A Long-term Safety Extension Study of Delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) in Multiple Sclerosis

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01610687
• Collaborator: (none)
• Enrollment: 137
• Location: 1
• Arm: 1
• Duration (Months): 43.1
• Patients Per Site Per Month: 3.2

Study Details

Study Description

Brief Summary

An extension study to evaluate the long-term safety, tolerability and efficacy of GW-1000-02 treatment in multiple sclerosis.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis; Spasticity	Drug: GW-1000-02	Phase 3

Detailed Description

Patients who participated in the placebo controlled phase of this study and opted to continue receiving open label GW-1000-02 entered the follow-on extension of the study and completed symptom assessments to determine whether they were continuing to receive clinical benefit from GW-1000-02.

Study Design

• Study Type: Interventional
• Actual Enrollment: 137 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Double Blind, Randomised, Parallel Group, Placebo Controlled Trial of a Combination of THC and CBD in Patients With Multiple Sclerosis, Followed by an Open Label Assessment and Study Extension
• Study Start Date: Jul 1, 2001
• Actual Primary Completion Date: Feb 1, 2005
• Actual Study Completion Date: Feb 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GW-1000-02 Active treatment	Drug: GW-1000-02; Contained THC and CBD as extract of Cannabis sativa L. Each 100 μl actuation delivered a dose containing 2.7 mg THC and 2.5mg CBD. The maximum permitted dose was eight actuations (22 mg THC and 20 mg CBD) in any three hour period, and 48 actuations (130 mg THC and 120 mg CBD) in any 24 hour period.; Other Names: Sativex

Outcome Measures

Primary Outcome Measures

1. Incidence of Adverse Events as a Measure of Patient Safety [up to1206 days]

   The number of patients who experienced an adverse event during the course of this extension study is presented

Secondary Outcome Measures

1. Mean Number of Sprays of Study Medication Taken During the Last 6 Days of Treatment [up to 1206 days]

   A categorical summary was produced of the mean number of sprays per day during the last six days of treatment, and the mean number of sprays was rounded to the nearest whole number for categorisation.

2. Change From Baseline in Mean Intoxication 100 mm Visual Analogue Scale Scores at Week 18. [18 weeks]

   Intoxication levels were recorded on a Visual Analogue Scale, where 0 equals 'no intoxication' and 10 equals 'extreme intoxication'. A decrease in score indicates an improvement in intoxication levels.

3. Investigator Assessed Global Severity Score at Week 18 [week 18]

   The investigator rated the global severity of the subject's primary condition since entry into the study using a five-point verbal rating scale-5: 1=much worse, 2=worse, 3=no change, 4=better, 5=much better. The number of patients which were considered better or much better (scores 4 and 5) at week 18 of the study better is presented.

4. Change From Baseline in the Mean Pain 100 mm Visual Analogue Scale Score at Week 18 [week 18]

   A clinical assessment of pain was made at each study visit using a 100 mm Visual Analogue Scale, where 0 = no pain and 100 = worst possible pain. A decrease in score indicates an improvement.

5. Change From Baseline in the Mean Spasticity 100 mm Visual Analogue Scale Score at Week 18 [week 18]

   A clinical assessment of spasticity was made at each study visit using a 100 mm Visual Analogue Scale, where 0 = no spasticity and 100 = worst possible spasticity. A decrease in score indicates an improvement.

6. Change From Baseline in the Mean Tremor 100 mm Visual Analogue Scale Score at Week 18 [week 18]

   A clinical assessment of tremor was made at each study visit using a 100 mm Visual Analogue Scale, where 0 = no tremor and 100 = worst possible tremor. A decrease in score indicates an improvement.

7. Change From Baseline in the Mean Bladder Problems 100 mm Visual Analogue Scale Score at Week 18 [18 weeks]

   A clinical assessment of bladder problems was made at each study visit using a 100 mm Visual Analogue Scale, where 0 = no bladder problems and 100 = worst possible bladder problems. A decrease in score indicates an improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Aged at least 18 years.

• Multiple Sclerosis of any type.

• Stable Multiple Sclerosis symptomatology during the four weeks before study entry.

• Symptoms of the required severity (>50 mm on a 100 mm Visual Analogue Scale severity scale) in least one of the specified impairment categories; spasticity, muscle spasms, disturbed bladder control, neuropathic pain, limb tremor.

• A stable medication regime during the four weeks before study entry.

• Willing to abstain from cannabis or cannabinoids for at least seven days before study entry, and during the study.

• Agreed either to use effective contraception during the study and for three months thereafter, or had been surgically sterilised or, if female, were post-menopausal.

