Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study

Background Modafinil is a unique wake-promoting agent that is chemically distinct from traditional stimulants. Results of a placebo-controlled study showed it to improve fatigue in multiple sclerosis (MS) at a dose of 200 mg daily, but not at a dose of 400 mg daily. Objective To establish the efficacy, safety and appropriate dose of modafinil in the treatment of fatigue and sleepiness in patients with multiple sclerosis. Method A total of 50 patients diagnosed with MS (mean age 40.4 ± 10.3 years, 30 females/20 males; MS type: 36 relapsing remitting, 1 primary progressive, 13 secondary progressive; mean disability level 3.8 ± 1.5 on the Kurtzke EDSS) and complaining of chronic fatigue were enrolled in a prospective 3-month, two-center, open-label study. Efficacy was evaluated with the Fatigue Severity Scale (FSS, score range 0-42), the Epworth Sleepiness Scale (ESS, score range 0-24) and by subjective patient appraisal of change of fatigue, quality of life and overall satisfaction with treatment. Adverse effects (AEs) were recorded throughout the study. Treatment was started with a single daily dose of 100 mg in all patients. In non-responders the dose was increased by 100 mg increments up to a maximum daily dose of 400 mg. Results Three patients discontinued modafinil because of AEs (nervousness, dizziness). Two patients (4 %) were treated with 50 mg, 25 (50 %) with 100 mg, 21 (42 %) with 200 mg and 2 (4 %) with 300 mg daily. No patient required 400 mg daily. Mean FSS scores were 30.3 ± 8.5 at baseline and 25.4 ± 3.7 at 3 months (p < 0.0001). Mean ESS scores were 9.7 ± 3.9 at baseline and 4.9 ± 2.9 at 3 months (p < 0.0001). Self-appraisal of change of fatigue showed clear improvement in 41 patients (87.2 %), some improvement in 4 (8.5 %) and no change in 2 (4.3 %). Overall clinical condition was clearly improved in 43 patients (91.5 %), somewhat improved in 1 patient (2.1 %), and unchanged in 3 patients (6.4 %). No patient reported worsening of overall clinical condition. Conclusions Treatment with modafinil significantly improves fatigue and sleepiness and is well tolerated by patients with MS. Unlike the higher dose regimen required in narcolepsy, a low-dose regimen of modafinil is effective in MS. Received: 10 August 2001 Received in revised form: 22 January 2002 Accepted: 25 January 2002     

Randomized controlled trial of modafinil for the treatment of fatigue in postpolio patients

The purpose of this study was to test whether modafinil is effective in alleviating the symptoms of fatigue in postpolio patients, because it has been helpful for such symptoms in other neurologic disorders. Using a double-blind, randomized, placebo-controlled cross-over design, 14 postpolio patients with moderate to severe fatigue were assigned to receive modafinil or placebo first. Piper Fatigue Scale, Epworth Sleepiness Scale, digit span, and reaction time tests were done at baseline and then at weekly intervals. The Piper Fatigue Scale scores improved by 27 +/- 40% (mean +/- SD) following modafinil and by 43 +/- 36% following placebo. Scores for most of the other tests did not change during the study. Therefore, we conclude that modafinil was not effective in alleviating the symptoms of fatigue in postpolio patients.     

A randomized,double‐blind,placebo‐controlled trial of pridopidine in Huntington's disease

We examined the effects of 3 dosages of pridopidine, a dopamine‐stabilizing compound, on motor function and other features of Huntington's disease, with additional evaluation of its safety and tolerability. This was a randomized, double‐blind, placebo‐controlled trial in outpatient neurology clinics at 27 sites in the United States and Canada. Two hundred twenty‐seven subjects enrolled from October 24, 2009, to May 10, 2010. The intervention was pridopidine, either 20 (n=56), 45 (n=55), or 90 (n=58) mg daily for 12 weeks or matching placebo (n=58). The primary outcome measure was the change from baseline to week 12 in the Modified Motor Score, a subset of the Unified Huntington's Disease Rating Scale Total Motor Score. Measures of safety and tolerability included adverse events and trial completion on the assigned dosage. After 12 weeks, the treatment effect (relative to placebo, where negative values indicate improvement) of pridopidine 90 mg/day on the Modified Motor Score was ?1.2 points (95% confidence interval [CI], ?2.5 to 0.1 points; P = .08). The effect on the Total Motor Score was ?2.8 points (95% CI, ?5.4 to ?0.1 points; nominal P = .04). No significant effects were seen in secondary outcome measures with any of the active dosages. Pridopidine was generally well tolerated. Although the primary analysis did not demonstrate a statistically significant treatment effect, the overall results suggest that pridopidine may improve motor function in Huntington's disease. The 90 mg/day dosage appears worthy of further study. Pridopidine was well tolerated. © 2013 International Parkinson and Movement Disorder Society     

A randomized,double‐blind,placebo‐controlled trial evaluating cysteamine in Huntington's disease

Background : Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease. Methods : Ninety‐six patients with early‐stage Huntington's disease were randomized to 1200 mg delayed‐release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed‐effects model for repeated measures was used to assess treatment effect, expressed as the least‐squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo. Results : At 18 months, the treatment effect was not statistically significant — least‐squares mean difference, ‐1.5 ± 1.71 (P = 0.385) — although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated. Conclusions : Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society     

Rivastigmine for mild cognitive impairment in Parkinson disease: A placebo‐controlled study

