STRIDE-PD: Efficacy and Safety of Carbidopa/Levodopa/Entacapone in Patients With Parkinson's Disease Requiring Initiation of Levodopa Therapy

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00099268
• Collaborator: Orion Corporation, Orion Pharma (Industry)
• Enrollment: 747
• Locations: 73
• Arms: 2
• Duration (Months): 50
• Patients Per Site: 10.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The CELC200A2401 study has been designed in order to evaluate the hypothesis that administering the combination carbidopa/levodopa/entacapone at the time that levodopa therapy is initiated results in a decrease in the risk of the development of motor complications for patients with Parkinson's disease.

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease	Drug: Carbidopa/levodopa/entacapone; Drug: Immediate release carbidopa/levodopa	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 747 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Long Term, Double-blind, Randomized, Parallel-group, Carbidopa/Levodopa Controlled, Multi-center Study to Evaluate the Effect of Carbidopa/Levodopa/Entacapone in Patients With Parkinson's Disease Requiring Initiation of Levodopa Therapy
• Study Start Date: Sep 1, 2004
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Carbidopa/levodopa/entacapone Patients received Carbidopa/levodopa/entacapone tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Drug: Carbidopa/levodopa/entacapone; Carbidopa/Levodopa/Entacapone 12.5/50/200 mg and 25/100/200 mg capsules.; Other Names: Stalevo
Active Comparator: Immediate release carbidopa/levodopa Patients received Immediate release carbidopa/levodopa tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Drug: Immediate release carbidopa/levodopa; Immediate release carbidopa/levodopa 12.5/50 mg and 25/100 mg capsules.; Other Names: Sinemet

Outcome Measures

Primary Outcome Measures

1. Time to First Occurrence of Dyskinesia [Treatment duration for an individual patient varied between a minimum of 134 weeks for those patients recruited last and a maximum of 208 weeks for those patients recruited first]

   Dyskinesia was assessed by a blinded rater at each visit. Time to dyskinesia was defined as the visit at which the rater first answered "yes" to the following question: "In your opinion, does this patient have dyskinesia?" Time to dyskinesia was estimated by Kaplan-Meier product limit estimate that takes into consideration patients who did not experience dyskinesia by censoring them at the end of the study.

Secondary Outcome Measures

1. Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Total Score (Parts II and III) [Baseline, Week 6 and Week 130]

   The UPDRS is a standardized assessment scale used to measure the patient's disease state. It was to be completed by a blinded rater. There are 6 parts to the UPDRS. Part II (items 5-17; total score 0-52 units on the scale) measures the patient's activities of daily living and part III (items 18-31; total score 0-56 units on the scale) measures the motor function of the patient. The total score ranges from 0 to 108 units on the scale. A higher score indicates greater disability. A negative change score indicates improvement.

2. Occurrence of Wearing-off [Baseline to Week 134]

   Wearing-off is defined as a perception of loss of mobility or dexterity, usually taking place gradually over minutes (up to an hour) and usually bearing a close temporal relationship to the timing of anti-parkinsonian medications; it does not include early-morning akinesia. To ascertain its occurrence, a blinded rater questioned the patient as to whether he/she had noticed that the benefits of the study drug were wearing-off.

3. Time to First Occurrence of Wearing-off [Baseline to end of study (134-208 weeks of treatment)]

   Wearing off is defined as a perception of loss of mobility or dexterity, usually taking place gradually over minutes (up to an hour) and usually bearing a close temporal relationship to the timing of anti-parkinsonian medications; it does not include early-morning akinesia. To ascertain its occurrence, a blinded rater questioned the patient whether he/she had noticed that the benefits of the study drug wear-off. A motor complications and patient questionnaire card were provided to assist the blinded rater in determining whether a patient had experienced wearing-off.

4. Occurrence of Dyskinesia [Baseline to Week 208]

   Dyskinesia was assessed by a blinded rater at each visit. Time to dyskinesia was defined as the visit at which the rater first answered "yes" to the following question: "In your opinion, does this patient have dyskinesia?"

