Comparison of analysis approaches for phase III clinical trials in amyotrophic lateral sclerosis

Introduction: In this study we explore several methods for incorporating survival information in the analysis of Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) scores. Methods: ALSFRS scores and patient survival times were simulated based on estimates from a recent clinical trial. Six analysis approaches were applied to the data. Each approach was based on ALSFRS scores, the survival time, or a combination of the 2. The power of each approach to detect potential treatment effects was estimated. Results: When the treatment acted solely on the change in ALSFRS, the shared parameter model provided the most power, although all of the models based on random effects were similar. As the effect on survival increased, rank‐based analysis showed potential gains in power. Survival analysis was superior under a small effect on ALSFRS and a larger effect on mortality. Conclusions: The shared parameter model and rank‐based approach can offer improvements in power over traditional approaches. Muscle Nerve 46: 501–511, 2012     

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.     

Xaliproden in amyotrophic lateral sclerosis: early clinical trials.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. We report the safety and functional efficacy results of a double-blind, placebo-controlled phase II study of xaliproden, a non-peptidic compound with growth factor activities, in 54 ALS patients treated for up to 32 weeks. In order to overcome the interference of mortality with functional assessment in exploratory studies, we identified from our ALS database prognostic factors to establish a staging process for selection pf patients: age, disease duration, slopes of deterioration of the functional scores calculated during the two months prior to the inclusion, and the value at entry of the forced vital capacity (FVC). The six months intent-to-treat analysis showed no statistically significant effect but a trend in favour of 2 mg xaliproden compared to placebo for reduction in the rate of deterioration of FVC, limbs functional score, and manual muscle testing score (MMT). The results in the completer analysis showed a significant 43% slower rate of deterioration in FVC (P=0.046) in xaliproden-treated patients but not in functional and MMT scores. These results support the use of a staging process to select suitable patients for phase II studies, and suggest that xaliproden may have potential effects in ALS and deserve further study.     

Sequential designs for clinical trials in amyotrophic lateral sclerosis.

BACKGROUND: The objective of this paper is to discuss the sequential trial design and its advantages in clinical trials for ALS. The sequential trial design is an alternative to the classical trial design, which permits stopping a study as soon as a treatment effect can be significantly demonstrated or denied. METHODS: As an example of a sequential survival analysis, a recently completed clinical trial is described. A secondary outcome measure used in the same trial, the decline of the vital lung capacity, was re-analyzed sequentially, in order to illustrate the use of the sequential method for a non-survival variable. To compare the classical with the sequential trial design, the number of patients needed in trials aiming at survival effects ranging from 10% to 20% with a power of 80% or 90% was calculated for both designs. RESULTS: In the given examples the time needed to prove the null hypothesis in the survival analysis, and the number of patients needed to prove the null hypothesis in the analysis of the vital capacity is lower than would have been the case in a classical analysis. In 18 of 24 different situations, the chance is at least 90% that with a sequential trial design fewer patients are needed. CONCLUSIONS: We argue that, particularly for ALS trials, a sequential design may be superior to a classical trial design, as it most often requires fewer patients than classically designed trials of equal power, and more importantly may avoid unnecessary continuation.     

Advances in clinical trials for amyotrophic lateral sclerosis

Because treatments are not yet powerful enough to reverse the symptoms of amyotrophic lateral sclerosis (ALS), randomized placebo-controlled trials remain the gold standard for testing new therapies. To date, only one drug, riluzole, has been shown to slow the course of ALS, albeit in a very modest way. Since the approval of riluzole almost 10 years ago, there have been a number of negative trials, and we still await the discovery of a medication with a truly meaningful effect. With each study, our sophistication in trial design grows, but hurdles remain, including how to use transgenic animal models optimally, which outcome measures most accurately reflect changes in the disease, and how to reduce the often high dropout rates in trials of ALS. This article is devoted to the recent evolution of clinical trials in ALS and discusses specific trials conducted during the past 5 years.     

