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Clinical Review Report: Levodopa/Carbidopa (Duodopa): (Abbvie Corporation): Indication: For the treatment of patients with advanced levodopa-responsive Parkinson’s disease who do not have satisfactory control of severe, debilitating motor fluctuations and hyper-/dyskinesia despite optimized treatment with available combinations of Parkinson’s medicinal products, and, for whom the benefits of this treatment may outweigh the risks associated with the insertion and long-term use of the percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) tube required for administration [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Sep.

Cover of Clinical Review Report: Levodopa/Carbidopa (Duodopa)

Clinical Review Report: Levodopa/Carbidopa (Duodopa): (Abbvie Corporation): Indication: For the treatment of patients with advanced levodopa-responsive Parkinson’s disease who do not have satisfactory control of severe, debilitating motor fluctuations and hyper-/dyskinesia despite optimized treatment with available combinations of Parkinson’s medicinal products, and, for whom the benefits of this treatment may outweigh the risks associated with the insertion and long-term use of the percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) tube required for administration [Internet].

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Results

Findings from the Literature

A total of 20 studies were identified from the literature for inclusion in the systematic review (Figure 1). The studies deemed pivotal by the manufacturer are summarized in Table 5. A list of excluded studies is presented in Appendix 3.

Figure 1. Flow Diagram for Inclusion and Exclusion of Studies.

Figure 1

Flow Diagram for Inclusion and Exclusion of Studies.

Table 5. Details of Included Studies.

Table 5

Details of Included Studies.

Included Studies

Description of Studies

Double-Blind, Randomized Controlled Trial (Study 001/002)

Studies S187-3-001 and S187-3-002 (N = 36 and N = 35, respectively) were similarly designed DB, double-dummy, multi-centre, multinational, active-controlled, phase III superiority RCTs that recruited patients from centres located in the US, Germany, and New Zealand. Subsequent to discussion with the FDA, the two trials were combined while they were ongoing (due to difficulty with recruitment) — before database lock and any data analyses — to provide one robust RCT, hereafter referred to as Study 001/002 (N = 71).53

The study objective was to evaluate the efficacy and safety of LCIG for the treatment of patients with advanced levodopa-responsive PD who did not have satisfactory control of severe, debilitating motor fluctuations and hyper-/dyskinesia despite optimized treatment with available combinations of PD medicinal products, and for whom the benefits of this treatment may outweigh the risks associated with the insertion and long-term use of the PEG-J tube required for administration. Further details pertaining to the included study are provided in Table 5.

Study 001/002 consisted of three different phases: a screening phase, a hospitalization phase, and a DB phase. During the screening phase, patients were switched and/or optimally titrated with open-label immediate-release (IR) OLC 100 mg/25 mg. They were also required to achieve a stable dose for other concomitant antiparkinsonian medication, and receive Parkinson disease home diary (PDHD) training. Sustained-released levodopa/carbidopa formulations, levodopa combined with peripheral decarboxylase inhibitors other than carbidopa (e.g., levodopa/benserazide), and apomorphine were to be discontinued. During the hospitalization phase, patients were admitted for up to 10 days as needed for the PEG-J placement. Patients were subsequently randomized (1:1 ratio LCIG: IR OLC and stratified by site) to the DB phase, which consisted of a four-week titration period and an eight-week maintenance period. Details outlining the study design are provided in Figure 2.

Figure 2. Study 001/002 Design.

Figure 2

Study 001/002 Design. CSR = Clinical Study Report; LC = levodopa/carbidopa; LCIG = levodopa/carbidopa intestinal gel; PD = Parkinson disease. Source: Study 001/002 CSR.

Clinic visits were to occur weekly for the first four weeks, then every two weeks through the end of the study. Following the titration period in the DB phase (beyond study week 4), in the weeks when no clinic visit was scheduled, the study site was to contact the patient by telephone. Patients were able to withdraw from participation in this study at any time and for any reason.

Patients who completed Study 001/002 had the option to enrol in an optional 12-month, open-label safety extension study (Study 003). Patients who completed Study 003 were able to enrol in Study 005 for up to five years of follow-up, (Study 003 and Study 005 are summarized in Appendix 6.)

Open-Label, Non-Comparative Study (Study 004)

The study design characteristics of the non-comparative multinational, multi-centre, open-label, long-term safety study (Study 004, N = 354) are summarized in Table 5. Patients included in this study were not previously treated with LCIG in Study 001/002. Rescue therapy during the trial was permitted only if clinically indicated. The use of other PD medications was permitted at the investigators’ discretion only 28 days post-LCIG initiation. Treatments with either apomorphine or controlled-release OLC formulations were not permitted. Patients who completed Study 004 were able to enrol in Study 005 for up to five years of follow-up (Study 005 is summarized in Appendix 6).

Additional Non-Comparative, Open-Label Studies

A total of 16 prospective, open-label, non-comparative trials were identified in the CDR systematic review.10–25 The sample size of these trials ranged between nine and 375 enrolled patients and follow-ups ranged between four and 36 months. Treatment with LCIG was administered to all patients. Change from baseline to the last study visits was evaluated for relevant outcomes. Given that Study 004 (also an open-label, non-comparative study) was deemed pivotal by the manufacturer, no further details will be provided in this CDR report for the 16 prospective, open-label, non-comparative trials identified in the systematic review.

Populations

Inclusion and Exclusion Criteria

Double-Blind, Randomized Controlled Trial (Study 001/002)

Investigators were to obtain approval from the Enrolment Steering Committee, which comprised three independent neurologists and movement disorder specialists, prior to enrolling a patient in the study.

Study 001/002 enrolled adults (aged ≥ 30 years) with advanced PD consistent with UK Brain Bank criteria that was complicated by “off” periods that could not be controlled satisfactorily with optimized medical therapy and who were eligible for jejunal placement of a percutaneous gastrojejunostomy tube. Optimized therapy was defined as an adequate trial (in the investigator’s judgment) of levodopa/carbidopa, a dopamine agonist, and at least one other class of antiparkinsonian therapy (i.e., a COMT or MAO-B inhibitor). Patients treated with sustained-release levodopa/carbidopa, Stalevo, or other formulations of levodopa were permitted in the study; however, they were switched to equivalent doses of IR OLC 100 mg/25 mg. Patients were to have remained on stable doses for at least four weeks before inclusion. Concurrent antiparkinsonian drugs (apart from apomorphine) were permitted if patients were on stable doses for four weeks before randomization, and if the dose was not changed during the study.

Atypical or secondary parkinsonism, previous neurosurgical treatment for PD, clinically significant medical, psychiatric, or laboratory abnormalities in the judgment of the investigator, or any condition that might interfere with absorption, distribution, metabolism, or excretion of study drug or contraindicate placement of a PEG-J tube were all considered criteria for exclusion.

Open-Label, Non-Comparative Study (Study 004)

Patients ≥ 30 years of age who were levodopa-responsive meeting the UK Parkinson’s Disease Society Brain Bank diagnostic criteria and who had severe motor fluctuations, defined as ≥ 3 hours of daily “off” time at baseline (confirmed through PD diary) despite currently available optimized PD therapies, were included in Study 004.

Baseline Characteristics

Double-Blind, Randomized Controlled Trial (Study 001/002)

Details of patients’ baseline characteristics are presented in Table 6, Table 7, and Table 8. Generally, the distributions of baseline patient characteristics were well balanced across treatment groups.

Table 6. Summary of Baseline Demographic Characteristics.

Table 6

Summary of Baseline Demographic Characteristics.

Table 7. Summary of Baseline Parkinson Disease Characteristics.

Table 7

Summary of Baseline Parkinson Disease Characteristics.

Table 8. Summary of PD Medications at Baseline.

Table 8

Summary of PD Medications at Baseline.

