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Clinical Trial Results:
The Effect of Rotigotine on Memory in Idiopathic Parkinson's Disease without Cognitive Impairment

Summary
EudraCT number	2014-000335-17
Trial protocol	GB
Global end of trial date	12 Jun 2015

Results information
Results version number	v1(current)
This version publication date	18 Jun 2016
First version publication date	18 Jun 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

MPR001

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University Hospitals of North Midlands NHS Trust

Sponsor organisation address

Newcastle Road, Staffordshire, United Kingdom, ST4 6QG

Public contact

Dr Darren Clement, University Hospitals of North Midlands NHS Trust , 0044 01782 675379, Darren.Clement@uhnm.nhs.uk

Scientific contact

Dr Darren Clement, University Hospitals of North Midlands NHS Trust , 0044 01782 675379, Darren.Clement@uhnm.nhs.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

12 Jun 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Jun 2015

Global end of trial reached?

Yes

Global end of trial date

12 Jun 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

This is not a hypothesis testing trial, but an acceptability and feasibility trial. The primary objectives are (i) to obtain estimates of memory performance which will inform a power calculation which will inform a larger, multi-centered, fully powered investigation, data collected during ON and OFF research sessions; (ii) management of symptoms during washout period, assessed using a semi-structured interview administered at the end of each patient-participant’s involvement in the trial. The study also performed the same memory assessments on healthy volunteers (no study drug administered).

Protection of trial subjects

This trial did not involve changing the patient-participants’ prescribed medication (drug or dose). The interventions included a memory/neuropsychological testing session conducted both following a medication withdrawal period (OFF-medication session) and on medications (ON -medication session). Each patient-participant was telephoned by a research nurse within two working days of their OFF-medication session and also participants had access to a 24 hour contact telephone number should concerns arise.

Background therapy

Participants were permitted a range of Parkinson's medications : A) PD patients currently medicated with rotigotine transdermal patch, dose range 2-16mg per 24 hours (with/without a controlled-release preparation of l-dopa, with/without a monoamine oxidase B inhibitor such as rasagiline/Azilect (0.5-1mg per 24 hours) or selegiline/ Eldepryl (5mg -12mg per 24 hours), Zelapar (1.25mg – 2.5mg per day). B) PD patients currently medicated with a controlled-release l-dopa preparation, dose range 150-1,200mg/per 24 hours (with/without a monoamine oxidase B inhibitor such as rasagiline/Azilect (0.5-1mg per 24 hours) or selegiline/ Eldepryl (5mg -12mg per 24 hours), Zelapar (1.25mg – 2.5mg per day).

Evidence for comparator

Actual start date of recruitment

13 Apr 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 14

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patient participants with Parkinson's Disease were recruited from the University Hospitals of North Midlands NHS Trust. Healthy volunteers (who did not receive any study drugs) who underwent the same regimen of memory testing were recruited at Keele University (a non-NHS Site).

Screening details

For Parkinson's patients : Screening visit/questionnaires: Review of inclusion/exclusion criteria, medical history and current medication, Functional assessment of mental capacity by Investigator, informed consent, mini-mental state exam, physical exam, vital signs, PD symptom assessment, Hospital Anxiety and Depression scale, subjective mood.

Number of subjects started

Number of subjects completed

Reason: Number of subjects

Screen fail: Had a family history of Parkinson's: 1

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Single blind

Roles blinded

Assessor ^[1]

Blinding implementation details

Keele researcher was blinded to the Parkinson's participants medication but not to the ON or OFF medication status.

Are arms mutually exclusive

Yes

Parkinson's : Rotigotine patients

Arm description

Patient medicated with rotigotine transdermal patch, dose range 2-16mg per 24 hours (with or without a controlled-release preparation of levodopa, with or without a monoamine oxidase B inhibitor such as rasagiline/Azilect or selegiline/ Eldepryl, Zelapar).

Arm type

Rotigotine

Investigational medicinal product name

Rotigotine transdermal patch

Investigational medicinal product code

ATC code: N04BC09

Other name

Pharmaceutical forms

Transdermal patch

Routes of administration

Transdermal use

Dosage and administration details

Dose range 2-16mg per 24 hours For the "ON" session, medication to be taken as usual For the "OFF" session: Patch to be removed at 9am the day prior to testing. Patch to be resumed after the testing session.