Neurophysiological measures in amyotrophic lateral sclerosis: markers of progression in clinical trials.

In this review we evaluate clinical neurophysiological methods, originally described for use in diagnosis that can be applied to measurement of change during the progress of amyotrophic lateral sclerosis (ALS). Such measurements are potentially important in clinical trials, and also in clinical practice. We have assessed methods for lower and upper motor neuron function, including conventional EMG, nerve conduction and F-wave studies, the derived Neurophysiological Index, motor unit counting methods (MUNE), and transcranial magnetic motor cortex stimulation. We have also addressed the validity of measurements of electromechanical coupling. Methods for measuring muscle strength are beyond the scope of this review. We conclude that MUNE, M-wave amplitude and the Neurophysiological Index are sufficiently reliable, sensitive, and relevant to the clinical problem of ALS, to be used in clinical trials in the disease. Transcranial magnetic stimulation is of limited value, but a combination of the measurements made as part of this technique may also be useful. We conclude that clinical neurophysiological techniques should now be used in measuring change in clinical trials in ALS.     

Screening the metallothionein III gene in sporadic amyotrophic lateral sclerosis.

Metallothioneins are proteins involved in antioxidant defence, essential metal homoeostasis and heavy metal detoxification, all mechanisms implicated in sporadic amyotrophic lateral sclerosis (SALS). We therefore looked for changes in the gene for nervous system-specific metallothionein III (MT3) that might explain susceptibility to SALS. DNA was extracted from 87 sporadic ALS and 174 matched controls. The gene for MT3 was sequenced in 20 SALS and 5 control subjects to identify single nucleotide polymorphisms (SNPs). These SNPs were then screened in all subjects. Eight novel SNPs were found in the 5' untranslated region and intron 2 of MT3. No differences were found in the frequency distribution of alleles or haplotypes for these SNPs between the SALS and control groups. The genotype distribution of one SNP (A1422C) was significantly different between ALS and control groups (p<0.02) but this is not likely to be biologically relevant. We conclude that changes in the MT3 gene are unlikely to be responsible for susceptibility to SALS.     

Spirometry in amyotrophic lateral sclerosis.

Clinical evaluation and pulmonary function tests were performed in 218 patients with motor neuron disease, mainly amyotrophic lateral sclerosis (ALS). Serial studies were obtained in 103 patients, in 31 until death from ALS. Most patients, regardless of the pattern of motor neuron involvement, had characteristic abnormalities in pulmonary function, including reduced forced vital capacity (FVC) and maximum voluntary ventilation (MVV). Reductions in the FVC and MVV to as low as 50% were commonly missed by clinical evaluators. Spirometry is therefore of value in detecting early involvement of respiratory neurons. Progressively greater reductions in the FVC and MVV in all the fatal cases indicate that serial spirometry has prognostic value in ALS.     

Optimizing telemedicine to facilitate amyotrophic lateral sclerosis clinical trials

Amyotrophic lateral sclerosis (ALS) has the largest drug pipeline among neuromuscular diseases, with over 160 companies actively involved in ALS research. There is a growing need to recruit trial participants, but ALS patients often have limited mobility and most ALS trials are conducted in a small number of major centers. These factors effectively limit patient participation, particularly for those in rural areas. The current coronavirus disease 2019 (COVID-19) pandemic has necessitated the more widespread use of telemedicine technology for clinical care, and has prompted consideration of its increased use for clinical trials. In this opinion piece, we describe the current state of telemedicine for recruitment, consenting, and screening of participants for clinical trials. We also summarize the available data on remote administration of outcome measures. Current challenges include validation of outcome measures for remote assessment, as well as technological, regulatory, and licensure barriers.     

Electrical impedance myography to assess outcome in amyotrophic lateral sclerosis clinical trials.

