Levodopa, Parkinson's Disease
Conditions
Keywords
Parkinson's Disease, Levodopa, motor fluctuations, gastroparesis
Brief summary
Gastroparesis (slow stomach emptying) is a common feature of Parkinson's Disease. Levodopa (Sinemet), a common medication for Parkinson's Disease, can make gastroparesis worse. Gastroparesis effects how the levodopa is absorbed and used by the body. This study will explore the possibility of using Erythromycin, a drug commonly used (off label) for gastroparesis, along with levodopa to determine if there is improved levodopa absorption and motor function.
Detailed description
Participants will be required to make four visits for evaluation. Visit 1 is a screening visit, participants will receive the study drug or a placebo during visits 2 and 3, and visit 4 is a follow up visit. Participants will provide blood and urine samples during the visits. Participants will also be required to complete questionnaires and a series of motor tests.
Interventions
DRUGErythromycin
DRUGplacebo
Sponsors
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Subjects must have a definitive diagnosis of Parkinson's Disease (per United Kingdom brain bank criteria), Hoehn and Yahr stage 1-3, * must exhibit unequivocal levodopa responsiveness * must be able to distinguish between the off versus on state * Subjects must be on a stable dose of levodopa for at least 28 days prior to enrollment and should be anticipated to maintain a stable dose throughout both study periods * Subjects may be on concomitant therapy with Monoamine oxidase B inhibitors, entacapone, and amantadine, though the doses of these medications must have remained stable for at least 28 days prior to enrollment and must be expected to remain stable throughout both study periods.
Exclusion criteria
* History of deep brain stimulation for Parkinson Disease * History of ablative (tissue removal) surgery for Parkinson Disease * Presence of dementia (MMSE\<25) * Presence of active psychosis * History of any chronic gastrointestinal diseases * History of any prior gastrointestinal surgeries except for appendectomy, cholecystectomy, and hysterectomy * Any gastrointestinal surgeries in the past 3 months * Severe dysphagia (difficulty swallowing) to pills or food * History of physiological or mechanical gastrointestinal obstruction * History of strictures or fistulae (abnormal or narrow connections) along the gastrointestinal tract * History of gastric bezoars (undigested mass) * Allergy to wheat, soy, milk, or nuts * Presence of portable electromechanical devices such as pacemaker, defibrillator, or infusion pump * Female subjects who are pregnant or lactating * Symptomatic orthostatic hypotension (low blood pressure) * Diabetes * Presence of symptomatic anemia * Abnormal liver or kidney function * Cardiac arrhythmia (past or present) or abnormal QT interval on entrance EKG * Known hypersensitivity to any of the study drugs * Subjects receiving certain medications during specified time frames
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gastric Emptying Time | 2 weeks, between visits 2 and 3 | Mean gastric emptying time in minutes as measured by SmartPill |
| Area Under the Curve 0-4 Hours for Plasma Levodopa After Erythromycin Versus Placebo | 2 weeks, between visits 2 and 3 | Mean Area under the Curve 0-4 hours for plasma levodopa after erythromycin versus placebo. Plasma samples were collected at the following times post-levodopa dose: 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and 240 minutes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Five Times Sit-to-stand Test | 2 weeks, between visits 2 and 3 | Change in motor function as measured by Five times sit-to-stand test. This test measures the total time to complete 5 repetitions of sit to stand. |
| Comfortable 20 Feet Gait Speed (CGS) | 2 weeks, between visits 2 and 3 | Change in motor function as assessed by comfortable 20 feet gait speed (CGS) |
| Timed up and go Test (TUAG) Comfortable Speed | 2 weeks, between visits 2 and 3 | Change in motor function as assessed by timed up and go test (comfortable speed). This test measures the total time to stand from a chair, walk 10 feet, and return to sitting. |
