Integrated safety of levodopa-carbidopa intestinal gel from prospective clinical trials

Abstract

Background: Continuous administration of levodopa-carbidopa intestinal gel (carbidopa-levodopa enteral suspension) through a percutaneous endoscopic gastrojejunostomy is a treatment option for advanced Parkinson disease (PD) patients with motor fluctuations resistant to standard oral medications. Safety data from 4 prospective studies were integrated to assess the safety of this therapy.

Methods: Safety data from 4 studies were summarized using 2 overlapping data sets, permitting the separation of procedure/device-associated (n = 395) from non-procedure/device adverse events (n = 412).

Results: At the data cutoff, median exposure to levodopa-carbidopa intestinal gel was 911 days (range, 1-1980 days) with 963 total patient-years of exposure. Procedure/device adverse events occurred in 300 patients (76%), and serious adverse events occurred in 68 (17%); most frequently reported procedure/device adverse events and serious adverse events were complications of device insertion (41% and 8%, respectively) and abdominal pain (36% and 4%, respectively). Non-procedure/device adverse events occurred in 92% (379), with most frequently reported being insomnia (23%) and falls (23%); 42% (171) had non-procedure/device serious adverse events, with most frequently reported being pneumonia (5%) and PD symptoms (2%). Adverse events led to discontinuation in 17% (72), most frequently because of complication of device insertion (2.4%). There were 34 treatment-emergent deaths (8.3%) in the overlapping data sets, 2 of which (0.5%) were considered "possibly related" to the treatment system.

Conclusion: In the largest collection of levodopa-carbidopa intestinal gel safety data from prospective clinical studies, procedure/device events were frequently reported and occasionally life threatening. Most non-procedure/device events were typical for levodopa treatment and an elderly population. These factors combined with high treatment efficacy led to a relatively low discontinuation rate in advanced PD patients.

Keywords: Levodopa-carbidopa intestinal gel; Parkinson's disease; infusion; percutaneous endoscopic gastrojejunostomy; safety.

Figure 1

Flowchart of patient populations in the study data sets. All PEG‐J, data set of patients who had PEG‐J placement; OLAS, open‐label LCIG analysis data set; PEG‐J, percutaneous endoscopic gastrojejunostomy; LCIG, levodopa‐carbidopa intestinal gel; IR‐LC, immediate‐release oral levodopa‐carbidopa; NJ, nasojejunal tube. a. Olanow et al. Lancet Neurol. 2014; 13(2):141‐9.9 b. Slevin et al. J Parkinson's Dis. 2015; 5(1):165‐74.11 c. Fernandez et al. Mov Disord. 2015; 30(4):500‐9.10 d. As of March 31, 2014. e. 71 patients from the double‐blind study and 354 from the open‐label safety study. f. Discontinued for any reason, including AE, lack of efficacy, withdrew consent, administrative, or protocol violation. g. An estimate based on patients who completed a study, did not roll over into an extension study, did not have their PEG‐J removed and lived in a country where LCIG was commercially available. Patients who lived in a country where LCIG was commercially available were not allowed to participate in the continuing of treatment extension. h. 4 converted to commercial LCIG after completing the double‐blind study, and 92 after participating in an open‐label study.

Figure 2

Prevalence of adverse events (AEs) and serious AEs (SAEs) over time. A single event could be coded to ≥1 preferred term. The AE term “Parkinson's disease” refers to the reemergence of Parkinson's symptoms, often because of interruption of drug delivery. All PEG‐J, data set of patients who had PEG‐J placement; OLAS, open‐label LCIG analysis data set; UTI, urinary tract infection.