Patients enrolled in Study 001/002 had a mean age of 64.4 years (standard deviation [SD]: 8.3); approximately half (51%) were under 65 years of age. Overall, more patients over 65 years of age were randomized to the PBO LCIG + IR OLC capsules group compared with the LCIG + PBO IR OLC capsules group (56% compared with 43%, respectively). Most enrolled patients were male (65%), non-Hispanic or Latino (96%), or white (93%), and were located in the US (73%).

The mean PD duration was 10.9 years (SD 5.2). Patients in the LCIG + PBO IR OLC group had a shorter duration of PD in comparison with patients in the PBO LCIG + IR OLC capsules group (10.0 years versus 11.8 years). All patients (100%) had symptoms of bradykinesia and muscular rigidity; most had tremor (78%) and postural instability (65%).

Patients in the LCIG + PBO IR OLC capsules group had lower mean “off” time compared with the PBO LCIG + IR OLC capsules group (6.3 hours versus 7.0 hours, respectively), and had a greater mean “on” time without troublesome dyskinesia (8.7 hours versus 7.8 hours respectively).

Mini-Mental State Examination (MMSE), Clinical Global Impression – Improvement (CGI-I), and UPDRS scores were similar between groups, with the exception of the UPDRS Part III (18.1 compared with 22.5) and Part I, II, and III overall scores (31.5 compared with 35.8 in the LCIG + PBO IR OLC capsules and the PBO LCIG + IR OLC capsules groups, respectively) and the PDQ-39 summary index score (35.1 compared with 38.6 in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively).

Approximately half (54%) of all the randomized patients were treated with three or more PD medications at baseline. Most patients (68%) were treated with dopamine agonists, with more patients in the PBO LCIG + IR OLC capsules group (76%) receiving dopamine agonists compared with the LCIG + PBO IR OLC capsules group (59%). Approximately half (46%) of all patients were treated with COMT inhibitors, with fewer patients in the PBO LCIG + IR OLC capsules group (44%) receiving COMT inhibitors compared with the LCIG + PBO IR OLC capsules group (49%). The minority of patients (30%) were treated with MAO-B inhibitors, with fewer patients in the PBO LCIG + IR OLC capsules group (18%) receiving MAO-B inhibitors compared with the LCIG + PBO IR OLC capsules group (41%).

Overall, patients in both groups were treated with a mean daily levodopa dose of 1,062.0 mg (SD 427.7). Patients in the PBO LCIG + IR OLC capsules group were treated with greater daily doses of levodopa compared with the LCIG + PBO IR OLC capsules group (1,005.4 mg versus 1,123.5 mg).

The majority of patients in both groups were historically treated with dopamine agonists (90%), MAO-B inhibitors (61%), or other dopaminergic drugs (72%), whereas approximately half (44%) were treated with adamantane derivatives. All patients (100%) were historically treated with dopamine or dopamine derivatives.

Open-Label, Non-Comparative Study (Study 004)

The baseline characteristics reported in Study 004 are summarized in Table 6, Table 7, and Table 8. Patients had a mean age of 64.1 (SD: 9.1). The majority of the patients were male (57%); 93% were white. Patients had lived an average of 12.5 (5.5) years with PD and were receiving a mean of 1,082.9 mg of levodopa per day (582.1). The majority of the patients (59%) were treated with two or more PD medications at baseline, of which the majority were levodopa or levodopa derivatives (73%) and dopamine agonists (55%). The mean hours per day of “off” time, “on” time without troublesome dyskinesia, and “on” time with troublesome dyskinesia were 6.75 (2.35), 7.65 (2.45), and 1.61 (2.03), respectively. The mean UPDRS overall score (Part I, II, and III) for patients was 48.4 (18.9); the mean Clinical Global Impression – Severity (CGI-S) score was 4.85 (0.85); the mean PDQ-39 score was 42.8 (15.1); the mean EuroQol 5-Dimensions (EQ-5D) summary index score was 0.588 (0.195); and the mean EuroQuol visual analogue scale (EQ VAS) score was 50.2 (21.0).

The minority (28%) of patients were not receiving any additional PD medications during Study 004, whereas, approximately half (52%) were taking one PD medication. The majority (68%) of patients were treated with levodopa or derivatives and approximately half (49%) were treated with levodopa only.

Interventions

Double-Blind, Randomized Controlled Trial (Study 001/002)

Overall, patients were asked to refrain from making any significant dietary changes during the study given that high protein diets could affect the efficacy of treatment with levodopa/carbidopa.

Screening Phase

During the screening phase (up to 28 days), patients treated with formulations other than IR OLC 100 mg/25 mg were switched to the latter. Doses of open-label IR OLC 100 mg/25 mg were subsequently titrated to optimize response and minimize AEs. If a fixed-dose regimen could not be achieved during this phase, randomization to the DB treatment phase was to be delayed until a stable regimen could be maintained for a full 28-day period. The conversion did not require a stabilization period if prior combination therapies contained a 4:1 formulation of levodopa/carbidopa 100 mg/25 mg IR (e.g., Stalevo 100). Patients were also required to achieve a stable dose for other concomitant antiparkinsonian medications unless contraindicated.

Most PD treatments were permitted with the exception of sustained-released levodopa/carbidopa formulations, levodopa combined with peripheral decarboxylase inhibitors other than carbidopa (e.g., levodopa/benserazide), and apomorphine.

Hospitalization Phase

Following the screening phase, patients were to be admitted to hospital for approximately 10 days, as needed, two days prior to PEG-J placement for pre-surgical procedures. The PEG-J tube was implanted on the day after admission by a qualified gastroenterologist or surgeon experienced with the placement and maintenance of PEG-J tubes and possessing a thorough knowledge of endoscopy, aspects of PD and neurological patients, and the LCIG infusion system and its related procedures.

A single dose of prophylactic antibiotics, such as first- or third-generation cephalosporin (or those with similar coverage) were required to be administered approximately 30 minutes prior to the PEG-J procedure.

Double-Blind Phase

Randomization was conducted centrally using an interactive voice response system (IVRS). It was based on computer-generated, predetermined, randomization codes and stratified by site, with a mixed block size of two or four. Patients who were implanted with a PEG-J tube were randomized in a 1:1 ratio (LCIG:IR OLC). Study 001/002 was a double-dummy design; therefore, patients received either LCIG for infusion in addition to overencapsulated oral placebo or IR OLC 100 mg/25 mg in addition to placebo intestinal gel for infusion.

LCIG was delivered as an aqueous solution containing 20 mg/mL levodopa and 5 mg/mL carbidopa monohydrate packaged in 100 mL cassettes or matching placebo gel containing sodium carboxymethylcellulose solution alone, administered as a morning bolus dose (5 mL to10 mL) followed by continuous infusion at a constant rate for the remainder of each patient’s waking day (approximately 16 hours). Infusions were stopped overnight. The tubing was to be disconnected from the pump and flushed with potable water every night.

IR OLC capsules 100 mg/25 mg or matching placebo capsules were administered at the same dose and frequency as determined during the screening phase (baseline dose and frequency) throughout the waking day (approximately 16 hours) and began at the same time as the infusion. The smallest possible dose of the IR OLC or matched placebo was one single capsule (the only available formulation).

Typical routine night-time treatment with open-label IR OLC 100 mg/25 mg capsules was permitted. Night-time doses (between daily discontinuation of study drug and up to two hours prior to the administration of the morning dose) were not considered as rescue medication; however, they were to be recorded in the daily dosing diary.

