Nabilone for Non-motor Symptoms in Parkinson's Disease (NMS-Nab)

• ClinicalTrials.gov Identifier: NCT03769896
• Recruitment Status: Completed
• First Posted: December 10, 2018
• Results First Posted: March 2, 2021
• Last Update Posted: March 2, 2021
• Sponsor: Medical University Innsbruck
• Information provided by (Responsible Party): Klaus Seppi, MD, Medical University Innsbruck

Study Description

Brief Summary:

This is a randomized placebo-controlled, double-blind, parallel-group, enriched enrollment randomized withdrawal study assessing the efficacy and safety of nabilone for non-motor symptoms in patients with Parkinson´s Disease. Nabilone is an analogue of tetrahydrocannabinol (THC), the psychoactive component of cannabis. Nabilone acts as a partial agonist on both Cannabinoid 1 (CB1) and Cannabinoid 2 (CB2) receptor in humans and therefore mimics the effect of THC but with more predictable side effects and less euphoria.

Part 1 is an open-label dose adjustment phase of the study. In eligible patients, a screening period is followed by an open-label nabilone dose optimization phase and a stable phase for at least 1 week. Treatment responders will be included in Part 2 of the study (randomized placebo-controlled, double-blind, parallel-grouped).

Part 2 is the placebo-controlled, double-blind, parallel-group randomized withdrawal phase of the study.

Condition or disease	Intervention/treatment	Phase
Parkinson Disease	Drug: Nabilone 0.25 mg; Drug: Placebo	Phase 2

Detailed Description:

This is a randomized placebo-controlled, double-blind, parallel-group, enriched enrollment randomized withdrawal study assessing the efficacy and safety of nabilone for non-motor symptoms in patients with Parkinson´s Disease. Nabilone is an analogue of tetrahydrocannabinol (THC), the psychoactive component of cannabis. Nabilone acts as a partial agonist on both Cannabinoid 1 (CB1) and Cannabinoid 2 (CB2) receptor in humans and therefore mimics the effect of THC but with more predictable side effects and less euphoria.

Part 1 is the open-label dose adjustment phase of the study. In Part 1, eligible subjects, who have signed the informed consent form at the screening visit, will receive open-label nabilone starting with a dosage of 0.25 mg in the evening. During dose titration and optimization, nabilone will be titrated in 0.25 mg increments (increase by 0.25 mg/ every one to four days) up to a maximum dose of 1 mg twice daily. Patients should be on a stable nabilone dose for at least 1 week afterwards until Baseline Visit (V 0).

Part 2 is the placebo-controlled, double-blind, parallel-group randomized withdrawal phase of the study. At Baseline Visit, treatment responders will be included in Part 2 of the study (randomized placebo-controlled, double-blind, parallel-grouped). Responders are randomized in a 1:1 ratio at Baseline Visit to receive either nabilone or matching placebo for 4 weeks + 2 days. The placebo-controlled, double-blind, randomized withdrawal phase will end with a clinic visit (Termination Visit V 1). Following this, the study medication will be tapered in all patients. During this period the patients will receive phone calls every other day. A Safety Telephone Call and a Safety Follow-Up Visit will be performed.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: randomized placebo-controlled, double-blind, parallel-group, enriched enrolment randomized withdrawal study
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: placebo-controlled, double-blind, parallel-group with 1 : 1 randomization
• Primary Purpose: Treatment
• Official Title: Nabilone for Non-motor Symptoms in Parkinson's Disease: A Randomized Placebo-controlled, Double-blind, Parallel-group, Enriched Enrolment Randomized Withdrawal Study
• Actual Study Start Date: October 3, 2017
• Actual Primary Completion Date: July 15, 2019
• Actual Study Completion Date: July 15, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Treatment Group; Nabilone 0.25 mg	Drug: Nabilone 0.25 mg; capsules, 0.25 mg up to 2 mg of nabilone taken orally on a daily basis
Placebo Comparator: Placebo Group; Placebo (corn starch)	Drug: Placebo; capsule, corn starch, daily basis

Outcome Measures

Primary Outcome Measures :

1. Changes of Non-motor Symptoms [ Time Frame: from baseline to 4 weeks + 2 days ]
   Changes in Movement Disorders Society - Unified Parkinson´s Disease Rating Scale (MDS-UPDRS) Part I minimum points: 0, maximum points: 52, higher score values indicate a worse outcome.

