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High-Dose Tamoxifen "Wins" Selection Trial in ALS

Key findings

  • In this randomized, double-blind, double-dummy selection trial, 60 patients with amyotrophic lateral sclerosis (ALS) were randomly assigned to creatine 30 g/day or one of two dosages of tamoxifen (40 or 80 mg/day)
  • Participants taking tamoxifen 80 mg/day experienced the slowest average rate of decline in several efficacy endpoints after adjustment for differences in baseline slow vital capacity, site of onset and diagnostic delay
  • Creatine 30 g/day ranked lowest among the three interventions for almost all efficacy and tolerability endpoints, but no major safety concerns were noted for this dosage
  • Based on these data and in keeping with the purpose of a selection trial, the researchers suggest that tamoxifen 80 mg/day is the best candidate for a traditional placebo-controlled trial

Multiple investigational drugs are in the pipeline for amyotrophic lateral sclerosis (ALS). To speed drug development along, newer phase II study designs are being used to determine which compounds should advance to later-stage trials.

One such design is a selection trial, a randomized trial in which multiple experimental treatments are compared simultaneously. At the end of follow-up, the therapies are ranked according to numerical superiority on the primary outcome, regardless of the statistical or clinical significance of any difference between them. This study design allows for a smaller sample and quicker progression to a definitive trial.

Based on the results of a selection trial, Suma Babu, MBBS, MPH, neurologist and neuromuscular specialist in the Department of NeurologyNazem Atassi, MD, associate director of the Neurological Clinical Research Institute, and Merit E. Cudkowicz, MD, MSc, chief of Neurology and director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, and colleagues have identified high-dose tamoxifen as a suitable candidate for an efficacy trial versus placebo. They published their results in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.

Study Methods

The researchers conducted a randomized, double-blind, double-dummy selection trial at nine centers in the U.S. Eligibility criteria included having an ALS diagnosis no more than 36 months before enrollment and slow vital capacity (SVC) ≥50% predicted. All participants were either not taking riluzole or were on a stable dose.

Between March 2011 and March 2012, 60 patients were randomly assigned to:

  • Creatine 30 g/day (CRE)
  • Tamoxifen 40 mg/day (T40)
  • Tamoxifen 80 mg/day (T80)

Following a 38-week treatment phase, which included three weeks of dose titration, patients were followed for 28 days.


Compared with T80 and T40, CRE was associated with a significantly higher rate of adverse events that were possibly related to study drug (P = 0.02).

In terms of specific adverse events, significant differences among groups were a higher incidence of muscle spasms with CRE and higher incidence of hot flushes and pneumonia with T80. No deaths were related to either study drug.


There was good study retention in all treatment groups (65%–82%). Factors that predicted early drug discontinuation were lower baseline SVC (HR, 0.66 per 10%-predicted increase in SVC; P < 0.001) and randomization to CRE (HR vs. T80, 3.21; P = 0.04).


The primary endpoint was an average decline in score on the ALS Functional Rating Scale–Revised. After adjustment for baseline SVC for the site of onset and diagnostic delay, the T80 group did best (−0.80 points per month vs. −0.84 for T40 and −0.85 for CRE).

Rates of decline in muscle strength, assessed with hand-held dynamometry and the Accurate Test of Limb Isometric Strength, were also slowest for T80. Therefore, T80 was declared the "winner" of the trial.

Platform Trial for ALS

Mass General is working with the Northeast ALS Consortium to develop a platform trial for ALS, another newer type of clinical study. Like a selection trial, a platform trial tests multiple drugs, but all drugs are compared against a common placebo and the efficacy of each is judged separately.

Also, drugs can be added or dropped in perpetuity, and minor design modifications are allowed, providing flexibility such as the ability to test for treatment-specific biomarkers. Thus, a platform trial can be adapted over time to the availability of new treatments and new standards of care.

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