1. Brief Description of Patient Group(s) Supplying Input

Three patient groups submitted input for this CADTH Common Drug Review (CDR): the Parkinson Association of Alberta (PAA), the Parkinson Society British Columbia (PSBC), and Parkinson Canada (PC).

PAA is an Alberta-based, registered charitable organization that provides support services, education, information/resources, referrals, and programs to patients with Parkinson disease (PD) and/or a Parkinson-plus syndrome, their families and care partners, health care professionals, community partners, and the general public. PAA funds innovative research in support of PD and receives its funds in the form of donations and fundraising activities.

PSBC was established in 1969 and provides advocacy, education, research, and support services for patients with PD. This organization receives donations from individuals, members, corporations, foundations, and fundraising.

PC is a national registered charity established in 1965 that provides advocacy, support services, and education for people living with Parkinson disease, their families, and their health care professionals. It also funds research programs for better treatments and a cure for PD.

None of the organizations declared any conflict of interest, other than receiving financial support from AbbVie in the past two years. PAA received between $10,001 and $50,000; PC and PSBC each received between $5,001 and $10,000.

2. Condition-Related Information

All three organizations gathered information through surveys (online or otherwise) and telephone or in-person interviews:

• PAA conducted a province-wide online survey between February 23, 2018 and March 1, 2018 that resulted in 41 responders. All but one responder were from Alberta; the majority were living in urban areas (49%) and had PD (68%); the rest were their care partners. Telephone interviews were conducted to collect information from 10 PD patients and their caregivers (five each) who had experience with Duodopa.
• PSBC conducted a provincial online survey and had 56 responders, including patients with advanced PD and their care partners. In addition, personal interviews were conducted with five patients who received Duodopa and their caregivers.
• PC conducted a survey between June 2017 and July 2017 with more than 850 responders representing all provinces and territories, of which 61% were patients with PD; the remainder were caregivers. Furthermore, 11 telephone interviews were conducted to gather information on Duodopa use.

PD is a progressive neurodegenerative disease of the nervous system that manifests in an inability to move normally; symptoms vary across patients. The most common symptoms are tremor while at rest, rigidity, slowness of movement, postural instability, and swallowing problems. Other symptoms include hypomimia, hypophonia, micrographia, changes in mind, mood, and memory, difficulties with sleep, constipation, pain, and fatigue. These symptoms negatively affect patients’ overall quality of life (QoL) as well their confidence and independence, socialization, relationships, recreational and everyday activities, and work. A distinct problem that many PD patients experience is “off” episodes, predominantly resulting from medication “wearing off” (i.e., the effect of medication stops), causing a resurgence of motor and non-motor Parkinson’s symptoms (e.g., freezing episodes, tremor, mood swings, panic attacks, etc.). These “off” episodes can vary in frequency and are not always predictable; therefore, significant preplanning is required. When asked to rank the PD symptoms that the patients considered most important to control or manage, patients in the PC survey responded with the following outcomes: slowness and stiffness, impaired balance, cognitive changes and memory, and rigidity of the muscles. On the other hand, the PAA survey responders reported that mood changes and difficulties with sleeping, swallowing, and speech were the most important symptoms to control, also indicating cognitive impairments and bladder and bowel issues.

“I spend approximately 65% of my waking day in the ‘off’ state when my medication is not working. This causes me to have difficulty moving independently, feeding myself, and performing basic tasks. The 35% I manage in the ‘on’ state is with troublesome dyskinesia, very violent movements that again prevent me from doing most activities.”

“I suffer from rigidity, bradykinesia, dystonia, tremor, and more recently, freezing while off. I fell and hurt my hip recently due to a freezing episode in the night when I was up to the washroom. Due to my low weight and new freezing, there is a real concern of a serious fall resulting in a fracture, which could lead to a further decline in my condition and the need for community support or an increased level of care.”

“I have a hard time with all aspects of daily life (recreational, meal prep, have to cancel planned activities with family and friends) because of the following: very low energy, fall asleep unexpectedly, emotional, difficulty walking for prolong period, hard time moving my body at night in bed.”

3. Current Therapy-Related Information

Currently available therapies to minimize PD symptoms include pharmacotherapy (e.g., levodopa, carbidopa), non-pharmacotherapy (e.g., deep brain stimulation [DBS]), rehabilitation therapy (e.g., physiotherapy, occupational therapy, speech therapy, and exercise) and psychotherapy (e.g., counselling). A balance between the side effects and benefits of the treatments often becomes more difficult with time as the disease progresses.

“The difference between optimal versus ineffective therapy may be the difference between a nursing home and independent living.”

The majority of respondents were on oral medications as part of their treatment options. While medications were necessary to control symptoms and improve functioning, a number of side effects were reported, including disturbed sleep, nausea, constipation, dyskinesia, fatigue, and hallucinations. Others reported difficulties in administering treatment, including overdosing, swallowing, pain, reduced impulse control, and interference with protein-based food. In addition, an increasing reliance on treatment and adjustments in dosage were necessary with disease progression. Due to complicated, frequent, and variable dosing throughout the day (based on symptom severity and fluctuations between “on” and “off” states), compliance with treatment is difficult to ensure.