OBJECTIVE: Standard outcome measures used for amyotrophic lateral sclerosis (ALS) clinical trials, including the ALS functional rating scale-revised (ALSFRS-R), maximal voluntary isometric contraction testing (MVICT), and manual muscle testing (MMT), are limited in their ability to detect subtle disease progression. Electrical impedance myography (EIM) is a new non-invasive technique that provides quantitative data on muscle health by measuring localized tissue impedance. This study investigates whether EIM could provide a new outcome measure for use in ALS clinical trials work. METHODS: Fifteen ALS patients underwent repeated EIM measurements of one or more muscles over a period of up to 18 months and the primary outcome variable, theta(z-max), measured. The theta(z-max) megascore was then calculated using the same approach as has been applied in the past for MVICT. This and the MMT data were then used to assess each measure's statistical power to detect a given effect on disease progression in a hypothetical planned clinical therapeutic trial. RESULTS: theta(z-max) showed a mean decline of about 21% for the test period, averaged across all patients and all tested muscles. The theta(z-max) megascore had a power of 73% to detect a 10% treatment effect in our planned hypothetical trial, as compared to a 28% power for MMT. These results also compared favorably to historical data for ALSFRS-R and MVICT arm megascore from the trial of celecoxib in ALS, where both measures had only a 23% power to detect the same 10% treatment effect. CONCLUSIONS: The theta(z-max) megascore may provide a powerful new outcome measure for ALS clinical trials. SIGNIFICANCE: The application of EIM to future ALS trials may allow for smaller, faster studies with an improved ability to detect subtle progression of the disease and treatment effects.     

High-dose dextromethorphan in amyotrophic lateral sclerosis: Phase I safety and pharmacokinetic studies

Much interest has focused on the role of glutamate-mediated excitotoxicity in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). We therefore conducted a phase I study of high-dose dextromethorphan (DM) in ALS. DM is a selective, noncompetitive antagonist of the N-methyl-D -aspartate subtype of the glutamate receptor. Thirteen patients were given DM in an escalating dose fashion, to a target of 10 mg/kg/day or the maximum tolerable dose, and then maintained on this dose for up to 6 months. Total daily doses ranged from 4.8 to 10 mg/kg (median, 7 mg/kg). Side effects were dose limiting in most patients. The most common side effects were light-headedness, slurred speech, and fatigue. Detailed pharmacokinetic and neuropsychology studies were performed. This study demonstrates the feasibility of long-term administration of high-dose DM in ALS, as well as in other conditions associated with glutamate excitotoxicity.     

Percutaneous gastrojejunostomy in amyotrophic lateral sclerosis.

We have performed a retrospective review of the use of a percutaneous gastrojejunostomy in patients with amyotrophic lateral sclerosis (ALS). Forty-one patients with initial bulbar manifestations of ALS and 32 patients with initial limb manifestations underwent a percutaneous gastrojejunostomy under fluoroscopic control using the Rankin gastrojejunostomy tube. Survival characteristics were compared with 86 bulbar onsetting and 207 limb onsetting ALS patients who did not require nutritional support. The 30-day mortality rate was 9.6% (respiratory death in three bulbar onsetting patients and four limb onsetting patients) and the 30 day morbidity rate was 4.1% (one operative site infection and intraperitoneal leakage in two patients). The most frequent long-term complication was the requirement for tube changing (blockage in six; dislodgment in two). Gastric reflux was not described amongst the treated patients. Overall survivorship (symptom onset to death) was less in the bulbar onsetting patients receiving a gastrojejunostomy tube than in the control population (median survival 22.0 vs. 33.7 months, respectively, P=0.005). As a group, the median survivorship for limb onsetting patients was not different for those receiving a gastrojejunostomy than for those who did not. However, a significant reduction in survival was observed in limb onsetting patients receiving a gastrojejunostomy early in the course of their disease (P=0.001) compared to those with a longer duration prior to the procedure. This was not observed in the bulbar onsetting patients. In both patient populations, no relationship was observed between survival post-gastrojejunostomy and the severity of pulmonary involvement at the time of the intervention, serum chloride, or age at onset. These studies demonstrate that a percutaneous gastrojejunostomy is a well-tolerated and safe alternative technique for enteral nutritional support in ALS patients. It also offers the advantage of not requiring either a general anaesthetic at the time of the procedure or instrumentation through the oropharynx. We have also observed that limb onsetting patients requiring a gastrojejunostomy early in the course of their illness are in a distinctive, less favorable, prognostic group.     