5. Change From Baseline in Health-related Quality of Life Assessed Using the 39-item Parkinson's Disease Questionnaire (PDQ-39) [Baseline to Week 156]

   The PDQ-39 instrument is used to assess quality of life in individuals with Parkinson's disease. The questionnaire provides scores on eight scales: Mobility, activities of daily living, emotions, stigma, social support, cognition, communication, and bodily discomfort. Questions are scored on a 5-point Likert scale ranging from 1 (never) to 3 (sometimes) to 5 (always). The total score can range from 39 to 190. A lower score indicates better quality of life. A negative change score indicates an improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Clinical diagnosis of idiopathic Parkinson's disease

• Diagnosis of Parkinson's disease for no more than 5 years

Exclusion Criteria:

• History, signs, or symptoms of atypical or secondary parkinsonism

• Presence at baseline of drug-related wearing-off symptoms, dyskinesia or other motor complications

• Levodopa exposure of more than 30 days or anytime within 8 weeks prior to visit 1

Other inclusion/exclusion criteria applied to this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Mayo Clinic	Scottsdale	Arizona	United States	85259
3	Coastal Neurological Medical Group	La Jolla	California	United States	92037
4	Keck School of Medicine, Division of Movement Disorders	Los Angeles	California	United States	90033
5	Reed Neurological Research Center	Los Angeles	California	United States	90095-1769
6	The Parkinson's Institute	Sunnyvale	California	United States	94085
7	Molecular NeuroImaging, LLC	New Haven	Connecticut	United States	06510
8	Parkinson's Disease and Movement Disorder Center	Boca Raton	Florida	United States	33486
9	University of Miami	Miami	Florida	United States	33136
10	Charlotte Neurological Service	Port Charlotte	Florida	United States	33952
11	University of South Florida	Tampa	Florida	United States	33606
12	Wesley Woods Health Center	Atlanta	Georgia	United States	30329
13	Medical College of Georgia	Augusta	Georgia	United States	30912
14	Northwestern University Medical School	Chicago	Illinois	United States	60611
15	Rush University Medical Center	Chicago	Illinois	United States	60612
16	Landon Center on Aging	Kansas City	Kansas	United States	66160
17	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
18	Boston University School of Medicine	Boston	Massachusetts	United States	02118
19	Clinical Neuroscience Center	Southfield	Michigan	United States	48034
20	Parkinson's Disease and Movement Disorder Center of Albany Medical	Albany	New York	United States	12208
21	Parkinson's Disease and Movement Disorders Center of Long Island	Commack	New York	United States	11725
22	Mount Sinai School of Medicine	New York	New York	United States	10029
23	Columbia University, Neurological Institute	New York	New York	United States	10032-3784
24	University of Rochester	Rochester	New York	United States	14618
25	Duke University Medical Center Movement Disorders Center	Durham	North Carolina	United States	27705
26	Pennsylvania Neurology Institute	Philadelphia	Pennsylvania	United States	19107
27	NeuroHealth, Inc.	Warwick	Rhode Island	United States	02886
28	Semmes-Murphey Clinic	Memphis	Tennessee	United States	38104
29	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390-9016
30	Baylor College of Medicine, Parkinson's Disease Center	Houston	Texas	United States	77030
31	Wisconsin Institute for Neurologic and Sleep Disorders	Milwaukee	Wisconsin	United States	53233
32	Novartis Investigative Site	Innsbruck		Austria
33	Novartis Investigative Site	Antwerpen		Belgium
34	Novartis Investigative Site	Brugge		Belgium
35	Novartis Investigative Site	Edmonton	Alberta	Canada
36	Novartis Investigative Site	London	Ontario	Canada
37	Novartis Investigative Site	Toronto	Ontario	Canada
38	Novartis Investigative Site	Montreal	Quebec	Canada
39	Novartis Investigative Site	Helsinki		Finland
40	Novartis Investigative Site	Kuopio		Finland
41	Novartis Investigative Site	Mikkeli		Finland
42	Novartis Investigative Site	Oulu		Finland
43	Novartis Investigative Site	Pori		Finland
44	Novartis Investigative Site	Lille		France
45	Novartis Investigative Site	Nantes		France
46	Novartis Investigative Site	Paris		France
47	Novartis Investigative Site	Toulouse		France
48	Novartis Investigative Site	Berlin		Germany
49	Novartis Investigative Site	Bochum		Germany
50	Novartis Investigative Site	Dresden		Germany
51	Novartis Investigative Site	Marburg		Germany
52	Novartis Investigative Site	Tubingen		Germany
53	Novartis Investigative Site	Ioannina		Greece
54	Novartis Investigative Site	Thessaloniki		Greece
55	Novartis Investigative Site	Catania		Italy
56	Novartis Investigative Site	Chieti Scalo		Italy
57	Novartis Investigative Site	Lido di Camaiore		Italy
58	Novartis Investigative Site	Napoli		Italy
59	Novartis Investigative Site	Pozzilli		Italy
60	Novartis Investigative Site	Roma		Italy
61	Novartis Investigative Site	Barcelona		Spain
62	Novartis Investigative Site	Madrid		Spain	28035
63	Novartis Investigative Site	Jonkoping		Sweden
64	Novartis Investigative Site	Linkoping		Sweden
65	Novartis Investigative Site	Norrkoping		Sweden
66	Novartis Investigative Site	Stockholm		Sweden
67	Novartis Investigative Site	Lausanne		Switzerland
68	Novartis Investigative Site	Zurich		Switzerland
69	Novartis Investigative Site	Istanbul		Turkey
70	Novartis Investigative Site	Birmingham		United Kingdom
71	Novartis Investigative Site	Glasgow		United Kingdom
72	Novartis Investigative Site	London		United Kingdom
73	Novartis Investigative Site	Newcastle Upon Tyne		United Kingdom