• Clinically acceptable laboratory results for pre-study screening.

• Willing and able to undertake and comply with all study requirements.

• Willing and able to read, consider and understand the subject information and consent form and give written informed consent. Subjects unable to read or to sign the document procedures were treated as detailed in the Declaration of Helsinki.

• Willing for their general practitioner, and consultant if appropriate, to be informed of study participation.

• Willing for their name to be notified to Home Office for participation in the study.

Exclusion Criteria:

• Known or strongly suspected to be abusing drugs, including alcohol.

• Not prepared to abstain from cannabis or cannabinoids during the study.

• Current or past addiction to cannabis.

• Known or suspected to have had an adverse reaction to cannabinoids causing psychosis or other severe psychiatric illness.

• History of any type of schizophrenia, any other psychotic illness, or other significant psychiatric illness or personality disorder other than depression associated with chronic illness.

• Received any drug containing levodopa (Sinemet®, Sinemet plus®, Levodopa®, L-dopa®, Madopar®, Benserazide®).

• Serious cardiovascular disorder including angina, uncontrolled hypertension, or an uncontrolled symptomatic cardiac arrhythmia.

• Significant renal or hepatic impairment as shown in medical history or indicated by laboratory results.

• History of epilepsy.

• Terminal illness or other condition in which placebo medication would be inappropriate.

• Pregnant, lactating or at risk of pregnancy.

• Participated in any other clinical research study during the 12 weeks before study entry.

• Planned hospital admission between study entry and Visit 6.

• Planned travel outside the UK between study entry and Visit 6.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rivermead Rehabilitation Centre	Oxford		United Kingdom	OX3 7LD

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Principal Investigator: Derick Wade, FRCP MD, Rivermead Rehabilitation Centre

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01610687
• Other Study ID Numbers: GWMS0001 EXT
• First Posted: Jun 4, 2012
• Last Update Posted: Jun 24, 2013
• Last Verified: Jun 1, 2013

• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Nabiximols

Study Results

Participant Flow

Arm/Group Title	GW-1000-02
Arm/Group Description	GW-1000-02 contains Δ tetrahydrocannabinol, 27 mg/ml and cannabidiol, 25 mg/ml as extract of Cannabis sativa L. Subjects received study medication delivered in 100 μl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours
Period Title: Overall Study
STARTED	137
COMPLETED	70
NOT COMPLETED	67

Baseline Characteristics

Arm/Group Title	GW-1000-02
Arm/Group Description	Active treatment
Overall Participants	137
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	127 92.7%
>=65 years	10 7.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.69 (9.531)
Sex: Female, Male (Count of Participants)
Female	83 60.6%
Male	54 39.4%
Region of Enrollment (participants) [Number]
United Kingdom	137 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Adverse Events as a Measure of Patient Safety
Description	The number of patients who experienced an adverse event during the course of this extension study is presented
Time Frame	up to1206 days

Outcome Measure Data

Analysis Population Description

All subjects who took at least one dose of study medication after the end of the Part B open-label phase of the acute study, and yielded on-treatment efficacy data was classed as the efficacy and safety population.

Arm/Group Title	GW-1000-02
Arm/Group Description	Contains THC (27 mg/ml) and CBD (25 mg/ml). Subjects received study medication delivered in 100 μl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours
Measure Participants	137
Number [participants]	126 92%

2. Secondary Outcome

Title	Mean Number of Sprays of Study Medication Taken During the Last 6 Days of Treatment
Description	A categorical summary was produced of the mean number of sprays per day during the last six days of treatment, and the mean number of sprays was rounded to the nearest whole number for categorisation.
Time Frame	up to 1206 days

Outcome Measure Data

Analysis Population Description

All subjects who took at least one dose of study medication after the end of the Part B open-label phase of the acute study, and yielded on-treatment efficacy data was classed as the efficacy and safety population.

Arm/Group Title	GW-1000-02
Arm/Group Description	Contains THC (27 mg/ml) and CBD (25 mg/ml). Subjects received study medication delivered in 100 μl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours
Measure Participants	137
Mean (Standard Deviation) [sprays of study medication]	8.09 (7.91)

3. Secondary Outcome

Title	Change From Baseline in Mean Intoxication 100 mm Visual Analogue Scale Scores at Week 18.
Description	Intoxication levels were recorded on a Visual Analogue Scale, where 0 equals 'no intoxication' and 10 equals 'extreme intoxication'. A decrease in score indicates an improvement in intoxication levels.
Time Frame	18 weeks

Outcome Measure Data

Analysis Population Description

All subjects who took at least one dose of study medication after the end of the Part B open-label phase of the acute study, and yielded on-treatment efficacy data was classed as the efficacy and safety population.

