Efficacy and Tolerability of IRL790 in Parkinson's Disease Dyskinesia

• Sponsor: Integrative Research Laboratories AB (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03368170
• Collaborator: The Clinical Trial Company (Industry)
• Enrollment: 75
• Locations: 20
• Arms: 2
• Actual Duration (Months): 14
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Mesdopetam (IRL790) is an experimental small molecule compound with psychomotor stabilizing properties. The primary target is the dopamine D3 receptor, a target implicated in the generation of levodopa-induced dyskinesia, a side-effect frequently occurring with long-term levodopa treatment in patients with Parkinson's disease. In experimental animals mesdopetam potently reduced levodopa-induced involuntary movement without impairing the antiparkinsonian effect of levodopa.

The primary purpose of the trial is to investigate whether mesdopetam given as adjunctive treatment can reduce levodopa induced dyskinesia in patients with Parkinson's disease. The trial will also help to establish the most optimal dosing of the compound.

Condition or Disease	Intervention/Treatment	Phase
Parkinson Disease	Drug: Mesdopetam (IRL790)	Phase 2

Detailed Description

METHODOLOGY:

This is a multicentre study where 74 patients with Parkinson's disease exhibiting levodopa induced dyskinesia will be randomised to receive study drug or placebo. Thirty seven patients will be randomised to mesdopetam and 37 patients to placebo (1:1 randomisation).

Patients will be screened for eligibility according to inclusion/exclusion criteria within four weeks of initiation of study treatment (Screening visit).

An outpatient study with the patients taking the study drug for four weeks at home. Mesdopetam will be taken twice daily (b.i.d.) as adjunctive treatment to the patients' regular and stable antiparkinsonian medication.

The first two weeks of treatment will allow for per patient titration of study medication to the highest tolerated predefined dose, after which patients will continue on this highest tolerated dose for an additional two weeks.

Changes in disease state and dyskinesia will be measured using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Unified Dyskinesia Rating Scale (UDysRS); furthermore, patients will administer two 24-hour diaries on run-in and on the fourth week of dosing to assess daily movements.

Pharmacokinetic (PK) samples will be collected for the determination of concentrations of mesdopetam and its metabolites IRL902 and IRL872 in plasma. They will be collected before and after IMP administration at two visits.

A Follow-up Visit will be performed for all patients five to eight days after last administration of IMP.

Study Design

• Study Type: Interventional
• Actual Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Double blind, placebo controlledDouble blind, placebo controlled
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Placebo-controlled, Phase IIa Study Evaluating the Efficacy and Tolerability of IRL790 in Parkinson's Disease Dyskinesia
• Actual Study Start Date: Apr 12, 2018
• Actual Primary Completion Date: Jun 12, 2019
• Actual Study Completion Date: Jun 12, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mesdopetam (IRL790) Capsule 2.5 mg, oral administration	Drug: Mesdopetam (IRL790); Mesdopetam (IRL790) capsule; Other Names: IRL790
Placebo Comparator: Placebo Identical capsule, oral administration	Drug: Mesdopetam (IRL790); Mesdopetam (IRL790) capsule; Other Names: IRL790

Outcome Measures

Primary Outcome Measures

1. Unified Dyskinesia Rating Scale (UDysRS) [Baseline and 4 weeks]

   The change from baseline to day 28 of treatment (Visit 4) in the sum of the items comprising the Unified Dyskinesia Rating Scale (UDysRS). The Unified Dyskinesia Rating Scale (UDysRS) is administered to assess dyskinesia. The scoring range is 0-104, where higher score means more dyskinesia.

Secondary Outcome Measures

1. Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV, Question 4.1 and 4.2 [Baseline and 4 weeks]

   Change in MDS-UPDRS sum score of questions 4.1 (Time spent with dyskinesias) and 4.2 (Functional impact of dyskinesias) in part IV from baseline to visit 4. Minimum score is 0 and maximum score is 8. A higher score means more dyskinesia.

2. Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part II and III [Baseline and 4 weeks]

   Change in MDS-UPDRS sum score of parts II+III (Motor aspects of Experiences of Daily living + Motor Examination) from baseline to visit 4. Minimum value is 0 and maximum value is 124. Higher score mean a worse outcome.