Sponsors and Collaborators

• Novartis Pharmaceuticals
• Orion Corporation, Orion Pharma

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00099268
• Other Study ID Numbers: CELC200A2401
• First Posted: Dec 10, 2004
• Last Update Posted: Apr 23, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by , ,: Parkinson's disease, levodopa therapy, dyskinesia
• Additional relevant MeSH terms: Parkinson Disease; Levodopa; Carbidopa; Carbidopa, levodopa drug combination; Entacapone

Study Results

Participant Flow

Arm/Group Title	Carbidopa/Levodopa/Entacapone	Carbidopa/Levodopa
Arm/Group Description	Patients received Carbidopa/levodopa/entacapone tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Patients received Immediate release carbidopa/levodopa tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.
Period Title: Overall Study
STARTED	374	373
Intent-to-Treat	373	372
COMPLETED	282	291
NOT COMPLETED	92	82

Baseline Characteristics

Arm/Group Title	Carbidopa/Levodopa/Entacapone	Carbidopa/Levodopa	Total
Arm/Group Description	Patients received Carbidopa/levodopa/entacapone tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Patients received Immediate release carbidopa/levodopa tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Total of all reporting groups
Overall Participants	373	372	745
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.6 (8.67)	59.8 (8.20)	60.2 (8.44)
Sex: Female, Male (Count of Participants)
Female	128 34.3%	150 40.3%	278 37.3%
Male	245 65.7%	222 59.7%	467 62.7%

Outcome Measures

1. Primary Outcome

Title	Time to First Occurrence of Dyskinesia
Description	Dyskinesia was assessed by a blinded rater at each visit. Time to dyskinesia was defined as the visit at which the rater first answered "yes" to the following question: "In your opinion, does this patient have dyskinesia?" Time to dyskinesia was estimated by Kaplan-Meier product limit estimate that takes into consideration patients who did not experience dyskinesia by censoring them at the end of the study.
Time Frame	Treatment duration for an individual patient varied between a minimum of 134 weeks for those patients recruited last and a maximum of 208 weeks for those patients recruited first

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population consisted of all patients randomized who received at least one dose of study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned at randomization.

Arm/Group Title	Carbidopa/Levodopa/Entacapone	Carbidopa/Levodopa
Arm/Group Description	Patients received Carbidopa/levodopa/entacapone tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Patients received Immediate release carbidopa/levodopa tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.
Measure Participants	373	372
Number (95% Confidence Interval) [weeks]	90.7 (47.9)	117.1 (51.5)

2. Secondary Outcome

Title	Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Total Score (Parts II and III)
Description	The UPDRS is a standardized assessment scale used to measure the patient's disease state. It was to be completed by a blinded rater. There are 6 parts to the UPDRS. Part II (items 5-17; total score 0-52 units on the scale) measures the patient's activities of daily living and part III (items 18-31; total score 0-56 units on the scale) measures the motor function of the patient. The total score ranges from 0 to 108 units on the scale. A higher score indicates greater disability. A negative change score indicates improvement.
Time Frame	Baseline, Week 6 and Week 130

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population consisted of all patients randomized who received at least one dose of study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned at randomization.

