Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis

Suma Babu, Eric A. Macklin, Katherine E. Jackson, Elizabeth Simpson, Katy Mahoney, Hong Yu, Jason Walker, Zachary Simmons, William S. David, Paul E. Barkhaus, Laura Simionescu, Mazen M. Dimachkie, Alan Pestronk, Johnny S. Salameh, Michael D. Weiss, Benjamin Rix Brooks, David Schoenfeld, Jeremy Shefner, Swati Aggarwal, Merit E. CudkowiczNazem Atassi

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (–0.80 vs. –0.84 T40, –0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.

Original languageEnglish (US)
JournalAmyotrophic Lateral Sclerosis and Frontotemporal Degeneration
DOIs
StateAccepted/In press - Jan 1 2019

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Creatine
Amyotrophic Lateral Sclerosis
Tamoxifen
Placebos
Vital Capacity
Muscle Strength
Drug-Related Side Effects and Adverse Reactions
Therapeutics
Sample Size
Analysis of Variance
Mortality
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Babu, Suma ; Macklin, Eric A. ; Jackson, Katherine E. ; Simpson, Elizabeth ; Mahoney, Katy ; Yu, Hong ; Walker, Jason ; Simmons, Zachary ; David, William S. ; Barkhaus, Paul E. ; Simionescu, Laura ; Dimachkie, Mazen M. ; Pestronk, Alan ; Salameh, Johnny S. ; Weiss, Michael D. ; Brooks, Benjamin Rix ; Schoenfeld, David ; Shefner, Jeremy ; Aggarwal, Swati ; Cudkowicz, Merit E. ; Atassi, Nazem. / Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis. In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2019.
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abstract = "Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82{\%} vs. 43{\%} T40, 47{\%} T80) and EDD (50{\%} vs. 24{\%} T40, 29{\%} T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (–0.80 vs. –0.84 T40, –0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.",
author = "Suma Babu and Macklin, {Eric A.} and Jackson, {Katherine E.} and Elizabeth Simpson and Katy Mahoney and Hong Yu and Jason Walker and Zachary Simmons and David, {William S.} and Barkhaus, {Paul E.} and Laura Simionescu and Dimachkie, {Mazen M.} and Alan Pestronk and Salameh, {Johnny S.} and Weiss, {Michael D.} and Brooks, {Benjamin Rix} and David Schoenfeld and Jeremy Shefner and Swati Aggarwal and Cudkowicz, {Merit E.} and Nazem Atassi",
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Babu, S, Macklin, EA, Jackson, KE, Simpson, E, Mahoney, K, Yu, H, Walker, J, Simmons, Z, David, WS, Barkhaus, PE, Simionescu, L, Dimachkie, MM, Pestronk, A, Salameh, JS, Weiss, MD, Brooks, BR, Schoenfeld, D, Shefner, J, Aggarwal, S, Cudkowicz, ME & Atassi, N 2019, 'Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis', Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. https://doi.org/10.1080/21678421.2019.1672750

Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis. / Babu, Suma; Macklin, Eric A.; Jackson, Katherine E.; Simpson, Elizabeth; Mahoney, Katy; Yu, Hong; Walker, Jason; Simmons, Zachary; David, William S.; Barkhaus, Paul E.; Simionescu, Laura; Dimachkie, Mazen M.; Pestronk, Alan; Salameh, Johnny S.; Weiss, Michael D.; Brooks, Benjamin Rix; Schoenfeld, David; Shefner, Jeremy; Aggarwal, Swati; Cudkowicz, Merit E.; Atassi, Nazem.

In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis

AU - Babu, Suma

AU - Macklin, Eric A.

AU - Jackson, Katherine E.

AU - Simpson, Elizabeth

AU - Mahoney, Katy

AU - Yu, Hong

AU - Walker, Jason

AU - Simmons, Zachary

AU - David, William S.

AU - Barkhaus, Paul E.

AU - Simionescu, Laura

AU - Dimachkie, Mazen M.

AU - Pestronk, Alan

AU - Salameh, Johnny S.

AU - Weiss, Michael D.

AU - Brooks, Benjamin Rix

AU - Schoenfeld, David

AU - Shefner, Jeremy

AU - Aggarwal, Swati

AU - Cudkowicz, Merit E.

AU - Atassi, Nazem

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (–0.80 vs. –0.84 T40, –0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.

AB - Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (–0.80 vs. –0.84 T40, –0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.

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