine 4 consent withdrawals 1 protocol violation 1 other Figure 1: Trial proﬁle
events and withdrawal of consent. Our per-protocol Placebo (n=144)
45 mg per day 90 mg per day Total (n=437)
Demographics and baseline characteristics of patients are shown in table 1. Patients were predominantly white. The mean age was 50·6 years (SD 10·5), with a mean time since diagnosis of Huntington’s disease of 4·8 years (3·5). 190 (43%) of 437 patients were taking antipsychotic drugs. The mean CAG repeat length was 44·7 (3·5).
34 patients (8%) needed dose de-escalation: ten patients (7%) in the placebo group, 11 (7%) in the 45 mg per day pridopidine group, and 13 (9%) in the 90 mg per day pridopidine group. Compliance was similar in all treatment groups. Throughout our study, the proportion of patients judged to be compliant was 94% (136 patients) in the placebo group, 93% (137) in the 45 mg per day pridopidine group, and 94% (137) in the 90 mg per day pridopidine group. This compares with 88% (126), 89% (132), and 83% (120), respectively, during the last 3 months of the study. 400 patients (92%) were taking concomitant drugs: 92% (132 patients) in the placebo group, 92% (136) Data are n (%) or mean (SD). CAG=cytosine–adenine–guanine. *CAG repeat length data were available for 426 patients.
in the 45 mg per day group pridopidine, and 91% (132) in the 90 mg per day pridopidine group.
Table 1: Baseline characteristics
At baseline, the mean mMS was 19·43 points (SD 8·28) in the placebo group and scores were similar in the respectively). Of these, 403 patients (92%) randomly pridopidine groups (18·38 points [6·76] in the 45 mg per assigned to study groups completed the study and day pridopidine and 18·57 [6·90] in the 90 mg per day 386 (88%) completed treatment (126 [88%] in the placebo pridopidine group). By week 26, the mean mMS had group, 136 [92%] in the 45 mg per day pridopidine group, decreased in the 90 mg per day pridopidine group relative and 124 [86%] in the 90 mg per day pridopidine group). to placebo (table 2), but there was no between-group The primary reasons for discontinuation were adverse diﬀerence because the p value did not reach our www.thelancet.com/neurology Vol 10 December 2011
prespeciﬁed threshold of p<0·025. Change from baseline Population
Between-group diﬀerences vs
at week 26 was 0·22 points (97·5% CI −0·55 to 0·99) in placebo (97·5% CI)
the placebo group, −0·14 (−0·90 to 0·63) in the 45 mg per day pridopidine group, and −0·77 (−1·54 to 0·00) in the 90 mg per day pridopidine group (ﬁgure 2).
In our per-protocol population, the between-group diﬀerence between 90 mg per day pridopidine and placebo was signiﬁcant at week 26 (table 2). The interaction terms Table 2: Change from baseline to week 26 in the modiﬁed motor score
“pooled study centre by treatment” and “antipsychotic medication use by treatment” had no signiﬁcant eﬀect on treatment (p=0·196 and p=0·649, respectively), so we did not identify any independent statistically signiﬁcant relation between the eﬀects of the treatment and the diﬀerent study centres or the use (or not) of antipsychotic drugs. The eﬀect of CAG repeat length was statistically signiﬁcant (p=0·009) although the interaction between CAG repeat length and treatment was not (p=0·470). By use of the mixed-eﬀects model for repeated measures, we identiﬁed similar results as for our primary analysis: at week 26, the mean between-group diﬀerence for 90 mg per day pridopidine versus placebo in the full analysis set was −1·11 points (97·5% CI −2·25 to 0·03; p=0·029).
