Study to Evaluate the Efficacy of Rotigotine on Parkinson's Disease-Associated Pain

A Multicenter, Multinational, Double-Blind, Placebo-Controlled, 2-Arm Study to Evaluate the Efficacy of Rotigotine on Parkinson's Disease-Associated Pain

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01744496

Acronym

DOLORES

Enrollment

Registered

2012-12-06

Start date

2012-11-30

Completion date

2014-01-31

Last updated

2015-05-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Advanced Idiopathic Parkinson's Disease

Keywords

Parkinson's Disease, Rotigotine, Chronic Pain, Nonmotor symptoms

Brief summary

This trial is being conducted to compare the impact of Rotigotine and Placebo on Chronic Pain associated with Parkinson's Disease among patients with advanced stages of the disease.

Interventions

DRUGRotigotine

Patches will contain 4 mg / 24 h (20 cm\^2), 6 mg/ 24 h (30 cm\^2), or 8 mg /24 h (40 cm\^2) of Rotigotine. Application of study medication starts at the Baseline Visit. Rotigotine will be administered once daily starting at 4 mg / 24 h. Doses will then be up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) is reached and the Maintenance Period can be started. The duration of the Titration Period will vary from 1 to 7 weeks ± 3 days. The Maintenance Period will last 12 weeks ± 5 days. Thereafter, during the De-escalation Period, the dose of study medication will be decreased by 2 mg / 24 h every other day. The De-escalation Period may last up to 12 days.

DRUGPlacebo

Placebo patches match the size of active patches 20 cm\^2, 30 cm\^2, or 40 cm\^2 and will contain Placebo. Application of Placebo patches starts at the Baseline Visit. Placebo patches will be administered once daily starting with the equivalent of 4 mg / 24 h. Doses will then be up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose is reached. The maximum dose is the equivalent to 16 mg / 24 h. The duration of the Titration Period will vary from 1 to 7 weeks. The Maintenance Period will last 12 weeks ± 5 days. During the De-escalation Period, the dose of Placebo will be decreased by the equivalent to 2 mg / 24 h every other day. The De-escalation Period may last up to 12 days.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Patient has advanced idiopathic Parkinson's Disease associated chronic pain assessed by a Likert Pain Scale * Patient is taking Levodopa with a stable daily dose of at least 200 mg for at least 21 days prior to start * Hoehn and Yahr stage score of II to IV * Mini-Mental State Examination (MMSE) score ≥ 25 * If an antidepressant drug is taken, the dose must be stable for at least 21 days

Exclusion criteria

* Therapy with a Dopamine Agonist within 21 days prior to start * Discontinuation from previous Dopamine Agonist Therapy due to lack of efficacy * Therapy with Dopamine-modulating substances 21 days prior to start * Therapy with analgesics for the treatment for pain, unless the dose has been stable * Chronic alcohol or drug abuse * Medical or psychiatric condition that, in the opinion of the investigator, could jeopardize or would compromise the patient's ability to participate in this study * Hypersensitivity to any components of the Investigational Medicinal Product (IMP) or comparative drugs * Atypical Parkinson's Disease Syndrome due to drugs * History of deep brain stimulation * Significant skin disease that would make transdermal drug use inappropriate * Electroconvulsive therapy within 12 weeks prior to start * Evidence of an Impulse Control Disorder * Previous diagnosis of severe Restless Legs Syndrome * Chronic Migraine * Severe Depression * Symptomatic Orthostatic Hypotension

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline to the End of the Maintenance Period in Pain Severity Assessed Using an 11-point Likert Pain Scale	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after an up to 7 weeks Titration Period)	An 11-Point Likert Scale was used to assess patients' average daily pain. The subject rated his/her average pain from 0 (no pain) to 10 (worst pain ever experienced). The average pain experienced in the last 7 days was calculated by the mean of the daily Likert Pain Scores within the 7 days prior to the respective visit (ie, Likert Pain Scores with a date of assessment before the date of visit and on or after the date of visit - 7 days). A negative value indicates an improvement.

