A Phase IIb Study of Nabiximols for Spasticity Due to Neuromyelitis Optica Spectrum Disorders

A Phase IIb Study of the Safety and Efficacy of Nabiximols in Subjects With Spasticity Due to Neuromyelitis Optica Spectrum Disorders: A Double-blind, Randomized, Placebo-Controlled, Crossover Study

The goal of this clinical trial is to evaluate the safety and efficacy of nabiximols, a cannabinoid spray, for the treatment of moderate to severe spasticity in adult patients with AQP4-IgG positive and antibody-negative NMOSD. The main question it aims to answer is whether treatment with nabiximols improves patient-reported spasticity ratings compared to treatment with a placebo. This trial will also answer whether nabiximols impact pain, spasm frequency, mood, walking ability, and sleep. Participants will be mailed the treatments and placebo treatments, and will be asked to complete study visits and questionnaires remotely. There is also an optional sub-study that involves in-person visits with ultrasound imaging and in-person neurologic exams.

Patients with NMOSD often have medication-resistant and severe spasticity due to longitudinally extensive spinal cord lesions. Existing treatments are limited by their efficacy and tolerability. Cannabinoids have been shown to quantitatively improve spasticity in mouse models of neuroinflammation, and nabiximols, a cannabinoid-based oromucosal spray, have demonstrated efficacy for medication-resistant spasticity in multiple sclerosis. However, no studies have as yet explored the use of nabiximols specifically in NMOSD, and there is a significant unmet need for new symptomatic treatments in this patient population. The goal of this study is to evaluate the safety and efficacy of nabiximols spray, for the treatment of moderate to severe spasticity in adult patients with AQP4-IgG positive and seronegative NMOSD. This study is designed as a phase IIb, single-site, double-blind, randomized, placebo-controlled 2x2 crossover clinical trial, with a 2-week washout period between treatment periods. After randomization, each participant enters into Period 1, which begins with a 2-week dose escalation period with a pre-defined dose escalation scheme, followed by a 4-week stable treatment period. After completion of Period 1, all participants have a 2-week washout period and then enter Period 2, where they again complete a 2-week dose escalation period and 4-week constant treatment period. The patient-reported 0-10 numeric rating scale for spasticity (NRS-S) is the primary outcome measure. All key study procedures are performed virtually, including a weekly electronic study diary, additional weekly surveys, and 8 virtual video-based study visits including a screening visit and safety follow up visit. Additional optional in-person assessments of spasticity (neurologic exam, modified Ashworth Scale and muscle ultrasound elastography) will be performed for a selection of local participants. In total, the study has a 20-week duration per participant, from the screening visit to the final study completion for safety follow-up visit, including 12 weeks of on-treatment time.

Inclusion Criteria:

• Confirmed diagnosis of NMOSD, meeting the International Panel for NMO Diagnosis (IPND) NMOSD criteria (Appendix 1), including NMOSD with AQP4-IgG, and NMOSD without AQP4-IgG
• Aged between 18 years or older, at the time of signing the informed consent
• Willing and able to give informed consent and to participate in all study procedures
• Moderate to severe spasticity, as defined by a score of > 3 on the 0-10 numerical rating scale for spasticity (NRS-S) at the time of screening
• Reports NMOSD-related spasticity symptoms ongoing for at least 6 months
• Spasticity is determined to be causally related to an NMOSD attack in the opinion of the investigator
• No relapses, and otherwise stable disease (i.e. no significant recovery from relapse or other change in disability) for at least 6 months, in the opinion of the investigator
• Anti-spasticity regimen, if on medications, maintained at a stable dose for the 30 days prior to enrollment without adequate relief of spasticity symptoms.
• Willing to maintain a stable dose of non-study-related anti-spasticity medication for the duration of the study, barring significant changes to their medical condition.
• Willing to allow his or her primary care doctor and primary neurologist, if appropriate, to be notified of participation in the study.
• Documentation of negative MOG-IgG, if diagnosis is NMOSD without AQP4-IgG positive status. Participant with presumptive diagnosis of NMOSD without AQP4-IgG and no prior MOG IgG testing can have MOG testing sent, and be eligible for participation if this is negative.
• For women of childbearing potential: participants who are not lactating, not pregnant, and not planning to become pregnant in the next 8 months and who agree to remain abstinent (refrain from heterosexual intercourse) or use adequate contraception during the treatment period and for at least 3 months after the final dose of nabiximols.
• For males with partners who are females of childbearing potential: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use adequate contraception during the treatment period and for at least 3 months after the final dose of nabiximols.
• Able to use the necessary electronic applications (either via smartphone, tablet, or desktop) and has an email address.

Exclusion Criteria:

• Consumption of cannabis herb or other cannabinoid-based drugs within 30 days prior to study entry.
• Unwillingness to abstain from consumption of cannabis herb or other cannabinoid-based drugs for the duration of the study.
• Known or suspected hypersensitivity or adverse reaction (including psychiatric adverse reactions) to cannabinoids or cannabinoid products, ethanol, peppermint oil or propylene glycol.
• Currently receiving a prohibited medication and unwilling or unable to stop for the duration of the study. Prohibited medications include: CYP3A4 inhibitors: clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, etc.; CYP3A4 inducers: rifampicin, phenobarbital, phenytoin, St. John's Wort. Of note, the CYP3A4 inducer carbamazepine is permitted, but a stable dosage must be maintained throughout the study (no as needed dosing permitted). Other prohibited medications: regular levodopa (Sinemet, Sinemet Plus, Levodopa, L-dopa, Madopar, Benserazide), sildenafil (Viagra), fentanyl, or antiarrhythmic medications.
• Receipt of an investigational medicinal product or participation in a therapeutic clinical trial within 30 days prior to the initial visit
• Received a Botulinum Toxin injection within four months prior to the screening visit or unwillingness to stop receiving Botulinum Toxin injections for the relief of spasticity for the duration of the study.
• Personal medical history of schizophrenia, severe personality disorders, other major psychotic disorders, or other major psychiatric disorders other than depression and anxiety.
• Family history in 1st degree relatives of schizophrenia or other psychotic disorders.
• Hospitalization for depression or anxiety within the 2 years prior to the screening visit.
• A documented history of attempted suicide or suicidal ideation of category 4 or 5 according to the Columbia Suicide Severity Rating Scale (C-SSRS) screening, OR if in the Investigator's judgment, the participant is at risk for a suicide attempt.
• Known or suspected history of a substance use disorder or heavy alcohol consumption excluding tobacco use disorder or cannabis use not meeting criteria for cannabis use disorder.
• History of myocardial infarction or clinically significant ischemic heart disease, arrhythmias (other than well controlled atrial fibrillation), poorly controlled hypertension or severe heart failure. .
• Significant renal or hepatic impairment, either in the opinion of the investigator, or by the following laboratory screening values: AST or ALT > 2 × upper limit of normal (ULN); Total bilirubin > 2 × ULN (unless due to Gilbert's syndrome); BUN > 2 × upper limit of normal (ULN)
• History of epilepsy or recurrent seizures.
• Concomitant disease or disorder that has symptoms of spasticity, and that in the opinion of the Investigator may influence the study outcome and endpoint assessment.
• Any other significant medical or psychiatric condition which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or may influence the result of the study or the participant's ability to participate in the study.
• Scheduled elective surgery or other procedures which require general anesthesia during the study period.
• Intention to donate blood during the study.
• Intention to travel internationally during the study.