Other Outcome Measures

1. Change in Daily Hours Spent in ON-time With Troublesome Dyskinesia as Assessed by 24-hour Patient Diaries [Run-in and 4 weeks]

   Change in ON-time with troublesome dyskinesia as assessed by patient completed 24-hour diaries, from run-in to visit 4. This is a self administered diary where patients assess their motor state every half hour during 24 hours. The different motor states assessed: ON, ON with troublesome dyskinesia, OFF and asleep.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female ≥18 and ≤79 years of age.

2. Signed a current Ethics Committee approved informed consent form.

3. Parkinson's disease, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria.

4. Waking day dyskinesia of ≥25% determined as a score of ≥2 as per Question 4.1 of the MDS-UPDRS.

5. On a stable regimen of antiparkinson medications for at least 30 days prior to screening, including a levodopa preparation administered not less than three times daily and willing to continue the same doses and regimens during study participation. Rescue medication such as Madopar dispersable and Apomorphine injections are allowed.

6. Taking a maximum of eight regular levodopa intakes per day, excluding bedtime and night time levodopa.

7. Any other current and allowed prescription/non-prescription medications and/or nutritional supplements taken regularly must have been at a stable dose and regimen for at least 30 days prior to screening and the patient must be willing to continue the same doses and regimens during study participation (this criterion does not apply to medications that are being taken pre-study only on an as-needed basis).

8. Patient must be willing and able to avoid direct exposure to sunlight from day 1 to day 28.

9. Able to complete at least one valid 24-hour patient diary at Visit 1.

Exclusion Criteria:

1. History of neurosurgical intervention related to Parkinson's disease (e.g. deep brain stimulation).

2. Treatment with pump delivered antiparkinsonian therapy (i.e. subcutaneous apomorphine or levodopa/carbidopa intestinal infusion).

3. History of seizures within two years prior to screening.

4. History of stroke or transient ischemic attack (TIA) within two years prior to screening.

5. History of cancer within five years prior to screening, with the following exceptions: adequately treated non-melanomatous skin cancers, localised bladder cancer, non-metastatic prostate cancer or in situ cervical cancer.

6. Presence of cognitive impairment, as evidenced by a Mini-Mental Status Examination (MMSE) score of less than 24 during screening.

7. A Hoehn and Yahr score of five when "off" as per Question 3.18 of the MDS-UPDRS, assessed during screening.

8. Any history of a significant heart condition or cardiac arrhythmias within the past 5 years, any repolarisation deficits or any other clinically significant abnormal ECG as judged by the Investigator

9. Severe or ongoing unstable medical condition including a history of poorly controlled diabetes; obesity associated with metabolic syndrome; uncontrolled hypertension; cerebrovascular disease, or any form of clinically significant cardiac disease; clinically significant symptomatic orthostatic hypotension; clinically significant hepatic disease, renal failure or abnormal renal function.

10. Any history of a neurological other than Parkinson's disease or a psychiatric disorder, including history of DSM IV diagnosed major depression or psychosis. Patients with illusions or hallucinations with no loss of insight will be eligible. Patients with mild depression who are well controlled on a stable dose of an antidepressant medication for at least 4 weeks before screening will be eligible.

11. Enrolment in any other clinical study involving medication, medical devices or surgical procedures, current or within three months prior to screening visit, or previous participation in the present study. Patients enrolled in non-interventional clinical trials will be eligible.

12. Drug and/or alcohol abuse.

13. History of severe drug allergy or hypersensitivity.

14. If female, is pregnant or lactating, or has a positive pregnancy test result pre-dose.

15. Patients unwilling to use two forms of contraception 90 days for men and 30 days for women after last IMP dose

16. Any planned major surgery within the duration of the study.

17. Any other condition or symptoms preventing the patient from entering the study, according to the Investigator's judgement.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sahlgrenska University hospital	Göteborg		Sweden
2	University hospital	Linköping		Sweden
3	University hospital	Lund		Sweden
4	Karolinska University hospital	Stockholm		Sweden
5	Bristol Brain Centre, Southmead Hospital	Bristol		United Kingdom
6	Fairfield General Hospital (Pennine Acute NHS Trust)	Bury		United Kingdom
7	Ninewells Hospital	Dundee		United Kingdom
8	Lincoln County Hospital	Lincoln		United Kingdom
9	Charing Cross Hospital, Imperial College Healthcare NHS Trust	London		United Kingdom
10	The National Hospital of Neurology and Neurosurgery (UCL)	London		United Kingdom
11	Luton and Dunstable University Hospital NHS Foundation Trust	Luton		United Kingdom
12	North Tyneside General Hospital	North Shields		United Kingdom
13	Qeens' Medical Centre	Nottingham		United Kingdom
14	John Radcliffe Hospital	Oxford		United Kingdom
15	Peterborough City Hospital	Peterborough		United Kingdom
16	Plymouth Hospitals NHS Trust - Derriford Hospital	Plymouth		United Kingdom	PL6 8DH
17	Queens's Hospital	Romford		United Kingdom
18	Royal Stoke University Hospital	Stoke-on-Trent		United Kingdom
19	Torbay hospital	Torquay		United Kingdom
20	Royal Cornwall Hospital	Truro		United Kingdom