| 9-hole Peg Test Right Hand | 2 weeks, between visits 2 and 3 | Change in motor function as assessed by 9-hole peg test for upper extremity manipulation/dexterity. This test measures the total time required to place and remove 9 holes in a pegboard. Each hand is tested separately. |
| Change in Dyskinesia | 2 weeks, between visits 2 and 3 | Mean total AIMS (Abnormal Involuntary Movements Scale) score after receiving erythromycin minus mean total AIMS score after receiving placebo. The AIMS test has a total of twelve items rating involuntary movements of various areas of the patient's body. Ten of the items are rated on a five-point scale of severity from 0-4. The scale is rated from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe). Two of the items are not scored. Total score range is from 0 to 40. Higher scores represent more severe dyskinesia (a worse outcome). |
| MDS-UPDRS Part 3 (Movement Disorders Society- Unified Parkinson's Disease Rating Scale) | 2 weeks, between visits 2 and 3 | Part 3 of this scale is a standardized physical assessment that quantifies the total burden of motor symptoms in Parkinson's disease patients. Each of the 18 items on the scale is rated from 0 (none, 1 (slight), 2 (mild), 3 (moderate) and 4 (severe). Scores range from 0-72. Higher scores represent a more severe burden of motor symptoms (a worse outcome). |
| Mean Cmax of Plasma Levodopa After Erythromycin Versus Placebo | 2 weeks, between visits 2 and 3 | Mean Cmax of plasma levodopa after erythromycin versus placebo. Plasma samples were collected at the following times post-levodopa dose: 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and 240 minutes. |
| Timed up and go Test (TUAG) Fast Speed | 2 weeks, between visits 2 and 3 | Change in motor function as assessed by timed up and go test (fast speed). This test measures the total time to stand from a chair, walk 10 feet, and return to sitting. |
| 9-hole Peg Test Left Hand | 2 weeks, between visits 2 and 3 | Change in motor function as assessed by 9-hole peg test for upper extremity manipulation/dexterity. This test measures the total time required to place and remove 9 holes in a pegboard. Each hand is tested separately. |
Countries
United States
Participant flow
Recruitment details
Eighteen patients were screened for eligibility between April 2013 and June 2015 at the Virginia Commonwealth University Parkinson's and Movement Disorders Center.
Pre-assignment details
10 of 18 participants were randomized. Of those not randomized, 7 did not meet eligibility criteria and 1 was withdrawn by the principal investigator prior to randomization due to noncompliance with the protocol.
Participants by arm
| Arm | Count |
|---|---|
| Placebo First Then Erythromycin One time IV dose of placebo followed by 1 time IV dose of Erythromycin (after 2 week washout) | 5 |
| Erythromycin Then Placebo One time IV dose of 100 mg Erythromycin followed by 1 time IV dose of placebo (after 2 week washout) | 5 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (1 Day) | participant withdrawn for noncompliance | 1 | 0 |
Baseline characteristics
| Characteristic | Erythromycin Then Placebo | Total | Placebo First Then Erythromycin |
|---|---|---|---|
| Age, Continuous | 64.0 years | 64.3 years | 64.6 years |
| Gender Female | 1 Participants | 2 Participants | 1 Participants |
| Gender Male | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 10 Participants | 5 Participants |
| Region of Enrollment United States | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 9 | 2 / 10 |
| serious Total, serious adverse events | 0 / 9 | 0 / 10 |
Outcome results
Primary
Area Under the Curve 0-4 Hours for Plasma Levodopa After Erythromycin Versus Placebo
Mean Area under the Curve 0-4 hours for plasma levodopa after erythromycin versus placebo. Plasma samples were collected at the following times post-levodopa dose: 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and 240 minutes.