Stapedial reflex in amyotrophic lateral sclerosis.

OBJECTIVE--To examine mechanisms controlling the stapedial reflex in patients with amyotrophic sclerosis (ALS). METHODS--The stapedial reflex was examined using impedance audiometry in 38 patients with sporadic ALS and in 25 age matched controls. RESULTS--All patients showed normal reflex decay test results. There were no significant differences between patients with ALS and control subjects in reflex threshold, latency, amplitude, or contraction time (C50). Although each reflex variable in the patients with classic or progressive muscular atrophy types of ALS showed no significant difference from that in control subjects, the patients with bulbar type ALS showed significantly longer latency, C50, and retraction time (D50), and significantly lower amplitude than control subjects. Three types of abnormal reflex waveforms (polyphasic, abnormally delayed retraction, and abnormally early retraction) were noted in six patients. CONCLUSION--The subclinical involvement of the stapedius motor neurons or of the supranuclear stapedius motor system might be responsible for the abnormalities of the stapedial reflex in ALS.     

End-plate morphology in amyotrophic lateral sclerosis.

Intercostal muscle end-plates were measured in patients with amyotrophic lateral sclerosis (ALS) and more benign motor neuron disease (MND). The length of the intact end-plates in ALS and MND was not different from the controls. Segmented end-plates were increased in both ALS and benign MND, and the end-plate length was greatest in ALS. In individual ALS cases, no correlation was found between the end-plate abnormalities and relevant clinical variables.     

Transcallosal inhibition in amyotrophic lateral sclerosis.

OBJECTIVE: Assessment of upper motor neuron (UMN) involvement is essential for the diagnosis of amyotrophic lateral sclerosis (ALS). In a number of ALS cases, mirror movements (MM) suggest an involvement of transcallosal fibre tracts in conjunction with UMN involvement. The present study analysed whether deficient transcallosal inhibition (TI) tested by TMS enables detection of cortical affection in ALS, even at early stages of the disease. METHODS: In three patients with definite ALS and 12 patients with early ALS (aged 64.1+/-7.8 years) TMS investigation included analysis of contralateral (cMEP) and ipsilateral (iMEP) motor evoked potentials as well as measurement of TI (latency, duration) with recording from both first dorsal interosseus muscles. RESULTS: Clinical UMN signs were present in four patients. 83.3% of patients showed a pathological TI (prolongation or loss of TI). Five out of eight ALS patients showing a pathological TI had no clinical UMN signs. Two of these patients showed MM. One patient displayed also pathological findings in TI investigation. CONCLUSIONS: Our findings suggest a functional deficit of transcallosal fibre tracts even at early stages of the disease still lacking clinical UMN signs. SIGNIFICANCE: Measurement of TI tested by TMS can detect an involvement of the cortical output system in ALS and may be helpful in an early assessment of the diagnosis.     

Muscle morphometry in amyotrophic lateral sclerosis.

Quadriceps muscle biopsies from 24 patients with amyotrophic lateral sclerosis (ALS) and 15 age-matched controls were prepared for histochemistry and analyzed morphometrically. Pathological features for denervation and reinnervation were observed in most ALS patients, although considerable variation between patients was noted. Myopathic changes were also seen in one-third of the cases. The morphometric data were not only related to the duration and mean diameter of type I fiber, but also to the duration and hypertrophy factor of type II fiber, suggesting that the progression and severity of ALS depends on the preservation of both fibers.