Randomized Evaluation of the 24-Hour Coverage: Efficacy of Rotigotine (RECOVER)

• ClinicalTrials.gov Identifier: NCT00474058
• Recruitment Status: Completed
• First Posted: May 16, 2007
• Results First Posted: April 12, 2010
• Last Update Posted: June 22, 2015
• Sponsor: UCB Pharma
• Information provided by (Responsible Party): UCB Pharma

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Parkinson's Disease
• Interventions: Drug: Rotigotine; Other: Placebo
• Enrollment: 287

Participant Flow

Recruitment Details	A total of 333 subjects were enrolled in this trial and comprised the Enrolled Set (ES). 287 subjects were randomized and all of them received at least 1 dose of trial medication, so they all belong to the Safety Set (SS). 267 subjects belong to the Full Analysis Set (FAS).
Pre-assignment Details	Participant Flow shows all 287 subjects who has been enrolled and randomized. Baseline Characteristics are described for the Full Analysis Set (FAS).

Arm/Group Title	Rotigotine	Placebo
Arm/Group Description	Rotigotine transdermal patch	Placebo transdermal patch
Period Title: Overall Study
Started	190	97
Completed	166	80
Not Completed	24	17
Reason Not Completed
Adverse Event	11	6
Lack of Efficacy	0	4
Withdrawal by Subject	11	7
Other	2	0

Baseline Characteristics

Arm/Group Title		Rotigotine	Placebo	Total
Arm/Group Description		Rotigotine transdermal patch	Placebo transdermal patch	Total of all reporting groups
Overall Number of Baseline Participants		178	89	267
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	178 participants	89 participants	267 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	87 48.9%	40 44.9%	127 47.6%
	>=65 years	91 51.1%	49 55.1%	140 52.4%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	178 participants	89 participants	267 participants
		64.7 (9.4)	64.5 (10.4)	64.6 (9.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	178 participants	89 participants	267 participants
	Female	61 34.3%	31 34.8%	92 34.5%
	Male	117 65.7%	58 65.2%	175 65.5%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	178 participants	89 participants	267 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	1 0.6%	1 1.1%	2 0.7%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	2 1.1%	1 1.1%	3 1.1%
	White	164 92.1%	79 88.8%	243 91.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	11 6.2%	8 9.0%	19 7.1%
Body Mass Index (BMI); Mean (Standard Deviation); Unit of measure: Kg/ m^2
	Number Analyzed	178 participants	89 participants	267 participants
		26.676 (4.164)	26.645 (4.569)	26.665 (4.295)
Height; Mean (Standard Deviation); Unit of measure: Cm
	Number Analyzed	178 participants	89 participants	267 participants
		169.04 (9.11)	170.73 (9.27)	169.60 (9.18)
Weight; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	178 participants	89 participants	267 participants
		76.6 (15.1)	78.0 (16.2)	77.1 (15.5)

Outcome Measures

1. Primary Outcome

Title	Change in Early Morning UPDRS Part III Score
Description	The Unified Parkinson´s Disease Rating Scale Part III score is an accepted and validated sumscore of 14 items for the assessment of motor function in Parkinson´s disease. Each of the 14 items in the UPDRS part III is measured on a scale of 0 to 4, where 0 is normal and 4 represents severe abnormalities.
Time Frame	From baseline to end of maintenance (after 4 weeks maintenance)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF).

Arm/Group Title	Rotigotine	Placebo
Arm/Group Description:	Rotigotine transdermal patch	Placebo transdermal patch
Overall Number of Participants Analyzed	178	89
Mean (Standard Deviation); Unit of Measure: units on a scale
	-7.0 (7.6)	-3.9 (7.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rotigotine, Placebo
	Comments	Analyses of covariance were performed for the efficacy variables with treatment and (pooled) sites as factors, and baseline value as covariate. Least square means (LS means) for treatment effect were calculated and differences between rotigotine and placebo were presented with 95% confidence intervals (CIs) and p- values.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	No p-value adjustment was necessary, since a multiple test procedure in a hierarchical sequentially rejective manner for the primary variable was applied.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.55
	Confidence Interval	95%; -5.37 to -1.73
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Change in Parkinson's Disease Sleep Scale (PDSS)
Description	The Parkinson´s Disease Sleep Scale (PDSS) is a questionnaire with 15 questions to assess sleep and nocturnal disability in Parkinson´s disease. The item- scores can range between 0= never and 4= very often. The PDSS score is a sumscore of all 15 questions.
Time Frame	From baseline to end of maintenance (after 4 weeks maintenance)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF).