Secondary

Measure	Time frame	Description
Change From Baseline to the End of the Maintenance Period in the Sum Score of the 8-Item Parkinson's Disease Questionnaire (PDQ-8)	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)	The 8-Item Parkinson's Disease Questionnaire (PDQ-8) (Peto et al, 1998) is a self-administered questionnaire that provides a reliable measure of overall health status. The PDQ-8 contains 8 items of daily living, with 1 item selected from each of the following 8 scales: mobility, Activities of Daily Living (ADL), emotional well being, stigma, social support, cognitions, communication, and bodily discomfort. The total PDQ-8 score is the sum of all the individual items converted to a summary index score between 0 and 100, with lower scores indicating better health. A negative value indicates an improvement.
Change From Baseline to the End of the Maintenance Period in the 7-Item Depression Subscore of the Hospital Anxiety and Depression Scale (HADS)	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)	The Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983) is a 14-item self-assessment scale for detecting states of depression and anxiety in the setting of a hospital medical outpatient clinic. It comprises a 7-item anxiety subscale and a 7-item depressive subscale that are also measures of severity of the emotional disorder. The 14 items are scored between 0 and 3. The 7-item depression subscore and 7-item anxiety subscore were calculated as the sum of the 7 corresponding individual scores. A negative value indicates an improvement.
Percentage of Responders at the End of the Maintenance Period	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)	Responders are defined as patients experiencing a 2-Point or more Reduction on an 11-Point Likert Pain Scale from Baseline to the End of the Maintenance Period. An 11-Point Likert Scale was used to assess patients' average daily pain. The patient rated his/her average pain from 0 (no pain) to 10 (worst pain ever experienced).
Change From Baseline to the End of the Maintenance Period in the Combined Score of the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (Activities of Daily Living [ADL] Subscale) and III (Motor Subscale)	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)	Part II of the Unified Parkinson's Disease Rating Scale (UPDRS) assesses the subject's activities of daily living. Part III assesses motor function. The UPDRS is completed by questioning the subject about his/her general state in conjunction with any observations made by the investigator (or designee) since the previous visit. Part II is subject-rated and Part III is physician-rated. The UPDRS Part II (Activities of Daily Living) consists of 13 items scored between 0 and 4. The sum score was calculated as the sum of these 13 individual scores. The UPDRS Part III (motor subscale) consists of 27 items and sub items scored between 0 and 4. The sum score was calculated as sum of these 27 individual scores. The sum score of UPDRS Parts II and III is the sum of the corresponding single sum scores. A negative value indicates an improvement.
Change From Baseline to the End of the Maintenance Period in the 7 Domain Scores of Classification of Pain in Parkinson's Disease	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)	The classification of pain in Parkinson's disease scale classifies pain in the following domains: musculoskeletal pain (item 1), chronic pain (items 2 and 3), fluctuation related pain (items 4, 5 and 6), nocturnal pain (items 7 and 8), oro-facial pain (items 9, 10 and 11), discoloration; edema/swelling (items 12 and 13), and radicular pain (item 14). Severity of the pain is measured on a scale from none (0) to severe (3) and frequency is measured on a scale from never (0) to very frequent (4). A score of a single item was calculated by multiplying severity with frequency. A domain score was calculated as the sum of every individual score related to the respective domain. A negative value indicates an improvement.
Change From Baseline to the End of the Maintenance Period in the 7-Item Anxiety Subscore of the Hospital Anxiety and Depression Scale (HADS)	Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)	The Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983) is a 14-item self-assessment scale for detecting states of depression and anxiety in the setting of a hospital medical outpatient clinic. It comprises a 7-item anxiety subscale and a 7-item depressive subscale that are also measures of severity of the emotional disorder. The 14 items are scored between 0 and 3. The 7-item depression subscore and 7-item anxiety subscore were calculated as the sum of the 7 corresponding individual scores. A negative value indicates an improvement.

Countries

Germany, Poland, Slovakia, United States

Participant flow

Recruitment details

The study was conducted in Europe and USA. Recruitment was planned to continue until approximately 64 patients were randomized in the study. Subjects were randomized in a 1:1 ratio to either Rotigotine or Placebo. To achieve this, approximately 28 investigational sites were planned to participate in this hypothesis-generating pilot study.

Pre-assignment details

The Participant Flow population refers to the Randomized Set (RS). The RS includes all subjects who were randomized.

