Effects of Levodopa-Carbidopa Intestinal Gel Compared with Optimized Medical Treatment on Nonmotor Symptoms in Advanced Parkinson's Disease: INSIGHTS Study

Background Nonmotor symptoms (NMS) are common in advanced Parkinson's disease (APD) and reduce health-related quality of life. Objective The aim of the study was to evaluate levodopa-carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) on NMS in APD. Methods INSIGHTS was a phase 3b, open-label, randomized, multicenter study in patients with APD (LCIG or OMT, 26 weeks) (NCT02549092). Primary outcomes assessed were total NMS (NMS scale (NMSS) and PD sleep scale (PDSS-2)). Key secondary outcomes included the Unified PD Rating Scale (UPDRS) Part II, Clinical Global Impression of Change (CGI-C), and PD Questionnaire-8 (PDQ-8). Additional secondary measures of Patient Global Impression of Change (PGIC), King's PD Pain Scale (KPPS), and Parkinson Anxiety Scale (PAS) also were evaluated. Finally, safety was assessed. Results Out of 89 patients randomized, 87 were included in the analysis (LCIG, n = 43; OMT, n = 44). There were no significant differences in NMSS or PDSS-2 total score changes (baseline to Week 26) between LCIG and OMT; within-group changes were significant for NMSS (LCIG, p < 0.001; OMT, p = 0.005) and PDSS-2 (LCIG, p < 0.001; OMT, p < 0.001). Between-group treatment differences were nominally significant for UPDRS Part II (p = 0.006) and CGI-C (p < 0.001) at Week 26 in favor of LCIG; however, statistical significance could not be claimed in light of primary efficacy outcomes. PGIC (Week 26) and KPPS (Week 12) scores were nominally significantly reduced with LCIG versus OMT (p < 0.001; p < 0.05). There were no significant differences in PDQ-8 or PAS. Adverse events (AEs) were mostly mild to moderate; common serious AEs were pneumoperitoneum (n = 2) and stoma-site infection (n = 2) (LCIG). Conclusions There were no significant differences between LCIG versus OMT in NMSS or PDSS-2; both LCIG and OMT groups significantly improved from baseline. AEs were consistent with the known safety profile.