For our secondary outcomes, by week 26, none of the changes from baseline were statistically signiﬁcant. In our CGI-I assess ment, mean changes were 4∙02 points
(95% CI 3∙86 to 4∙19) in the placebo group, Figure 2: Mean change from baseline in the modiﬁed motor score
4∙03 (3∙86 to 4∙19) in the 45 mg per day pridopidine Data at week 26 are also shown after adjustment for non-completers with last observation carried forward (LOCF).
group, and 4∙00 (3∙84 to 4∙16) in the 90 mg per day
pridopidine group—a score of 4 points represents no
overall change in CGI-I. Mean changes in the Stroop word reading test were −1∙30 points (95% CI −3∙31 to 0∙71) in the placebo group, −1∙10 (−2∙81 to 0∙61) in the 45 mg per day pridopidine group, and −0∙80 (−2∙77 to 1∙17) in the 90 mg per day pridopidine group. Respective changes in the total UHDRS behavioural assessment were 0∙12 points (95% CI −2∙13 to 2∙37), −0∙41 (−3∙13 to 2∙31), and −2∙22 (−4∙02 to −0∙42), and in the total hospital anxiety and depression scale score were −0∙10 (−1∙13 to 0∙93), −0∙73 (−1∙85 to 0∙39), and 0∙13 (−0∙87 to 1∙13).
At baseline, the mean UHDRS–TMS was 42·78 points (SD 17·28) in the placebo group, and scores were similar in the pridopidine groups (41·14 [15·83] in the 45 mg per day pridopidine group and 41·81 [14·87] in the 90 mg per day pridopidine group). The mean UHDRS–TMS change Figure 3: Mean change from baseline in the UHDRS–TMS
from baseline to week 26 was 1·77 points (95% CI Data at week 26 are also shown after adjustment for non-completers using last observation carried forward (LOCF). UHDRS–TMS=uniﬁed Huntington’s disease rating scale total motor score. *p=0·004 for the between-group 0·35 to 3·19) in the placebo group, 0·90 (−0·50 to 2·29) diﬀerence (90 mg per day pridopidine vs placebo).
in the 45 mg per day pridopidine group, and −1·19 (−2·60 to 0·22) in the 90 mg per day pridopidine group (full analysis set; ﬁgure 3). The between-group Population
Between-group diﬀerences vs
diﬀerence (90 mg per day pridopidine vs placebo) of placebo (95% CI)
−2·96 points (−4·96 to −0·97) was signiﬁcant (p=0·004; table 3). Figure 4 shows the mean diﬀerence between 90 mg per day pridopidine and placebo in the change in individual UHDRS–TMS items from baseline to study end. Other tertiary motor and non-motor endpoints did Table 3: Change from baseline to week 26 in uniﬁed Huntington’s disease rating scale total motor score
not reach statistical signiﬁcance.
www.thelancet.com/neurology Vol 10 December 2011
Diﬀerence in score change from baseline to week 26 (95% CI) Maximal chorea (RLE)Retropulsion pull test Figure 4: Mean diﬀerence between 90 mg per day pridopidine and placebo in the change from baseline to week 26 for individual items in the UHDRS–TMS
Black circles represent items included in the modiﬁed motor score. Shading denotes groups of similar items. H=horizontal. L=left. LLE=left lower extremity. LUE=left
upper extremity. R=right. RLE=right lower extremity. RUE=right upper extremity. V=vertical. UHDRS–TMS=uniﬁed Huntington’s disease rating scale total motor score.
Within the mMS, the main drivers of improvement Diﬀerence (95% CI)
were hand movements and gait and balance. In addition to these, the main drivers of improvement in the (table 4). Results of our exploratory analysis on the mMS, including both CAG repeat length and age, conﬁrmed that the eﬀect of CAG repeat length was statistically *Equivalent to the sum of uniﬁed Huntington’s disease rating scale total motor signiﬁcant (p=0·007), but the eﬀect of age was not score (UHDRS–TMS) items 1–3 (ocular pursuit, saccade initiation, and saccade (p=0·171); the treatment diﬀerence between 90 mg per velocity). †Equivalent to the sum of UHDRS–TMS items 6–8 (ﬁnger taps, pronate day pridopidine and placebo was −1·12 (p=0·024). For the and supinate hands, and Luria ﬁst–hand–palm sequencing). ‡Equivalent to the sum UHDRS–TMS, between-group diﬀerences for 90 mg per of UHDRS–TMS items 13–15 (gait, tandem walking, and retropulsion pull test).
day pridopidine versus placebo were similar to those in Table 4: Between-group diﬀerences (90 mg per day pridopidine vs
our main model including the CAG repeat length placebo) for the change from baseline to week 26 in groups of items
interaction with treatment (−2·91 points, 95% CI −4·91 to from the UHDRS-TMS
−0·92) and the CAG repeat length and age interaction (−3·02, −5·02 to −1·01).
