Nabilone for Non-motor Symptoms in Parkinson's Disease

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.

Inclusion criteria

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

• Age ≥30 years
• Diagnosis of Parkinson´s Disease (PD): PD should be either de novo or on stable medication without disturbing motor fluctuations or dyskinesia.
• 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)
• 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
• 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
• 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
• Contraception

• 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.
• 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:

• Patient previously participated in any study with nabilone.
• Current use of cannabinoids or use of cannabinoids within 30 days prior to screening.
• Patient is currently participating in or has participated in another study of investigational products within 30 days prior to screening.
• Patient has any form of secondary or atypical parkinsonism (e.g., drug-induced, post stroke).
• 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)
• Hoehn and Yahr stage > 3
• Evidence of disturbing (i.e. requiring treatment) impulse control disorder in the participant. Can be resolved through a structural interview during screening period.
• History of neurosurgical intervention for PD
• presence of symptomatic orthostatic hypotension at screening (MDS-UPDRS 1.12 > 2)
• 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, ...)
• 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.
• Patients with known or newly diagnosed sinus tachycardia in ECG evaluation at Screening or within 4 weeks prior to Screening.
• 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)
• Patients who had a recent suicidal attempt (active, interrupted, aborted) within the past five years or report suicidal ideation within the past 6 months.
• presence of dementia (MDS-UPDRS 1.1 > 2, Mini-Mental State Examination of <24 at the Screening visit)
• 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).
• Patients with moderate or severe hepatic or renal impairment.
• Patient has a history of chronic alcohol or drug abuse within the last 2 years.
• women of child-bearing potential who do not practice an acceptable method of birth control
• Pregnant women or women planning to become pregnant during the course of the study and nursing women.
• Patients who are knowingly hypersensitive to any of the components of the investigational medicinal product or excipients.
• Patient is legally incapacitated or persons held in an institution by legal or official order
• Persons with any kind of dependency on the investigator or employed by the Sponsor or investigator