Time frame: 2 weeks, between visits 2 and 3
Population: Of the original ten participants; one participant's data was excluded due to symptomatic orthostasis which likely confounded her results, one participant was withdrawn early due to noncompliance, and one participant had undetectable plasma levodopa levels through out the study and was thus excluded from the pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin | Area Under the Curve 0-4 Hours for Plasma Levodopa After Erythromycin Versus Placebo | 123237 ng/mL*min | Standard Deviation 137561 |
| Placebo | Area Under the Curve 0-4 Hours for Plasma Levodopa After Erythromycin Versus Placebo | 103584 ng/mL*min | Standard Deviation 106271 |
Primary
Gastric Emptying Time
Mean gastric emptying time in minutes as measured by SmartPill
Time frame: 2 weeks, between visits 2 and 3
Population: Of the original ten participants; one participant's data was excluded due to symptomatic orthostasis which likely confounded her results, one participant was withdrawn early due to noncompliance, and four participants were unable to complete a SmartPill evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin | Gastric Emptying Time | 105 minutes | Standard Deviation 66.5 |
| Placebo | Gastric Emptying Time | 180 minutes | Standard Deviation 40.6 |
p-value: 0.036t-test, 2 sided
Secondary
9-hole Peg Test Left Hand
Change in motor function as assessed by 9-hole peg test for upper extremity manipulation/dexterity. This test measures the total time required to place and remove 9 holes in a pegboard. Each hand is tested separately.
Time frame: 2 weeks, between visits 2 and 3
Population: Of the original 10 participants, one participant's data was excluded due to symptomatic orthostasis which likely confounded her results and one participant was withdrawn early due to noncompliance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin | 9-hole Peg Test Left Hand | 29.36 seconds | Standard Deviation 6.27 |
| Placebo | 9-hole Peg Test Left Hand | 27.33 seconds | Standard Deviation 6.45 |
p-value: 0.18t-test, 2 sided
Secondary
9-hole Peg Test Right Hand
Change in motor function as assessed by 9-hole peg test for upper extremity manipulation/dexterity. This test measures the total time required to place and remove 9 holes in a pegboard. Each hand is tested separately.
Time frame: 2 weeks, between visits 2 and 3
Population: Of the original 10 participants, one participant's data was excluded due to symptomatic orthostasis which likely confounded her results and one participant was withdrawn early due to noncompliance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin | 9-hole Peg Test Right Hand | 25.36 seconds | Standard Deviation 4.37 |
| Placebo | 9-hole Peg Test Right Hand | 25.80 seconds | Standard Deviation 4.23 |
p-value: 0.65t-test, 2 sided
Secondary
Change in Dyskinesia
Mean total AIMS (Abnormal Involuntary Movements Scale) score after receiving erythromycin minus mean total AIMS score after receiving placebo. The AIMS test has a total of twelve items rating involuntary movements of various areas of the patient's body. Ten of the items are rated on a five-point scale of severity from 0-4. The scale is rated from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe). Two of the items are not scored. Total score range is from 0 to 40. Higher scores represent more severe dyskinesia (a worse outcome).
Time frame: 2 weeks, between visits 2 and 3
Population: Of the original 10 participants, one participant's data was excluded due to symptomatic orthostasis which likely confounded her results and one participant was withdrawn early due to noncompliance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin | Change in Dyskinesia | 0.875 units on a scale | Standard Deviation 1.458 |
| Placebo | Change in Dyskinesia | 0.375 units on a scale | Standard Deviation 1.061 |
p-value: 0.1546t-test, 2 sided
Secondary
Comfortable 20 Feet Gait Speed (CGS)
Change in motor function as assessed by comfortable 20 feet gait speed (CGS)
Time frame: 2 weeks, between visits 2 and 3
Population: Of the original 10 participants, one participant's data was excluded due to symptomatic orthostasis which likely confounded her results and one participant was withdrawn early due to noncompliance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin | Comfortable 20 Feet Gait Speed (CGS) | 4.26 seconds | Standard Deviation 0.44 |
| Placebo | Comfortable 20 Feet Gait Speed (CGS) | 4.10 seconds | Standard Deviation 0.69 |
p-value: 0.6011t-test, 2 sided
Secondary
Five Times Sit-to-stand Test
Change in motor function as measured by Five times sit-to-stand test. This test measures the total time to complete 5 repetitions of sit to stand.
