Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

Abstract

Background: Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial.

Methods: In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25-75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed.

Findings: Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsened by 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean difference of -3·5 points (-6·7 to -0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions.

Interpretation: Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials.

Funding: Michael J Fox Foundation for Parkinson's Research.

Figure 1. Trial profile

Individuals who withdrew before 12 weeks could not contribute data to the primary outcome, and so were replaced per protocol. All 60 patients who completed at least the initial 12-week follow-up were included in the primary analysis.

Figure 2. MDS-UPDRS part 3 scores (A) and changes in MDS-UPDRS part 3 scores (B), by study visit Data are means for the off-medication state. Error bars represent standard error of the mean

MDS-UPDRS=Movement Disorders Society Unified Parkinson’s Disease Rating Scale.

Figure 3. ANCOVA comparing decline in DaTscan binding between the placebo and exenatide groups

(A) Placebo group: reduced DaTscan binding in the left caudate, right caudate, and left putamen. (B) Exenatide group: reduced DaTscan binding in the left caudate and right caudate. (C) Significant clusters derived from the first level of analysis used to do an ANCOVA between placebo and exenatide groups showing a reduced rate of decline in the right caudate, left putamen, and right putamen. (D) Boxplots of mean change in DaTscan binding ratio for the relevant volume of interest. Montreal Neurological Institute of standardised space are shown in each slice; the error bars represent 1·5 times the IQR. ANCOVA=analysis of covariance. DaTscan= [¹²³I]FP-CIT single photon emission CT.