New Evidence Identified in the Current Review

A total of 20 trials met the inclusion criteria of the CDR systematic review.

Efficacy

Compared with the IR OLC group, the LCIG group had a statistically significant reduction in daily normalized “off” time at week 12 (the primary outcome) based on their Parkinson disease diary entries. Overall, “off” time was identified as being among the most important end points by the patient groups who provided input for this CDR submission. Sensitivity analyses of the primary end point using MMRM and those requested by the FDA considering different approaches (including and excluding certain covariates) to the primary ANCOVA analysis were also consistent with the primary analysis. The robustness of the treatment effect was also noted by the FDA.^53,67,68 Although not provided in the manufacturer’s submission, the FDA conducted a worst-case analysis in which the data for the primary end point were imputed with the overall mean average baseline “off” time for the dropouts in the LCIG group, and with the overall mean average “off” time at week 12 for those in the OLC group. Overall, the results were also consistent with those of the primary analysis (P = 0.0046).^53,67,68 Despite the robustness of the primary end point, the FDA also noted that a decrease in “off” time is a somewhat indirect outcome, given that it may not necessarily lead to desirable outcomes — for example, if the decrease in “off” time was replaced with an increase in “asleep” time or “on” time with troublesome dyskinesia.^53,67,68

The evaluation of “off” time as the primary end point in Study 001/002 was supported by the evaluation of a key secondary end point (adjusted for multiple statistical testing): “on” time without troublesome dyskinesia (a composite of “on” time without dyskinesia and “on” time with non-troublesome dyskinesia). Improvement in functional “on” time is considered by the FDA as the most important end point for treating patients with motor fluctuations and is said to provide a better indication of improvement in patient functioning.^53,67,68 Furthermore, the patient input submitted for this review highlighted the importance of “on” time as a desirable outcome. Overall, the LCIG group also had a statistically significant improvement in daily normalized “on” time without troublesome dyskinesia at week 12. The results were primarily driven by the increase in “on” time without dyskinesia, whereas the change in “on” time with non-troublesome dyskinesia was not statistically significant. These results support the benefit in “on” time associated with LCIG treatment, especially because the results are being driven by the more desirable component (“on” time without dyskinesia). Although statistical analyses demonstrate that there is no statistically significant difference in “on” time with troublesome dyskinesia was reported between the two groups, it should be noted that Study 001/002 was not powered to detect a difference in this end point. Similar observations were also noted by the FDA.^53,67,68

In general, the PDHD has been shown to demonstrate acceptable predictive validity in the assessment of the amount of “on” and “off” time that patients experience in a 24-hour period. 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. The PDHD has also demonstrated good reproducibility, test–retest reliability, and precision. One study conducted by Hauser et al. suggests that a one-hour reduction in “off” time was considered to be an MCID in actively treated patients.⁶¹ Given that the benefit associated with LCIG treatment exceeds the reported MCID −1.00 hour, the improvement in “off” time reported in Study 001/002 is considered clinically meaningful. No MCID was identified for the change in “on” time.

Although the study protocol indicated that primary end point analyses would be performed for the subgroups of patients with PD for a duration of ≤ 10 years and ≥ 10 years, the results of these analyses were not provided in the manufacturer-submitted materials. An examination of the interaction of treatment by duration of PD was conducted by the FDA; the result suggested that the interaction was not statistically significant (P = 0.135).^53,67,68 However, Study 001/002 was not powered to detect a difference in the subgroups of patients with PD for a duration ≤ 10 years and ≥ 10 years.

Overall, randomization appeared to be successful; however, patients experienced less “off” time and less “on” time at baseline in the LCIG + PBO IR OLC capsules group, which may indicate less severe PD. Given that PD is a degenerative disease, patients with more severe PD may not benefit from treatment to the same extent as those with less severe disease. Limiting the benefit in the PBO LCIG + IR OLC capsules group could potentially result in overestimating the 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. Furthermore, compliance with the active IR OLC capsules in the PBO LCIG + IR OLC capsules group was 76%. Patients who were not compliant with the IR OLC capsules in this treatment group would not receive any PD therapies (i.e., only 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 inadvertently have been 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 also evaluated aspects of health not captured under general health questionnaires that may be relevant to patients with PD using the PDQ-39 summary index score (adjusted for multiple statistical testing). Overall, the PDQ-39 has been validated and demonstrated to be comprehensive, feasible, responsive, and reliable, with good internal consistency and test–retest reliability. Findings from one study conducted by Peto et al. showed a mean MCID of −1.6 for the summary index score.⁶² In Study 001/002, LCIG was associated with a statistically significant reduction in the summary index score compared with IR OLC. Given that the benefit associated with LCIG treatment exceeds the reported MCID (−1.6), the improvement in PDQ-39 summary index score is considered clinically meaningful. Overall, the results of the individual domains score were consistent with the summary index score. Although scores for the individual domains of the PDQ-39 were also provided, they were not adjusted for multiple statistical testing and should be considered hypothesis-generating.

