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A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease with motor neuron degeneration. Riluzole is the only available treatment. Two-thirds of ALS patients present with growth hormone (GH) deficiency. The aim of this study is to determine if add-on of GH to riluzole, with an individually regulated dose based on Insulin-like growth factor 1 (IGF-I) production, was able to reduce neuronal loss in the motor cortex, reduce mortality, and improve motor function of ALS patients. Patients with definite/probable ALS, in treatment with riluzole, aged 40–85 years, and with disease duration ≤3 years were enrolled. The study was randomized, placebo controlled, and double blind. Before treatment, patients were tested with a GH releasing hormone (GHRH) + arginine test. The initial dose of GH was 2 IU s.c. every other day, and was progressively increased to a maximum of 8 IU. Primary endpoint was N-acetylaspartate/(creatine + choline) (NAA/Cre + Cho) ratio in motor cortex assessed by magnetic resonance spectroscopy performed at months 0, 6, and 12. Secondary endpoints were mortality and ALS functional rating scale revised (ALSFRS-R). The NAA/(Cre + Cho) ratio decreased in all patients who completed the trial. No significant difference was noted between treated and placebo group. At baseline, although IGF-I levels were within the normal range, 73% of patients had GH deficiency, being severe in half of them. Compared with bulbar onset, spinal-onset patients showed more depressed GH response to the GHRH + arginine stimulation test (10.4 ± 7.0 versus 15.5 ± 8.1 ng/mL; p < 0.05). Insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] increased from 2.1 ± 1.0 at baseline to 4.6 ± 1.9 at 12 months (p < 0.001). Insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) decreased from 8,435 ± 4,477 ng/mL at baseline to 3,250 ± 1,780 ng/mL at 12 months (p < 0.001). The results show that GH exerted no effect on cerebral NAA or clinical progression assessed by ALSFRS-R. Two-thirds of ALS patients had GH deficit, with higher levels in the bulbar-onset group. During follow-up, patients showed progressive increase in HOMA-IR and decrease in IGFBP-3 levels.

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Acknowledgments

This study was supported by grants from Agenzia Italiana del Farmaco (no. FARM53XBKT), Ministero della Salute (progetto ordinario RF-SDN-2007-666932). We thank Merck Serono S.p.A. (Roma, Italy) for donating the study drug and blind packaging.

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Authors and Affiliations

  1. Department of Neurological Sciences, University Federico II, Via Pansini, 5, 80131, Naples, NA, Italy

    Francesco Saccà, Carlo Rinaldi, Tecla Tucci, Raffaele Piro, Gaetano Perrotta, Giuseppe De Michele, Vincenzo Brescia Morra & Alessandro Filla

  2. Biostructure and Bioimaging Institute, National Research Council, Naples, Italy

    Mario Quarantelli, Barbara Carotenuto, Angela Marsili, Arturo Brunetti & Marco Salvatore

  3. U.O.C. Neurofisiopatologia, PO S. Gennaro ASL Napoli 1, Naples, Italy

    Vincenzo Palma

Authors
  1. Francesco Saccà
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  2. Mario Quarantelli
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  3. Carlo Rinaldi
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  4. Tecla Tucci
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  7. Barbara Carotenuto
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  10. Giuseppe De Michele
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  11. Arturo Brunetti
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  12. Vincenzo Brescia Morra
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  13. Alessandro Filla
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  14. Marco Salvatore
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Correspondence to Francesco Saccà.

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Saccà, F., Quarantelli, M., Rinaldi, C. et al. A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results. J Neurol 259, 132–138 (2012). https://doi.org/10.1007/s00415-011-6146-2

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  • DOI: https://doi.org/10.1007/s00415-011-6146-2

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