45 mg per day
90 mg per day
Overall, the mean exposure to study drug was pridopidine (n=148)
169·4 days (SD 44·1; median 182, IQR 180–188) and was similar across the three groups: 170·5 days (SD 42·9; median 182, IQR 180–188) in the placebo group, 172·5 (SD 38·9; median 182, IQR 181–188) in the 45 mg per day pridopidine group, and 165·0 (SD 49·9; median 182, IQR 179–188) in the 90 mg per day pridopidine group. Pridopidine was well tolerated and had an adverse event proﬁle similar to that of placebo. Most patients in each group reported at least one adverse event (table 5). The most common adverse events were falls, chorea, diarrhoea, dizziness, and nausea. 47 patients (11%) experienced an adverse event that needed intervention Both the worsening of a pre-existing symptom or disorder and the appearance of any new symptom or disorder were reported as adverse events.
or withdrawal of study drug, and 185 (42%) reported an adverse event judged to be related to study drug Table 5: Adverse events
(65 patients [45%] in the placebo group, 56 [38%] in the www.thelancet.com/neurology Vol 10 December 2011
45 mg per day pridopidine group, and 64 [44%] in the been reproduced in a phase 2b trial run in parallel with 90 mg per day pridopidine group). The incidence of our study,24 suggesting that they warrant further serious adverse events was similar across all groups investigation. The UHDRS–TMS is a scale of 31 items (11 [8%], ten [7%], and nine [6%], respectively). There used to rate diﬀerent motor deﬁcits in patients with were three deaths during our study: one in the placebo Huntington’s disease, such as incoordination, akinesia, group (suicide) reported as possibly related to study chorea, dys tonia, and ocular movements. The scale has a drug, one in the 45 mg per day pridopidine group maximum score of 124 points. By comparison, the mMS (urosepsis), and one in the 90 mg per day pridopidine (with a maximum score of 52 points) focuses mainly on group (subarachnoid haemorrhage). The deaths in the clinical deﬁcits related to akinesia and includes only pridopidine groups were judged unlikely to be related to 13 items (chorea, dystonia, and ocular movements are excluded). Our choice of mMS as the primary endpoint was based on the ﬁndings of a 4 week phase 2 study that Discussion
used the UHDRS–TMS and did not show an eﬀect of Our ﬁndings show that the mean reduction of treatment on the excluded items.18 We expected the 0·99 points in the mMS in patients receiving 90 mg per exclusion of these items from the mMS in our study to day pridopidine compared with those receiving placebo reduce potential noise in the motor results. In retrospect, (p=0·042) fell short of the threshold that we predeﬁned the UHDRS–TMS would have been chosen as a primary for multiple comparisons in our full analysis set endpoint rather than the mMS; although the eﬀects of (p<0·025). We did not identify any statistically signiﬁcant 90 mg per day pridopidine on the mMS in our study were improvements in non-motor secondary and tertiary not statistically signiﬁcant, they were detectable in a outcome measures, which assessed deﬁcits in cognition broader spectrum of motor symptoms than we expected. and functional capacity, and were included to test This ﬁnding might be due to the fact that some potential eﬀects of pridopidine on symptom domains neurological symptoms and signs take longer to respond other than motor function. In view of the complexity of to treatment than others. For example, the improvement the disease, it is perhaps unsurprising that signiﬁcance in dystonia that we recorded might have been possible was not reached on these non-motor endpoints. Also, because of a longer study duration than that of the the scales might have been insensitive to changes over previous phase 2 study, allowing changes in synaptic the timescale of our study. For example, the UHDRS plasticity (ie, improvements in dystonia might need functional capacity assessment encompasses ﬁve diverse areas such as the ability to handle ﬁnancial aﬀairs, to There is an unmet need for treatments for patients keep a job, or to maintain independence in activities of with Huntington’s disease. Tetrabenazine is eﬀective for normal daily living.19 Patients in the present study had a the treatment of chorea27 and other drugs, including baseline score of 7 points on this scale and an neuroleptics, are also used to treat chorea, to treat other improvement of one point would constitute a major dyskinesias, and to mitigate psychotic behaviour.13 change, such as being able to be at home (2 points) However, previous studies have not shown any rather than requiring chronic care (1 point), or being signiﬁcant improvements in a range of voluntary motor able to perform a job partially (1 point) or not at all symptoms or the overall motor phenotype. Indeed, a (0 points). Thus, it seems unlikely that a change of this size would occur over a 6 month period with a Panel: Research in context