Sponsors and Collaborators

• Integrative Research Laboratories AB
• The Clinical Trial Company

Investigators

• Principal Investigator: Camille Carroll, MD, Plymouth University Peninsula Schools of Medicine and Dentistry

Study Documents (Full-Text)

• Study Protocol - Jan 14, 2019
• Statistical Analysis Plan - Jun 13, 2019

More Information

Publications

None provided.

• Responsible Party: Integrative Research Laboratories AB
• ClinicalTrials.gov Identifier: NCT03368170
• Other Study ID Numbers: IRL790C003
• First Posted: Dec 11, 2017
• Last Update Posted: Mar 31, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Integrative Research Laboratories AB: Levodopa induced dyskinesia
• Additional relevant MeSH terms: Parkinson Disease; Dyskinesias

Study Results

Participant Flow

Recruitment Details	The study was conducted as an outpatient trial and patients were identified from 20 sites across two countries. The first patient was enrolled 13 April 2018 and the last past completed 12 June 2019.
Pre-assignment Detail	Patients completed two 24-hour diaries during run-in of which one had to be valid prior randomization.

Arm/Group Title	Mesdopetam	Placebo
Arm/Group Description	Mesdopetam capsule, 2.5 mg oral administration. Dose given twice daily (5 mg, 7.5 mg or 10 mg b.i.d.) The first two weeks of treatment allowed for per patient titration of study medication to the highest tolerated predefined dose, after which patients continued on this highest per patient tolerated dose for an additional two weeks.	Matching placebo capsule, oral administration. Dose given twice daily. The first two weeks of treatment allowed for per patient titration of study medication to the highest tolerated number of placebo capsules (1 capsule x 4), after which patients continued on this highest tolerated dose for an additional two weeks.
Period Title: Overall Study
STARTED	39	36
COMPLETED	37	35
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Mesdopetam	Placebo	Total
Arm/Group Description	Mesdopetam (IRL790): 2.5 mg white hard HPMC capsule, oral administration	Placebo: Matching placebo capsule, white hard HPMC capsule, oral administration	Total of all reporting groups
Overall Participants	39	36	75
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.5 (8.9)	67.7 (7.7)	66.6 (8.36)
Sex: Female, Male (Count of Participants)
Female	20 51.3%	13 36.1%	33 44%
Male	19 48.7%	23 63.9%	42 56%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 2.8%	1 1.3%
Not Hispanic or Latino	39 100%	35 97.2%	74 98.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 2.6%	0 0%	1 1.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	38 97.4%	35 97.2%	73 97.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 2.8%	1 1.3%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.6 (7.2)	25.3 (4.2)	26 (5.92)
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	166.7 (10.3)	169 (9.4)	168 (9.87)
Years with Parkinson's disease (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.7 (5.9)	10.7 (4.3)	10.7 (5.15)

Outcome Measures

1. Primary Outcome

Title	Unified Dyskinesia Rating Scale (UDysRS)
Description	The change from baseline to day 28 of treatment (Visit 4) in the sum of the items comprising the Unified Dyskinesia Rating Scale (UDysRS). The Unified Dyskinesia Rating Scale (UDysRS) is administered to assess dyskinesia. The scoring range is 0-104, where higher score means more dyskinesia.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (all randomized and treated patients who received one or more doses and who provided post baseline data whether or not they fully complied with the requirements of the protocol).

Arm/Group Title	Mesdopetam	Placebo
Arm/Group Description	Mesdopetam: 2.5 mg white hard HPMC capsule, oral administration	Placebo: Matching placebo capsule, white hard HPMC capsule, oral administration
Measure Participants	36	34
Least Squares Mean (95% Confidence Interval) [score on a scale]	-4.2	-7.0

2. Secondary Outcome

Title	Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV, Question 4.1 and 4.2
Description	Change in MDS-UPDRS sum score of questions 4.1 (Time spent with dyskinesias) and 4.2 (Functional impact of dyskinesias) in part IV from baseline to visit 4. Minimum score is 0 and maximum score is 8. A higher score means more dyskinesia.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (all randomized and treated patients who received one or more doses and who provided post baseline data whether or not they fully complied with the requirements of the protocol).