Participants by arm

Arm	Count
Placebo Placebo Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm\^2, 30 cm\^2, or 40 cm\^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	33
Rotigotine Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm\^2), 6 mg/ 24 h (30 cm\^2), or 8 mg /24 h (40 cm\^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.	35
Total	68

Withdrawals & dropouts

Period	Reason	FG000	FG001
Maintenance Period	Adverse Event	1	3
Maintenance Period	Protocol Violation	1	0
Maintenance Period	Subject left town	1	0
Maintenance Period	Withdrawal by Subject	1	1
Titration Period	Adverse Event	2	1
Titration Period	Personal reasons	0	1

Baseline characteristics

Characteristic	Placebo	Rotigotine	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	18 Participants	23 Participants	41 Participants
Age, Categorical Between 18 and 65 years	15 Participants	12 Participants	27 Participants
Age, Continuous	65.3 years STANDARD_DEVIATION 13.8	66.5 years STANDARD_DEVIATION 11.9	65.9 years STANDARD_DEVIATION 12.8
Body Mass Index (BMI)	28.54 kilogram per squaremeter STANDARD_DEVIATION 6.21	27.42 kilogram per squaremeter STANDARD_DEVIATION 4.74	27.96 kilogram per squaremeter STANDARD_DEVIATION 5.49
Height	167.17 centimeters STANDARD_DEVIATION 9.92	168.63 centimeters STANDARD_DEVIATION 9.87	167.92 centimeters STANDARD_DEVIATION 9.85
Race/Ethnicity, Customized American Indian / Alaskan native	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Asian	1 participants	0 participants	1 participants
Race/Ethnicity, Customized Black	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Other / mixed	0 participants	0 participants	0 participants
Race/Ethnicity, Customized White	32 participants	35 participants	67 participants
Sex: Female, Male Female	16 Participants	16 Participants	32 Participants
Sex: Female, Male Male	17 Participants	19 Participants	36 Participants
Weight	80.15 kilograms STANDARD_DEVIATION 20	77.80 kilograms STANDARD_DEVIATION 13.71	78.94 kilograms STANDARD_DEVIATION 16.97

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	17 / 33	20 / 35
serious Total, serious adverse events	1 / 33	2 / 35

Outcome results

Primary

Change From Baseline to the End of the Maintenance Period in Pain Severity Assessed Using an 11-point Likert Pain Scale

An 11-Point Likert Scale was used to assess patients' average daily pain. The subject rated his/her average pain from 0 (no pain) to 10 (worst pain ever experienced). The average pain experienced in the last 7 days was calculated by the mean of the daily Likert Pain Scores within the 7 days prior to the respective visit (ie, Likert Pain Scores with a date of assessment before the date of visit and on or after the date of visit - 7 days). A negative value indicates an improvement.

Time frame: Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after an up to 7 weeks Titration Period)

Population: The Analysis Population refers to the Full Analysis Set (FAS). The FAS is a subset of the Safety Set and includes all subjects who were randomized, received at least 1 dose of study medication, and had a valid primary efficacy Baseline measurement and at least 1 valid post-Baseline Maintenance or valid Withdrawal primary efficacy measurement.

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline to the End of the Maintenance Period in Pain Severity Assessed Using an 11-point Likert Pain Scale	-2.2 scores on a scale	Standard Deviation 2.78
Rotigotine	Change From Baseline to the End of the Maintenance Period in Pain Severity Assessed Using an 11-point Likert Pain Scale	-2.8 scores on a scale	Standard Deviation 1.84

p-value: 0.17295% CI: [-1.87, 0.34]ANCOVA

Secondary

Change From Baseline to the End of the Maintenance Period in the 7 Domain Scores of Classification of Pain in Parkinson's Disease

The classification of pain in Parkinson's disease scale classifies pain in the following domains: musculoskeletal pain (item 1), chronic pain (items 2 and 3), fluctuation related pain (items 4, 5 and 6), nocturnal pain (items 7 and 8), oro-facial pain (items 9, 10 and 11), discoloration; edema/swelling (items 12 and 13), and radicular pain (item 14). Severity of the pain is measured on a scale from none (0) to severe (3) and frequency is measured on a scale from never (0) to very frequent (4). A score of a single item was calculated by multiplying severity with frequency. A domain score was calculated as the sum of every individual score related to the respective domain. A negative value indicates an improvement.