Introduction
Parkinson's disease (PD) has traditionally been characterized according to the appearance of cardinal motor symptoms; however, nonmotor symptoms (NMS) included in the original PD description by James Parkinson are increasingly recognized as being critical to identifying and treating patients [1,2]. NMS such as autonomic disorders and sleep disturbances often appear before motor symptoms [3,4] and can be more detrimental to health-related quality of life [5].
Levodopa is the most efcacious symptomatic treatment regimen in patients with PD and remains the gold standard for treatment [6][7][8][9]. However, long-term use of oral levodopa (5 to 10 years) is associated with the development of disabling motor complications, which are often associated with NMS [6,7]. Furthermore, after oral levodopa administration, unsteady plasma dopamine concentrations are evident due to fuctuating levodopa concentrations, stemming from the short half-life of levodopa combined with variable gastric emptying and intestinal absorption [6,[10][11][12].
Levodopa-carbidopa intestinal gel (LCIG) is a carboxymethyl-cellulose aqueous gel enteric suspension that is currently approved for use by the US Food and Drug Administration and the EU countries' Mutual Recognition Procedure for the treatment of patients with PD [7,[13][14][15][16]. LCIG is continuously delivered to the upper intestine, ensuring plasma concentrations of levodopa remain more stable than with oral administration [7,12]. A systematic review found that steady plasma levodopa concentrations reduce motor complications and improve control of NMS [17].
At the time of initiation of the current study, few studies had been conducted on both motor and NMS efects of LCIG in patients with PD. One prior randomized study showed signifcant improvements in motor symptoms and quality of life measures with 12week LCIG vs. oral levodopa-carbidopa in patients with PD (n � 37 and n � 34) [18]. In an open-label, phase 3b, 60-week study, patients with APD treated with LCIG showed signifcant improvement from baseline in NMS scale (NMSS) total scores (n � 35 at 12 weeks and n � 28 at 60 weeks) [19]. In addition, since the study initiation, a series of observational trials have been completed. Tough limited by the open-label, single-arm nature of these studies, they have provided evidence for the reduction of motor complications and improved NMS with LCIG therapy in patients with PD (e.g., GLORIA, DUOGLOBE, MONOTREAT, and COSMOS) [7,12,20,21]. According to these observational studies, 6 to 24 months of LCIG therapy led to improvements in motor fuctuations, including reductions in dyskinesia time and severity, as well as improvements in NMS symptoms, caregiver strain, and other health-related outcomes in patients with advanced PD (APD) [7,12,20,21]. Furthermore, evidence from the retrospective, cross-sectional, postmarketing observational COSMOS study demonstrated that LCIG is a potentially efective long-term monotherapy strategy for the reduction of motor and certain nonmotor symptoms (e.g., anxiety, pain, depression, and constipation) in patients with APD, which may eliminate the need for multiple medications in patients with APD [22].
Tere continues to be a need for randomized trials comparing LCIG to optimized medical treatment (OMT) in patients with APD. Te investigation of NMS in patients with PD is an evolving feld; however, clear and widely accepted guidance on how NMS should be evaluated is not yet available. Developments in tools validated for assessing NMS have allowed clinical trials to incorporate nonmotor measures as outcomes [23]. For example, the NMSS, validated in 2007, was developed to capture a broad range of NMS in PD [24]. Te PD Sleep Scale-2 (PDSS-2), validated in 2011, serves as a bedside screening tool for identifying sleep problems in PD [25,26].
Te INSIGHTS study aimed to examine the efect of LCIG relative to that of OMT on NMS associated with APD as assessed by NMSS and PDSS-2 total scores. Te study also evaluated the impact of LCIG compared with OMT on motor symptoms or complications, health-related outcome measures, safety, and tolerability.  (Figure 1). All procedures were completed in accordance with the ethical standards of the Independent Ethics Committees/Institutional Review Boards of the institution where data were collected. Patients were randomized in a 1 : 1 ratio, stratifed by country, to receive either LCIG or OMT. Patients in the LCIG group must have tapered all anti-PD medications except levodopa formulations (e.g., dopamine agonists, catechol-o-methyl transferase inhibitors, amantadine, monoamine oxidase-B inhibitors, anticholinergics, and subcutaneous apomorphine) within 14 days after randomization so that all medications were stopped before LCIG initiation. All anti-PD medications could be restarted 28 days after LCIG initiation if medically necessary to treat the Parkinsonian symptoms, with the exception of continuous subcutaneous delivery of apomorphine or levodopa-containing formulations.

Materials and Methods
Patients in the LCIG group received the study drug via percutaneous endoscopic gastronomy with a jejunal extension (PEG-J) tube. An optional temporary nasojejunal (NJ) tube could be used initially with the infusion pump to determine if patients responded favorably to intraintestinal drug delivery and optimize LCIG dose before treatment with a permanent PEG-J tube was started. Once tube placement was confrmed by the investigator, initiation and titration of LCIG infusion started on Day 1. Te dose of LCIG was adjusted for an optimal clinical response for each patient over ≤14 days. Te optimal clinical response refers to maximizing the functional "On" time during the day by minimizing the number and duration of "Of" episodes (bradykinesia) and minimizing "On" time with disabling dyskinesia. Once optimized, dose adjustments could be made up to Day 28, as needed, at the discretion of the investigator. After Day 28, the LCIG dose was to remain stable for the duration of the study unless adjustments were needed for safety reasons, as discussed with the clinical trial medical monitor. Te total daily dose was composed of three components: morning dose, continuous maintenance infusion dose (approximately 16 consecutive waking hours each day starting with a morning dose), and extra doses. Patients had visits at Weeks 2, 6, 12, 17, 22, 26, and 27 (follow-up) (Figure 1(a)).
Patients in the OMT group remained on their current optimized treatment regimen and did not receive NJ/PEG-J tube placement. Study visits occurred at the end of Weeks 2, 6, 12, and 26 following randomization (Figure 1(a)). During the treatment phase, changes to OMT, including adjustments to anti-PD and NMS medications, were to be made if medically justifed or if indicated for serious safety reasons.
In calculating sample size, parameters were set as follows: NMSS total score improvement of (mean ± SD) 8.2 ± 24 in OMT and 24.8 ± 24 in LCIG, PDSS-2 total score improvement of (mean ± SD) 4.3 ± 12.2 in OMT and 13.1 ± 12.2 in LCIG. From these criteria, it was determined that 44 patients per group would provide 90% power to declare statistical signifcance on at least one of these two alternative primary endpoints, after multiplicity adjustment using the Hochberg procedure with the further assumption of a 10% dropout rate.