Arm/Group Title	Mesdopetam	Placebo
Arm/Group Description	Mesdopetam: 2.5 mg white hard HPMC capsule, oral administration	Placebo: Matching placebo capsule, white hard HPMC capsule, oral administration
Measure Participants	37	35
Least Squares Mean (95% Confidence Interval) [score on a scale]	-1.3	-0.6

3. Secondary Outcome

Title	Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part II and III
Description	Change in MDS-UPDRS sum score of parts II+III (Motor aspects of Experiences of Daily living + Motor Examination) from baseline to visit 4. Minimum value is 0 and maximum value is 124. Higher score mean a worse outcome.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (all randomized and treated patients who received one or more doses and who provided post baseline data whether or not they fully complied with the requirements of the protocol).

Arm/Group Title	Mesdopetam	Placebo
Arm/Group Description	Mesdopetam: 2.5 mg white hard HPMC capsule, oral administration	Placebo: Matching placebo capsule, white hard HPMC capsule, oral administration
Measure Participants	37	35
Least Squares Mean (95% Confidence Interval) [score on a scale]	-3.0	-2.2

4. Other Pre-specified Outcome

Title	Change in Daily Hours Spent in ON-time With Troublesome Dyskinesia as Assessed by 24-hour Patient Diaries
Description	Change in ON-time with troublesome dyskinesia as assessed by patient completed 24-hour diaries, from run-in to visit 4. This is a self administered diary where patients assess their motor state every half hour during 24 hours. The different motor states assessed: ON, ON with troublesome dyskinesia, OFF and asleep.
Time Frame	Run-in and 4 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (all randomized and treated patients who received one or more doses and who provided post baseline data whether or not they fully complied with the requirements of the protocol).

Arm/Group Title	Mesdopetam	Placebo
Arm/Group Description	Mesdopetam: 2.5 mg white hard HPMC capsule, oral administration	Placebo: Matching placebo capsule, white hard HPMC capsule, oral administration
Measure Participants	37	34
Least Squares Mean (95% Confidence Interval) [daily hours]	-3.3	-1.7

Adverse Events

Time Frame	5 weeks
Arm/Group Title	Mesdopetam		Placebo
Arm/Group Description	Mesdopetam (IRL790): 2.5 mg white hard HPMC capsule, oral administration		Placebo: Matching placebo capsule, white hard HPMC capsule, oral administration
All Cause Mortality
	Mesdopetam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/39 (0%)		0/36 (0%)
Serious Adverse Events
	Mesdopetam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/39 (0%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Mesdopetam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/39 (74.4%)		28/36 (77.8%)
Gastrointestinal disorders
Nausea	0/39 (0%)		4/36 (11.1%)
General disorders
Fatigue	2/39 (5.1%)		9/36 (25%)
Infections and infestations
Urinary tract infection	2/39 (5.1%)		2/36 (5.6%)
Injury, poisoning and procedural complications
Fall	4/39 (10.3%)		3/36 (8.3%)
Musculoskeletal and connective tissue disorders
Muscle spasm	0/39 (0%)		2/36 (5.6%)
Muscoloskeletal stiffness	1/39 (2.6%)		3/36 (8.3%)
Nervous system disorders
Dizziness	2/39 (5.1%)		3/36 (8.3%)
Dyskinesia	4/39 (10.3%)		2/36 (5.6%)
Freezing phenomenon	1/39 (2.6%)		4/36 (11.1%)
Headache	5/39 (12.8%)		5/36 (13.9%)
On and off phenomenon	2/39 (5.1%)		1/36 (2.8%)
Parkinsonism	9/39 (23.1%)		3/36 (8.3%)
Gait disturbance	0/39 (0%)		2/36 (5.6%)
Psychiatric disorders
Insomnia	2/39 (5.1%)		2/36 (5.6%)
Sleep disorder	3/39 (7.7%)		2/36 (5.6%)
Skin and subcutaneous tissue disorders
Erythema	0/39 (0%)		2/36 (5.6%)

Limitations/Caveats

There were technical difficulties in the administration of UDysRS objective score. It was not administered in a manner that would enable an unambiguous interpretation of the results.

More Information

Certain Agreements

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

There is NOT 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.