All patients, caregivers, and investigators were blinded to treatment allocation. Data analysts were also masked until after the database was locked. Furthermore, to maintain the integrity of the DB, double-dummy nature of the study, patients were not allowed to split or divide levodopa/carbidopa or matching placebo capsules. Furthermore, the last scheduled daily oral capsule dose was required to be a single capsule (levodopa/carbidopa 100 mg/25 mg IR or matching placebo), which allowed for the required end-of-infusion PEG-J flush (3 mL of LCIG gel infusion in the dead space of the tubing, equal to approximately 60 mg of levodopa). Any change in the dose of an active intervention in a participant had to be matched by a corresponding change in the alternative treatment, so that both treatments (active and placebo) for each patient were adjusted at the same time. In this way, the masking was maintained for patients in both groups to maintain the integrity of the masking. Masking of participants and investigators was not formally assessed.

Titration Period

Study 001/002 had a second titration period during the DB phase in which the LCIG and IR OLC doses along with their matching placebo doses were optimally titrated for four weeks. Dosing could be adjusted once daily during the first two weeks (during an in-patient hospital stay) and weekly thereafter (during scheduled outpatient visits).

During this second titration period, the morning bolus dose of LCIG (or matching placebo gel) was initially administered at 80% of the usual optimally titrated oral levodopa morning dose established prior to randomization (screening phase).

The initial continuous infusion dose (i.e., the continuous infusion rate over the 16-hour waking day) was calculated based on the total oral daily dose minus the morning dose and the last dose of the day. The initial continuous daily dose was divided by 16 hours to determine the continuous hourly dose. Only the doses of IR OLC 100 mg/25 mg tablets taken during the waking 16-hour day were used to calculate the total oral daily dose (i.e., they did not include the doses of levodopa/carbidopa that were taken at night when the continuous infusion was not administered).

Continuous infusion of LCIG or matching placebo gel could be adjusted by changing the levodopa infusion rate in 100 mg daily increments based on the investigator’s judgment of efficacy of the previous day’s dose and any oral rescue doses (patients were not permitted to make any adjustments).

Given that simultaneous titration of active and placebo therapies was required for patients in both groups, IR OLC could be adjusted by increasing one or more doses by 100 mg; however, the frequency of dosing could not be changed.

If judged absolutely necessary by the investigator, temporary disruption of both the gel and capsule formulations was permitted for patients who developed unsafe dyskinesia or other levodopa-related complications until symptoms had improved to a clinically acceptable level. If treatment was interrupted, patients were required to stop both active and placebo treatments in order to maintain the DB, double-dummy study design. Patients were subsequently treated with open-label IR OLC 100 mg/25 mg capsules (as per the dose received prior to randomization and adjusted as clinically indicated) until the problem was resolved and the gel infusion could be resumed. If cessation of treatment lasted less than 24 hours, treatment was resumed the following morning at the same dose (infusion gel and oral) received prior to the interruption. If cessation lasted longer than 24 hours, the investigator was to consult the medical monitor prior to restarting treatment.

Maintenance Period

The titration phase was followed by a maintenance phase (eight weeks) during which patients were maintained on stable doses of their assigned treatments. Adjustments beyond the titration period (study week 4) were not permitted. However, an exception was made when a decrease in the study drug was clinically indicated in order to manage AEs. Open-label IR OLC could be used as rescue therapy for persistent “off” episodes for patients in either group.

Open-Label, Non-Comparative Study (Study 004)

LCIG was delivered as an aqueous solution containing 20 mg/mL levodopa and 5 mg/mL carbidopa monohydrate packaged in 100 mL cassettes administered as morning bolus doses followed by continuous infusion at a constant rate for the remainder of each patient’s waking day (approximately 16 hours) with additional rescue doses during the day, if clinically indicated. Infusions were stopped overnight and typical routine night-time treatment with IR OLC was permitted. The initial infusion doses of LCIG were based on patients’ previous dose of daily OLC. During the screening period (up to 28 days), patients received PD diary training and were converted to and stabilized on levodopa monotherapy. All patients were subsequently hospitalized for the placement of the NJ and PEG-J tubes and initiation of LCIG titration. Study 004 consisted of two titration periods. The first (up to 14 days) was a test period for LCIG infusion through an NJ tube followed by a dose-optimizing titration period (up to 14 days) through a PEG-J tube. Once patients were optimally titrated, they entered the long-term PEG-J treatment period (up to 54 weeks). Assessments began on day 28 of the period.

Outcomes

Double-Blind, Randomized Controlled Trial (Study 001/002)

During the screening phase, patients (and caregivers, if applicable) were instructed on how to understand PD symptoms and how to complete the PDHD through an instruction DVD. Patients were required to have at least 75% concordance with investigator rating and at least 75% compliance in completion of the PDHD to meet the inclusion criteria of the study.

The evaluation of compliance could not be repeated due to inadequate “off” time (less than three hours per day on each of the three days). If no transitions occurred between “off” and “on” states during the time of concordance evaluation or if concordance and compliance were lower than 75%, the time (screening period) in which concordance was evaluated could be prolonged. For patients who did not achieve the compliance criteria (75%), retraining in completion of the PDHD was required prior to re-evaluation of compliance with the diary.

Study visits were done at baseline, weekly through study week 4 (weeks 1, 2, 3, and 4), and biweekly thereafter (weeks 6, 8, 10, and 12). The PDHD was to be completed by patients every 30 minutes for 24 hours for three consecutive days prior to each visit and should have indicated if they were in an “off” state, “on” state without dyskinesia, “on” state with non-troublesome dyskinesia, “on” state with troublesome dyskinesia, or “asleep.” If patients were unable to complete their diaries, their caregivers were to complete the entries on their behalf. During the assessment days, no rescue doses of IR OLC were to be taken because of their potential impact on efficacy measures, unless absolutely required (medically necessary). One study conducted by Hauser et al. suggests that a one-hour reduction in “off” time was considered to be a minimal clinically important difference (MCID) in actively treated patients.61 More information regarding the PDHD can be found in Appendix 5.

Primary Outcome

The primary efficacy outcome was change between baseline and final visit (week 12) in the mean number of “off” hours collected on the PDHD during the three consecutive days prior to study visit, normalized to a 16-hour waking day. Normalized “off” time was calculated by dividing the absolute “off” time by the daily awake time (defined as the sum of absolute “off” time, “on” time without dyskinesia, “on” time with non-troublesome dyskinesia, and “on” time with troublesome dyskinesia) and multiplying by 16 hours. The baseline value was defined as the average normalized “off” time for the three PDHD days closest to, but not on or after, the day of the PEG-J procedure. If only two valid symptom diary days were available prior to a clinic visit, data from the two days were used to calculate the average daily “off” time. If only one valid symptom diary day was available, the average daily from the previous week was be averaged with the daily “off” time from the one valid diary day. Patients with no valid symptom diary days for a visit or who were completely missing a visit had the average daily “off” time set to missing for that visit.

Key Secondary Outcome

The predefined key secondary outcome was change from baseline to final visit (week 12) in the mean number of normalized “on” hours without troublesome dyskinesia (defined as a composite of “on” time without dyskinesia and “on” time with non-troublesome dyskinesia) collected in the PDHD during the three consecutive days prior to the study visit. The baseline value was defined as the average normalized “on” time for the three PDHD days closest to but not on or after the day of the PEG-J procedure.

Secondary Outcomes

Other secondary outcome measures included change from baseline in PDQ-39 summary index score, CGI-I score, UPDRS Part II (ADL subscore), UPDRS Part III (motor subscore), EuroQol 5-Dimensions 3-Levels questionnaire (EQ-5D-3L) summary index score, and Zarit Burden Interview (ZBI) score. More information regarding the secondary outcomes can be found in Appendix 5.