Participants.
Patients with APD (aged ≥30 years) were included. Inclusion criteria included the following: diagnosis of advanced levodopa-responsive PD with persistent motor fuctuations despite optimized therapy and no further improvement expected by the investigator regardless of any additional manipulations of levodopa and/or other antiparkinsonian medication; minimum PDSS-2 total score of 18 at baseline; able to complete the dosing diary; and able to provide informed consent as approved by the Independent Ethics Committees/Institutional Review Board or have informed consent signed by a legal representative. Patients were excluded for the following reasons: PD diagnosis was unclear; suspicion that the patient had parkinsonian syndrome; previous surgery for PD; current or history of signifcant sleep attacks, impulsive behavior, psychosis, or delusions within three months before screening; had any neurological defcit that might interfere with study assessments, and had vitamin defciencies (e.g., low B-12 level or low/normal B-12 level (<300 pg/mL) with elevated methylmalonic acid). In addition, neurologic examinations provided continuous monitoring for the onset or worsening of potential peripheral neuropathy throughout the study due to the high prevalence in patients with PD [27]. Tough patients were monitored for peripheral neuropathy, they were not excluded from the study due to the beneft: risk relationship and monitoring/treatment techniques at the time of the study.

Assessments
2.3.1. Efcacy. Efcacy variables were measured in Weeks 6, 12, and 26. Baseline values for efcacy variables were evaluated at randomization prior to anti-PD medication tapering and LCIG initiation. Te two alternative primary endpoints were the change from baseline to Week 26 in NMSS total score and PDSS-2 total score. Te key secondary endpoints were related to motor and health-related outcomes and included the following: change from baseline to Week

Patients.
Te study was conducted at 32 sites in nine countries. Out of 144 patients screened, 89 were randomized and 87 were included in the analysis (LCIG, n � 43; OMT, n � 44) (Figure 1(b)). Two patients randomized to LCIG did not have devices placed; thus, they did not receive study treatment and were not included in the analysis. Patients were mostly male (LCIG, 67.4% and OMT, 54.5%), with a mean (standard deviation (SD)) age of 66.9 (7.3) years for the LCIG group and 68.6 (6.2) years for the OMT group (Table 1). Te mean (SD) years of PD duration since diagnosis was 11.7 (4.9) for the LCIG group and 11.9 (6.0) for the OMT group (   Figure 3); again, statistical signifcance could not be claimed in light of primary efcacy outcomes.
Further secondary endpoints included additional UPDRS scores, PGIC, KPPS, and PAS scores. Between-       Figure 2A). PAS showed no signifcant diferences in changes from baseline between LCIG and OMT groups at any time point throughout the study (Supplemental Figure 2B).
Overall, seven patients (16.3%) in the LCIG group and eight patients (18.2%) in the OMT group reported one or more sleep attacks during the 26-week treatment period (Supplemental Table 1). Tere were no positive screens reported for any MIDI module during the 26-week treatment in the LCIG group, and four patients (9.1%) in the OMT group had a positive screen during the 26-week treatment (Supplemental Table 2). According to afrmative responses for the C-SSRS, the number of patients with suicidal behaviors or ideations was similar between the LCIG and OMT groups during the 26-week treatment (Supplemental Table 3).