Secondary Outcome Measures :

1. Changes in Motor and Different Non-motor Symptoms of PD [ Time Frame: from baseline to 4 weeks + 2 days ]

   Changes in Movement Disorders Society - Unified Parkinson´s Disease Rating Scale (MDS-UPDRS) Part II: minimum points: 0, maximum points: 52, higher score values indicate a worse outcome.

   Part III: minimum points: 0, maximum points: 132, higher score values indicate a worse outcome.

2. Changes in Different Domains of Non-motor Symptoms of PD [ Time Frame: from baseline to 4 weeks + 2 days ]
   mood/anxiety domain of MDS-UPDRS Part I (items 1.3 and 1.4) and different other domains of NMSS and MDS-UPDRS part I Each items scores 0 to 4 points with higher score values indicating a worse outcome.
3. Changes in Non-motor Symptoms of PD [ Time Frame: from baseline to 4 weeks + 2 days ]
   Non Motor Symptoms Scale (NMSS) Minimum: 0, maximum: 360, higher score values indicate a worse outcome.
4. Changes in Non-motor Symptoms of PD [ Time Frame: from baseline to 4 weeks + 2 days ]
   Hospital anxiety and depression scale (HAD-S) Minimum: 0, maximum: 42, higher score values indicate a worse outcome.
5. Changes in Non-motor Symptoms of PD [ Time Frame: from baseline to 4 weeks + 2 days ]
   Epworth Sleepiness Scale (ESS) Minimum: 0, maximum: 24, higher score values indicate a worse outcome.
6. Changes in Non-motor Symptoms of PD [ Time Frame: from baseline to 4 weeks + 2 days ]
   Fatigue Severity Scale (FSS) Minimum: 9, maximum: 63, higher score values indicate a worse outcome.
7. Changes in Non-motor Symptoms of PD [ Time Frame: from baseline to 4 weeks + 2 days ]
   King's Parkinson's disease pain scale (KPPS) Minimum: 0, maximum: 168, higher score values indicate a worse outcome.
8. Changes in Non-motor Symptoms of PD [ Time Frame: from baseline to 4 weeks + 2 days ]
   Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) Minimum: 0, maximum: 112, higher score values indicate a worse outcome.
9. Changes in Non-motor Symptoms of PD [ Time Frame: from baseline to 4 weeks + 2 days ]
   Montreal Cognitive Assessment (MoCA) Minimum: 0, maximum: 30, higher score values indicate better outcome.
10. Changes in Non-motor Symptoms of PD [ Time Frame: from baseline to 4 weeks + 2 days ]
    Visual Analog Scale (VAS) of Pain Minimum: 0 mm, maximum: 10 mm, higher score values indicate a worse outcome.
11. Clinical Global Impression - Global Improvement (CGI-I) Scale [ Time Frame: Values of the Termination visit (4 weeks + 2 days from baseline) ]
    Clinical Global Impression - Global Improvement (CGI-I) scale Minimum: 1, maximum: 7, higher score values indicate a worse outcome.
12. Incidence of AEs and Number of Withdrawals in PD Patients Taking Nabilone. [ Time Frame: from baseline to 4 weeks + 2 days ]

    Safety and tolerability will be evaluated with reference to the following:

    Number of subjects (%) who discontinue the study Number of subjects (%) who discontinue the study due to AE Adverse Events (AE): total number of patients with all adverse events is reported (no reporting threshold)

13. Suicidality in PD Patients Taking Nabilone. [ Time Frame: from baseline to 4 weeks + 2 days ]

    Assessment of aggregated data (suicidality present / no suicidality) of the Columbia-Suicide Severity Rating Scale (C-SSRS). The scale consists of questions for suicidality that can be answered with either "yes" or "no". The answer "no" indicates no wish to be dead, no suicidal ideations, or suicidal attempts.

    No minimum or maximum score values can be provided. The values provided represent the number of patients with (new) suicidality.