Parkinson’s Disease Questionnaire 39

The PDQ-39 is a self-administered, disease-specific instrument of HRQoL (HRQoL) designed to measure aspects of health not captured under general health questionnaires that may be relevant to patients with PD. The PDQ-39 comprises 39 items addressing eight domains considered to be adversely affected by the disease, including:

  • Mobility (e.g., fear of falling when walking)
  • ADL (e.g., difficulty cutting food)
  • Emotional well-being (e.g., feelings of isolation)
  • Stigma (e.g., social embarrassment)
  • Social support
  • Cognition
  • Communication
  • Bodily discomfort

The PDQ-39 scores ranged between 0 and 100, with lower scores indicating a better-perceived health status. Findings from one study conducted by Peto et al. showed a varying mean MCID for different domains: mobility (−3.2), ADL (−4.4, emotional well-being (−4.2), stigma (−5.6), social support (−1.4), cognitions (−1.8), communications (−4.2), bodily discomfort

(−2.1), and summary index score (−1.6).62

Clinical Global Impression – Improvement

The CGI-I scale is a global assessment of the change in a patient’s clinical status. Baseline scores were established through the CGI-S two days prior to randomization. Scores on the Severity of Illness subscale range from 1 (“not ill at all”) to 7 (“among the most extremely ill”). The CGI-I is rated from 1 to 7 where 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. No MCID was identified in PD.

Unified Parkinson’s Disease Rating Scale

The UPDRS is a standard investigator rating tool for measuring parkinsonian signs and symptoms. The UPDRS assessments were administered by qualified individuals (third-party trained and certified raters). Every effort was made to ensure that each patient was rated by the same rater throughout the study.

The UPDRS comprises the following sections:

  • Part I – Mentation, Behaviour, and Mood (4 items; possible scores range between 0 and 16)
  • Part II – Activities of Daily Living (13 items; possible scores range between 0 and 52)
  • Part III – Motor Examination (14 items; possible scores range between 0 and 56)
  • Part IV – Complications of Therapy (including dyskinesias; [11 items; possible scores range between 0 and 23])

The UPDRS assessments were performed at the same time of day throughout the study during “off” times (only during the screening phase) defined as the morning prior to the patients taking their first daily dose of antiparkinsonian medication and during the best “on” time (throughout the study), defined as two to four hours following the morning dose of study drug or PD medications, but prior to lunch. Individual items in parts I to III are scored on a 5-point scale (0 to 4), with higher scores indicating worse symptoms, while Part IV also includes a number of items for which scoring is 0 (no) or 1 (yes). A total UPDRS (Part I to IV) score of 0 represents “no disability” and a score of 199 represents “worst disability.” Among available studies, the estimated MCID for the ADL component (Part II) and motor component (Part III) were 2.3 and 6.5 points, respectively, in patients with advanced PD.63

EuroQol 5-Dimensions 3-Levels

The EQ-5D-3L is a generic HRQoL instrument that may be applied to a wide range of health conditions and treatments. The first of two parts of the EQ-5D-3L is a descriptive system that classifies respondents (aged ≥ 12 years) based on the following five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D-3L has three possible levels (1, 2, or 3) for each domain, representing “no problems,” “some problems,” and “extreme problems,” respectively. Index scores less than 0 represent health states that are valued by society as being worse than dead, while scores of 0 and 1.00 are assigned to the health states “dead” and “perfect health,” respectively. The second part is a 20 cm visual analogue scale (the EQ VAS) that has end points labelled 0 and 100, with respective anchors of “worst imaginable health state” and “best imaginable health state.” Although the MCID for the EQ-5D-3L in PD remains unclear, differences of 0.033 to 0.074 in the index score are typically clinically meaningful in other conditions. A systematic review reported an estimated MCID of 0.10 (range: 0.04 to 0.17) and 0.11 (range: 0.08 to 0.14) based on the UPDRS and PSQ-39 score, respectively; however, these PD-specific MCIDs were obtained from a conference abstract, and, as such, limited information was presented on the methodology used in their estimation.64

Zarit Burden Interview

The ZBI is a self-administered 22-item questionnaire measuring caregiver burden. The questions refer to the caregiver/patient relationship and evaluate the caregiver’s health condition, psychological well-being, finances, and social life. The caregiver burden is evaluated by the total score obtained from the sub-total of 22 questions. The ZBI was not completed if the patient did not have a caregiver. Each of the 22 items are scored on a 5-point Likert scale, ranging from 0 (never) to 4 (nearly always). Scores are then summed to create a total score that can range between 0 and 88, with higher score indicating greater burden. No MCID was identified in PD.

Other Outcomes

Other “on” time outcomes included the change from baseline to final visit (week 12) in the mean number of “on” hours without dyskinesia, with non-troublesome dyskinesia, and with troublesome dyskinesia recorded in the PDHD during the three consecutive days prior to study visit. The baseline value was defined as the average normalized “on” time for the three PDHD days closest to but not on or after the day of the PEG-J procedure.

Harms

An independent Data Safety Monitoring Board (DSMB) composed of three members (including two physicians whose expertise included neurology or gastroenterology and a biostatistician with clinical experience) reviewed unblinded safety data and provided the sponsor with recommendations regarding study modification, continuation, or termination. A dedicated charter in accordance with the FDA Guidance for Clinical Trial Sponsors/Establishment and Operation of Clinical Trial Data Monitoring Committees (March 2006) and the European Medicines Agency/Committee for Medicinal Products for Human Use Guideline on Data Monitoring (January 2006) was developed to address the mode of operations of the DSMB so that the integrity of the study was protected.

AEs were defined as any untoward medical occurrences in a patient-administered medicinal product (or a system consisting of drug, device, and surgical procedure) and which does not necessarily have a causal relationship with this treatment. Therefore, an AE can be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom (including an AE occurring from drug abuse, drug withdrawal, or any failure of expected pharmacological action), or disease temporally associated with the use of a medicinal product or device, whether or not considered related to the medicinal product or device.

SAEs were defined as any untoward medical occurrence that at any dose that resulted in death or was life-threatening (an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if the event were more severe); required in-patient hospitalization or prolongation of an existing hospitalization; resulted in persistent or significant disability/incapacity; or was considered a congenital anomaly/birth defect.

Open-Label, Non-Comparative Study (Study 004)

The primary objective was to evaluate the long-term safety of LCIG based on AEs, device complications, and number of completers. All AEs were considered as treatment-emergent adverse events (TEAEs), defined as those that began or worsened from the time of NJ tube insertion until 30 days after PEG-J removal.

Long-term efficacy (as measured by “off” time, “on” time with and without troublesome dyskinesia, UPDRS) and QoL (as measured by PDQ-39, EQ-5D-3L, EQ VAS, and CGI-I) were evaluated as secondary end points.

Statistical Analysis

Double-Blind, Randomized Controlled Trial (Study 001/002)

Determination of Sample Size

Study 001/002 was designed as a superiority trial to assess the beneficial effects of LCIG using the change from baseline in normalized “off” time as the primary end point. Based on available literature (including trials with similar study design and other compounds used for the management of advanced-stage PD using the change from baseline in “off” time as a primary efficacy end point), a difference of 2.5 hours between LCIG and IR OLC in change in “off” time hours from baseline and an SD of 2.85 were assumed to be reasonable.51,65,66 Further, no more than 5% of the randomized patients were expected to be excluded from the full analysis set (FAS). Based on these assumptions, a sample size of approximately 62 patients (31 patients using a 1:1 randomization ratio) would give 90% power to detect a difference between the LCIG and IR OLC groups at the alpha = 0.05 level of significance.

