A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis

No satisfactory treatment is available for ALS. Insulin-like growth factor I (IGF-I), a pleiotropic polypeptide (molecular weight, 7.6 kd), has been shown to exert a trophic effect on motor neurons in vitro and in vivo.¹ Phase 1 clinical studies with recombinant human IGF-I (rhIGF-I) shows good tolerability for subcutaneous administration.² The goal of this study was to determine whether rhIGF-I could slow the progression of ALS as measured by the Appel ALS rating scale (AALS).

Methods. Patients who were 20 years of age or older with a clinical diagnosis of probable or definite sporadic ALS (according to the El Escorial criteria of the World Federation of Neurology) were eligible for screening at eight European centers (see *appendix*). Inclusion/exclusion criteria, screening period, and randomization criteria were identical to those of the recently published North American trial.³

The primary efficacy measure was the AALS total score.⁴ The AALS includes assessments of bulbar and respiratory function, upper and lower extremity function, and muscle strength. The total score ranges from 30 points (normal subject) to 164 points (maximal dysfunction). A secondary endpoint was the Sickness Impact Profile (SIP), a health-related quality of life measure.⁵ All patients were evaluate as baseline and monthly for up to 9 months for the AALS score. The SIP was assessed by independent interviewers at baseline and then every 3 months.

Patients were randomized in groups of six, stratified by center. Within each group, four patients received rhIGF-I (0.05 mg/kg) and two patients received placebo (indistinguishable vehicle in identical vials) on a double-blind basis as twice daily subcutaneous injections. This regimen achieved blood level similar to those effective in the animal models.⁶ The monthly average serum trough level (mean± SEM) of IGF-I was 580 ± 220 ng/mL in the active treatment group and 170 ± 70 ng/mL in the placebo treatment group.

If patients reached an AALS total score of >115, or a forced vital capacity (FVC) of <39% of the predicted value, they were withdrawn from the double-blind study and were offered open-label medication. Patients who completed the 9-month double-blind phase were also eligible for open-label medication. RhIGF-I (Myotrophin [mecasermin (recombinant DNA origin)] Injection) and placebo were supplied by Cephalon, Inc. (West Chester, PA).

The primary efficacy variable was the change in AALS total score from baseline to study endpoint (i.e., to the last available observed value) for each individual patient. Analyses of this variable included all patients receiving treatment with at least one postbaseline AALS assessment(n = 176). For patients who died or were discontinued before 9 months, their last available AALS total score was carried forward for all months subsequent to study termination, regardless of the reason (last observation carried forward [LOCF] method). An ANOVA model, adjusting for investigator and disease severity at baseline (low severity 40-60 AALS points, high severity >60 AALS points) was used. Treatment-by-investigator interaction was examined at a significance level of 0.1. The SIP was evaluated as change from baseline including all patients with at least one post-baseline assessment (n = 147). Data were expressed as mean± SEM, p values are two-tailed.

Results. Of 183 patients randomized (17 to 37/center), four were found in retrospect not to fulfill inclusion criteria at baseline (one patient with an FVC of 49.3%, three patients with insufficient progression during screening); these patients were included in the statistical analysis. Seven patients (six in the rhIGF-I group and one in the placebo group) were excluded from the analysis of the AALS change score because they did not have at least one postbaseline evaluation. For the most part, the treatment group characteristics at baseline were well balanced. (Details of the study demographic can be obtained from the National Auxiliary Publication Service [NAPS]; see note at end of article.) However, a retrospective survival analysis showed that a disproportionate number of patients at a higher death risk were randomized to the rhIGF-I group (see below). The AALS total score at baseline was 68.6 ± 1.8 for the placebo group, and 68.9± 1.3 for the rhIGF-I group. The patient enrollment and completion status is shown in the table.

The mean change in AALS total score from baseline of the patients treated with rhIGF-I was 21.9 ± 1.5 versus 25.2 ± 2.3 for the placebo group (Δ = -3.3 points; 95%CI -8.7, 2.0; p = 0.22)(figure). No significant difference between treatment groups was found in the SIP scores (change from baseline: rhIGF-I, 9.4± 1.1; placebo, 10.5 ± 1.6; p = 0.59). The most frequent clinical adverse experiences were weakness, injection site pain, dyspnea, sweating, dysarthria, headache, and dysphagia. The incidence of adverse experiences was not significantly different between treatment groups.

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Figure. Change from baseline of the Appel ALS rating scale (AALS) total score by month (mean ± SEM, last observation carried forward for all discontinued patients regardless of the reason for termination).

During the double-blind phase, 15% of the patients in the rhIGF-I group died, compared with 8% in the placebo group (p = 0.34, Fisher's exact test). All but two deaths were caused by respiratory failure. One patient committed suicide, and one patient with a history of colonic tumor resection and recurring ileus died of paralytic ileus. Both were in the rhIGF-I group. A detailed review of all deaths revealed no suspicion of hypoglycemia or cardiovascular events as the cause of death. A post hoc risk factor analysis showed a higher incidence of deaths in patients with FVC<80% or age ≥55 years at baseline. Both variables are known to correlate strongly with survival in ALS.⁷ The proportion of patients from the highest risk cohort (age ≥ 55 and FVC < 80%) randomized to the rhIGF-I group, compared with placebo, was almost 3:1, instead of the expected 2:1 ratio. Kaplan-Meier survival curves, when corrected for this imbalance, showed no difference between treatment groups.(Additional safety data and details of the risk factor analysis can be obtained from NAPS.)

Discussion. Although high expectations have been placed on the application of neurotrophic factors in neurodegenerative diseases, ciliary neurotrophic factor (CNTF)^8,9 and brain-derived neurotrophic factor (BDNF) have failed to show a clinical benefit in ALS (W. Bradley, personal communication, 1997). However, a study of rhIGF-I in 266 patients with ALS, recently completed in North America, reported a statistically significant slowing of disease progression by 26% over 9 months, based on AALS score slopes.³

The difference in progression observed in our study is not statistically significant, and probably not clinically meaningful. The 2:1 randomization scheme resulted in a small placebo group (59 patients), which reduced the statistical power of our study. Thus, a difference similar to that observed in the North American study may have escaped detection. It should be noted that the primary efficacy variables were slightly different in the two trials, and that the LOCF analysis used in the European study has limitations. The failure to reproduce the North American result is not caused by differences in pharmacokinetics because serum trough concentrations of rhIGF-I were similar in both studies.

As reported in clinical trials in several diseases,¹⁰ we found rhIGF-I to be well tolerated. The higher mortality rate observed in the rhIGF-I group was not statistically significant, and was not observed in the North American study. A risk factor analysis showed a randomization imbalance with patients having poorer prognostic factors (age and FVC) assigned to the rhIGF-I group. After appropriate correction for this imbalance is made, the difference in survival is no longer present.

Thus, the European study does not show a beneficial effect of rhIGF-I on the progression of ALS. Analysis of the pooled data from the North American and European trials is in progress. Such information may be helpful in designing future prospective studies of rhIGF-I in ALS.

Acknowledgment

The authors thank all the patients and their families for their participation in this study.

Appendix