Rehabilitation and counselling sessions were a common form of therapy among patients to support their physical and mental well-being; however, lack of motivation, wait times, and difficulties with communication were reported as a drawback of these therapies. In addition, treatment “wearing off” was reported to occur more quickly with vigorous exercise or intensive mental activity.

DBS is a surgically implanted neurostimulator (similar to a heart pacemaker) that delivers electrical stimulation to targeted areas in the brain that control movement, blocking the abnormal nerve signals that cause tremor and other PD symptoms. While DBS restores patients’ ability to work and reduces or eliminates the need for medication, there is a considerable waitlist for the treatment. In some cases, the wait may be to five years, by which time a patient may no longer be an eligible candidate due to worsening symptoms.

Duodopa is a levodopa and carbidopa combination in the form of a gel that is delivered continuously throughout the day with a pump through a percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) tube. This type of treatment is intended for use in patients with advanced PD who have severe and disabling motor symptoms that cannot be well controlled with currently available therapies. While this form of treatment results in a reduction in PD symptoms and fluctuations in “on” and “off” times, a number of factors significantly limit its accessibility to patients, including: the high cost of treatment, multiple hospital visits for surgery and titration, long wait-lists, lack of integration between PD specialists and general health care providers, and a shortage of appropriate health care professionals, particularly outside of big cities.

“Cost, constantly travelling to drug store to pick up something as the insurance company only releases the coverage dependent of the individual cost. Very frustrating to have to drive back and forth 4x to get the pills I need for my husband every month.”

4. Expectations About the Drug Being Reviewed

Survey respondents expected a number of improvements that current therapies do not presently provide, either adequately or at all. A common expectation of new treatments across the patient groups was durable response that lasts longer and limits or eliminates “off” episodes. The majority of patients also highlighted their desire to have improved PD symptoms while minimizing treatment-associated side effects, such as dyskinesia, constipation, hallucination, sleep disturbances, and dystonia.

“My main focus is on quality of life and I weigh the benefit of the treatment in terms of having less off periods and the ability to enjoy life as fully as possible.”

“Medication that takes more rapid effect, does not lose its effectiveness before the next dose is due (effectiveness wears off), and is more effective in treating inertia (freezing) and inability to walk; also medication to permit intelligible and normal speech. These improvements would enable more normal mobility and communication with family and others.”

Patients included in the surveys who had experience with Duodopa had received it through provincial insurance or their neurologists. The clinical benefit of Duodopa was a common theme among all experienced responders. Patients reported that Duodopa had an instantaneous effect on their physical symptoms, including a reduction in dyskinesia and stiffness and improvements in speech, walkability, and balance. The use of Duodopa resulted in a decrease in (or the complete elimination of) “off” times. It also replaced oral medications entirely or partially reduced the dosage, resulting in more time for patients to travel, socialize, perform chores, and engage in pastimes, thereby improving their overall QoL.

A few side effects were noted by some patients, including constipation, frequent freezing, dizziness, and headache. Duodopa was considered relatively easy to use compared with oral medications or prior therapies; however, a few discomfort-causing issues related to the device or procedure were reported. Notably among these were the size and weight of the pump, difficulty when dressing, special consideration when showering or swimming, the need to clean the tube daily, the need to change the battery regularly, and infections and itchiness at the stoma. In addition, travelling was inconvenient, as cassettes need to be refrigerated. However, patients unanimously stated that the clinical benefits outweighed the side effects and complications related to the device or the procedure.

“It’s made a huge difference in my quality of life. This doesn’t fix Parkinson’s, but because the medication goes directly into my brain in small doses every minute, it evens things out more, and I’m not tied to my watch.” The care partner of this patient stated- “Now she has less dyskenisa and can press a button and the tremor goes away in 15-20 minutes. No more watch, life is good. I spend 5 minutes in the morning getting a new cartridge and 5 minutes at night flushing the tubes. That’ is it.”

“I’m always ‘on’ when I am plugged in to my pump! I have energy and motivation to try and live a reasonably normal life. It’s miraculous! My mood is much better knowing that the medication is infusing into me at a regular, constant rate; I don’t have to wonder if the next dosage of oral meds is going to get absorbed and work for me.”

5. Additional Information

Given the nature of PD symptoms, almost all aspects of patients’ lives are affected by the disease. Access to medications that minimize symptoms, side effects, and unpredictable “off” periods are crucial to patients’ daily functioning and QoL. Given its exceptional benefits, the request for coverage for Duodopa was shared by all patient groups to ensure its affordability and accessibility, which would otherwise pose a significant economic burden on the patients and their families, since many of them have to leave the workforce or reduce their work hours as the disease progresses.