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950 www.thelancet.com/neurology Vol 9 October 2010

5 Piepers S, Veldink JH, de Jong SW, et al. Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis. Ann Neurol 2009; 66: 227–34.

6 Kriz J, Gowing G, Julien JP. Effi cient three-drug cocktail for disease induced by mutant superoxide dismutase. Ann Neurol 2003; 53: 429–36.

7 Ioannidis JP. Why most discovered true associations are infl ated. Epidemiology 2008; 19: 640–48.

of detecting small or moderate therapeutic eff ects, provided there are no safety concerns. A drug with a small therapeutic eff ect, such as riluzole, could be included in future combination treatments that have greater eff ects and could be important for the understanding of disease mechanisms.6 A more moderate (and realistic) eff ect of lithium cannot be ruled out in this trial design. Pilot studies often fi nd large eff ect sizes, which after careful follow-up seem to be much smaller, albeit true.7 We therefore propose that stopping rules in futility or sequential trial designs should be based on eff ect size in the range of the eff ect of riluzole.5

Futility or sequential trial designs for ALS are a promising alternative to a classic trial design in which sample size is fi xed, because they allow stopping of a study as soon as a treatment eff ect can be signifi cantly demonstrated or denied. However, realistic and more moderate stopping rules should be applied, and we believe a double-blind, placebo-controlled trial is still needed to show or exclude a more moderate eff ect of lithium in ALS. We have no confl icts of interest.

Esther Verstraete, Jan H Veldink, Leonard H van den Bergl.h.vandenBerg@umcutrecht.nl

University Medical Centre Utrecht, Department of Neurology of the Rudolf Magnus Institute of Neuroscience, PO Box 85500, 3508 GA, Netherlands

1 Aggarwal SP, Zinman L, Simpson E, et al, for the Northeast and Canadian Amyotrophic Lateral Sclerosis consortia. Safety and effi cacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010; 9: 481–88.

2 Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 1994; 330: 585–91.

3 Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 1996; 347: 1425–31.

4 Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2008; 105: 2052–57.

does so by only 3–6 months.2,3 After the publication of a pilot study from Italy,4 which showed a favourable eff ect of lithium in a transgenic mouse model of ALS and in an open-label study in 44 patients, Aggarwal and colleagues undertook their larger trial in Canada and the USA. This trial was designed to detect an eff ect of similar size to that in the pilot study, in which a 40% decrease in the rate of neurological decline was reported. Criteria for early stopping in the study by Aggarwal and colleagues were defi ned on the basis of this eff ect size and, indeed, the fi rst interim analysis met the criterion for futility and the trial was stopped. This design has more advantages than the classic trial design, especially in the possibility for increased speed of drug screening; however, we have a few concerns.

First, we are concerned about the short treatment duration. The eff ect of riluzole was demonstrated in two placebo-controlled studies: the fi rst included 155 patients with 21 months’ follow-up,2 and the second was a dose-ranging study in 959 patients with 18 months’ follow-up.3 In the study by Aggarwal and colleagues, on average, patients were on lithium or placebo for only 5·4 months, and 9 weeks were needed to reach therapeutic lithium serum concentrations. Of the 40 patients in the lithium group, six did not reach therapeutic drug concentrations, and only 27 patients were receiving lithium up to the fi nal analysis. Could a treatment eff ect be expected in patients with ALS after such short exposure to the study drug? Second, the mean age of patients in the lithium group was higher than that in the placebo group (58·3 years vs 55·5 years). Because age is the most important prognostic factor for disease progression, this diff erence could have obscured a potential favourable eff ect of lithium. Randomisation according to the minimisation method could have prevented this drawback.5 Third, we would like to emphasise the relevance

Authors’ replyVerstraete and colleagues are correct that our study1 would not have had adequate power to detect a treatment eff ect of similar size to that of riluzole. The sample size of 250 patients and the futility stopping rule used in our trial design—which were chosen because of the large eff ect seen in the pilot study2 and lack of reproducibility of clinical data by other amyotrophic lateral sclerosis (ALS) scientists—would have allowed the study to continue if there was a positive eff ect after 85 patients were assessed.

Clinical trials of potential treatments for amyotrophic lateral sclerosis (ALS) are hindered by the relative rarity of the disease and the large number of drugs to test. If we tested each drug in a trial of 600–1000 patients, in 10 years we would have tested only two or three drugs. Our strategy has therefore been to test drugs using study sizes that vary in accordance with our beliefs about the prior probability of the drug’s eff ectiveness. We would screen most drugs with small, phase 2 studies and futility stopping rules; large studies would be done only for drugs that either passed the fi rst screen or that had a high chance of success on the basis of preliminary data. Our strategy is the most appropriate if one assumes that few drugs will work, and that of those that do, some will work very well. If most drugs in our pipeline have a moderate eff ect, Verstraete and colleagues’ strategy of testing all drugs for an eff ect similar to riluzole would be better than ours. We did not believe that lithium had a high chance of success because of the small size of the previous clinical trial2 and because two studies did not replicate

Correspondence

www.thelancet.com/neurology Vol 9 October 2010 951

MC has served as a consultant for Acceleron Pharma and on a data safety monitoring board for Trophos. The other authors have no confl icts of interest.