Investigational medicinal product name

Levodopa + Benserazide

Investigational medicinal product code

Other name

e.g. Madopar

Pharmaceutical forms

Capsule, hard, Dispersible tablet, Prolonged-release capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Levodopa + carbidopa

Investigational medicinal product code

Other name

e.g. Sinemet

Pharmaceutical forms

Prolonged-release tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

Levodopa dose range 150-1,200mg / 24 hours. Combination of controlled release and immediate release was permitted. For the "ON" session, medication to be taken as usual For the "OFF" session: L-dopa withdrawn 12 hours (i.e. overnight) before the OFF -medication session The following combinations were permitted: Sinemet 12.5mg/50mg, (12.5mg anhydrous carbidopa +50mg levodopa), Sinemet 10mg/100mg (10mg anhydrous carbidopa +100mg levodopa), Simemet Plus (25mg/100mg (25mg anhydrous carbidopa + 100mg levodopa), Sinemet 25mg/250mg (25mg anhydrous carbidopa + 250mg levodopa) CR (50mg anhydrous carbidopa +200mg levodopa) Prolonged Release tablets and Half Sinemet CR (25mg anhydrous carbidopa+100mg levodopa)

Investigational medicinal product name

Selegiline hydrochloride (monoamine oxidase B inhibitor)

Investigational medicinal product code

Other name

e.g. Elderpryl or Zelapar

Pharmaceutical forms

Oral lyophilisate, Tablet

Routes of administration

Oral use, Sublingual use

Dosage and administration details

Tablet: 12mg/ 24 hours permitted Oral Lyophilisate: 1.25-2.5 mg / 24 hours For the "ON" session, medication to be taken as usual For the "OFF" session: withdrawn 12 hours (i.e. overnight) before the OFF -medication session

Investigational medicinal product name

Rasagiline (MAO-B inhibitor)

Investigational medicinal product code

Other name

e.g. Azilect

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Dose range 0.5 - 1mg / 24 hours. For the "ON" session, medication to be taken as usual For the "OFF" session: MOA-B Inhibitor withdrawn 12 hours (i.e. overnight) before the OFF -medication session

Parkinson's L-Dopa patients

Arm description

Patient medicated with controlled-release preparation of levodopa (in combination with an immediate release formulation was permitted), with or without a monoamine oxidase B inhibitor such as rasagiline/Azilect or selegiline/ Eldepryl, Zelapar).

Arm type

Active comparator

Investigational medicinal product name

Levodopa + Benserazide

Investigational medicinal product code

Other name

e.g. Madopar

Pharmaceutical forms

Capsule, hard, Dispersible tablet, Prolonged-release capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Levodopa + carbidopa

Investigational medicinal product code

Other name

e.g. Sinemet

Pharmaceutical forms

Prolonged-release tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Selegiline hydrochloride (monoamine oxidase B inhibitor)

Investigational medicinal product code

Other name

e.g. Elderpryl or Zelapar

Pharmaceutical forms

Oral lyophilisate, Tablet

Routes of administration

Oral use, Sublingual use

Dosage and administration details

Tablet: 5mg to 12mg/ 24 hours permitted Oral Lyophilisate: 1.25-2.5 mg / 24 hours For the "ON" session, medication to be taken as usual For the "OFF" session: withdrawn 12 hours (i.e. overnight) before the OFF -medication session

Investigational medicinal product name

Rasagiline (MAO-B inhibitor)

Investigational medicinal product code

Other name

e.g. Azilect

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Dose range 0.5 - 1mg / 24 hours. For the "ON" session, medication to be taken as usual For the "OFF" session: MOA-B Inhibitor withdrawn 12 hours (i.e. overnight) before the OFF -medication session

Healthy Volunteers

Arm description

This arm underwent memory assessments only. No study drugs were administered.

Arm type

Memory assessments only

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Notes
[1] - The roles blinded appear inconsistent with a simple blinded trial.
Justification: Keele researcher was blinded to the Parkinson's participants medication but not to the ON or OFF medication status. There was no blinding for the healthy volunteers.

Number of subjects in period 1 ^[2]	Parkinson's : Rotigotine patients	Parkinson's L-Dopa patients	Healthy Volunteers
Started	1	2	10
Overall Trial	1	2	10
Completed	1	1	10
Not completed	0	1	0
Unable to schedule memory session	-	1	-

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 14 participants were enrolled. One patient did not meet the inclusion / exclusion criteria at the screening visit and therefore had to be withdrawn. One participant could not schedule a memory testing session with the Keele researcher prior to the researcher's end of contract and had to be withdrawn.

Baseline characteristics

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Reporting group title

Parkinson's : Rotigotine patients

Reporting group description

Reporting group title

Parkinson's L-Dopa patients

Reporting group description

Reporting group title

Healthy Volunteers

Reporting group description

This arm underwent memory assessments only. No study drugs were administered.