Mild cognitive impairment (MCI) in Parkinson's disease (PD) may be associated with subtle functional impairment and worse quality of life. The objective of this study was to determine the efficacy and tolerability of rivastigmine for PD‐MCI. Patients with PD‐MCI (n = 28) were enrolled in a 24‐week, randomized, double‐blind, placebo‐controlled, crossover, single‐site study of the rivastigmine transdermal patch. The primary outcome measure was the Alzheimer's Disease Cooperative Study—Clinical Global Impression of Change (ADCS‐CGIC). Secondary outcomes included the Montreal Cognitive Assessment (MoCA), Dementia Rating Scale‐2 (DRS‐2), Neurotrax computerized cognitive battery, the Everyday Cognition Battery (ECB), and the Parkinson's Disease Questionnaire (PDQ‐8). Twenty‐six participants (92.9%) completed both study phase assessments, and 23 (82.1%) completed both phases on study medication. The CGIC response rate demonstrated a trend effect in favor of rivastigmine (regression coefficient for interaction term in linear mixed‐effects model = 0.44, F[df] = 3.01 [1, 24], P = 0.096). For secondary outcomes, a significant rivastigmine effect on the ECB (regression coefficient = –2.41, F[df] = 5.81 [1, 22.05], P = 0.03) was seen, but no treatment effect was found on any cognitive measures. Trend effects also occurred in favor of rivastigmine on the PDQ‐8 (regression coefficient = 4.55, F[df] = 3.93 [1, 14. 79], P = 0.09) and the State Anxiety Inventory (regression coefficient = –1.24, F[df] = 3.17 [1, 33], P = 0.08). Rivastigmine in PD‐MCI showed a trend effect for improvements on a global rating of cognition, disease‐related health status, and anxiety severity, and significant improvement on a performance‐based measure of cognitive abilities. © 2015 International Parkinson and Movement Disorder Society     

Short‐term effects of coenzyme Q10 in progressive supranuclear palsy: A randomized,placebo‐controlled trial

Mitochondrial complex I appears to be dysfunctional in progressive supranuclear palsy (PSP). Coenzyme Q₁₀ (CoQ₁₀) is a physiological cofactor of complex I. Therefore, we evaluated the short‐term effects of CoQ₁₀ in PSP. We performed a double‐blind, randomized, placebo‐controlled, phase II trial, including 21 clinically probable PSP patients (stage ≤ III) to receive a liquid nanodispersion of CoQ₁₀ (5 mg/kg/day) or matching placebo. Over a 6‐week period, we determined the change in CoQ₁₀ serum concentration, cerebral energy metabolites (by ³¹P‐ and ¹H‐magnetic resonance spectroscopy), motor and neuropsychological dysfunction (PSP rating scale, UPDRS III, Hoehn and Yahr stage, Frontal Assessment Battery, Mini Mental Status Examination, Montgomery Åsberg Depression Scale). CoQ₁₀ was safe and well tolerated. In patients receiving CoQ₁₀ compared to placebo, the concentration of low‐energy phosphates (adenosine‐diphosphate, unphosphorylated creatine) decreased. Consequently, the ratio of high‐energy phosphates to low‐energy phosphates (adenosine‐triphosphate to adenosine‐diphosphate, phospho‐creatine to unphosphorylated creatine) increased. These changes were significant in the occipital lobe and showed a consistent trend in the basal ganglia. Clinically, the PSP rating scale and the Frontal Assessment Battery improved slightly, but significantly, upon CoQ₁₀ treatment compared to placebo. Since CoQ₁₀ appears to improve cerebral energy metabolism in PSP, long‐term treatment might have a disease‐modifying, neuroprotective effect. © 2008 Movement Disorder Society     

ALSFRS and appel ALS scores: discordance with disease progression

Progression of disease and effectiveness of therapy in patients with amyotrophic lateral sclerosis (ALS) are determined by both questionnaire- and examination-based measures. To determine whether both types of measurement tools are equally predictive at all stages of disease, we compared questionnaire-based ALS Functional Rating Scale (ALSFRS) scores to the examination-based Appel ALS (AALS) scores at different stages of disease. Same-day scores were obtained during 174 visits in 62 patients with definite or probable ALS. Using normalized scores, correlation between the scales and predictability were best in mildly affected patients. Predictions of ALSFRS based on AALS scores were less than half as precise in the later stages of disease. Both scales showed significant change with disease progression, but ALSFRS consistently underestimated disease severity defined by AALS (P < 0.001). Questionnaire-based measurements should be compared against objective scales at all stages of disease severity before they are accepted as primary endpoint measures.     

Lamotrigine as add‐on treatment to lithium and divalproex: lessons learned from a double‐blind,placebo‐controlled trial in rapid‐cycling bipolar disorder

Kemp DE, Gao K, Fein EB, Chan PK, Conroy C, Obral S, Ganocy SJ, Calabrese JR. Lamotrigine as add‐on treatment to lithium and divalproex: lessons learned from a double‐blind, placebo‐controlled trial in rapid‐cycling bipolar disorder.
Bipolar Disord 2012: 14: 780–789. © 2012 John Wiley & Sons A/S. Objectives: A substantial portion of the morbidity associated with rapid‐cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add‐on therapy for rapid‐cycling bipolar depression non‐responsive to the combination of lithium plus divalproex. Methods: During Phase 1 of this trial, hypomanic, manic, mixed, and/or depressed outpatients (n = 133) aged 18–65 years with DSM–IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16 weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n = 49) (i.e., remained in or cycled into the depressed phase) were randomly assigned to double‐blind, adjunctive lamotrigine (n = 23) or adjunctive placebo (n = 26). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery‐Åsberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed‐models analysis. Results: During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13/133; 10%) and study non‐adherence (22/133; 17%). Only 14% (19/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double‐blind adjunctive treatment phase, mean ± standard error change from baseline on the MADRS total score was ?8.5 ± 1.7 points for lamotrigine and ?9.1 ± 1.5 points for placebo (p = not significant; mixed‐models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo. Conclusions: The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double‐blind treatment.