Comment
Therapy of amyotrophic lateral sclerosis remains a challenge Published Online October 6, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70179-6 See Articles page 1083
For more on innovative imaging see www.NISALS.org For more on whole-genome sequencing technology see www.ProjectMinE.com
1062
Amyotrophic lateral sclerosis is a devastating fatal disease of motor neurons in the brain, brainstem, and spinal cord. It affects otherwise healthy people and can develop at any point in adulthood. Worldwide, more than 150 000 people die from the disease every year, on average 3 years after symptom onset. Laboratory and patient-oriented research during the past two decades has led to major improvements in our understanding of the pathogenesis of amyotrophic lateral sclerosis, including newly discovered genes, improved in-vitro and in-vivo modelling of the disease, generation of patient-derived motor neurons through induced pluripotent stem cell technology, the discovery of TDP43 protein aggregates in motor neurons, innovative imaging and whole-genome sequencing technology initiatives, the identification of endophenotypes, and the association of the disease with frontotemporal dementia. The successful amyotrophic lateral sclerosis Ice Bucket Challenge, which went viral on social media during the summer, has raised awareness and extended funds for research. However, the real challenge in the coming years will be to translate both the newly acquired knowledge about the disease and the raised awareness and funding into an effective treatment for the thousands of patients with this progressive disease. An essential step in the translational process towards an effective treatment for amyotrophic lateral sclerosis is the execution of well-designed clinical trials. In The Lancet Neurology, Merit Cudkowicz and colleagues from the Ceftriaxone Study Group report the safety and efficacy results of ceftriaxone for amyotrophic lateral sclerosis from a randomised, double-blind, placebocontrolled trial, using a novel three-stage, nonstop study design that combines phase 1, 2, and 3 clinical studies.1 The design and initial results of phase 1 and 2 have previously been published.2 In stages 1 and 2, 66 patients were randomly allocated (21 patients received placebo, 23 patients ceftriaxone 2 g per day, and 22 patients ceftriaxone 4 g per day). Stage 1 established linear pharmacokinetics and sufficient CSF trough levels, and stage 2 showed that ceftriaxone was well tolerated at doses of up to 4 g per day. In stage 3, the 66 patients who had completed stage 2 continued on the same treatment and 448 additional patients were enrolled and randomly assigned 2:1 to
ceftriaxone 4 g per day or placebo, to make a total of 514 patients in stage 3. The article in The Lancet Neurology reports the efficacy results from stages 1, 2, and 3: during stages 1 and 2, functional decline was 0·51 (SD 0·24, 95% CI 0·02–1·00) units per month slower in participants taking 4 g ceftriaxone than in those taking placebo (p=0·0416), whereas in stage 3, ceftriaxone had no significant effect on functional decline after interim or final analyses (difference 0·09 units per month, 95% CI –0·06 to 0·24; p=0·2370). Survival did not differ significantly between the groups in stage 3 (HR 0·90, 95% CI 0·71 to 1·15; p=0·4146). Importantly, because of the seamless phase 1–3 design, all participants who started in stage 1 and 2 were also included in the final stage 3 efficacy analyses. The findings from stage 3 of this study emphasise the importance of well powered phase 3 studies to establish the efficacy of treatment. Amyotrophic lateral sclerosis is probably a heterogeneous disease in which only specific subgroups of patients might respond to a trial treatment. It remains difficult to exclude the unlikely possibility that specific subgroups of patients that are more responsive to the trial drug were overrepresented in the smaller phase 2 stage of the study, as was suggested in the EMPOWER study of dexpramipexole in amyotrophic lateral sclerosis.3,4 Improved and generally accepted methods for post-hoc trial analysis that take into account disease heterogeneity and identify subgroups of responders are needed. A trial design involving combination treatment with more than one drug might be another way to move forward. Unravelling of disease heterogeneity in amyotrophic lateral sclerosis on the basis of clinical, genetic, environmental, or lifestyle factors, validated biomarkers, or a combination thereof, could have enormous consequences for molecular diagnostic and therapeutic strategies in the disorder.5,6 Amyotrophic lateral sclerosis databases and biobanks, designed and standardised on a national or multinational level for data-sharing purposes, are the basis to achieve this. Unfortunately, to set up the infrastructure for projects that only collect clinical datasets and biosamples is not always the most appealing option for funding agencies. A three-stage, nonstop trial design, as used in this study,1 could expedite the testing of new promising compounds, and is beneficial for patient recruitment since www.thelancet.com/neurology Vol 13 November 2014
Comment
patients who enter phase 1 or phase 2 remain in the study for subsequent phases. Usually, patients are excluded from trials if they have had previous exposure to the study drug. Additionally, this trial design efficiently takes into account the pharmacokinetic profile and correct dosing of the drug, the importance of which for the trial outcome might have been underestimated in previous amyotrophic lateral sclerosis trials. Future trials might benefit from the following: a 1:1 randomisation ratio of treatment to placebo to reduce sample size (and costs and study duration); inclusion of patients with a symptom duration of less than 24 months (instead of