Reporting group values	Parkinson's : Rotigotine patients	Parkinson's L-Dopa patients	Healthy Volunteers	Total
Number of subjects	1	2	10	13
Age categorical
Age of participants
Units: Subjects
Adults (18-64 years)	0	0	1	1
From 65-84 years	1	2	9	12
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	77.4 ( 0 )	73.5 ( 7.7 )	70.1 ( 5.1 )	-
Gender categorical
Gender of participants
Units: Subjects
Female	0	0	5	5
Male	1	2	5	8

Subject analysis set title

Memory Assessments (PD patients)

Subject analysis set type

Full analysis

Subject analysis set description

This was a feasibility study. Due to the small sample size, no formal comparison of memory assessments was undertaken.

Subject analysis set title

End of Study Interviews

Subject analysis set type

Full analysis

Subject analysis set description

End of study interviews for the two Parkinson's patients.

Subject analysis set title

Memory Assessments (Healthy volunteers)

Subject analysis set type

Full analysis

Subject analysis set description

Healthy control data was collected from 10 volunteers which was smaller than the 25 target, but sufficient for analysis. They completed the same neurological test battery with the purpose of providing normal / baseline performance data, however the small number of participants recruited to the rotigotine / levodopa arms precluded any meaningful statistical comparison of data

Subject analysis sets values	Memory Assessments (PD patients)	End of Study Interviews	Memory Assessments (Healthy volunteers)
Number of subjects	2	2	10
Age categorical
Age of participants
Units: Subjects
Adults (18-64 years)			1
From 65-84 years	2	2	9
85 years and over
Age continuous
Units: years
arithmetic mean (standard deviation)	72.7 ( 6.6 )	72.7 ( 6.6 )	70.1 ( 5.1 )
Gender categorical
Gender of participants
Units: Subjects
Female	0	0	5
Male	2	2	5

End points

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Reporting group title

Parkinson's : Rotigotine patients

Reporting group description

Reporting group title

Parkinson's L-Dopa patients

Reporting group description

Reporting group title

Healthy Volunteers

Reporting group description

This arm underwent memory assessments only. No study drugs were administered.

Subject analysis set title

Memory Assessments (PD patients)

Subject analysis set type

Full analysis

Subject analysis set description

This was a feasibility study. Due to the small sample size, no formal comparison of memory assessments was undertaken.

Subject analysis set title

End of Study Interviews

Subject analysis set type

Full analysis

Subject analysis set description

End of study interviews for the two Parkinson's patients.

Subject analysis set title

Memory Assessments (Healthy volunteers)

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Estimates of memory performance

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End point title

Estimates of memory performance ^[1]

End point description

For Parkinson's Patients, memory assessments performed for the ON research session involved the patient taking medications as usual. For the OFF session, medication was delayed prior to the memory recollection research session. Medication was resumed following completion of the memory assessments. For the healthy volunteers, these underwent two memory assessments (called "blue" and "green" to mirror the Parkinson's patients assessments. The healthy volunteers underwent no change in medications.

End point type

Primary

End point timeframe

This was a feasibility study. Primary endpoint was to obtain estimates of memory performance which will inform a power calculation, data collected during ON and OFF research sessions

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This was a feasibility study. There was insufficient recruitment to provide estimates to inform a power calculation.

End point values	Parkinson's : Rotigotine patients	Parkinson's L-Dopa patients	Healthy Volunteers	Memory Assessments (PD patients)	End of Study Interviews	Memory Assessments (Healthy volunteers)
Number of subjects analysed	0 ^[2]	0 ^[3]	0 ^[4]	0 ^[5]	0 ^[6]	0 ^[7]
Units: Memory recall
number (not applicable)

Notes
[2] - This was a feasibility study. There was insufficient recruitment for analysis.
[3] - This was a feasibility study. There was insufficient recruitment for analysis.
[4] - This was a feasibility study. There was insufficient recruitment for analysis.
[5] - This was a feasibility study. There was insufficient recruitment for analysis.
[6] - End of study interviews provided valuable data for the feasibility study
[7] - This was a feasibility study. There was insufficient recruitment for analysis.

No statistical analyses for this end point

Primary: Semi-structured interview

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End point title

Semi-structured interview ^[8]

End point description

Semi structured interview for Parkinson's patients at the end of the trial.

End point type

Primary

End point timeframe

Primary End point: management of symptoms during washout period, assessed using a semi-structured interview administered at the end of each patient-participant’s involvement in the trial.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The healthy volunteers did not require an end of study interview for this feasibility study.

