Safety and Efficacy on Spasticity Symptoms of a Cannabis Sativa Extract in Motor Neuron Disease (CANALS)

• ClinicalTrials.gov Identifier: NCT01776970
• Recruitment Status: Completed
• First Posted: January 28, 2013
• Last Update Posted: March 9, 2017
• Sponsor: Ospedale San Raffaele
• Collaborators: Fondazione Salvatore Maugeri; Niguarda Hospital; University of Padova
• Information provided by (Responsible Party): Giancarlo Comi, Ospedale San Raffaele

Tracking Information

• First Submitted Date: January 24, 2013
• First Posted Date: January 28, 2013
• Last Update Posted Date: March 9, 2017
• Study Start Date: January 2013
• Actual Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 24, 2013)

modified 5 - points modified Ashworth scale (AS). [ Time Frame: Week 7 (6 weeks after randomization) ]

Improvement in the modified 5 - points modified Ashworth scale (AS). The variable for analysis will be the change in AS from the baseline (visit 2, Week 2) to the end of treatment (visit 4, Week 7).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 24, 2013)

Mean weekly spasticity, spasm frequency and sleep disruption Numeric Rating Scale (NRS) score [ Time Frame: Week 7 (6 weeks after randomizazion) ]

Mean weekly spasticity, spasm frequency and sleep disruption NRS score at the end of treatment. The variable for analysis will be the change in mean NRS from the baseline (days 0-7) to the last week of treatment (usually days 42-49). Proportion of subjects completing the study and showing an improvement of 30% or more and 50% or more in NRS from Baseline (Week 1) and end of study (last seven days of treatment)

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: January 24, 2013)

• Pain NRS score [ Time Frame: Week 7 (6 weeks ater randomization) ]
  Pain will be measured with the mean of the last 3 days 0 - 10 daily pain intensity NRS.
• Appetite increase [ Time Frame: Week 7 (6 weeks after randomization) ]
  Weight difference before and at the end of the study.
• Function (Ten meters walk test, ALS-FRS, Barthel ADL Index) [ Time Frame: Week 7 (6 weeks aftar randomization) ]
  The time taken for the 10-metre walk, ALS-FRS and Barthel ADL Index will be analysed using the Visit 2 (week 1)result as baseline.
• Global Impression of Change [ Time Frame: Week 7 (6 weeks after randomization) ]
  Carer Global Impression of Change and ease of transfer Physician Global Impression of Change Subject Global Impression of Change
• Safety [ Time Frame: Week 4, week 7 ]
  Adverse events, Vital Signs, Physical Examination , oral examination

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Safety and Efficacy on Spasticity Symptoms of a Cannabis Sativa Extract in Motor Neuron Disease
• Official Title: A Fase II, Randomized, Double-Blind, Placebo-Controlled, Multicentre Study for the Safety and Efficacy on Spasticity Symptoms of a Cannabis Sativa Extract in Motor Neuron Disease Patients

Brief Summary

The clinical primary hypothesis is that there will be a difference between a Cannabis Sativa extract and placebo in their effect on spasticity in Motor Neuron Disease (MND) patients with signs of involvement of the upper motor neuron (UMN) resulting in disabling spasticity.

Secondary goals of the study are to evidence of improvement in other symptoms (in particular pain), and to show favourable trends on functionality measures. Finally, cannabis based drug safety and tolerability will be studied through vital parameters (including weight and pulmonary function) measurement, and analyzing ALS function rating scale progression slope hopefully, showing a slowing of the functional values decrease, owing to cannabis neuroprotective effects)

Detailed Description

CANALS project has as a main objective to analyse the safety profile, tolerability and efficacy of a Cannabis Sativa (Sativex) derivative on patients affected by spasticity due to motor neuron disease.

Muscular rigidity (or spasticity) is a symptom that affects many patients with motor neuron disease, concurring to reduce personal autonomy, patients' quality of life and can potentially cause secondary symptomatology (as pain or secondary muscular retractions). Currently available anti-spasticity drugs are often unsatisfactory and their pharmacological action can cause weakness as a secondary effect. There many arguments supporting the use of cannabinoid derivatives in motor neuron diseases. Cannabinoids receptor is expresses both in the brain and in the spinal cord. In animal models cannabinoids have an anti-spasticity effect. Moreover recent studies on ALS animal models demonstrated a neuroprotective effect of cannabinoids, including the preservation of the motor ability and a survival increase of the treated animals. Recently many clinical trials (some of them performed at the Neurological Division of San Raffaele Hospital) demonstrated cannabinoid efficacy on spasticity in Multiple Sclerosis patients. CAnnabinois would be able to reduce spasticity with no secondary weakness effect on treated patients. The results of these studies led to the drug approval in certain countries and by the European Community for the treatment of spasticity in Multiple Sclerosis.