Discussion
Within-group diferences demonstrated signifcant improvements in NMSS and PDSS-2 with LCIG and OMT; however, a signifcant change from baseline to Week 26 with LCIG vs. OMT was not met with either alternative primary  Results on the improvement of NMS and motor symptoms from baseline with LCIG from INSIGHTS are in line with fndings of other studies (e.g., GLORIA [7], DUOGLOBE [20], and MONOTREAT [12]) in which six to 24 months of treatment with LCIG improved motor complications and NMS in patients with PD, as demonstrated by signifcant changes from baseline in NMSS, PDQ-8, and UPDRS Part II [7,12,20]. Te randomized design and wide range of endpoints used in INSIGHTS lend further validity to these fndings obtained from studies with observational designs.
Tere are several limitations of the current study, which may have impacted its outcome. One of the study's main limitations is the nonsystematic capture of add-on medications, both dopaminergic and nondopaminergic, which limits the interpretation of their infuence on current fndings. Te study was initially set up to allow anti-PD medications (except for subcutaneous apomorphine or levodopa-containing formulations) to be restarted after Day 28; thus, the focus on capturing data on add-on medications was on anti-PD medications and not the capture of all medications. In addition, the patient population included in the study was somewhat heterogeneous based on the wide range of NMSS scores. Tough PDSS-2 was part of the inclusion criteria for INSIGHTS, patient selection for future studies would beneft from the enrollment of patients enriched for selected NMS who are likely to improve with levodopa optimization. Other limitations may stem from the impact of frequent monitoring and the placebo efect associated with the potential benefts and expectations of clinical trial participation in the OMT group. Additionally, OMT may not have been the most optimal comparator because of the current lack of evidence for NMS benefts with OMT. Furthermore, the study ultimately was not powered as planned since treatment diferences were lower and the observed variance in NMSS scores was higher than those assumed to estimate sample size requirements. Te open-label design and potential interrater variability in the application of study scales are variables that may have impacted study results. Terefore, the efect on outcomes of other medications on NMS could not be assessed. Future randomized trials are needed that focus on patients enriched for NMS that is clearly defned by dopaminergic or nondopaminergic responses; incorporate the use of updated, fully validated tools for the measurement of NMS (e.g., updated questionnaire); and evaluate the impact of the change in medications and doses throughout treatment. Furthermore, LCIG was delivered only during the waking day, thus greater sleep efects may have been reported if administered during nighttime. As an inherent aspect of the treatment, the LCIG group had the NJ or PEG-J placement, a procedure requiring surgery, which may have introduced AEs or side efects that may have impacted sleep and quality of life or PD-related symptoms or introduced bias due to the unblinded design. A follow-up duration of over 26 weeks with a blinded design in terms of NJ or PEG-J placement may be benefcial in future studies in determining diferences between LCIG and OMT groups.

Conclusions
Te INSIGHTS study demonstrated comparable improvement of NMS with LCIG therapy versus OMT in patients with APD over the course of 26 weeks. LCIG is a potential alternative treatment strategy to OMT for the control of long-term NMS and motor symptoms in patients with APD and may also ofer benefts to health-related quality of life. Tough NMS was included in the original description of PD by James Parkinson [1,2], the study of NMS in patients with PD is not yet well-established. Further support for NMS assessment approaches is needed to guide future investigations. Additional studies with longer follow-up periods are required to understand the diferences in NMS control with LCIG versus oral levodopa in both an APD patient population enriched for NMS and in an APD heterogeneous population.

Data Availability
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. Tis includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. Tis includes requests for clinical trial data for unlicensed products and indications. Tis clinical trial data can be requested by any qualifed researchers who engage in rigorous, independent scientifc research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinicaltrials/clinical-trials-data-and-information-sharing/data-andinformation-sharing-with-qualifed-researchers.html.

Conflicts of Interest
MC was a study investigator and has received honoraria or consultation fees for lecturing or advisory boards from AbbVie, Zambon, and Bial; she has received research

Supplementary Materials
Supplemental Table 1: Sleep attacks reported at baseline and during the 26-week treatment period in the safety population. Supplemental Table 2: Positive screens reported for each MIDI module at baseline and during the 26-week treatment period in the safety population. Supplemental Table 3: Afrmative responses reported for C-SSRS at baseline and during the 26-week treatment period in the safety population. Supplemental Table 4: Change from baseline to Weeks 12 and 26 in clinical laboratory evaluations and vital signs in the safety population. Supplemental