Swati Aggarwal, Lorne Zinman, David Schoenfeld, Jeremy Shefner, Merit Cudkowicz swatihshah@gmail.com

B-2 Adishwar Apartments, Ahmedabad, Gujarat 380063, India (SA); Sunnybrook Health Sciences Centre, Toronto, ON, Canada (LZ); Massachusetts General Hospital, Department of Biostatistics, Charlestown, MA, USA (DS); State University of New York Upstate Medical University, Syracuse, NY, USA (JS); Massachusetts General Hospital, Neurology Clinical Trials Unit, Charlestown, MA, USA (MC)

1 Aggarwal SP, Zinman L, Simpson E, et al, for the Northeast and Canadian Amyotrophic Lateral Sclerosis consortia. Safety and effi cacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010; 9: 481–88.

2 Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2008; 105: 2052–57.

3 Gill A, Kidd J, Vieira F, Thompson K, Perrin S. No benefi t from chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using a standard mouse model of familial ALS. PLoS One 2009; 4: e6489.

4 Pizzasegola C, Caron I, Daleno C, et al. Treatment with lithium carbonate does not improve disease progression in two diff erent strains of SOD1 mutant mice. Amyotroph Lateral Scler 2009; 10: 221–28.

5 Perry PJ, Alexander B, Dunner FJ, Schoenwald RD, Pfohl B, Miller D. Pharmacokinetic protocol for predicting serum lithium levels. J Clin Psychopharmacol 1982; 2: 114–18.

6 Beach ML, Meier P. Choosing covariates in the analysis of clinical trials. Control Clin Trials 1989; 10 (suppl 4): 161–75.

7 Cudkowicz ME, Shefner JM, Schoenfeld DA, et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol 2006; 60: 22–31.

8 Chio A, Mora G, Corbo M, et al. Lithium carbonate in ALS: a treatment failure. 2010 American Academy of Neurology annual meeting; Toronto, USA; April 10–17, 2010. (abstr A200).

9 Miller R, Forshew D, Katz J, et al. Phase II controlled trial of lithium carbonate in patients with amyotrophic lateral sclerosis. 2010 American Academy of Neurology annual meeting; Toronto, USA; April 10–17, 2010. (abstr A200–01).

with lithium concentrations in the target range. However, the DSMB decided against these options because the strength of the evidence was suffi cient to pass the prespecifi ed futility threshold.

Verstraete and colleagues also suggest that we should have corrected for the 3-year diff erence in mean age between patients in the two treatment groups. Small diff erences in baseline characteristics are not unusual in randomised clinical trials, especially when they are terminated prematurely. The age diff erence would probably have been reduced if the full cohort of 250 patients was enrolled. There is no statistical imperative to correct for imbalances in prognostic characteristics in a randomised clinical trial.6 According to data from the celecoxib trial,7 a 3-year diff erence in age would result in a 4% diff erence in the rate of change in ALS functional rating scale revised (ALSFRS), which would not obscure a robust treatment eff ect. Randomisation with minimisation is hard to accomplish especially if one wants to have some degree of institutional balancing. Given that minimisation is diffi cult and has a minor eff ect, it is rarely used.

Our results1 are consistent with those from two other clinical trials,8,9 which also indicate that there is no large positive eff ect of lithium in patients with ALS. Results from these three studies do not support the initiation of further clinical trials of lithium carbonate in patients with this disease. A phase 3 clinical trial to detect a smaller eff ect of lithium would be warranted only if additional, preclinical science supports the testing of lithium carbonate in patients with ALS.

the neuroprotective eff ect of lithium in mouse models of ALS.3,4 However, physicians have a duty to patients with ALS to replicate or refute the results of pilot studies quickly in appropriately designed, randomised, clinical trials.

Futility and sequential designs can be used for phase 2 testing of experimental therapeutics. Our time-to-failure study design provides an alternative design for the testing of unapproved therapeutics. The conversion to active treatment for patients who are assigned to placebo and who reach the failure endpoint provides an incentive to participate in a placebo-controlled trial even when the drug is easily available. As indicated by Verstraete and colleagues, more moderate stopping boundaries can be used depending on which scientifi c question is being addressed. Design choice, sample-size determination, and futility boundaries should be based on the primary objective of the study. One design or sample-size calculation might not be ideal for all potential ALS therapeutics.

We recognise that the target lithium concentrations in our study took several months to achieve; however, we checked serum lithium at only monthly intervals for the fi rst 3 months to avoid inconvenience to patients, and stable lithium concentrations were reached within 1 week of dose adjustment.5 In the pilot study,2 the eff ect of lithium was noticeable after 3 months in the treatment group versus the placebo group. The independent data safety monitoring board (DSMB) considered follow-up of the 84 originally enrolled patients or enrolment of additional patients masked to treatment to increase the percentage of participants