Our sensitivity analyses on the primary endpoint revealed Systematic review
similar ﬁndings to the primary analysis and suggest that We reviewed references within a recent Cochrane systematic review12 and searched PubMed pridopidine might have some eﬀect on motor function. (from 2007 to December, 2010) with the terms “Huntington’s disease”, “HD”, “Huntington’s Indeed, for our tertiary endpoint the UHDRS–TMS (from disease treatment eﬃcacy”, and the limits “human, randomized controlled trial, English”. which the mMS is derived), there was a signiﬁcant We also undertook an unlimited search of PubMed with the terms “pridopidine”, “ACR16” improvement with 90 mg per day pridopidine, which was (the development name for pridopidine) and “(–)-OSU6162” (a pridopidine-related driven by improvements in dystonia and eye movements. compound). By use of the quality of evidence criteria described in the Guide to Clinical The motor symptoms that improved in our study (hand Preventative Services,26 one study was identiﬁed as level 1 (class A): TETRA-HD,27 reporting movements, and gait and balance) are recognised by the symptomatic treatment of chorea with tetrabenazine.
physicians as clinically meaningful. For example, the Interpretation
improvement in hand movements might mean that a Our study is a level 1 (class A) study; pridopidine did not produce a statistically signiﬁcant patient becomes able to handle cutlery and feed himself or change in the primary endpoint or in any functional assessment scales, but 90 mg per day herself, and the improvement in gait and balance might pridopidine produced a slight improvement in a tertiary endpoint, the uniﬁed mean that the patient is less likely to fall.
Huntington’s disease rating scale total motor score. Whether pridopidine might Although the UHDRS–TMS results are interesting, complement available treatments in patients with Huntington’s disease, by improving this was only a tertiary endpoint and limited conclusions motor deﬁcits other than chorea, merits further investigation.
can be made from these ﬁndings. However, these have www.thelancet.com/neurology Vol 10 December 2011
Cochrane review12 concludes that no statement can be more granular scale (ie, consisting of smaller made on the best medical practice for the control of incremental changes, providing greater resolution). motor and non-motor symptoms of Huntington’s Inclusion of more granular scales is warranted in future disease (panel). Pridopidine has the potential to studies. Finally, no symptoms worsened and pridopidine complement available treatments by improving a was well tolerated, suggesting a potentially favourable diﬀerent range of motor deﬁcits. Its lack of severe side- eﬀects, irrespective of antipsychotic use, suggests that Contributors
pridopidine might be useful, even for those patients RAB was the original principal investigator and was involved in the
who are treated at sites that are not centres of excellence
study design, data collection, and in writing the report. BL was involved in the study design, data collection, data analysis and interpretation, and writing the report. MKM was involved in data collection. RR was The pharmacological mode of action of pridopidine involved in data collection, data analysis and interpretation, and writing entails fast-oﬀ competitive inhibition of D2 receptors28 the report. ÅR was involved in the study design, data interpretation, and and enhanced cortical levels of synaptic dopamine. in writing the report. AR was involved in data collection, data Cortical dopamine activates synaptic NMDA receptor- interpretation, and writing the report. CS was involved in data collection, data analysis, and writing the report. FS was involved in data collection mediated transmission,17 strengthening corticostriatal and writing the report. AS was involved in data analysis. JT was involved connectivity. Preclinically, the major behavioural conse- in the study design, data analysis, writing the report, and searching quence is normalisation of disrupted motor activity published work. JGdY was the principal investigator and was involved in the study design, data collection, and writing the report.