Time frame: 2 weeks, between visits 2 and 3
Population: Of the original 10 participants, one participant's data was excluded due to symptomatic orthostasis which likely confounded her results and one participant was withdrawn early due to noncompliance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin | Five Times Sit-to-stand Test | 11.09 seconds | Standard Deviation 2.24 |
| Placebo | Five Times Sit-to-stand Test | 10.09 seconds | Standard Deviation 2.48 |
p-value: 0.4405t-test, 2 sided
Secondary
MDS-UPDRS Part 3 (Movement Disorders Society- Unified Parkinson's Disease Rating Scale)
Part 3 of this scale is a standardized physical assessment that quantifies the total burden of motor symptoms in Parkinson's disease patients. Each of the 18 items on the scale is rated from 0 (none, 1 (slight), 2 (mild), 3 (moderate) and 4 (severe). Scores range from 0-72. Higher scores represent a more severe burden of motor symptoms (a worse outcome).
Time frame: 2 weeks, between visits 2 and 3
Population: One participant's data was excluded due to symptomatic orthostasis which likely confounded her results and one participant was withdrawn early due to noncompliance.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Erythromycin | MDS-UPDRS Part 3 (Movement Disorders Society- Unified Parkinson's Disease Rating Scale) | Before or off levodopa | 30.75 units on a scale | Standard Deviation 13.26 |
| Erythromycin | MDS-UPDRS Part 3 (Movement Disorders Society- Unified Parkinson's Disease Rating Scale) | After or on levodopa | 17.13 units on a scale | Standard Deviation 11.48 |
| Placebo | MDS-UPDRS Part 3 (Movement Disorders Society- Unified Parkinson's Disease Rating Scale) | Before or off levodopa | 25.37 units on a scale | Standard Deviation 11.09 |
| Placebo | MDS-UPDRS Part 3 (Movement Disorders Society- Unified Parkinson's Disease Rating Scale) | After or on levodopa | 16.50 units on a scale | Standard Deviation 8.38 |
p-value: 0.0314t-test, 2 sided
Secondary
Mean Cmax of Plasma Levodopa After Erythromycin Versus Placebo
Mean Cmax of plasma levodopa after erythromycin versus placebo. Plasma samples were collected at the following times post-levodopa dose: 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and 240 minutes.
Time frame: 2 weeks, between visits 2 and 3
Population: Of the original ten participants; one participant's data was excluded due to symptomatic orthostasis which likely confounded her results, one participant was withdrawn early due to noncompliance, and one participant had undetectable plasma levodopa levels throughout the study and was thus excluded from the pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin | Mean Cmax of Plasma Levodopa After Erythromycin Versus Placebo | 1267 ng/mL | Standard Deviation 1012 |
| Placebo | Mean Cmax of Plasma Levodopa After Erythromycin Versus Placebo | 1395 ng/mL | Standard Deviation 1015 |
Secondary
Timed up and go Test (TUAG) Comfortable Speed
Change in motor function as assessed by timed up and go test (comfortable speed). This test measures the total time to stand from a chair, walk 10 feet, and return to sitting.
Time frame: 2 weeks, between visits 2 and 3
Population: Of the original 10 participants, one participant's data was excluded due to symptomatic orthostasis which likely confounded her results and one participant was withdrawn early due to noncompliance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin | Timed up and go Test (TUAG) Comfortable Speed | 8.67 seconds | Standard Deviation 1.33 |
| Placebo | Timed up and go Test (TUAG) Comfortable Speed | 8.26 seconds | Standard Deviation 1.05 |
p-value: 0.8923t-test, 2 sided
Secondary
Timed up and go Test (TUAG) Fast Speed
Change in motor function as assessed by timed up and go test (fast speed). This test measures the total time to stand from a chair, walk 10 feet, and return to sitting.
Time frame: 2 weeks, between visits 2 and 3
Population: Of the original 10 participants, one participant's data was excluded due to symptomatic orthostasis which likely confounded her results and one participant was withdrawn early due to noncompliance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin | Timed up and go Test (TUAG) Fast Speed | 6.79 seconds | Standard Deviation 0.927 |
| Placebo | Timed up and go Test (TUAG) Fast Speed | 6.85 seconds | Standard Deviation 1.06 |
p-value: 0.832t-test, 2 sided