Arm/Group Title	Rotigotine	Placebo
Arm/Group Description:	Rotigotine transdermal patch	Placebo transdermal patch
Overall Number of Participants Analyzed	178	89
Mean (Standard Deviation); Unit of Measure: units on a scale
	-5.9 (7.6)	-1.9 (8.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rotigotine, Placebo
	Comments	Analyses of covariance were performed for the efficacy variables with treatment and (pooled) sites as factors, and baseline value as covariate. Least square means (LS means) for treatment effect were calculated and differences between rotigotine and placebo were presented with 95% confidence intervals (CIs) and p- values.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	No p-value adjustment was necessary, since a multiple testing in a hierarchical sequentially rejective manner for the primary variable was applied.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.26
	Confidence Interval	95%; -6.08 to -2.45
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Change in Nocturnal Akinesia, Dystonia, and Cramps Score (NADCS)
Description	Subjects were asked to assess nocturnal akinesia, dystonia and cramps, using an ordinal severity scale. While a score of 0= normal and 4= maximal severity, subjects could also rate their symptoms with values of 0.5, 1.5, 2.5, 3.5. The nocturnal akinesia score was used to evaluate motor performance while the dystonia and cramps scores were used to evaluate sleep.
Time Frame	From baseline to end of maintenance (after 4 weeks maintenance)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS).

Arm/Group Title	Rotigotine	Placebo
Arm/Group Description:	Rotigotine transdermal patch	Placebo transdermal patch
Overall Number of Participants Analyzed	163	78
Mean (Standard Deviation); Unit of Measure: units on a scale
	-1.3 (1.8)	-0.9 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rotigotine, Placebo
	Comments	Analyses of covariance were performed for the efficacy variables with treatment and (pooled) sites as factors, and baseline value as covariate. Least square means (LS means) for treatment effect were calculated and differences between rotigotine and placebo were presented with 95% confidence intervals (CIs) and p- values.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0301
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.41
	Confidence Interval	95%; -0.79 to -0.04
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Change in Number of Nocturias
Description	Nocturia is the need to get up during the night and interrupt sleep in order to urinate. It is a typical nocturnal symptom of Parkinson´s disease. The change from baseline in number of nocturias was used to evaluate improvements in sleep disorders.
Time Frame	From baseline to end of maintenance (after 4 weeks maintenance)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS).

Arm/Group Title	Rotigotine	Placebo
Arm/Group Description:	Rotigotine transdermal patch	Placebo transdermal patch
Overall Number of Participants Analyzed	161	78
Mean (Standard Deviation); Unit of Measure: nocturias
	-0.3 (1.3)	-0.2 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rotigotine, Placebo
	Comments	Analyses of covariance were performed for the efficacy variables with treatment and (pooled) sites as factors, and baseline value as covariate. Least square means (LS means) for treatment effect were calculated and differences between rotigotine and placebo were presented with 95% confidence intervals (CIs) and p- values.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8842
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	95%; -0.29 to 0.25
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Adverse Events (AEs) were collected up to 22 weeks from Visit 1 to the Safety Follow- Up Visit.
Adverse Event Reporting Description	Serious and non- serious Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all subjects who are randomized and received at least one dose of trial medication.
Arm/Group Title	Rotigotine		Placebo
Arm/Group Description	Rotigotine transdermal patch		Placebo transdermal patch
All-Cause Mortality
	Rotigotine		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Rotigotine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/191 (5.24%)		5/96 (5.21%)
Gastrointestinal disorders
Diarrhoea † 1	1/191 (0.52%)	1	0/96 (0.00%)	0
General disorders
Oedema peripheral † 1	0/191 (0.00%)	0	1/96 (1.04%)	1
Hepatobiliary disorders
Cholecystitis † 1	1/191 (0.52%)	1	0/96 (0.00%)	0
Infections and infestations
Urosepsis † 1	1/191 (0.52%)	1	0/96 (0.00%)	0
Injury, poisoning and procedural complications
Ankle fracture † 1	1/191 (0.52%)	2	0/96 (0.00%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion † 1	1/191 (0.52%)	1	0/96 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chronic lymphocytic leukaemia † 1	0/191 (0.00%)	0	1/96 (1.04%)	1
Basal cell carcinoma † 1	0/191 (0.00%)	0	1/96 (1.04%)	1
Nervous system disorders
Cerebrovascular accident † 1	0/191 (0.00%)	0	1/96 (1.04%)	1
Syncope † 1	1/191 (0.52%)	1	0/96 (0.00%)	0
Pregnancy, puerperium and perinatal conditions
Abortion † 1	1/191 (0.52%)	1	0/96 (0.00%)	0
Psychiatric disorders
Panic attack † 1	0/191 (0.00%)	0	1/96 (1.04%)	1
Completed suicide † 1	0/191 (0.00%)	0	1/96 (1.04%)	1
Hallucination, visual † 1	1/191 (0.52%)	1	0/96 (0.00%)	0
Sleep attacks † 1	1/191 (0.52%)	1	0/96 (0.00%)	0
Renal and urinary disorders
Nephrotic syndrome † 1	0/191 (0.00%)	0	1/96 (1.04%)	1
Renal impairment † 1	0/191 (0.00%)	0	1/96 (1.04%)	1
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	1/191 (0.52%)	1	0/96 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration † 1	0/191 (0.00%)	0	1/96 (1.04%)	1
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (9.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Rotigotine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/191 (36.65%)		21/96 (21.88%)
Gastrointestinal disorders
Nausea † 1	41/191 (21.47%)	54	9/96 (9.38%)	14
Nervous system disorders
Dizziness † 1	20/191 (10.47%)	27	6/96 (6.25%)	6
Headache † 1	13/191 (6.81%)	14	5/96 (5.21%)	5
Dyskinesia † 1	15/191 (7.85%)	16	4/96 (4.17%)	4
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (9.1)