Primary End Point

The primary analysis of the primary end point (change in normalized “off” time) was conducted in the FAS population using an analysis of covariance (ANCOVA) model stratified by treatment group and country as fixed effects and with baseline “off” time, and natural logarithm of mean daily dose of rescue levodopa on days with non-missing PDHD data as covariates. Missing data were imputed based on the last observation carried forward (LOCF) approach. Patients with more than one observation for the same 30-minute time period split the time evenly among the number of events (e.g., recorded as 15 minutes “on” and 15 minutes “off”). Patients who did not complete at least 12 awake hours of PDHD data (excluding time asleep) had that daily data set to missing (i.e., the data set was not considered as a valid PDHD day) and there was no imputation of data for these days. The average daily dose of rescue levodopa on non-missing PDHD days was calculated as the total milligrams of levodopa taken as a rescue dose on valid PDHD days divided by the number of non-missing PDHD days in the DB phase. Data were presented as least squares mean difference (LSMD) in the change from baseline compared with IR OLC, with corresponding 95% confidence intervals (CI). Treatment with LCIG was to be considered superior to IR OLC if the two-sided P value was less than or equal to 0.05.

Sensitivity Analyses

Sensitivity analyses were also performed for the primary end point and analyzed using a mixed-effects models for repeated measures (MMRM) model using an unstructured matrix for the covariance of the within-participant repeated measures, which included change from baseline as a fixed effect covariate and treatment, country, and time (scheduled assessment visits) as fixed effect (categorical) factors. The MMRM also considered time by treatment interaction as well as time by baseline interaction.

Further sensitivity analyses were also performed for the primary end point at the request of the FDA, and were conducted in a manner similar to those used for the primary analysis (i.e., ANCOVA). However, the sensitivity analyses considered different approaches to the primary ANCOVA analysis by excluding the covariate of rescue medication on valid PDHD days, including the covariate of rescue medication over the treatment period, including the values on final PDHD days with rescue medication use replaced by average daily normalized “off” time at baseline, and excluding values on final PDHD days with rescue medication use.

All sensitivity analyses were not adjusted for multiple statistical tests.

Subgroup Analyses

The treatment effect on the primary efficacy end point was also evaluated within each of the following pre-specified subgroups: gender, race, age (< 65 or ≥ 65 years), country (US, ex-US), and duration of PD (< 10 or ≥ 10 years). Only the duration-of-PD subgroup was of interest for this review (identified in Table 4). Subgroup analyses were not to be completed for subgroups comprising < 20% of the randomized patients. No hypothesis testing was to be performed on these subgroups for this study.

Subgroup analyses were also performed in the FAS population and were analyzed in a manner similar to the primary end point (i.e., ANCOVA). Randomization was not stratified for any of the pre-specified subgroups and none of the subgroup analyses were adjusted for multiple statistical tests.

Secondary End Points

All secondary end point analyses were performed in the FAS population and analyzed in a manner similar to the primary end point (i.e., ANCOVA), and included effects for treatment, country, and corresponding baseline variables as a covariate. Missing data for secondary end points was also imputed using the LOCF method.

Pre-specified hierarchical testing and a gatekeeping procedure were used to maintain the family-wise error rate at 0.05. This method allows testing at a significance level of 0.05 without adjustment. Subsequent to the statistical significance (at alpha = 0.05) of the primary efficacy variable, a testing hierarchy was performed on the secondary efficacy variables. The statistical testing hierarchy stopped when an end point was found to be statistically insignificant at alpha = 0.05.

The statistical testing order was as follows:

  • “On” time without troublesome dyskinesia (“on” time without dyskinesia or with non-troublesome dyskinesia) at week 12
  • PDQ-39 summary index score at week 12
  • CGI-I score at week 12
  • UPDRS Part II score at week 12
  • UPDRS Part III score at week 12
  • EQ-5D-3L summary index score at week 12
  • ZBI score at week 12

Harms

Proportions of patients with at least one AE, SAE, and AE leading to discontinuation were summarized and compared between treatment groups using descriptive statistics. For safety end points, all analyses were based on the observed data (i.e., with no imputation of missing data) and the safety set.

Open-Label, Non-Comparative Study (Study 004)

A sample of 320 patients was planned to satisfy regulatory requirements for exposure assessments at six and 12 months.

All efficacy outcomes were based on the mean within-group change from baseline to the last study visit. A one-sample t-test was used to assess within-group changes from baseline to each visit and end point. No adjustments for multiple statistical testing were performed.

Analysis Populations

Double-Blind, Randomized Controlled Trial (Study 001/002)

Efficacy was assessed in the FAS, which included all randomly allocated participants with data for baseline and at least one post-baseline assessment. The completers set was a pre-specified subset of the FAS that included only patients who completed the study.

Safety was assessed in the safety set, which included all randomly allocated patients (all patients who underwent the PEG-J procedure).

Open-Label, Non-Comparative Study (Study 004)

All patients who received LCIG during the post-PEG-J period and who completed at least one post-baseline assessment were included in the efficacy analyses, whereas all patients who had NJ placement and completed at least one post-baseline safety assessment were included in all safety analyses.

Patient Disposition

Double-Blind, Randomized Controlled Trial (Study 001/002)

Of the 97 patients screened in Study 001/002, approximately 27% did not meet the criteria for enrolment. The most common reason for exclusion was protocol violations (78%) followed by withdrawal of consent (20%) and AEs (4%). The majority of patients completed the study through week 12 (93%). A similar number of patients discontinued the study across treatment groups (5% compared with 9% in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively). The most common reason for discontinuation in both groups was AEs.

A similar number of patients deviated from the protocol across treatment groups (24% compared with 27% in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively). The most common reason for protocol deviations was receiving the wrong treatment or an incorrect dose (22% compared with 27% in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively). Details about patient disposition in Study 001/002 are provided in Table 9.

Table 9. Patient Disposition.

Table 9

Patient Disposition.

Open-Label, Non-Comparative Study (Study 004)

The patient disposition is summarized in Table 9. Of the 422 patients screened in Study 004, approximately 16% did not meet the criteria for enrolment. The majority of patients completed the study through the NJ tube test period (92%). The most common reasons for discontinuation were AEs (8%) and withdrawal of consent (8%). The majority of patients completed Study 004 through the PEG-J treatment phase (77%).

Exposure to Study Treatments

Double-Blind, Randomized Controlled Trial (Study 001/002)

Details about exposure in Study 001/002 are provided in Table 10 and Table 11.

Table 10. Summary of Treatment Exposure.

Table 10

Summary of Treatment Exposure.

Table 11. Summary of Treatment Exposure Other Than Study Drugs (Safety Set).

Table 11

Summary of Treatment Exposure Other Than Study Drugs (Safety Set).

Patients had their levodopa doses titrated for a mean of approximately seven to eight days (SD: 2.5) in the screening phase, during which the average mean daily levodopa dose was 1,096.5 mg (SD: 438.3). By the end of the titration phase, patients in the LCIG + PBO IR OLC capsules group were treated with less levodopa (1,127.6) mg [SD: 531.8]) than patients in the PBO LCIG + IR OLC capsules group versus (1,400.0 mg [SD: 698.5]).

Patients were treated for a mean of approximately 80 days in the DB treatment phase, during which the average mean daily levodopa dose was less in the LCIG + PBO IR OLC capsules group (1,117.3 mg [SD: 473.7]) compared with the PBO LCIG + IR OLC capsules group (1,350.6 mg [SD: 617.9]). By the end of the DB treatments phase, patients in the LCIG + PBO IR OLC capsules group were treated with less levodopa (1,131.1 mg [SD 435.1]) than patients in the PBO LCIG + IR OLC capsules group (1,374.1 mg [SD: 615.0]).

The majority of patients used rescue medication on valid diary days. The proportion of patients requiring rescue medication was similar between groups throughout the study (97% in the LCIG + PBO IR OLC capsules group versus 91% in the PBO LCIG + IR OLC capsules group). Overall, fewer patients in the LCIG + PBO IR OLC capsules group (37%) required rescue medication at week 12 compared with the PBO LCIG + IR OLC capsules group (42%). Patients mostly required ≤ 14 days of rescue medication during the study across both treatment groups (72% in the LCIG + PBO IR OLC capsules group versus 65% in the PBO LCIG + IR OLC capsules group). The average mean doses of rescue IR OLC during the study were similar between treatment groups (180.6 mg [SD: 156.2] in the LCIG + PBO IR OLC capsules group versus 139.8 [SD: 81.3] in the PBO LCIG + IR OLC capsules group). Conversely, mean doses of rescue medication at week 12 were lower in the LCIG + PBO IR OLC capsules group (115.3 mg [SD: 67.8]) compared with the PBO LCIG + IR OLC capsules group (210.3 mg [SD: 201.3]).

