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Abstract
Objective: The purpose of this study was to evaluate the safety and efficacy of hydroxyurea (HU) in spinal muscular atrophy (SMA) in a randomized, double-blind, placebo-controlled trial.
Methods: Twenty-eight patients with type 2 SMA and 29 patients with type 3 SMA were randomly assigned (2:1) to receive HU or matching placebo for 18 months. HU was initiated at 10 mg/kg/day with an 8-week titration to 20 mg/kg/day. Subjects were assessed at baseline (T0) and monthly for the first 2 months (T1–T2) and then every 2 months throughout treatment (T3–T10) and posttreatment periods (T11–T13). The primary outcome measures were the Gross Motor Function Measure (GMFM), Manual Muscle Test (MMT), and serum full-length survivor motor neuron (flSMN) mRNA. The secondary outcome measures were Modified Hammersmith Functional Motor Scale and forced vital capacity (FVC).
Results: Fifty-five patients completed this trial, which lasted from March 2007 to June 2009. Except for neutropenia, we found no differences in adverse events between the 2 groups. Compared with the placebo group, the HU group had −1.88 for GMFM (p = 0.11), −0.55 for MMT (p = 0.49), and 2.17 for flSMN mRNA (p = 0.13). Similarly, we found no difference in mean improvement of the secondary endpoints. Both groups had a trend toward a decline in FVC with little change in strength and motor function.
Conclusion: Under the current regimen and schedule, HU brought about no improvement in patients with type 2 and 3 SMA, and its main side effect was neutropenia.
Classification of evidence: This trial provides Class I evidence that HU 20 mg/kg/day does not effectively treat SMA.
Footnotes
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↵* These authors contributed equally to this work.
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Study funding: Supported by Department of Health, Executive Yuan, Taiwan (DOH96-TD-I-111-TM013) and in part by Sun's KMU-SMA fund.
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Supplemental data at www.neurology.org
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- AE
- adverse event
- ANCOVA
- analysis of covariance
- ΔCT
- relative cycle threshold
- flSMN
- full-length survival motor neuron
- FVC
- forced vital capacity
- GMFM
- Gross Motor Function Measure
- HU
- hydroxyurea
- ITT
- intent-to-treat
- LOCF
- last observation carried forward
- MHFMS
- Modified Hammersmith Functional Motor Scale
- MMT
- Manual Muscle Test
- SAE
- severe adverse event
- SCD
- sickle cell disease
- SMA
- spinal muscular atrophy
- SMN
- survival motor neuron.
- Received April 1, 2010.
- Accepted September 7, 2010.
- Copyright © 2010 by AAN Enterprises, Inc.
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