End point values	Parkinson's : Rotigotine patients	Parkinson's L-Dopa patients	End of Study Interviews
Number of subjects analysed	1 ^[9]	1 ^[10]	2 ^[11]
Units: N/A	1	1	2

Notes
[9] - One patient from this group has a semi-structured interview
[10] - One patient from this group has a semi-structured interview
[11] - Two participants underwent semi-structured interviews

End of Study Interviews

Statistical analysis description

Qualitative data only

Comparison groups

Parkinson's : Rotigotine patients v Parkinson's L-Dopa patients v End of Study Interviews

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

other ^[12]

P-value

= 0 ^[13]

Method

NOT DONE

Confidence interval

Notes
[12] - Qualitative data: Interviews identified the following main themes: 1-Trial contact: Participants were happy with the approach 2-Trial information: Felt it was interesting but possibly too much jargon 3-Reasons for taking part: In general: altruism and making a contribution to a break through; specifically to learn more about their own medication and its effects. 4-Experience of taking part: Participants enjoyed the assessments and it wasn’t a burden This was a feasibility study only.
[13] - NOTE: No P-value calculated "0" entered above to fulfil validation report only. Please ignore value.

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected from consent to the last study visit. Participants were telephoned by the research nurses after the last visit to collect any adverse event information.

Adverse event reporting additional description

Worsening of Parkinson's symptoms during the "OFF" medication session were not considered to be adverse events as they were expected during an unmedicated state. No adverse events were reported for this trial.

Assessment type

Systematic

Dictionary name

WHO ICD-10

Dictionary version

2016

Reporting group title

Overall trial

Reporting group description

Adverse events for overall trial (note no adverse events were reported)

Serious adverse events	Overall trial
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 2 (0.00%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Overall trial
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 2 (0.00%)

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: There were only two Parkinson's participants who completed the trial (and 10 healthy volunteers in the healthy volunteer arm). There were no adverse events reported.

More information

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Were there any global substantial amendments to the protocol? Yes

26 Jan 2015

Administrative amendment to the MHRA. Change in sponsor name from University Hospitals of North Staffordshire NHS trust to University Hospitals of North Midlands NHS Trust.

13 Feb 2015

Change in recruiting Trust Name from University Hospitals of North Staffordshire to University Hospitals of North Midlands NHS Trust (Note: MHRA administrative change Amendment 01)  Patient who also take immediate release preparation L-Dopa, in addition to a controlled released preparation as part of their Parkinson’s treatment are now eligible to participate.  Added English as a first language in to the inclusion of the healthy volunteer group to match up in line with the patient-participant inclusion criteria.  Current or planned participation in another research trial changed to another drug trial to include those patients on other observational, non interventional research studies.  Treatment for Cancer has been changed to Treatment for Cancer (excluding Basal Cell Carcinoma).  Hypotension has been changed to Clinically significant Hypotension  Major Head injury has been changed to Major Head injury in the last twelve months (Healthy volunteers) Changes to Contraindicated Treatments  Anticholinergics have been changed to centrally acting anticholinergic (e.g Orphenadrine, Trihexyphenidyl Procyclidine)  Added the statement: Note: Anticholinergics used the treatment of asthma that do not cross the blood brain barrier (e.g Atrovent) are permitted. Follow up  Each patient Participant will now be telephoned by a research nurse within two working days of their OFF-medication session Patient-participants will also be telephone within 7-28 days of completing their participation in the trial to discuss any adverse events that they experience during the trial.  Updated reference safety information and formulations and dosages of each IMP  Added instructions on dispensing, modification of trial treatment, overdose management, accountability, compliance and destruction. Adverse Events  Added worsening of Parkinson’s symptoms during the ‘OFF’ session are not to be recorded as adverse events as this is expected during the patient’s unmediated state

23 Mar 2015

MHRA approved 23-Mar-2015 Ethics approved 24-Mar-2015 For the MHRA, this amendment includes all changes specified in previous amendment plus the following: Levodopa maximum dose amended from 1000mg to 1200mg/24 hours Clarified that Rotigotine patch to be removed at 9:00am the day prior to the off testing session. Recent Head Injury added to exclusion criteria (patient-participants) End of study interviews to include first 3 levodopa and first 3 rotigotine patients Epworth sleepiness scale added to ON session assessments Updated HADS, Mini-mental and submitted Mental capacity Act for completeness Updates to other study documents in line with the above.

17 Apr 2015

Added Keele as a NON-NHS Site for the healthy volunteer assessments.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

It is important to note that at this stage in the program of research there is still no firm evidence that dopaminergic medication affects memory. Therefore people with Parkinson’s should NOT change their medication based on this feasibility study.

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Clinical trials

Clinical Trial Results:
The Effect of Rotigotine on Memory in Idiopathic Parkinson's Disease without Cognitive Impairment

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Estimates of memory performance

Primary: Estimates of memory performance

Primary: Semi-structured interview

Primary: Semi-structured interview

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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Clinical trials

Clinical Trial Results: The Effect of Rotigotine on Memory in Idiopathic Parkinson's Disease without Cognitive Impairment

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Estimates of memory performance

Primary: Estimates of memory performance

Primary: Semi-structured interview

Primary: Semi-structured interview

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
The Effect of Rotigotine on Memory in Idiopathic Parkinson's Disease without Cognitive Impairment