Replacement mean IR OLC doses due to study drug interruptions were smaller in the LCIG + PBO IR OLC capsules group (302.8 mg [SD: 243.7]) compared with the PBO LCIG + IR OLC capsules group (431.8 mg [SD: 494.1]), whereas night-time IR OLC doses were similar between the two groups (126.1 mg [SD: 60.5] in the LCIG + PBO IR OLC capsules group versus 132.9 mg [SD 104.0] in the PBO LCIG + IR OLC capsules group).

Overall compliance with treatment (defined as between ≥ 80% and ≤ 120% compliance at each visit with available data) was 89% for the LCIG group and 81% for the PBO IR OLC capsules group in the LCIG + PBO IR OLC capsules group and 97% for the PBO LCIG and 76% for the IR OLC capsules in the PBO LCIG + IR OLC capsules group. Details regarding treatment compliance in Study 001/002 are provided in Table 12.

Table 12. Summary of Treatment Compliance.

Table 12

Summary of Treatment Compliance.

Open-Label, Non-Comparative Study (Study 004)

Patients were treated with a mean of 1,082.9 mg of levodopa daily at screening. Patients were subsequently optimized to mean daily doses of 1,547.4 mg by the last day of the titration periods over a mean of 4.5 (2.2) days. During the treatment phase, mean daily levodopa doses ranged between 1,551.0 mg and 1,630.5 mg. Among the 28% patients receiving daily dose of IR OLC during the treatment phase, the mean daily dose during the night was174.6 mg.

The minority of patients (28%) were not receiving concomitant PD medications during Study 004, whereas, approximately half (52%) were taking one PD medication. The majority (68%) of patients were treated with levodopa or derivatives and approximately half (49%) were treated with levodopa only. Details pertaining to concomitant medication during Study 004 are presented in Table 13.

Table 13. Concomitant Parkinson Disease Medications in Study 004.

Table 13

Concomitant Parkinson Disease Medications in Study 004.

Critical Appraisal

Double-Blind, Randomized Controlled Trial (Study 001/002)

Internal Validity

Study 001/002 was designed as a DB, active-controlled RCT that used appropriate methods to randomize patients (i.e., IVRS) and conceal treatment allocation. The objective of Study 001/002 was to assess the efficacy and safety of LCIG based on a primary end point of change from baseline to 12 weeks in normalized “off” time.

Although randomization appeared to be successful, patients experienced less “off” time and more “on” time at baseline in the LCIG + PBO IR OLC capsules group, which may indicate less severe PD. Patients with more severe PD (i.e., the PBO LCIG + IR OLC capsules group) may not benefit from treatment to the same extent as those with less severe disease, which could result in the overestimation of treatment effect associated with LCIG therapy. However, the clinical expert consulted for this CDR review suggested that any such bias is unlikely to explain the magnitude of the treatment effect.

Overall compliance with the active IR OLC capsules in the PBO LCIG + IR OLC capsules group was 76%. Therefore, patients who were not compliant with the IR OLC capsules in this treatment group would not be receiving any levodopa therapies (i.e., only receiving PBO LCIG). Given that the symptoms of PD are well known (i.e., “off” state symptoms, such as tremors or immobility) and that non-compliant patients may have experienced symptoms of uncontrolled PD, some patients may have been inadvertently unblinded to treatment status. Unblinding may lead to biases in the reporting of subjective outcomes (i.e., “on” and “off” states, HRQoL, and AEs).

Study 001/002 was designed as a superiority trial; therefore, analyses should ideally be conducted in an intention-to-treat (ITT) population. However, all efficacy analyses were conducted using the FAS population, defined as all randomly allocated participants with data for baseline and at least one post-baseline assessment. The exclusion of patients is inconsistent with the true definition of an ITT analysis, in which all randomized participants are included. However, given the small number of exclusions (one patient in each group), the potential for bias is not of concern.

In the adjusted ANCOVA model used in the primary analysis, missing data were imputed using the LOCF approach. To assess the robustness of the treatment effect, sensitivity analyses were conducted using different covariates in the ANCOVA model and different methods to impute missing data (MMRM).

Study 001/002 included multiple end points based on change in “off” and “on” time captured by means of PDHDs. All patients were trained in the completion of the diary by an instructional DVD and were required to demonstrate 75% completion and concordance with the investigators, leading to more consistent results. Patients who were unable to complete their diaries had their caregivers complete the entries on their behalf. The level of agreement between patients’ and their caregivers’ perceptions of “off” time and “on” time was not assessed in this trial and remains unclear.

A statistical testing hierarchy to control for type I error was used to examine secondary outcomes. Subsequent to the statistical significance (at alpha = 0.05 level) of the primary efficacy variable, a testing hierarchy was performed on the secondary efficacy variables. The statistical testing hierarchy stopped when an end point was found not to be statistically significant at the alpha = 0.05 level. However, the manufacturer does not appear to have adhered to its pre-specified testing strategy by continuing statistical testing for superiority after statistical insignificance was established. Overall, statistical testing should have stopped after the change in the UPDRS Part III end point (fifth in the order of secondary analyses). It is important to note that statistical inference should only be made for the outcomes up to and including the UPDRS Part III. No statistical inference can be made for EQ-5D-3L and ZBI end points even though they were included in the in the statistical testing hierarchy because they were conducted subsequent to the failure of a prior end point.

All other outcomes, including “on” time without dyskinesia, “on” time with non-troublesome dyskinesia, “on” time with troublesome dyskinesia, domain scores of the PDQ-39 (mobility, ADL, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort), Part I and Part IV of the UPDRS (including the sum of Part I, II, and III) as well as the EQ VAS were not included in the statistical testing hierarchy and not adjusted for multiplicity. Therefore, there is a risk of type I error. As such, the results should only be considered hypothesis-generating.

External Validity

Study 001/002 was multinational; however, it did not include any sites or patients from Canada. Overall, 27% of patients were screening failures, mostly due to protocol violations. Stringent inclusion and exclusion criteria can result in large number of screening failures and can potentially lead to the inclusion of a select population that may not be completely representative of the advanced PD population in Canada. This can potentially limit the generalizability of the trial results. Despite the large number of screening failures, the clinical experts consulted by CDR for this review highlighted that Study 001/002 appears to have recruited patients with characteristics similar to those with advanced PD who would be considered eligible for treatment with LCIG.

Furthermore, patients were required to have at least 75% concordance with investigator rating and at least 75% compliance in completion of the PDHD to meet the inclusion criteria of the study. Including only those who demonstrate agreement with the investigator in the completion of the PDHD can also lead to the inclusion of a select population that may not be completely representative of the advanced PD population in Canada. This can also potentially limit the generalizability of the trial results.

The evaluation of “off” time as the primary end point (identified as among the most important end points by the patient groups who provided input for this CDR submission) was supported by the evaluation of a key secondary end point: “on” time without troublesome dyskinesia (a composite of “on” time without dyskinesia and “on” time with non-troublesome dyskinesia). The FDA considers improvement in functional “on” time to be the most important end point for treating patients with motor fluctuations; it is also said to provide a better indication of improvement in patient functioning compared with “off” time.53,67,68 Furthermore, the patient input submitted for this review also highlighted the importance of “on” time as a desirable outcome.