Limitations and Caveats

During the course of the trial, the manufacturing process for rotigotine was changed. At that time, the expiry date for trial medication was Apr 2009, recruitment for SP889 had to be stopped effective on 17 Nov 2008.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

"UCB has > 60 days but <= 180 days to review results communications prior to public release and may delete information that is confidential and compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome."

Results Point of Contact

• Name/Title: UCB Clinical Trial Call Center
• Organization: UCB
• Phone: +1877 822 9493

Publications of Results:

Ghys L, Surmann E, Whitesides J, Boroojerdi B. Effect of rotigotine on sleep and quality of life in Parkinson's disease patients: post hoc analysis of RECOVER patients who were symptomatic at baseline. Expert Opin Pharmacother. 2011 Sep;12(13):1985-98. doi: 10.1517/14656566.2011.604031. Epub 2011 Jul 27.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kassubek J, Chaudhuri KR, Zesiewicz T, Surmann E, Boroojerdi B, Moran K, Ghys L, Trenkwalder C. Rotigotine transdermal system and evaluation of pain in patients with Parkinson's disease: a post hoc analysis of the RECOVER study. BMC Neurol. 2014 Mar 6;14:42. doi: 10.1186/1471-2377-14-42.

Swick TJ, Friedman JH, Chaudhuri KR, Surmann E, Boroojerdi B, Moran K, Ghys L, Trenkwalder C. Associations between severity of motor function and nonmotor symptoms in Parkinson's disease: a post hoc analysis of the RECOVER Study. Eur Neurol. 2014;71(3-4):140-7. doi: 10.1159/000355019. Epub 2014 Jan 21.

Trenkwalder C, Kies B, Rudzinska M, Fine J, Nikl J, Honczarenko K, Dioszeghy P, Hill D, Anderson T, Myllyla V, Kassubek J, Steiger M, Zucconi M, Tolosa E, Poewe W, Surmann E, Whitesides J, Boroojerdi B, Chaudhuri KR; Recover Study Group. Rotigotine effects on early morning motor function and sleep in Parkinson's disease: a double-blind, randomized, placebo-controlled study (RECOVER). Mov Disord. 2011 Jan;26(1):90-9. doi: 10.1002/mds.23441. Epub 2010 Nov 18.

• Responsible Party: UCB Pharma
• ClinicalTrials.gov Identifier: NCT00474058
• Other Study ID Numbers: SP0889; EudraCT No.: 2006-006752-35 ( Other Identifier: EudraCT )
• First Submitted: May 14, 2007
• First Posted: May 16, 2007
• Results First Submitted: February 25, 2010
• Results First Posted: April 12, 2010
• Last Update Posted: June 22, 2015