(eg, hypoactivity, dyskinesias, and hyperactivity).29 This
seems to correlate with a clinical improvement of Conﬂicts of interest
RAB has received honoraria from Teva/Lundbeck and payment from hypokinetic and hyperkinetic features. These beneﬁts the European Huntington’s Disease Network for the REGISTRY study. might be linked to the eﬀects of pridopidine on BL has received honoraria from NeuroSearch, consultancy fees from D2 receptors, and to an indirect enhancement of the CHDI Foundation and Siena Biotech SpA, and research grants from corticostriatal connectivity. Eye movement abnormalities CHDI Foundation, and is a board member of Siena Biotech SpA. RR has received payments for consultancies, clinical trial services, or lectures are one of the ﬁrst signs of Huntington’s disease30 and from Siena Biotech, Novartis Pharma, Wyeth Pharma, the Cure might be directly related to weakened corticostriatal Huntington’s Disease Initiative Inc, Neurosearch AB, Medivation/Pﬁzer, connectivity.31 Temmler Pharma, LinkMedicine, and Meda Pharma. He also serves on Our study has certain limitations. First, our primary the advisory board of the Jacques and Gloria Gossweiler Foundation; receives grant support from the High-Q-Foundation, the Cure hypothesis was not met. However, we believe the Huntington’s Disease Initiative Foundation, and the European UHDRS–TMS data we present, which are from a larger Huntington’s Disease Network (EHDN); and serves as lead facilitator of and longer study than those data reported previously,18 the EDHN motor and neuroprotective therapy working groups. ÅR is an warrant further investigation. Second, the sensitivity to employee of NeuroSearch. CS has received honoraria from Temmler Pharma GmbH & Co KG, payment from the European Huntington’s treatment eﬀects of the mMS has not been validated; Disease Network for the REGISTRY study, payment from Novartis however, there is no intervention for Huntington’s Pharmaceuticals Switzerland for the AFQ056 study, and research support disease against which it could have been validated from Teva Pharma GmbH. FS has received support from the Italian (tetrabenazine targets only chorea). Although our last association of HD families (Associazione-Italiana-Corea-di-Huntington- Neuromed—“5×1000” fund); from Istituto di Ricovero e Cura a Carattere observation carried forward method has the potential to Scientiﬁco Neuromed (“5×1000” fund), Ministry of Health, Italy (Ricerca introduce bias, especially if large numbers of patients Corrente); from the Italian Society of Hospital Neurologists (SNO, drop out, sensitivity analyses with our per-protocol “Lascito Gobessi”); and from the European Huntington’s Disease population and our mixed-eﬀects model for repeated Network for the REGISTRY study. AS has received consultancy fees from NeuroSearch. JT is an employee of NeuroSearch and is listed as an measures (observed cases only) yielded similar results author on patent application number WO146145 A1. JGdY has received to the primary analysis, in terms of eﬀect size and institutional funding from the Centro de Investigación Biomedica en Red signiﬁcance. Furthermore, few patients dropped out of de Enfermedades Neurodegenerativas (CIBERNED); Ministry of Science, our study, suggesting that any potential bias with the Spain; the Fondo de Investigaciones Sanitarias from the Institute of Health “Carlos III” Ministry of Health; the Science Department of the last observation carried forward would be very low. Government of Madrid; the EHDN; and NeuroSearch A/S. MKM and AR
Reduced motor performance is known to be associated declare that they have no conﬂicts of interest.