14. Change in Hallucinations in PD Patients Taking Nabilone [ Time Frame: from baseline to 4 weeks + 2 days ]
    Number of patients with changes in the points of the Hallucination item (1.2) of the Movement Disorders Society - Unified Parkinson´s Disease Rating Scale (MDS-UPDRS).
15. Orthostatic Hypotension in PD Patients Taking Nabilone [ Time Frame: from baseline to week 4 + 2 days ]
    Changes in points of the Orthostatic hypotension (OH) item (1.12) of Movement Disorders Society - Unified Parkinson´s Disease Rating Scale (MDS-UPDRS), minimum of 0, maximum of 4 points, higher score values representing a worse outcome.
16. Day-time Sleepiness in PD Patients Taking Nabilone: MDS-UPDRS [ Time Frame: from baseline to week 4 + 2 days ]
    Changes in points of the Day-time sleepiness item (1.8) of Movement Disorders Society - Unified Parkinson´s Disease Rating Scale (MDS-UPDRS) , minimum of 0, maximum of 4 points, higher score values representing a worse outcome
17. Subject Incompliance in PD Patients Taking Nabilone [ Time Frame: from baseline to week 4 + 2 days ]
    subject incompliance as per drug accountability.
18. Weight (kg) in PD Patients Taking Nabilone. [ Time Frame: from baseline to week 4 + 2 days ]
    changes in weight (kg)
19. Changes in Temperature (Degree Celsius) in PD Patients Taking Nabilone. [ Time Frame: from baseline to week 4 + 2 days ]
    changes in temperature (degree Celsius)
20. Changes in Supine and Standing Blood Pressure Measurements (mmHg) in PD Patients Taking Nabilone. [ Time Frame: values from baseline and week 4 + 2 days ]

    changes in supine and standing blood pressure measurements (mmHg)

    Row titles:

    1. Mean Change of systolic blood pressure readings (SBP) from supine to standing position for 3 min at the baseline visit
    2. Mean Change of systolic blood pressure readings (SBP) from supine to standing position for 3 min at the week 4 - visit
    3. Mean Change of diastolic blood pressure readings (DBP) from supine to standing position for 3 min at the baseline visit
    4. Mean Change of diastolic blood pressure readings (DBP) from supine to standing position for 3 min at the week 4 - visit
21. Changes in Quality of Life of PD [ Time Frame: from baseline to week 4 + 2 days ]
    Parkinson´s Disease Questionnaire - 39 (PDQ-39) Minimum: 0, maximum: 156, higher score values indicate a worse outcome. Values were standardized = PDQ-39 Summary Index (SI, the score of each subdomain was divided by the number of questions of that domain and then multiplied by hundred, the sum score is the sum of the results of all 8 domains)

Other Outcome Measures:

1. The Exploratory Objective of This Study Will be an Eye-tracking Evaluation in PD Patients Taking Nabilone or Placebo. [ Time Frame: Maximum of 104 days ]
   Change of the reaction time (seconds) between the Screening visit (Part 1) and the Termination visit (Part 2) as measured by the Eye-tracking examination.
2. The Exploratory Objective of This Study Will be an Eye-tracking Evaluation in PD Patients Taking Nabilone or Placebo. [ Time Frame: Maximum of 104 days ]
   Change of attention span and ability to concentrate (error rate, correct trials) between the Screening visit (Part 1) and the Termination visit (Part 2) as measured by the Eye-tracking examination.

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

In order to be eligible for the study subjects must meet all inclusion criteria:

1. Age ≥30 years
2. Diagnosis of Parkinson´s Disease (PD): PD should be either de novo or on stable medication without disturbing motor fluctuations or dyskinesia.
3. NMS with a score of ≥4 on MDS-UPDRS Part 1. One of the following domains have to be affected with a score ≥2: 1.4 (anxious mood) or 1.9 (pain)
4. On a stable regimen of anti-parkinson medications for at least 30 days prior to screening and willing to continue the same doses and regimens during study participation
5. 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 subject must be willing to continue the same doses and regimens during study participation
6. Patient is informed and had enough time and opportunity to think about his/her participation in the study and has signed a current Institutional Review Board-approved informed consent form

7. Contraception

   1. Women of childbearing potential must use or attest an acceptable method* of contraception starting 4 weeks prior to study drug administration and for a minimum of 1 month after study completion.
   2. Men with a potentially fertile partner must be willing to use an acceptable method of contraception for the duration of the study and for 3 months after study drug discontinuation or have had a vasectomy.

