A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS.

Combining agents with different mechanisms of action may be necessary for meaningful results in treating ALS. The combinations of minocycline-creatine and celecoxib-creatine have additive effects in the murine model. New trial designs are needed to efficiently screen the growing number of potential neuroprotective agents. Our objective was to assess two drug combinations in ALS using a novel phase II trial design. We conducted a randomized, double-blind selection trial in sequential pools of 60 patients. Participants received minocycline (100 mg)-creatine (10 g) twice daily or celecoxib (400 mg)-creatine (10 g) twice daily for six months. The primary objective was treatment selection based on which combination best slowed deterioration in the ALS Functional Rating Scale-Revised (ALSFRS-R); the trial could be stopped after one pool if the difference between the two arms was adequately large. At trial conclusion, each arm was compared to a historical control group in a futility analysis. Safety measures were also examined. After the first patient pool, the mean six-month decline in ALSFRS-R was 5.27 (SD=5.54) in the celecoxib-creatine group and 6.47 (SD=9.14) in the minocycline-creatine group. The corresponding decline was 5.82 (SD=6.77) in the historical controls. The difference between the two sample means exceeded the stopping criterion. The null hypothesis of superiority was not rejected in the futility analysis. Skin rash occurred more frequently in the celecoxib-creatine group. In conclusion, the celecoxib-creatine combination was selected as preferable to the minocycline-creatine combination for further evaluation. This phase II design was efficient, leading to treatment selection after just 60 patients, and can be used in other phase II trials to assess different agents.

Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial.

BACKGROUND: Minocycline has anti-apoptotic and anti-inflammatory effects in vitro, and extends survival in mouse models of some neurological conditions. Several trials are planned or are in progress to assess whether minocycline slows human neurodegeneration. We aimed to test the efficacy of minocycline as a treatment for amyotrophic lateral sclerosis (ALS). METHODS: We did a multicentre, randomised placebo-controlled phase III trial. After a 4-month lead-in phase, 412 patients were randomly assigned to receive placebo or minocycline in escalating doses of up to 400 mg/day for 9 months. The primary outcome measure was the difference in rate of change in the revised ALS functional rating scale (ALSFRS-R). Secondary outcome measures were forced vital capacity (FVC), manual muscle testing (MMT), quality of life, survival, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00047723. FINDINGS: ALSFRS-R score deterioration was faster in the minocycline group than in the placebo group (-1.30 vs -1.04 units/month, 95% CI for difference -0.44 to -0.08; p=0.005). Patients on minocycline also had non-significant tendencies towards faster decline in FVC (-3.48 vs -3.01, -1.03 to 0.11; p=0.11) and MMT score (-0.30 vs -0.26, -0.08 to 0.01; p=0.11), and greater mortality during the 9-month treatment phase (hazard ratio=1.32, 95% CI 0.83 to 2.10; p=0.23) than did patients on placebo. Quality-of-life scores did not differ between the treatment groups. Non-serious gastrointestinal and neurological adverse events were more common in the minocycline group than in the placebo group, but these events were not significantly related to the decline in ALSFRS-R score. INTERPRETATION: Our finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocycline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in patients with ALS.

A screening assessment of cognitive impairment in patients with ALS.

We wished to determine whether a screening test battery for cognitive impairment can be given practicably in a busy multidisciplinary ALS clinic, and to assess initial test performance in a sequentially drawn ALS population. We administered a word generation task (letter fluency), the Frontal Behavioral Inventory (FBI), and the Beck Depression Inventory (BDI) to 49 ALS patients and their caregivers during a visit to our ALS clinic. We also computed Clinical Dementia Rating (CDR) scale and ALS Functional Rating Scale (ALSFRS-R) scores for patients. Pearson correlation coefficients and regression analyses assessed associations between outcome measures. The test battery took 30 min to administer. Word generation was associated with the FBI score (r = -0.36, p = 0.01), and time to ALS diagnosis (p = 0.01). Caregiver depressive symptoms (BDI) correlated with the FBI (r = 0.40, p = 0.005) and motor severity (r = -0.47, p<0.01) in patients. CDR scores were associated with behavioral abnormalities and lower ALSFRS-R scores. We concluded that a screen of cognition could be administered during multidisciplinary ALS clinics. Frontostriatal cognitive impairment may be associated with behavioral syndromes and more rapid forms of ALS. Behavioral and motor impairment is associated with depressive symptoms in caregivers. Studies with formal neuropsychological tests are needed to determine the sensitivity and specificity of the screen in ALS.

The Timed Up and Go test: predicting falls in ALS.

There are few functionally meaningful clinical measures used to guide management of patients with ALS. Falls are common, can be debilitating, and result in increased health care costs. We assessed the performance and ability to predict falls of the Timed Up and Go (TUG) test, which quantifies walking ability, in a prospective longitudinal study. Thirty-one patients underwent six monthly TUG, ALSFRS-R, forced vital capacity, muscle testing (MMT) and quality of life assessments. Linear and generalized linear mixed effects models assessed the associations among variables and ability to predict falls. The increase in TUG time was linear over six months, and TUG time was negatively associated with ALSFRS-R (p< or =0.001) and MMT scores (p< or =0.001). The TUG test was the only variable that was associated with the chance of falling (p = 0.024); patients with TUG times of 14 s had a 10% chance of falling during the study. In conclusion, TUG performance declined linearly in this longitudinal study, was correlated with standard outcome measures, and predicted falls. The TUG test can guide management of patients with ALS; a time of 14 s can be used to prompt the recommendation for mobility aids to prevent falls.

Outcome measures for early phase clinical trials.

As the number of potential neuroprotective agents for ALS increases, the need for early phase trials that screen drugs before proceeding to efficacy trials also grows. However, it is not known which outcome measures perform best and also provide the most meaningful information in brief small trials. We assessed the performance of different outcome measures for use in early phase clinical trials in ALS, and determined what degree of change in the ALSFRS-R that patients could perceive. Thirty patients underwent six monthly ALS Functional Rating Scale (ALSFRS-R), forced vital capacity, manual muscle testing (MMT) and quality of life assessments. Patients rated their perceived level of change with algorithm scales. Linear mixed effects models assessed the associations among variables and Cox proportional-hazards models examined the ability to predict survival. The quantity of missing data was assessed using descriptive statistics. Correlations were found between all variables. The ALSFRS-R provided the most complete data (99.5%), showed a large within-subject correlation (0.91), and best predicted survival (p = 0.002). One-unit change in patient-perceived clinical function paralleled a 9-point decrease in the ALSFRS-R (p = 0.025; 95% CI 8, 10). This trial assessed just 30 patients over six months, but the standard outcome measures each performed dependably; all could be used in short-duration, early phase trials. The ALSFRS-R most strongly predicted survival and provided the most complete data, but large changes may be necessary before patients perceive treatment effects.