The CGI-I was also evaluated in Study 001/002 and provided an overall assessment of the clinician’s view of the patient’s global functioning, which is used to compare before- and after-treatment changes. Patients treated with LCIG experienced a statistically significant reduction in the CGI-I scale compared with patients in the IR OLC group. Although the CGI-I was validated and demonstrated correlation with the Hoehn and Yahr stage, no information was found on the MCID; therefore, the clinically meaningfulness of the results remains unclear.

The UPDRS was also analyzed in Study 001/002. The UPDRS is a standard investigator rating tool for measuring parkinsonian signs and symptoms. Only parts II and III of the UPDRS were part of the testing hierarchy (adjusted for multiple statistical testing). Overall, the UPDRS has been validated and demonstrated to be feasible and reliable. Furthermore, Parts II and III specifically have shown good inter-rater reproducibility. Among available studies, the estimated MCID for the ADL component (Part II) and motor component (Part III) were −2.3 and −6.5 points in patients with advanced PD, respectively.⁶³ Compared with IR OLC capsules, LCIG was associated with a statistically significant reduction in the UPDRS Part II score. Given that the benefit associated with LCIG treatment exceeds the reported MCID (−3.0 and −2.3, respectively), the improvement in the UPDRS Part II is considered clinically meaningful. Conversely, no statistically significant difference in the UPDRS Part III score was reported between the two treatment groups. Study 001/002 also evaluated other components of the UPDRS (Part I, Part IV, Part I, II, and II summary score as well as questions 32, 33, and 34 only in Part IV). Given that these end points were not adjusted for multiple statistical testing, no statistical interpretation should be made; therefore, the clinical importance of these changes remains unclear.

Study 001/002 also evaluated HRQoL using the EQ-5D-3L and caregiver burden using the ZBI. The adjusted LSMD from baseline to week 12 in both the EQ-5D-3L summary index score and the ZBI total score were not statistically significant across treatment groups. The results for the EQ VAS should be considered exploratory; the clinical importance of these changes remains unclear given that this end point was not considered in the statistical testing hierarchy.

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) that provided longer-term safety and efficacy associated with LCIG therapy. Study 003 (summarized in Appendix 6) began immediately after Study 001/002. All patients (N = 62) were hospitalized and re-titrated to the optimum LCIG dose for two to seven days, after which they continued on open-label LCIG infusion for the remainder of the 52 weeks. The LCIG intervention was administered in a similar manner as Study 001/002 — i.e., continuous infusion during the day (for approximately 16 hours) and cessation at night, when all patients were permitted to take rescue IR OLC if medically indicated. The primary objective was to evaluate the long-term safety of LCIG based on the frequency and severity of AEs; however, efficacy and QoL were also evaluated as secondary end points. In general, LCIG-naive patients (i.e., those treated with active IR OLC capsules in Study 001/002) experienced a significant reduction in daily normalized “off” time at week 52 compared with their baselines, while LCIG-experienced patients (i.e., those treated with active LCIG in Study 001/002) continued to experience reduced daily normalized “off” time at week 52. The change from baseline to week 52 in “on” time without troublesome dyskinesia (a composite of “on” time without dyskinesia and “on” time with non-troublesome dyskinesia) was also evaluated in Study 003. In general, improvement was reported in both LCIG-naive patients and LCIG-experienced patients in daily normalized “on” time without troublesome dyskinesia at week 52. Although the efficacy results of Study 003 were consistent with the results observed in Study 001/002, it is important to note the limitations, which include uncontrolled open-label study design and the fact that the trial enrolled patients who were deemed likely to benefit from LCIG.

Longer-term safety and efficacy associated with LCIG therapy were also evaluated in Study 004 (54-week follow-up) which included a much larger sample of patients (N = 354) compared with Study 003. The LCIG intervention was administered in a manner similar to Study 001/002 — i.e., continuous infusion during the day (approximately 16 hours) and cessation at night, when all patients were permitted to take IR OLC if medically indicated. In general, patients experienced a significant reduction in daily normalized “off” time at week 54 compared with their baselines. The change from baseline to week 54 in “on” time without troublesome dyskinesia (a composite of “on” time without dyskinesia and “on” time with non-troublesome dyskinesia) was also evaluated in Study 004. In general, improvement was also reported in daily normalized “on” time without troublesome dyskinesia at week 54.

Patients who completed either Study 003 or Study 004 were eligible to enroll into Study 005 (N = 262), a prospective, open-label, non-comparative trial that evaluated the safety and efficacy of LCIG with up to 6.9 years of follow-up. The LCIG intervention was administered in a manner similar to that of Study 001/002 — i.e., continuous infusion during the day (approximately 16 hours) and cessation at night, when all patients were permitted to take IR OLC if medically indicated. The primary objective was to evaluate the long-term safety; however, efficacy and QoL were also evaluated as secondary end points. Overall, efficacy and safety were consistent with the results observed in Study 001/002; however, as with Study 003, it is important to note the limitations, which include uncontrolled open-label study design and the fact that the trial enrolled patients who were deemed likely to benefit from LCIG.

A total of 16 other prospective, open-label, non-comparative trials were also identified in the CDR systematic review.^10–25 The efficacy results of the open-label trials were similar to the results observed in Study 001/002; however, the limitations were similar to those of Study 001/002.

Harms

Given that LCIG is administered through a PEG-J tube, harms that should be considered include complications related to the device (e.g., its pump and tubes), the administration of LCIG, and the procedures required for the initial insertion, possible replacement, or repositioning of the PEG-J tube.^53,67,68

A similar proportion of patients experienced AEs across both treatment groups. The most common AEs were fall, atelectasis, anxiety, confusional state, oedema peripheral, oropharyngeal pain, and upper respiratory tract infection. More patients experienced SAEs in the PBO LCIG + IR OLC capsules group compared with the LCIG + PBO IR OLC capsules group. The most common SAEs were confusional state and pneumonia. Overall, few patients withdrew due to AEs in both groups. The most common reasons were hallucinations, psychotic disorder, peritonitis, post-procedural complication, and post-procedural discharge. No deaths were reported in Study 001/002.

Most patients experienced device-related complications in both treatment groups. Overall, a similar proportion of patients experienced long-term complications of PEG-J and risks related to PEG-J insertion. The most common long-term complications of PEG-J were complication of device insertion, procedural pain, and incision-site erythema, while the most common risks of PEG-J insertion were abdominal and pneumoperitoneum. In general, a similar number of patients also experienced GI AEs, the most common being nausea, constipation, and flatulence. More patients experienced psychiatric disorders in the LCIG + PBO IR OLC capsules group compared with the PBO LCIG + IR OLC capsules group. The most common were depression, insomnia, anxiety, and confusional state, which are typically associated with levodopa. A minority of patients experienced polyneuropathy and associated signs and symptoms, the most common reason being balance disorder. Fewer patients experienced nervous system disorders in the LCIG + PBO IR OLC capsules group compared with the PBO LCIG + IR OLC capsules group. The most common were dyskinesia, dizziness, and headache. In general, a similar number of patients experienced vascular disorders, the most common being orthostatic hypotension and hypertension.

Device insertion, abdominal pain, pneumoperitoneum, nausea, and depression were notable AEs that occurred more frequently in the LCIG + PBO IR OLC capsules group compared with the PBO LCIG + IR OLC capsules group, while post-operative wound infection, vomiting, and orthostatic hypotension occurred more frequently in the PBO LCIG + IR OLC capsules group. However, given the small sample size of Study 001/002, it is difficult to make any definitive conclusions in regard to safety.

Generally, serious and non-serious AEs reported in Study 001/002 were consistent with the known AE profile of levodopa/carbidopa (e.g., depression, anxiety, confusion) and of PD patients who have undergone the PEG-J procedure. Further, the comparator group in Study 001/002 included levodopa/carbidopa as a treatment; thus, between-treatment differences in AE related to levodopa/carbidopa were not expected. It is theoretically possible that continuous infusion may result in a reduced frequency of total or specific drug-related AEs by minimizing peaks and troughs in levodopa plasma levels in the same way motor complications of levodopa may be reduced.⁷¹ However, the included trials are likely too small to detect many potential differences.

The primary objective of Study 003 was to evaluate the long-term safety of LCIG based on the frequency and severity of AEs after 12 months of treatment. Similar to Study 001/002, most patients experienced AEs that were consistent with the safety profiles of levodopa/carbidopa and the PEG-J procedures. Overall, no new safety signals were identified after one year of treatment. Safety results reported in Study 004 and in Study 005 also highlighted that most patients experienced AEs that were consistent with the safety profiles of levodopa/carbidopa and the PEG-J procedures, with no new safety signals following up to five years of treatment. A total of 16 other prospective, open-label, non-comparative trials were also identified in the CDR systematic review and were supportive of the results from Study 004 and Study 005.^10–25

Other Considerations

The Health Canada–approved product monograph indicates that the PEG-J tube required for the administration of LCIG will likely require periodic replacement (emergency tube replacement as well as routine standard of care).⁹ The Health Canada–approved product monograph indicates that a total of 14% of patients required at least one PEG tube replacement and 43% of patients required one J-tube replacement.⁹ Approximately half of the patients who had at least one J-tube replacement also required a subsequent J-tube replacement.⁹

Patients who undergo the PEG-J procedure require antibiotic prophylaxis given that they are potentially at risk for post-operative peristomal infections. The Health Canada–approved product monograph indicates that a total of 21% of patients had post-operative AEs related to wound infection.⁹ Antibiotic prophylaxis has been shown to markedly reduce the risk of peristomal infection; therefore, it is recommended for all patients undergoing PEG-J placement.⁹

Currently the only available treatment option for patients with more advanced PD is DBS, a surgery in which a high-frequency current is delivered through electrodes inserted deep into the brain. The 2009 CDR review noted that DBS is likely the most relevant comparator, given that both LCIG and DBS will likely be indicated for similar patient populations and that access to both treatments would also likely be similar (i.e., not available in all centres). However, no trials comparing LCIG and DBS were identified in either the previous (2009) or current CDR systematic review.

Potential Place in Therapy²

Since its introduction into clinical practice almost 50 years ago, levodopa remains the most effective treatment for the motor manifestations of PD. However, levodopa is only a symptomatic treatment. It does not slow the underlying neurodegenerative process of PD; the number of functioning nigrostriatal pathway neurons continues to decline. As the number of remaining functioning nigrostriatal neurons falls, the midbrain’s ability to convert levodopa to dopamine — and thereby stimulate the striatum — becomes increasingly impaired. Clinically, this decline in the nigrostriatal neuron population is experienced by patients as a gradual transition from the initial months or years in which levodopa produces a sustained, continuous improvement in motor function to a state in which individual doses of levodopa produce increasingly shorter periods of improvement that wear off quickly. As PD advances, the patient increasingly alternates between “on” periods, when they are mobile, and “off” periods, when they are immobile. Generally, the fluctuation between the “on” and “off” states can be related to when individual doses of levodopa are administered. To some extent, these fluctuations can be minimized by spacing levodopa doses closer together and using additional drugs, such as sustained-release levodopa preparations, drugs that inhibit the metabolism of levodopa, or direct dopamine agonists (the latter generally have a longer duration of action than levodopa, but are also generally less effective). For relatively rapid relief of fluctuations, particularly those that occur unpredictably, injectable apomorphine is another option. Although patients can learn to adapt to these fluctuations to some extent, the fluctuations can be unpredictable, severe, and have a major impact on their ability to carry out ADL.

A key limitation of oral pharmacological strategies for managing “on” and “off” fluctuations is the suboptimal absorption of the drugs from the GI tract. This is particularly problematic for levodopa, which must compete with other small amino acids to gain access to the same small-amino-acid transporter in the gastric mucosa in order to pass from the lumen of the stomach into the bloodstream. LCIG alleviates this problem because levodopa is delivered directly to the jejunum through a jejunostomy tube. In addition to improving the reliability of levodopa absorption, the jejunostomy tube allows the patient to absorb levodopa at a more or less constant rate. This implies that levodopa can be delivered to the brain at a relatively constant rate, which is presumed to help patients achieve a more normal physiological state. In patients treated with LCIG, it is generally possible to reduce or even discontinue the oral medications the patient was previously receiving.

The patient most likely to benefit from LCIG is one with moderately advanced levodopa-responsive PD (disabled, but ambulatory and at least semi-independent) whose waking hours are characterized by frequent fluctuations between the “on” and “off” states despite receiving optimized therapy with existing drugs. Identifying a patient as such would be part of routine neurological follow-up. In some centres, where neurosurgical expertise is available, DBS might be considered an option in such patients. In some instances, the patient’s wishes or general medical condition may make either DBS or jejunostomy tube placement impossible, and the only option may be to continue on optimized oral medication. The potential benefits of LCIG would need to be weighed against the inconvenience and potential complications of insertion and living with a jejunostomy tube and infusion pump. The jejunostomy tube insertion requires collaboration with an endoscopist (gastroenterologist or surgeon), implying added cost to the health care system; follow-up of patients requires some expertise with the maintenance of the infusion pump. Otherwise, the use of Duodopa would not require any new or specific diagnostic testing. At follow-up visits, the patient’s functional status would be assessed to ensure that LCIG is still providing benefit. If in doubt, the infusion rate could be reduced and the impact on function observed directly, usually during a day-long clinic visit.