Exclusion Criteria:

Patients with any of the following characteristics will be excluded from entering the study:

1. Patient previously participated in any study with nabilone.
2. Current use of cannabinoids or use of cannabinoids within 30 days prior to screening.
3. Patient is currently participating in or has participated in another study of investigational products within 30 days prior to screening.
4. Patient has any form of secondary or atypical parkinsonism (e.g., drug-induced, post stroke).
5. Patient presents with motor complications which are, based on the investigator's judgment, not adequately controlled (i.e. a score ≥2 on one of the items of the MDS-UPDRS Part IV at screening)
6. Hoehn and Yahr stage > 3
7. Evidence of disturbing (i.e. requiring treatment) impulse control disorder in the participant. Can be resolved through a structural interview during screening period.
8. History of neurosurgical intervention for PD
9. presence of symptomatic orthostatic hypotension at screening (MDS-UPDRS 1.12 > 2)
10. Use of prohibited medication (e.g. benzodiazepines (except for clonazepam up to a maximum of 1.5 mg per d), lithium, opioids, buspirone, muscle relaxing agents, central nervous system depressing substances, ...)
11. Patients with laboratory values that are out-of-range at Screening (or within 4 weeks prior to Screening) and haven´t been reviewed and documented as not clinically significant by the investigator. Lab Tests can be repeated for confirmation.
12. Patients with known or newly diagnosed sinus tachycardia in ECG evaluation at Screening or within 4 weeks prior to Screening.
13. presence of an acute or chronic major psychiatric disorder (e.g., Major Depressive Disorder, psychosis) or symptom (e.g., hallucinations, agitation, paranoia) (MDS-UPDRS 1.2 and/or 1.3 > 2)
14. Patients who had a recent suicidal attempt (active, interrupted, aborted) within the past five years or report suicidal ideation within the past 6 months.
15. presence of dementia (MDS-UPDRS 1.1 > 2, Mini-Mental State Examination of <24 at the Screening visit)
16. clinically significant or unstable medical or surgical condition at Screening or Baseline visit that may preclude safety and the completion of the study participation (based on the investigator's judgment).
17. Patients with moderate or severe hepatic or renal impairment.
18. Patient has a history of chronic alcohol or drug abuse within the last 2 years.
19. women of child-bearing potential who do not practice an acceptable method of birth control
20. Pregnant women or women planning to become pregnant during the course of the study and nursing women.
21. Patients who are knowingly hypersensitive to any of the components of the investigational medicinal product or excipients.
22. Patient is legally incapacitated or persons held in an institution by legal or official order
23. Persons with any kind of dependency on the investigator or employed by the Sponsor or investigator

Contacts and Locations

Locations

Austria

Department of Neurology - Medical University Innsbruck

Innsbruck, Tyrol, Austria, 6020

Sponsors and Collaborators

Medical University Innsbruck

  Study Documents (Full-Text)

Documents provided by Klaus Seppi, MD, Medical University Innsbruck:

Study Protocol and Statistical Analysis Plan  [PDF] June 8, 2018

More Information

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

Peball M, Seppi K, Krismer F, Knaus HG, Spielberger S, Heim B, Ellmerer P, Werkmann M, Poewe W, Djamshidian A. Effects of Nabilone on Sleep Outcomes in Patients with Parkinson's Disease: A Post-hoc Analysis of NMS-Nab Study. Mov Disord Clin Pract. 2022 May 31;9(6):751-758. doi: 10.1002/mdc3.13471. eCollection 2022 Aug.

Peball M, Krismer F, Knaus HG, Djamshidian A, Werkmann M, Carbone F, Ellmerer P, Heim B, Marini K, Valent D, Goebel G, Ulmer H, Stockner H, Wenning GK, Stolz R, Krejcy K, Poewe W, Seppi K; Collaborators of the Parkinson's Disease Working Group Innsbruck. Non-Motor Symptoms in Parkinson's Disease are Reduced by Nabilone. Ann Neurol. 2020 Oct;88(4):712-722. doi: 10.1002/ana.25864. Epub 2020 Aug 31.

• Responsible Party: Klaus Seppi, MD, Principal Investigator, Medical University Innsbruck
• ClinicalTrials.gov Identifier: NCT03769896
• Other Study ID Numbers: 1.4
• First Posted: December 10, 2018
• Results First Posted: March 2, 2021
• Last Update Posted: March 2, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: The results of this study will be published according to the principles of publication policy. There are no arrangements on publication issues with subsiding parties.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Klaus Seppi, MD, Medical University Innsbruck:

Parkinson´s Disease; cannabinoids; non-motor symptoms

Additional relevant MeSH terms:

Parkinson Disease; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Nabilone; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Anti-Anxiety Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs