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

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.

Amyotrophic lateral sclerosis and environmental factors

“…GH was not found to be dangerous for motor neuron survival; rather, it showed a trophic effect on the nervous system. Moreover, GH deficiency in ALS patients has been reported in the literature (Saccà et al, 2012;Pellecchia et al, 2010). A deficiency in GH secretion similar to that seen in human ALS has been reported in hSOD1 (G39A) transgenic mice; moreover, a reduction in the expres-sion of the IGF-1 receptor α-subunit in skeletal muscle and lumbar spinal cords suggested impaired signaling within these tissues (Steyn et al, 2012).…”

“…A deficiency in GH secretion similar to that seen in human ALS has been reported in hSOD1 (G39A) transgenic mice; moreover, a reduction in the expres-sion of the IGF-1 receptor α-subunit in skeletal muscle and lumbar spinal cords suggested impaired signaling within these tissues (Steyn et al, 2012). However, a recent clinical trial failed to detect clinical and survival improvement in ALS patients administered GH (Saccà et al, 2012). Branched-chain amino acids (leucine, isolucine and valine) are widely used among athletes to stimulate muscle protein synthesis, improve physical resistance and reduce delayed onset muscular soreness.…”

Review of Phase II and Phase III clinical trials for Duchenne muscular dystrophy

“…There have been several treatment trials using free IGF-1 therapy in amyotrophic lateral sclerosis (ALS) [68][69][70] and one trial of free IGF-1 complexed with IGF-1 binding protein-3 in myotonic dystrophy [71]. ALS trials failed to show a clear beneficial result but demonstrated safety of IGF-1 in these patients.…”

“…The trial in myotonic dystrophy showed encouraging results in seven of the nine patients treated. Two patients discontinued treatment because of cardiovascular complications [68][69][70][71][72]. More recently, treatment trials in children with primary growth hormone deficiency, elderly women following hip replacement surgery and patients with complications of HIV infection, have trialed IGF-1 complexed with IGF-1 binding protein-3, and each group of patients have tolerated this preparation without significant side effects [74][75][76].…”

Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials

“…GH has evaluated in a phase II trial (NCT00635960) with no effects on disease progression (Sacca et al, 2011).…”