Overall, Study 001/002 was relatively short in duration (12 weeks) considering that PD therapies would be expected to continue for a patient’s lifetime. However, patients enrolled in Study 001/002 were provided the opportunity to continue treatment in a 12-month, open-label, safety extension study (Study 003) providing longer-term safety and efficacy associated with LCIG therapy (Appendix 6).

Open-Label, Non-Comparative Study (Study 004)

Internal Validity

There are several limitations to the long-term, open-label, non-randomized, non-comparative safety trial Study 004. First, given that this was an uncontrolled study, it remains unclear whether the changes observed in the safety and efficacy profile were due to a natural course of the disease or to long-term treatment with LCIG through a PEG-J tube. Open-label trial designs in which both the investigators and the participants are not blinded to treatment allocation may have an impact on subjective outcomes, such as some of the patient-reported AEs, and on outcomes related to efficacy and HRQoL. Reporting of “off” and “on” time is also subjective; therefore, it is subject to bias. In addition, during Study 004, patients were able to continue concomitant anti-PD medication; this makes it difficult to ascertain the safety and efficacy of the intervention in isolation. Also of note, data were incomplete for some outcomes, which may increase the potential for bias in the patient-reported outcomes if those with complete data had more favourable responses. Further, adjustments for multiple comparisons were not performed for the efficacy outcomes; thus, the risk of type I error is introduced.

External Validity

Study 004 was multinational and included sites and patients from Canada. Overall, 16% of patients were screening failures; however, the most common reasons were not provided. Stringent inclusion and exclusion criteria can result in large screening failures and can potentially lead to the inclusion of a select population that may not be completely representative of the advanced PD population in Canada, potentially limiting the generalizability of the trial results. Despite the large screening failures, Study 004 appears to have recruited patients with characteristics similar to those included in Study 001/002, who were identified as being representative of those with advanced PD and would be considered eligible for treatment with LCIG.

Overall, 354 patients in Study 004 were treated with LCIG through a PEG-J tube and followed for 54 weeks, making Study 004 the largest open-label, non-comparative safety study available. Considering that PD therapies would be expected to continue for a patient’s lifetime, the duration and sample size of Study 004 can provide important information with respect to the long-term harms profile.

Efficacy

Only those efficacy outcomes identified in the review protocol are reported in Table 4. See Appendix 4 for detailed efficacy data.

“Off” Time

Double-Blind, Randomized Controlled Trial (Study 001/002)

Compared with IR OLC capsules, the LCIG group had a statistically significant reduction in daily normalized “off” time at week 12 (the primary outcome). The adjusted LSMD in change from baseline was −1.91 hours (95% CI, −3.05 to −0.76; P = 0.0015) in favour of LCIG. Details regarding the primary outcomes in Study 001/002 are provided in Table 14. The results of the sensitivity analyses of the primary outcome were based on MMRM for imputed data and ANCOVA models (without covariate of rescue medication on valid PDHD days, with covariate of rescue medication over the treatment period, with values on final PDHD days, with rescue medication use replaced by average daily normalized “off” time at baseline, and excluding values on final PDHD days with rescue medication use). These results were consistent with the primary analysis (Table 22).

Table 14. Summary of “Off” Time.

Table 14

Summary of “Off” Time.

Daily absolute “off” time at week 12 was also evaluated and was consistent with the results of the primary analysis (normalized “off” time at week 12). Details regarding the absolute change in daily “off” time at week 12 in Study 001/002 are provided in Table 23.

Although the study protocol indicated that the analyses of the primary end point would be performed in the subgroups of patients with PD for ≤ 10 years and ≥ 10 years, the analyses were not provided in the manufacturer-submitted materials.

Open-Label, Non-Comparative Study (Study 004)

Overall, the mean amount of “off” time decreased from baseline to the last study visit (−4.4 hours [SD: 2.9], P < 0.001). Details pertaining to the change in “off” time during Study 004 are presented in Table 14. The “off” time end point in Study 004 was not corrected for multiple statistical testing.

“On” Time

Double-Blind, Randomized Controlled Trial (Study 001/002)

Compared with IR OLC capsules, the LCIG group had a statistically significant improvement in daily normalized “on” time without troublesome dyskinesia at week 12 (the key secondary outcome). The adjusted LSMD in change from baseline was 1.86 hours (95% CI, 0.56 to 3.17; P = 0.0059) in favour of LCIG. This end point was driven by two components: daily normalized “on” time without dyskinesia and daily normalized “on” time with non-troublesome dyskinesia (adjusted LSMD in change from baseline were 2.28 [95% CI, 0.47 to 4.09; P = 0.0142] and −0.73 [95% CI, −2.22 to 0.76; P = 0.3294], respectively). No statistically significant differences were reported in daily normalized “on” time with troublesome dyskinesia (adjusted LSMD in change from baseline: −0.08 [95% CI, −0.98 to 0.82; P = 0.8574]). Details regarding “on” time in Study 001/002 are provided in Table 15.

Table 15. Summary of “On” Time.

Table 15

Summary of “On” Time.

Daily absolute “on” time at week 12 was also evaluated and was consistent with the results of the secondary analyses (normalized “on” time at week 12). Details regarding the absolute change in daily “on” time at week 12 in Study 001/002 are provided in Table 23.

Open-Label, Non-Comparative Study (Study 004)

The mean amount of “on” time without troublesome dyskinesia increased from baseline to the last study visit (4.8 hours [SD: 3.4], P < 0.001), whereas the mean amount of “on” time with troublesome dyskinesia decreased from baseline to the last study visit (−0.4 hours [SD: 2.8], P = 0.023). Results for “on” time without dyskinesia and daily normalized “on” time with non-troublesome dyskinesia were not reported. Details pertaining to the change in “on” time during Study 004 are presented in Table 15. The “on” time end points in Study 004 were not corrected for multiple statistical testing.

39-Item Parkinson’s Disease Questionnaire

Double-Blind, Randomized Controlled Trial (Study 001/002)

Compared with IR OLC capsules, the LCIG group had a statistically significant reduction in the PDQ-39 summary index score. The adjusted LSMD in change from baseline was −7.0 (95% CI, −12.6 to −1.4; P = 0.0155) in favour of LCIG. Details regarding the PDQ-39 summary index score and its subscales (not adjusted for multiple statistical testing) in Study 001/002 are provided in Table 16.

Table 16. Summary of 39-Item Parkinson’s Disease Questionnaire.

Table 16

Summary of 39-Item Parkinson’s Disease Questionnaire.

Open-Label, Non-Comparative Study (Study 004)

The change from baseline at the final study visit in the PDQ-39 summary index score was – 6.9 (14.1, P < 0.001). Details pertaining to the change in PDQ-39 scores and subscales during Study 004 are presented in Table 16. The PDQ-39 end points in Study 004 were not corrected for multiple statistical testing.

Clinical Global Impression – Improvement

Double-Blind, Randomized Controlled Trial

Compared with IR OLC capsules, the LCIG group had a statistically significant reduction in the CGI-I. The adjusted LS mean difference in change from baseline was −0.7 (95% CI, −1.4 to −0.1; P = 0.0258) in favour of LCIG. Details regarding the CGI-I score in Study 001/002 are provided in Table 17.

Table 17. Summary of Clinical Global Impression – Improvement (Full Analysis Set).

Table 17

Summary of Clinical Global Impression – Improvement (Full Analysis Set).

Open-Label, Non-Comparative Study (Study 004)

CGI-I scores were not reported. Overall, the majority of patients (92%) improved, 3% did not change, and 4% worsened in the

CGI-I score from baseline to the last study visit. Details pertaining to the change in CGI-I scores during Study 004 are presented in Table 17. The CGI-I end points in Study 004 were not corrected for multiple statistical testing.