Arm/Group Title	Carbidopa/Levodopa/Entacapone	Carbidopa/Levodopa
Arm/Group Description	Patients received Carbidopa/levodopa/entacapone tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Patients received Immediate release carbidopa/levodopa tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.
Measure Participants	373	372
Change from baseline to Week 6	21.9 (11.96)	21.8 (11.24)
Change from baseline to Week 130	23.2 (13.38)	22.8 (13.21)

3. Secondary Outcome

Title	Occurrence of Wearing-off
Description	Wearing-off is defined as a perception of loss of mobility or dexterity, usually taking place gradually over minutes (up to an hour) and usually bearing a close temporal relationship to the timing of anti-parkinsonian medications; it does not include early-morning akinesia. To ascertain its occurrence, a blinded rater questioned the patient as to whether he/she had noticed that the benefits of the study drug were wearing-off.
Time Frame	Baseline to Week 134

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population consisted of all patients randomized who received at least one dose of study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned at randomization. Subjects who discontinued treatment before 134 weeks without wearing-off were excluded.

Arm/Group Title	Carbidopa/Levodopa/Entacapone	Carbidopa/Levodopa
Arm/Group Description	Patients received Carbidopa/levodopa/entacapone tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Patients received Immediate release carbidopa/levodopa tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.
Measure Participants	305	333
Number [Participants]	139 (45.6) 37.3%	161 (48.3) 43.3%

4. Secondary Outcome

Title	Time to First Occurrence of Wearing-off
Description	Wearing off is defined as a perception of loss of mobility or dexterity, usually taking place gradually over minutes (up to an hour) and usually bearing a close temporal relationship to the timing of anti-parkinsonian medications; it does not include early-morning akinesia. To ascertain its occurrence, a blinded rater questioned the patient whether he/she had noticed that the benefits of the study drug wear-off. A motor complications and patient questionnaire card were provided to assist the blinded rater in determining whether a patient had experienced wearing-off.
Time Frame	Baseline to end of study (134-208 weeks of treatment)

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population consisted of all patients randomized who received at least one dose of study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned at randomization.

Arm/Group Title	Carbidopa/Levodopa/Entacapone	Carbidopa/Levodopa
Arm/Group Description	Patients received Carbidopa/levodopa/entacapone tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Patients received Immediate release carbidopa/levodopa tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.
Measure Participants	373	372
Mean (Standard Error) [Weeks]	131.7 (3.8)	129.5 (3.6)

5. Secondary Outcome

Title	Occurrence of Dyskinesia
Description	Dyskinesia was assessed by a blinded rater at each visit. Time to dyskinesia was defined as the visit at which the rater first answered "yes" to the following question: "In your opinion, does this patient have dyskinesia?"
Time Frame	Baseline to Week 208

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population consisted of all patients randomized who received at least one dose of study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned at randomization. Subjects who discontinued from treatment before 134 weeks without dyskinesia were excluded.

Arm/Group Title	Carbidopa/Levodopa/Entacapone	Carbidopa/Levodopa
Arm/Group Description	Patients received Carbidopa/levodopa/entacapone tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Patients received Immediate release carbidopa/levodopa tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.
Measure Participants	307	318
Number [Participants]	128 (41.7) 34.3%	103 (32.4) 27.7%

6. Secondary Outcome

Title	Change From Baseline in Health-related Quality of Life Assessed Using the 39-item Parkinson's Disease Questionnaire (PDQ-39)
Description	The PDQ-39 instrument is used to assess quality of life in individuals with Parkinson's disease. The questionnaire provides scores on eight scales: Mobility, activities of daily living, emotions, stigma, social support, cognition, communication, and bodily discomfort. Questions are scored on a 5-point Likert scale ranging from 1 (never) to 3 (sometimes) to 5 (always). The total score can range from 39 to 190. A lower score indicates better quality of life. A negative change score indicates an improvement.
Time Frame	Baseline to Week 156

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population consisted of all patients randomized who received at least one dose of study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned at randomization.

Arm/Group Title	Carbidopa/Levodopa/Entacapone	Carbidopa/Levodopa
Arm/Group Description	Patients received Carbidopa/levodopa/entacapone tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.	Patients received Immediate release carbidopa/levodopa tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.
Measure Participants	201	213
Mean (Standard Deviation) [Units on a scale]	4.1 (12.06)	1.8 (11.79)