with functional impairment,32 and improvements were Acknowledgments
identiﬁed in clinically relevant domains such as hand We gratefully acknowledge the help of the investigators and staﬀ (see
See Online for webappendix
movements and balance and gait. However, the webappendix) at the 32 participating sites and Dieter Meier (former Chief Medical Oﬃcer, NeuroSearch) for their contributions to the improvements in recorded motor performance did not design, implementation, and interpretation of the study. Writing and translate into an overall functional improvement, as editorial assistance in preparing the report was provided by
measured by the UHDRS independence, functional Abi Woollard and Jeremy Bright from Oxford PharmaGenesis Ltd
capacity, and functional assessments. This might be (funded by NeuroSearch A/S).
because the size of the change was insuﬃcient to References
produce a functional eﬀect. However, in view of the 1
Walker FO. Huntington’s disease. Lancet 2007; 369: 218–28.
The Huntington’s Disease Collaborative Research Group. aforementioned limitations of the functional scales and A novel gene containing a trinucleotide repeat that is expanded their insensitivity to detect a change, it is also possible and unstable on Huntington’s disease chromosomes. Cell 1993; that a functional eﬀect could have been detected with a 72: 971–83.
www.thelancet.com/neurology Vol 10 December 2011
Rosas HD, Salat DH, Lee SY, et al. Cerebral cortex and the clinical 19 Huntington Study Group. Uniﬁed Huntington’s Disease Rating expression of Huntington’s disease: complexity and heterogeneity. Scale: reliability and consistency. Mov Disord 1996; 11: 136–42.
Brain 2008; 131: 1057–68.
20 Huntington Study Group. A randomized, placebo-controlled trial of Heinsen H, Rub U, Bauer M, et al. Nerve cell loss in the thalamic coenzyme Q and remacemide in Huntington’s disease. Neurology mediodorsal nucleus in Huntington’s disease. Acta Neuropathol 2001; 57: 397–404.
1999; 97: 613–22.
21 Waters S, Tedroﬀ J, Kieburtz K. Validation of the modiﬁed motor Feigin A, Tang C, Ma Y, et al. Thalamic metabolism and symptom score (mMS): a subscale of the Uniﬁed Huntington’s Disease onset in preclinical Huntington’s disease. Brain 2007; 130: 2858–67.
Rating Scale (UHDRS) motor score. Neurotherapeutics 2010; 7: 144.
Oyanagi K, Takeda S, Takahashi H, Ohama E, Ikuta F. 22 Waters S, Tedroﬀ J, Waters N, European Huntington’s Disease A quantitative investigation of the substantia nigra in Network. Correlations between functional measures, voluntary Huntington’s disease. Ann Neurol 1989; 26: 13–19.
and involuntary motor symptoms in HD—multivariate analysis Spargo E, Everall IP, Lantos PL. Neuronal loss in the hippocampus of cross-sectional and longitudinal REGISTRY data. in Huntington’s disease: a comparison with HIV infection. J Neurol Neurosurg Psychiatry 2010; 81: A25–26.
J Neurol Neurosurg Psychiatry 1993; 56: 487–91.
23 Guy W. Clinical global impression (CGI). In: Guy W, ed. ECDEU Ciarmiello A, Cannella M, Lastoria S, et al. Brain white-matter assessment manual for psychopharmacology. Rockville, MD: volume loss and glucose hypometabolism precede the clinical US Department of Health, Education, and Welfare, 1976: 218–22.
symptoms of Huntington’s disease. J Nucl Med 2006; 47: 215–22.
24 K Kieburtz, on behalf of the HSG HART study investigators. Mahant N, McCusker EA, Byth K, Graham S. Huntington’s disease: A randomized, double-blind, placebo-controlled trial of ACR16 clinical correlates of disability and progression. Neurology 2003; in Huntington’s disease. Neurotherapeutics 2011; 8: 135.