Therapy of amyotrophic lateral sclerosis remains a challenge Published Online October 6, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70179-6 See Articles page 1083
For more on innovative imaging see www.NISALS.org For more on whole-genome sequencing technology see www.ProjectMinE.com
1062
Amyotrophic lateral sclerosis is a devastating fatal disease of motor neurons in the brain, brainstem, and spinal cord. It affects otherwise healthy people and can develop at any point in adulthood. Worldwide, more than 150 000 people die from the disease every year, on average 3 years after symptom onset. Laboratory and patient-oriented research during the past two decades has led to major improvements in our understanding of the pathogenesis of amyotrophic lateral sclerosis, including newly discovered genes, improved in-vitro and in-vivo modelling of the disease, generation of patient-derived motor neurons through induced pluripotent stem cell technology, the discovery of TDP43 protein aggregates in motor neurons, innovative imaging and whole-genome sequencing technology initiatives, the identification of endophenotypes, and the association of the disease with frontotemporal dementia. The successful amyotrophic lateral sclerosis Ice Bucket Challenge, which went viral on social media during the summer, has raised awareness and extended funds for research. However, the real challenge in the coming years will be to translate both the newly acquired knowledge about the disease and the raised awareness and funding into an effective treatment for the thousands of patients with this progressive disease. An essential step in the translational process towards an effective treatment for amyotrophic lateral sclerosis is the execution of well-designed clinical trials. In The Lancet Neurology, Merit Cudkowicz and colleagues from the Ceftriaxone Study Group report the safety and efficacy results of ceftriaxone for amyotrophic lateral sclerosis from a randomised, double-blind, placebocontrolled trial, using a novel three-stage, nonstop study design that combines phase 1, 2, and 3 clinical studies.1 The design and initial results of phase 1 and 2 have previously been published.2 In stages 1 and 2, 66 patients were randomly allocated (21 patients received placebo, 23 patients ceftriaxone 2 g per day, and 22 patients ceftriaxone 4 g per day). Stage 1 established linear pharmacokinetics and sufficient CSF trough levels, and stage 2 showed that ceftriaxone was well tolerated at doses of up to 4 g per day. In stage 3, the 66 patients who had completed stage 2 continued on the same treatment and 448 additional patients were enrolled and randomly assigned 2:1 to
ceftriaxone 4 g per day or placebo, to make a total of 514 patients in stage 3. The article in The Lancet Neurology reports the efficacy results from stages 1, 2, and 3: during stages 1 and 2, functional decline was 0·51 (SD 0·24, 95% CI 0·02–1·00) units per month slower in participants taking 4 g ceftriaxone than in those taking placebo (p=0·0416), whereas in stage 3, ceftriaxone had no significant effect on functional decline after interim or final analyses (difference 0·09 units per month, 95% CI –0·06 to 0·24; p=0·2370). Survival did not differ significantly between the groups in stage 3 (HR 0·90, 95% CI 0·71 to 1·15; p=0·4146). Importantly, because of the seamless phase 1–3 design, all participants who started in stage 1 and 2 were also included in the final stage 3 efficacy analyses. The findings from stage 3 of this study emphasise the importance of well powered phase 3 studies to establish the efficacy of treatment. Amyotrophic lateral sclerosis is probably a heterogeneous disease in which only specific subgroups of patients might respond to a trial treatment. It remains difficult to exclude the unlikely possibility that specific subgroups of patients that are more responsive to the trial drug were overrepresented in the smaller phase 2 stage of the study, as was suggested in the EMPOWER study of dexpramipexole in amyotrophic lateral sclerosis.3,4 Improved and generally accepted methods for post-hoc trial analysis that take into account disease heterogeneity and identify subgroups of responders are needed. A trial design involving combination treatment with more than one drug might be another way to move forward. Unravelling of disease heterogeneity in amyotrophic lateral sclerosis on the basis of clinical, genetic, environmental, or lifestyle factors, validated biomarkers, or a combination thereof, could have enormous consequences for molecular diagnostic and therapeutic strategies in the disorder.5,6 Amyotrophic lateral sclerosis databases and biobanks, designed and standardised on a national or multinational level for data-sharing purposes, are the basis to achieve this. Unfortunately, to set up the infrastructure for projects that only collect clinical datasets and biosamples is not always the most appealing option for funding agencies. A three-stage, nonstop trial design, as used in this study,1 could expedite the testing of new promising compounds, and is beneficial for patient recruitment since www.thelancet.com/neurology Vol 13 November 2014
Comment
patients who enter phase 1 or phase 2 remain in the study for subsequent phases. Usually, patients are excluded from trials if they have had previous exposure to the study drug. Additionally, this trial design efficiently takes into account the pharmacokinetic profile and correct dosing of the drug, the importance of which for the trial outcome might have been underestimated in previous amyotrophic lateral sclerosis trials. Future trials might benefit from the following: a 1:1 randomisation ratio of treatment to placebo to reduce sample size (and costs and study duration); inclusion of patients with a symptom duration of less than 24 months (instead of