Adverse Events

Arm/Group Title	Carbidopa/Levodopa/Entacapone		Carbidopa/Levodopa
Arm/Group Description	Patients received Carbidopa/levodopa/entacapone tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.		Patients received Immediate release carbidopa/levodopa tablets. The study was designed as a flexible dose trial (200-1000 mg/day levodopa). The target dose was 400 mg/day levodopa administered orally as 4 equal doses 4 times a day with 3.5-hour dosing intervals for a treatment period of 134 to 208 weeks.
All Cause Mortality
	Carbidopa/Levodopa/Entacapone		Carbidopa/Levodopa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Carbidopa/Levodopa/Entacapone		Carbidopa/Levodopa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	91/373 (24.4%)		84/371 (22.6%)
Blood and lymphatic system disorders
Lymphocytosis	1/373 (0.3%)		0/371 (0%)
Cardiac disorders
Acute myocardial infarction	1/373 (0.3%)		0/371 (0%)
Angina pectoris	2/373 (0.5%)		5/371 (1.3%)
Angina unstable	1/373 (0.3%)		1/371 (0.3%)
Aortic valve stenosis	0/373 (0%)		1/371 (0.3%)
Atrial fibrillation	2/373 (0.5%)		1/371 (0.3%)
Atrial flutter	1/373 (0.3%)		0/371 (0%)
Bradycardia	0/373 (0%)		1/371 (0.3%)
Cardiac arrest	1/373 (0.3%)		0/371 (0%)
Cardiac failure	0/373 (0%)		1/371 (0.3%)
Cardiac failure congestive	2/373 (0.5%)		0/371 (0%)
Cardiac flutter	1/373 (0.3%)		0/371 (0%)
Coronary artery disease	2/373 (0.5%)		2/371 (0.5%)
Coronary artery stenosis	1/373 (0.3%)		2/371 (0.5%)
Myocardial infarction	5/373 (1.3%)		0/371 (0%)
Palpitations	1/373 (0.3%)		0/371 (0%)
Supraventricular tachycardia	0/373 (0%)		1/371 (0.3%)
Ventricular tachycardia	0/373 (0%)		1/371 (0.3%)
Congenital, familial and genetic disorders
Muscular dystrophy	1/373 (0.3%)		0/371 (0%)
Vitello-intestinal duct remnant	0/373 (0%)		1/371 (0.3%)
Ear and labyrinth disorders
Vertigo	0/373 (0%)		1/371 (0.3%)
Eye disorders
Chalazion	1/373 (0.3%)		0/371 (0%)
Eyelid ptosis	0/373 (0%)		1/371 (0.3%)
Gastrointestinal disorders
Abdominal adhesions	1/373 (0.3%)		1/371 (0.3%)
Abdominal discomfort	1/373 (0.3%)		0/371 (0%)
Anal fissure	1/373 (0.3%)		0/371 (0%)
Colitis ulcerative	1/373 (0.3%)		0/371 (0%)
Colonic obstruction	0/373 (0%)		1/371 (0.3%)
Constipation	1/373 (0.3%)		0/371 (0%)
Diarrhoea	2/373 (0.5%)		0/371 (0%)
Flatulence	0/373 (0%)		1/371 (0.3%)
Gastric ulcer perforation	1/373 (0.3%)		0/371 (0%)
Gastrooesophageal reflux disease	1/373 (0.3%)		0/371 (0%)
Hiatus hernia	0/373 (0%)		1/371 (0.3%)
Inguinal hernia	3/373 (0.8%)		2/371 (0.5%)
Intestinal ischaemia	1/373 (0.3%)		0/371 (0%)
Intestinal obstruction	2/373 (0.5%)		0/371 (0%)
Nausea	0/373 (0%)		3/371 (0.8%)
Pancreatitis	1/373 (0.3%)		0/371 (0%)
Peritonitis	0/373 (0%)		1/371 (0.3%)
Small intestinal obstruction	0/373 (0%)		1/371 (0.3%)
Vomiting	0/373 (0%)		1/371 (0.3%)
General disorders
Chest discomfort	2/373 (0.5%)		1/371 (0.3%)
Chest pain	0/373 (0%)		2/371 (0.5%)
General physical health deterioration	1/373 (0.3%)		0/371 (0%)