25 Cersosimo MG, Raina GB, Piedimonte F, Antico J, Graﬀ P, 10 Rawlins M. Huntington’s disease out of the closet? Lancet 2010; Micheli FE. Pallidal surgery for the treatment of primary 376: 1372–73.
generalized dystonia: long-term follow-up. Clin Neurol Neurosurg 11 Spinney L. Uncovering the true prevalence of 2008; 110: 145–50.
Huntington’s disease. Lancet Neurol 2010; 9: 760–61.
26 US Preventative Services Task Force. Guide to clinical 12 Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C. Therapeutic preventative services. Darby, PA: Diane Publishing, 1989.
interventions for symptomatic treatment in Huntington’s disease. 27 Ondo WG, Tintner R, Thomas M, Jankovic J. Tetrabenazine Cochrane Database Syst Rev 2009; 3: CD006456.
treatment for Huntington’s disease-associated chorea. 13 Burgunder J-M, Guttman M, Perlman S, et al. An international Clin Neuropharmacol 2002; 25: 300–02.
survey-based algorithm for the pharmacologic treatment of chorea 28 Dyhring T, Nielsen EO, Sonesson C, et al. The dopaminergic in Huntington’s disease. Plos Curr 2011; published online April 30. stabilizers pridopidine (ACR16) and (–)-OSU6162 display dopamine D(2) receptor antagonism and fast receptor dissociation properties. 14 Andre VM, Cepeda C, Levine MS. Dopamine and glutamate in Eur J Pharmacol 2010; 628: 19–26.
Huntington’s disease: a balancing act. CNS Neurosci Ther 2010; 29 Pontén H, Carlsson A, Kullingsjö J, et al. The dopamine stabilizer 16: 163–78.
ACR16 prevents L-DOPA induced sensitization in the 15 Seeman P, Tokita K, Matsumoto M, Matsuo A, Sasamata M, 6-OHDA-lesioned rat. 32nd Annual Meeting, Society for Miyata K. The dopaminergic stabilizer ASP2314/ACR16 selectively Neuroscience; Orlando, FL, USA; Nov 2–7, 2002. Programme no interacts with D2 (High) receptors. Synapse 2009; 63: 930–34.
16 Pettersson F, Ponten H, Waters N, Waters S, Sonesson C. 30 Penney JB Jr, Young AB, Shoulson I, et al. Huntington’s disease in Synthesis and evaluation of a set of 4-phenylpiperidines and Venezuela: 7 years of follow-up on symptomatic and asymptomatic 4-phenylpiperazines as D2 receptor ligands and the discovery individuals. Mov Disord 1990; 5: 93–99.
of the dopaminergic stabilizer 4-[3-(methylsulfonyl)phenyl]-1- 31 Kloppel S, Draganski B, Golding CV, et al. White matter propylpiperidine (huntexil, pridopidine, ACR16). J Med Chem connections reﬂect changes in voluntary-guided saccades in 2010; 53: 2510–20.
pre-symptomatic Huntington’s disease. Brain 2008; 131: 196–204.
17 Ponten H, Kullingsjo J, Lagerkvist S, et al. In vivo pharmacology 32 Marder K, Zhao H, Myers RH, et al. Rate of functional of the dopaminergic stabilizer pridopidine. Eur J Pharmacol 2010; decline in Huntington’s disease. Neurology 2000; 54: 452–58.
18 Lundin A, Dietrichs E, Haghighi S, et al. Eﬃcacy and safety of the dopaminergic stabilizer pridopidine (ACR16) in patients with
Huntington’s disease. Clin Neuropharmacol 2010; 33: 260–64.
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I dette notat gives en række råd vedrørende forstørret prostata – opdelt i svagt, moderat og stærkt forstørret prostata – samt prostatakræft. De givne råd er baseret på indtagelse af almindelige fødemidler, urtedrikke, plantemedicin samt homøopatisk, antroposofisk og ayurvedisk medicin. Notatet indeholder ingen generelle anatomiske eller fysiologiske oplysninger om prostata og sygd