Unified Parkinson’s Disease Rating Scale

Double-Blind, Randomized Controlled Trial

Compared with IR OLC capsules, the LCIG group had a statistically significant reduction in the UPDRS Part II score. The adjusted LSMD in change from baseline was −3.0 (95% CI, −5.3 to −0.8; P = 0.0086) in favour of LCIG. Conversely, no statistically significant difference in the UPDRS Part III score was reported. The adjusted LSMD in change from baseline was 1.4 (95% CI, −2.8 to 5.6; P = 0.5020). Details regarding the UPDRS and its individual parts in Study 001/002 are provided in Table 18. (Only parts II and III were adjusted for multiple statistical testing.)

Table 18. Summary of Unified Parkinson’s Disease Rating Scale.

Table 18

Summary of Unified Parkinson’s Disease Rating Scale.

Open-Label, Non-Comparative Study (Study 004)

Overall, UPDRS II scores decreased from baseline to the last study visit (−4.4 [SD 6.5], P < 0.001). Other UPDRS score values were not reported. Details pertaining to the change in UPDRS scores during Study 004 are presented in Table 18. The UPDRS end points in Study 004 were not corrected for multiple statistical testing.

EuroQol 5-Dimensions 3-Levels Questionnaire

Double-Blind, Randomized Controlled Trial

The EQ-5D-3L summary index score was also evaluated as a secondary outcome in Study 001/002. The adjusted LSMD in change from baseline was 0.07 (95% CI, −0.01 to 0.15; P = 0.0670). The EQ VAS (not adjusted for multiple statistical testing) was also evaluated and the adjusted LSMD in change from baseline was 11.4 (95% CI, 4.0 to 18.9; P = 0.0033). Details regarding the EQ-5D-3L in Study 001/002 are provided in Table 19.

Table 19. Summary of EuroQol 5-Dimensions 3-Levels Questionnaire.

Table 19

Summary of EuroQol 5-Dimensions 3-Levels Questionnaire.

Open-Label, Non-Comparative Study (Study 004)

Overall, the EQ-5D-3L summary index score increased from baseline to the last study visit (0.064 [SD 0.203]; P < 0.001). The EQ VAS also increased from baseline to the last study visit (14.0 [SD 24.8]; P < 0.001). Details pertaining to the change in EQ-5D during Study 004 are presented in Table 19. The EQ-5D end points in Study 004 were not corrected for multiple statistical testing.

Zarit Burden Interview

Double-Blind, Randomized Controlled Trial

The ZBI total score was also evaluated as a secondary outcome in Study 001/002. The adjusted LSMD in change from baseline was −4.5 (95% CI, −10.7 to 1.7; P = 0.1501). Details regarding the ZBI in Study 001/002 are provided in Table 20.

Table 20. Summary of Zarit Burden Interviews.

Table 20

Summary of Zarit Burden Interviews.

Open-Label, Non-Comparative Study (Study 004)

No details with regards to the ZBI were provided in Study 004.

Harms

Only those harms identified in the review protocol are reported in Table 4. Detailed harms data are presented in Table 21.

Table 21. Harms.

Table 21

Harms.

Double-Blind, Randomized Controlled Trial

Adverse Events

Overall, 95% and 100% of patients experienced AEs in the LCIG + PBO IR OLC capsules group and the PBO LCIG + IR OLC capsules group, respectively. The frequencies of AEs were relatively similar across treatment groups. The most common AEs were fall (11% versus 12%), atelectasis (8% versus 0%), anxiety (8% versus 3%), confusional state (8% versus 3%), oedema peripheral (8% versus 0%), oropharyngeal pain (8% versus 0%), and upper respiratory tract infection (8% versus 0%) in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively.

Serious Adverse Events

Fewer patients experienced SAEs in the LCIG + PBO IR OLC capsules group compared with the PBO LCIG + IR OLC capsules group (14% versus 21%, respectively). The most common SAEs were confusional state (5% versus 0%) and pneumonia (0% versus 6%) in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively.

Withdrawals Due to Adverse Events

Overall, one patient (3%) and two patients (6%) withdrew due to AEs in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively. The most common reasons were hallucination (3% versus 0%), psychotic disorder (3% versus 0%), peritonitis (0% versus 3%), post-procedural complication (0% versus 3%), and post-procedural discharge (0% versus 3%) in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively.

Mortality

No deaths were reported in Study 001/002.

Notable Harms

Most patients experienced device-related complications across both treatment groups (92% and 85% in the LCIG + PBO IR OLC capsules group and PBO LCIG + IR OLC capsules group, respectively).

Overall, 76% compared with 79% of patients and 57% compared with 56% of patients experienced long-term complications of PEG-J and risks of PEG-J insertion in the LCIG + PBO IR OLC capsules group and the PBO LCIG + IR OLC capsules group, respectively. The most common long-term complications of PEG-J were complication of device insertion (57% versus 44%), procedural pain (30% versus 35%), and incision-site erythema (19% versus 12%), while the most common risks of PEG-J insertion were abdominal pain (51% versus 32%) and pneumoperitoneum (11% versus 3%) in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively.

In general, a similar number of patients (70% compared with 71%) experienced GI AEs, the most common being nausea (30% versus 21%), constipation (22% versus 21%), and flatulence (16% versus 12%) in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively.

More patients experienced psychiatric disorders in the LCIG + PBO IR OLC capsules group compared with the PBO LCIG + IR OLC capsules group (46% compared with 29%). The most common were depression (11% versus 3%), insomnia (11% versus 12%), anxiety (8% versus 3%), and confusional state (8% versus 3%) in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively.

A total of 3% and 9% of patients experienced polyneuropathy and associated signs and symptoms, the most common reason being balance disorder (3% compared with 6%) in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively.

Fewer patients experienced nervous system disorders in the LCIG + PBO IR OLC capsules group compared with the PBO LCIG + IR OLC capsules group (30% compared with 47%). The most common were dyskinesia (14% versus 12%), dizziness (8% versus 6%), and headache (8% versus 12%) in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively.

In general, a similar number of patients (22% compared with 27%) experienced vascular disorders, the most common being orthostatic hypotension (14% versus 24%) and hypertension (8% versus 0%) in the LCIG + PBO IR OLC capsules and PBO LCIG + IR OLC capsules groups, respectively.

Open-Label, Non-Comparative Study (Study 004)

Nearly all (92%) patients experienced at least one AE. The most frequently reported AEs were nausea, fall (15%), constipation (15%), insomnia (14%), and urinary tract infection (11%). SAEs were reported in 32% of patients, the most common reasons being complication of device insertion (7%), abdominal pain (3%), peritonitis (3%), polyneuropathy (3%), PD (3%), pneumoperitoneum (3%), hip fracture (2%), pneumonia (2%), device dislocation (2%), and depression (1%).

Overall, 27 patients discontinued the trial due to AEs. Five patients (2%) withdrew during the NJ period and 22 patients (7%) withdrew during the PEG-J period. The most common reasons for discontinuation were complications of device insertion (2%) and procedure- or device-related AEs (2%).

A total of eight deaths occurred during Study 004; however, none were considered by the investigators to be related to the study drug.

The majority of patients (87%) experienced device-related complications, most of which were intestinal tube-related (51%). Furthermore, the majority (69%) also experienced procedure- and/or device-related AEs. The most frequently reported notable harms were complication of device insertion (34%), abdominal pain (27%), procedural pain (20%), excessive granulation tissue (15%), post-operative wound infection (15%), incision-site erythema (13%), procedural-site reaction (9%), post-procedural discharge (8%), incisionsite pain (6%), and pneumoperitoneum (6%). Aspiration-related AEs occurred in 15% of patients and polyneuropathy-related AEs occurred in 7% of patients.

Copyright © 2018 Canadian Agency for Drugs and Technologies in Health.

The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

Bookshelf ID: NBK539553
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