Non-cardiac chest pain	0/373 (0%)		1/371 (0.3%)
Oedema peripheral	0/373 (0%)		1/371 (0.3%)
Orthostatic intolerance	0/373 (0%)		1/371 (0.3%)
Hepatobiliary disorders
Cholelithiasis	2/373 (0.5%)		0/371 (0%)
Infections and infestations
Acute sinusitis	0/373 (0%)		1/371 (0.3%)
Appendicitis	1/373 (0.3%)		1/371 (0.3%)
Arthritis bacterial	0/373 (0%)		1/371 (0.3%)
Bronchitis	1/373 (0.3%)		1/371 (0.3%)
Bursitis infective	1/373 (0.3%)		0/371 (0%)
Campylobacter gastroenteritis	1/373 (0.3%)		0/371 (0%)
Erysipelas	1/373 (0.3%)		0/371 (0%)
Gastroenteritis	1/373 (0.3%)		1/371 (0.3%)
Gastroenteritis viral	0/373 (0%)		1/371 (0.3%)
Herpes zoster	1/373 (0.3%)		0/371 (0%)
Lobar pneumonia	0/373 (0%)		1/371 (0.3%)
Pneumonia	2/373 (0.5%)		0/371 (0%)
Pneumonia pneumococcal	1/373 (0.3%)		0/371 (0%)
Postoperative wound infection	1/373 (0.3%)		1/371 (0.3%)
Urinary tract infection	1/373 (0.3%)		0/371 (0%)
Viral infection	0/373 (0%)		1/371 (0.3%)
Injury, poisoning and procedural complications
Accident at work	1/373 (0.3%)		0/371 (0%)
Anaesthetic complication	1/373 (0.3%)		0/371 (0%)
Ankle fracture	2/373 (0.5%)		0/371 (0%)
Back injury	1/373 (0.3%)		0/371 (0%)
Clavicle fracture	1/373 (0.3%)		0/371 (0%)
Drug administration error	1/373 (0.3%)		0/371 (0%)
Facial bones fracture	0/373 (0%)		1/371 (0.3%)
Fall	7/373 (1.9%)		7/371 (1.9%)
Femoral neck fracture	1/373 (0.3%)		1/371 (0.3%)
Fractured sacrum	0/373 (0%)		1/371 (0.3%)
Hip fracture	0/373 (0%)		1/371 (0.3%)
Joint sprain	1/373 (0.3%)		0/371 (0%)
Limb traumatic amputation	1/373 (0.3%)		0/371 (0%)
Lower limb fracture	0/373 (0%)		1/371 (0.3%)
Medical device complication	1/373 (0.3%)		0/371 (0%)
Meniscus lesion	2/373 (0.5%)		1/371 (0.3%)
Muscle rupture	0/373 (0%)		1/371 (0.3%)
Pelvic fracture	1/373 (0.3%)		0/371 (0%)
Post procedural haemorrhage	1/373 (0.3%)		0/371 (0%)
Postoperative fever	1/373 (0.3%)		0/371 (0%)
Rib fracture	1/373 (0.3%)		0/371 (0%)
Road traffic accident	2/373 (0.5%)		2/371 (0.5%)
Scrotal haematoma	0/373 (0%)		1/371 (0.3%)
Spinal fracture	1/373 (0.3%)		2/371 (0.5%)
Stress fracture	0/373 (0%)		1/371 (0.3%)
Tendon rupture	0/373 (0%)		1/371 (0.3%)
Thermal burn	0/373 (0%)		1/371 (0.3%)
Traumatic brain injury	0/373 (0%)		1/371 (0.3%)
Wrist fracture	2/373 (0.5%)		0/371 (0%)
Investigations
Weight decreased	1/373 (0.3%)		0/371 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	0/373 (0%)		1/371 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/373 (0.3%)		3/371 (0.8%)
Arthritis	0/373 (0%)		1/371 (0.3%)
Back pain	0/373 (0%)		3/371 (0.8%)
Bursa calcification	0/373 (0%)		1/371 (0.3%)
Compartment syndrome	0/373 (0%)		1/371 (0.3%)
Intervertebral disc degeneration	1/373 (0.3%)		1/371 (0.3%)
Intervertebral disc disorder	1/373 (0.3%)		0/371 (0%)
Intervertebral disc protrusion	4/373 (1.1%)		5/371 (1.3%)
Intervertebral disc space narrowing	1/373 (0.3%)		0/371 (0%)
Lumbar spinal stenosis	1/373 (0.3%)		0/371 (0%)
Mobility decreased	1/373 (0.3%)		0/371 (0%)
