Treatment with the growth factor, recombinant human insulin-like growth factor I, for amyotrophic lateral sclerosis (motor neuron disease)

Recombinant human insulin-like growth factor (rhIGF-I) is a genetically engineered human protein. Theoretically, it is expected to enhance the survival of motor neurons which degenerate in amyotrophic lateral sclerosis (ALS, also known as motor neuron disease (MND)). It is given by daily subcutaneous injection (injection under the skin). Three randomised controlled trials (RCTs) involving 779 participants measured disease progression on special clinical rating scales of disease severity in ALS. The review authors collected data about adverse events from the included trials. The combined results from the two included studies that used the rating scale (AALSRS) showed a small significant benefit in favour of rhIGF-I. Significant flaws in the trial designs make the statistically significant benefits in some outcomes of questionable relevance. There was an increased risk of injection site reactions with rhIGF-I. A third study using a different outcome measure showed no difference between treatment and placebo. Taken together, the available RCTs do not provide information supporting the hypothesis that rhIGF-I is an effective disease modifying treatment for ALS. All three included studies showed a high risk of bias. These issues very seriously detracted from the ability of this review to fulfil its objectives.

Authors' conclusions: 

Meta-analysis revealed a significant difference in favour of rhIGF-I treatment; however, the quality of the evidence from the two included trials was low. A third study showed no difference between treatment and placebo. There is no evidence for increase in survival with IGF1. All three included trials were at high risk of bias.

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Background: 

Recombinant human insulin-like growth factor I (rhIGF-I) is a possible disease modifying therapy for amyotrophic lateral sclerosis (ALS, which is also known as motor neuron disease (MND)).

Objectives: 

To examine the efficacy of rhIGF-I in affecting disease progression, impact on measures of functional health status, prolonging survival and delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival in ALS. Occurrence of adverse events was also reviewed.

Search strategy: 

We searched the Cochrane Neuromuscular Disease Group Specialized Register (21 November 2011), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to November 2011) and EMBASE (January 1980 to November 2011) and sought information from the authors of randomised clinical trials and manufacturers of rhIGF-I.

Selection criteria: 

We considered all randomised controlled clinical trials involving rhIGF-I treatment of adults with definite or probable ALS according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months of treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events.

Data collection and analysis: 

Each author independently graded the risk of bias in the included studies. The lead author extracted data and the other authors checked them. We generated some missing data by making ruler measurements of data in published graphs. We collected data about adverse events from the included trials.

Main results: 

We identified three randomised controlled trials (RCTs) of rhIGF-I, involving 779 participants, for inclusion in the analysis. In a European trial (183 participants) the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08). In a North American trial (266 participants), the MD after nine months was -6.00 (95% CI -10.99 to -1.01). The combined analysis from both RCTs showed a MD after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. There was an increased risk of injection site reactions with rhIGF-I (risk ratio 1.26, 95% CI 1.04 to 1.54). . A second North American trial (330 participants) used a novel primary end point involving manual muscle strength testing. No differences were demonstrated between the treated and placebo groups in this study. All three trials were at high risk of bias.

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