The aim of this study is to analyze the safety, tolerability and efficacy profile of a Cannabis Sativa (Sativex) derivative on patients affected by spasticity due to motor neuron disease ( Amyotrophic Lateral Sclerosis and Primary Lateral Sclerosis). The study will be performed along 7 weeks. During the first week will be asked patients to note down in the clinical diary elements related to their symptomatology. Afterwards patients will be randomized in two groups: drug-treated and placebo treated. The study will be followed by a 6-weeks open-label phase during which all patients will receive the active drug (Phase B)

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Supportive Care

Condition

• Motor Neuron Disease
• Amyotrophic Lateral Sclerosis (ALS)

Intervention

Drug: Cannabis Sativa extract Oromucosal spray

Comparison between active drug (Cannabis Sativa extract Oromucosal spray, containing THC (27 mg/ml):CBD (25 mg/ml) vs placebo

Other Name: Sativex

Study Arms

• Experimental: Sativex
  Cannabis Sativa extract Oromucosal spray, containing THC (27 mg/ml):CBD (25 mg/ml)
  Intervention: Drug: Cannabis Sativa extract Oromucosal spray
• Placebo Comparator: Placebo
  Placebo oromucosal spray
  Intervention: Drug: Cannabis Sativa extract Oromucosal spray

• Publications *: Riva N, Mora G, Soraru G, Lunetta C, Ferraro OE, Falzone Y, Leocani L, Fazio R, Comola M, Comi G; CANALS Study Group. Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2019 Feb;18(2):155-164. doi: 10.1016/S1474-4422(18)30406-X. Epub 2018 Dec 13.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 24, 2013): 60
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: December 2015
• Actual Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

Subjects must fulfil ALL of the following criteria:

• Written informed consent
• Subject able and willing to comply with all study requirements
• Affected by ALS, either of definite, probable or possible category according to the El Escorial revised criteria or by primary lateral sclerosis (Pringle's criteria)
• Affected of spasticity, equal or above 1 in the Ashworth Scale for spasticity in 2 or more muscle groups
• Who will judge spasticity a relevant cause of movements impairment
• Subject has spasticity due to MND of at least three months duration, which is not wholly relieved with current anti-spasticity therapy

• Subject fulfils at least one of the two criteria below. Subject must be either:

  1. Currently established on a regular dose of anti-spasticity therapy, or
  2. Previously tried and failed, or could not tolerate suitable anti-spasticity therapy
• Stabilization of factors affecting spasticity: any physiotherapy regimen or medication likely to affect spasticity will be optimised before the study and not altered in the 3 weeks before start of treatment
• Subject is willing for his or her name to be notified to the responsible authorities for participation in this study, as applicable.

Additional inclusion Criteria to be met at baseline

• Subjects have registered spasticity NRS scores via the personal clinical diary over the 6 days (day 2 to day 7) before randomization

Exclusion criteria:

• Any concomitant disease or disorder that has spasticity-like symptoms or that may influence the subject's level of spasticity
• Subjects receiving Botulinum Toxin during the preceding 6 months
• Bedridden and tracheotomised patients
• Fixed-tendon contractures
• Severe cognitive impairment
• Currently using or has used cannabis, cannabinoid-based medications or Acomplia (Rimonabant) within 30 days of study entry and unwilling to abstain for the duration of the study
• Any history or immediate family history of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition
• Any known or suspected history of a diagnosed dependence disorder, current heavy alcohol consumption, current use of an illicit drug or current non-prescribed use of any prescription drug
• Subjects with poorly controlled epilepsy or recurrent seizures (Subjects who have had one or more fits in the year prior to Visit 1 will be excluded)
• Any known or suspected hypersensitivity to cannabinoids or any of the excipients
• Subject has experienced myocardial infarction or clinically relevant cardiac dysfunction within the last 12 months or has a cardiac disorder that, in the opinion of the investigator would put the subject at risk of a clinically relevant arrhythmia or myocardial infarction
• Subject has a diastolic blood pressure of <50 mmHg or >105 mmHg (when measured in a sitting position at rest for five minutes) or a postural drop in the systolic blood pressure of greater than 20 mmHg
• Personal history suggestive of relevant impaired renal or hepatic function
• Female subjects of child bearing potential, unless willing to ensure that they or their partner use effective contraception during the study and for three months thereafter
• Female subject who is pregnant, lactating or planning pregnancy during the course of the study and for three months thereafter
• Subjects who have received any IMP within the 8 weeks before Visit 1
• Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or may influence the result of the study, or the subject's ability to participate in the study
• Unwilling to abstain from donation of blood during the study
• Patients will be asked not to drive while they will be receiving medication

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT01776970
• Other Study ID Numbers: CANALS
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Giancarlo Comi, Ospedale San Raffaele
• Original Responsible Party: Same as current
• Current Study Sponsor: Ospedale San Raffaele
• Original Study Sponsor: Same as current

Collaborators

• Fondazione Salvatore Maugeri
• Niguarda Hospital
• University of Padova

Investigators

• Principal Investigator: Giancarlo Comi, MD; San Raffaele Scientific Institute

• PRS Account: Ospedale San Raffaele
• Verification Date: March 2017