Muscle spasms	0/373 (0%)		1/371 (0.3%)
Musculoskeletal chest pain	0/373 (0%)		1/371 (0.3%)
Musculoskeletal pain	1/373 (0.3%)		0/371 (0%)
Osteoarthritis	5/373 (1.3%)		2/371 (0.5%)
Osteonecrosis	1/373 (0.3%)		0/371 (0%)
Pain in extremity	1/373 (0.3%)		0/371 (0%)
Spinal column stenosis	0/373 (0%)		1/371 (0.3%)
Spinal osteoarthritis	1/373 (0.3%)		1/371 (0.3%)
Spondylolisthesis	1/373 (0.3%)		0/371 (0%)
Synovial cyst	1/373 (0.3%)		2/371 (0.5%)
Torticollis	0/373 (0%)		1/371 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	1/373 (0.3%)		0/371 (0%)
Basal cell carcinoma	6/373 (1.6%)		5/371 (1.3%)
Bowen's disease	0/373 (0%)		1/371 (0.3%)
Breast cancer	1/373 (0.3%)		2/371 (0.5%)
Cartilage neoplasm	0/373 (0%)		1/371 (0.3%)
Colon adenoma	1/373 (0.3%)		0/371 (0%)
Gastric cancer	0/373 (0%)		1/371 (0.3%)
Leiomyosarcoma	1/373 (0.3%)		0/371 (0%)
Lung adenocarcinoma metastatic	1/373 (0.3%)		0/371 (0%)
Lung neoplasm malignant	1/373 (0.3%)		0/371 (0%)
Lymphoma	1/373 (0.3%)		0/371 (0%)
Malignant melanoma	0/373 (0%)		1/371 (0.3%)
Metastases to bone	1/373 (0.3%)		0/371 (0%)
Metastases to central nervous system	1/373 (0.3%)		0/371 (0%)
Metastases to lung	1/373 (0.3%)		0/371 (0%)
Metastases to lymph nodes	0/373 (0%)		2/371 (0.5%)
Multiple myeloma	1/373 (0.3%)		0/371 (0%)
Oesophageal cancer metastatic	1/373 (0.3%)		0/371 (0%)
Ovarian cancer	1/373 (0.3%)		0/371 (0%)
Prostate cancer	9/373 (2.4%)		2/371 (0.5%)
Renal cell carcinoma	0/373 (0%)		1/371 (0.3%)
Skin cancer	0/373 (0%)		1/371 (0.3%)
Squamous cell carcinoma	2/373 (0.5%)		4/371 (1.1%)
Uterine leiomyoma	0/373 (0%)		1/371 (0.3%)
Uterine leiomyosarcoma	1/373 (0.3%)		0/371 (0%)
Nervous system disorders
Amnesia	1/373 (0.3%)		0/371 (0%)
Autonomic nervous system imbalance	0/373 (0%)		1/371 (0.3%)
Balance disorder	0/373 (0%)		1/371 (0.3%)
Carotid artery stenosis	0/373 (0%)		1/371 (0.3%)
Coma	0/373 (0%)		1/371 (0.3%)
Depressed level of consciousness	1/373 (0.3%)		0/371 (0%)
Dystonia	1/373 (0.3%)		0/371 (0%)
Facial palsy	1/373 (0.3%)		1/371 (0.3%)
Loss of consciousness	1/373 (0.3%)		2/371 (0.5%)
Parkinson's disease	2/373 (0.5%)		1/371 (0.3%)
Parkinsonism	2/373 (0.5%)		2/371 (0.5%)
Restless legs syndrome	1/373 (0.3%)		0/371 (0%)
Ruptured cerebral aneurysm	1/373 (0.3%)		0/371 (0%)
Sciatica	2/373 (0.5%)		0/371 (0%)
Spinal claudication	1/373 (0.3%)		0/371 (0%)
Stupor	0/373 (0%)		1/371 (0.3%)
Subarachnoid haemorrhage	1/373 (0.3%)		2/371 (0.5%)
Sudden onset of sleep	1/373 (0.3%)		2/371 (0.5%)
Syncope	0/373 (0%)		1/371 (0.3%)
Transient ischaemic attack	0/373 (0%)		1/371 (0.3%)
Tremor	1/373 (0.3%)		0/371 (0%)
Psychiatric disorders
Delirium	1/373 (0.3%)		0/371 (0%)
Depression	1/373 (0.3%)		0/371 (0%)
Disorientation	1/373 (0.3%)		0/371 (0%)
Hallucination	1/373 (0.3%)		0/371 (0%)
Hallucination, visual	1/373 (0.3%)		0/371 (0%)
Hypersexuality	1/373 (0.3%)		0/371 (0%)
Mental status changes	0/373 (0%)		2/371 (0.5%)
