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

Primary Purpose

Motor Neuron Disease, Amyotrophic Lateral Sclerosis (ALS)

Status

Completed

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

Cannabis Sativa extract Oromucosal spray

About this trial

This is an interventional supportive care trial for Motor Neuron Disease focused on measuring Motor Neuron Disease, Amyotrophic lateral sclerosis, Cannabinoids, Sativex, Spasticity

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

San Raffaele Scientific Institute
Fondazione Salvatore Maugeri IRCCS, Istituto Scientifico
NEuroMuscular Omnicentre (NEMO), Fondazione Serena - H Cà granda
Universita' Degli Studi Di Padova, Azienda Ospedaliera Di Padova, Neurologic Department;

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Sativex

Placebo

Arm Description

Cannabis Sativa extract Oromucosal spray, containing THC (27 mg/ml):CBD (25 mg/ml)

Placebo oromucosal spray

Outcomes

Primary Outcome Measures

modified 5 - points modified Ashworth scale (AS).

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).

Secondary Outcome Measures

Mean weekly spasticity, spasm frequency and sleep disruption Numeric Rating Scale (NRS) score

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)

Full Information

NCT ID

NCT01776970

First Posted

January 24, 2013

Last Updated

March 7, 2017

Sponsor

Ospedale San Raffaele

Collaborators

Fondazione Salvatore Maugeri, Niguarda Hospital, University of Padova

1. Study Identification

Unique Protocol Identification Number

NCT01776970

Brief Title

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

Acronym

CANALS

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2017

Overall Recruitment Status

Completed

Study Start Date

January 2013 (undefined)

Primary Completion Date

December 2015 (Actual)

Study Completion Date

December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Ospedale San Raffaele

Collaborators

Fondazione Salvatore Maugeri, Niguarda Hospital, University of Padova

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Motor Neuron Disease, Amyotrophic Lateral Sclerosis (ALS)

Keywords

Motor Neuron Disease, Amyotrophic lateral sclerosis, Cannabinoids, Sativex, Spasticity

7. Study Design

Primary Purpose

Supportive Care

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

60 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sativex

Arm Type

Experimental

Arm Description

Cannabis Sativa extract Oromucosal spray, containing THC (27 mg/ml):CBD (25 mg/ml)

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo oromucosal spray

Intervention Type

Drug

Intervention Name(s)

Cannabis Sativa extract Oromucosal spray

Other Intervention Name(s)

Sativex

Intervention Description

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

Primary Outcome Measure Information:

Title

modified 5 - points modified Ashworth scale (AS).

Description

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).

Time Frame

Week 7 (6 weeks after randomization)

Secondary Outcome Measure Information:

Title

Mean weekly spasticity, spasm frequency and sleep disruption Numeric Rating Scale (NRS) score

Description

Time Frame

Week 7 (6 weeks after randomizazion)

Other Pre-specified Outcome Measures:

Title

Pain NRS score

Description

Pain will be measured with the mean of the last 3 days 0 - 10 daily pain intensity NRS.

Time Frame

Week 7 (6 weeks ater randomization)

Title

Appetite increase

Description

Weight difference before and at the end of the study.

Time Frame

Week 7 (6 weeks after randomization)

Title

Function (Ten meters walk test, ALS-FRS, Barthel ADL Index)

Description

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.

Time Frame

Week 7 (6 weeks aftar randomization)

Title

Global Impression of Change

Description

Carer Global Impression of Change and ease of transfer Physician Global Impression of Change Subject Global Impression of Change

Time Frame

Week 7 (6 weeks after randomization)

Title

Safety

Description

Adverse events, Vital Signs, Physical Examination , oral examination

Time Frame

Week 4, week 7

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

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: Currently established on a regular dose of anti-spasticity therapy, or 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Giancarlo Comi, MD

Organizational Affiliation

San Raffaele Scientific Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

San Raffaele Scientific Institute

City

Milan

ZIP/Postal Code

20132

Country

Italy

Facility Name

Fondazione Salvatore Maugeri IRCCS, Istituto Scientifico

City

Milan

Country

Italy

Facility Name

NEuroMuscular Omnicentre (NEMO), Fondazione Serena - H Cà granda

City

Milan

Country

Italy

Facility Name

Universita' Degli Studi Di Padova, Azienda Ospedaliera Di Padova, Neurologic Department;

City

Padova

Country

Italy

12. IPD Sharing Statement

Citations:

PubMed Identifier

30554828

Citation

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.

Results Reference

derived

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

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