Context: Nerve growth factor is a neurotrophic factor that promotes the survival of small fiber sensory neurons and sympathetic neurons in the peripheral nervous system. Recombinant human nerve growth factor (rhNGF) has demonstrated efficacy as treatment for peripheral neuropathy in experimental models and phase 2 clinical trials. Objective: To evaluate the efficacy and safety of a 12-month regimen of rhNGF in patients with diabetic polyneuropathy. Design: Randomized, double-blind, placebo-controlled phase 3 trial conducted from July 1997 through May 1999. Setting: Eighty-four outpatient centers throughout the United States. Patients A total of 1019 men and women aged 18 to 74 years with either type 1 or type 2 diabetes and a sensory polyneuropathy attributable to diabetes. Interventions: Patients were randomly assigned to receive either rhNGF, 0.1 μg/kg (n = 504), or placebo (n = 515) by subcutaneous injection 3 times per week for 48 weeks. Patients were assessed at baseline, 12 weeks, 24 weeks, and 48 weeks. Main Outcome Measures: The primary outcome measure was a change in neuropathy between baseline and week 48, demonstrated by the Neuropathy Impairment Score for the Lower Limbs, compared between the 2 groups. Secondary outcome measures included quantitative sensory tests using the CASE IV System, the Neuropathy Symptom and Change questionnaire, the Patient Benefit Questonnaire (PBQ), and a global symptom assessment, as well as nerve conduction studies and occurrence of new plantar foot ulcers. Patients also were evaluated for presence of adverse events. Results: Among patients who received rhNGF, 418 (83%) completed the regimen compared with 461 (90%) who received placebo. Administration of rhNGF was safe, with few adverse events attributed to treatment apart from injection site pain/hyperalgesia and other pain syndromes. However, neither the primary end point (P=.25) nor most of the secondary end points demonstrated a significant benefit of rhNGF. Exceptions were the global symptom assessment (P=.03) and 2 of 32 comparisons within the PBQ, which showed a modest but significant benefit of rhNGF (P=.05 for severity of pain in the legs and P=.003 for 6-month symptoms in the feet and legs). Conclusion: Unlike previous phase 2 trials, this phase 3 clinical trial failed to demonstrate a significant beneficial effect of rhNGF on diabetic polyneuropathy.
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