Rapid eye movements sleep abnormal	1/373 (0.3%)		1/371 (0.3%)
Stress	1/373 (0.3%)		0/371 (0%)
Renal and urinary disorders
Urinary fistula	1/373 (0.3%)		0/371 (0%)
Urinary retention	2/373 (0.5%)		0/371 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/373 (0.3%)		0/371 (0%)
Ovarian cyst	0/373 (0%)		1/371 (0.3%)
Prostatitis	1/373 (0.3%)		0/371 (0%)
Uterine prolapse	1/373 (0.3%)		0/371 (0%)
Vaginal prolapse	0/373 (0%)		1/371 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/373 (0%)		1/371 (0.3%)
Asthma	0/373 (0%)		1/371 (0.3%)
Dyspnoea	2/373 (0.5%)		3/371 (0.8%)
Pharyngeal hypoaesthesia	1/373 (0.3%)		0/371 (0%)
Pneumonia aspiration	1/373 (0.3%)		0/371 (0%)
Pulmonary embolism	1/373 (0.3%)		0/371 (0%)
Skin and subcutaneous tissue disorders
Precancerous skin lesion	1/373 (0.3%)		0/371 (0%)
Vascular disorders
Aortic aneurysm	0/373 (0%)		1/371 (0.3%)
Circulatory collapse	0/373 (0%)		2/371 (0.5%)
Deep vein thrombosis	1/373 (0.3%)		0/371 (0%)
Orthostatic hypotension	1/373 (0.3%)		2/371 (0.5%)
Peripheral ischaemia	1/373 (0.3%)		0/371 (0%)
Phlebitis superficial	1/373 (0.3%)		0/371 (0%)
Subclavian artery stenosis	1/373 (0.3%)		0/371 (0%)
Thrombosis	1/373 (0.3%)		1/371 (0.3%)
Varicose vein	0/373 (0%)		1/371 (0.3%)
Other (Not Including Serious) Adverse Events
	Carbidopa/Levodopa/Entacapone		Carbidopa/Levodopa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	310/373 (83.1%)		291/371 (78.4%)
Gastrointestinal disorders
Constipation	50/373 (13.4%)		44/371 (11.9%)
Diarrhoea	65/373 (17.4%)		28/371 (7.5%)
Dry mouth	19/373 (5.1%)		13/371 (3.5%)
Dyspepsia	14/373 (3.8%)		20/371 (5.4%)
Nausea	114/373 (30.6%)		70/371 (18.9%)
Vomiting	22/373 (5.9%)		9/371 (2.4%)
General disorders
Fatigue	40/373 (10.7%)		42/371 (11.3%)
Oedema peripheral	27/373 (7.2%)		34/371 (9.2%)
Infections and infestations
Bronchitis	20/373 (5.4%)		20/371 (5.4%)
Nasopharyngitis	34/373 (9.1%)		43/371 (11.6%)
Upper respiratory tract infection	19/373 (5.1%)		17/371 (4.6%)
Urinary tract infection	20/373 (5.4%)		24/371 (6.5%)
Injury, poisoning and procedural complications
Fall	28/373 (7.5%)		36/371 (9.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	38/373 (10.2%)		43/371 (11.6%)
Back pain	47/373 (12.6%)		53/371 (14.3%)
Muscle spasms	20/373 (5.4%)		21/371 (5.7%)
Pain in extremity	37/373 (9.9%)		32/371 (8.6%)
Nervous system disorders
Dizziness	59/373 (15.8%)		46/371 (12.4%)
Dyskinesia	21/373 (5.6%)		10/371 (2.7%)
Headache	37/373 (9.9%)		26/371 (7%)
Somnolence	37/373 (9.9%)		28/371 (7.5%)
Tremor	11/373 (2.9%)		26/371 (7%)
Psychiatric disorders
Abnormal dreams	25/373 (6.7%)		17/371 (4.6%)
Anxiety	37/373 (9.9%)		27/371 (7.3%)
Depression	57/373 (15.3%)		51/371 (13.7%)
Insomnia	47/373 (12.6%)		53/371 (14.3%)
Skin and subcutaneous tissue disorders
Rash	13/373 (3.5%)		19/371 (5.1%)
Vascular disorders
Hypertension	19/373 (5.1%)		27/371 (7.3%)
Orthostatic hypotension	19/373 (5.1%)		11/371 (3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.