Arm/Group Title	GW-1000-02
Arm/Group Description	Contains THC (27 mg/ml) and CBD (25 mg/ml). Subjects received study medication delivered in 100 μl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours
Measure Participants	121
Mean (Standard Deviation) [units on a scale]	2.65 (14.15)

4. Secondary Outcome

Title	Investigator Assessed Global Severity Score at Week 18
Description	The investigator rated the global severity of the subject's primary condition since entry into the study using a five-point verbal rating scale-5: 1=much worse, 2=worse, 3=no change, 4=better, 5=much better. The number of patients which were considered better or much better (scores 4 and 5) at week 18 of the study better is presented.
Time Frame	week 18

Outcome Measure Data

Analysis Population Description

All subjects who took at least one dose of study medication after the end of the Part B open-label phase of the acute study, and yielded on-treatment efficacy data was classed as the efficacy and safety population.

Arm/Group Title	GW-1000-02
Arm/Group Description	Contains THC (27 mg/ml) and CBD (25 mg/ml). Subjects received study medication delivered in 100 μl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours
Measure Participants	135
Number [participants]	92 67.2%

5. Secondary Outcome

Title	Change From Baseline in the Mean Pain 100 mm Visual Analogue Scale Score at Week 18
Description	A clinical assessment of pain was made at each study visit using a 100 mm Visual Analogue Scale, where 0 = no pain and 100 = worst possible pain. A decrease in score indicates an improvement.
Time Frame	week 18

Outcome Measure Data

Analysis Population Description

All subjects who took at least one dose of study medication after the end of the Part B open-label phase of the acute study, and yielded on-treatment efficacy data was classed as the efficacy and safety population.

Arm/Group Title	GW-1000-02
Arm/Group Description	Contains THC (27 mg/ml) and CBD (25 mg/ml). Subjects received study medication delivered in 100 μl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours
Measure Participants	74
Mean (Standard Deviation) [units on a scale]	-31.34 (27.20)

6. Secondary Outcome

Title	Change From Baseline in the Mean Spasticity 100 mm Visual Analogue Scale Score at Week 18
Description	A clinical assessment of spasticity was made at each study visit using a 100 mm Visual Analogue Scale, where 0 = no spasticity and 100 = worst possible spasticity. A decrease in score indicates an improvement.
Time Frame	week 18

Outcome Measure Data

Analysis Population Description

All subjects who took at least one dose of study medication after the end of the Part B open-label phase of the acute study, and yielded on-treatment efficacy data was classed as the efficacy and safety population.

Arm/Group Title	GW-1000-02
Arm/Group Description	Contains THC (27 mg/ml) and CBD (25 mg/ml). Subjects received study medication delivered in 100 μl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours
Measure Participants	118
Mean (Standard Deviation) [units on a scale]	-27.81 (24.46)

7. Secondary Outcome

Title	Change From Baseline in the Mean Tremor 100 mm Visual Analogue Scale Score at Week 18
Description	A clinical assessment of tremor was made at each study visit using a 100 mm Visual Analogue Scale, where 0 = no tremor and 100 = worst possible tremor. A decrease in score indicates an improvement.
Time Frame	week 18

Outcome Measure Data

Analysis Population Description

All subjects who took at least one dose of study medication after the end of the Part B open-label phase of the acute study, and yielded on-treatment efficacy data was classed as the efficacy and safety population.

Arm/Group Title	GW-1000-02
Arm/Group Description	Contains THC (27 mg/ml) and CBD (25 mg/ml). Subjects received study medication delivered in 100 μl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours
Measure Participants	43
Mean (Standard Deviation) [units on a scale]	-26.23 (23.90)

8. Secondary Outcome

Title	Change From Baseline in the Mean Bladder Problems 100 mm Visual Analogue Scale Score at Week 18
Description	A clinical assessment of bladder problems was made at each study visit using a 100 mm Visual Analogue Scale, where 0 = no bladder problems and 100 = worst possible bladder problems. A decrease in score indicates an improvement.
Time Frame	18 weeks

Outcome Measure Data

Analysis Population Description

All subjects who took at least one dose of study medication after the end of the Part B open-label phase of the acute study, and yielded on-treatment efficacy data was classed as the efficacy and safety population.

Arm/Group Title	GW-1000-02
Arm/Group Description	Contains THC (27 mg/ml) and CBD (25 mg/ml). Subjects received study medication delivered in 100 μl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours
Measure Participants	96
Mean (Standard Deviation) [units on a scale]	-33.60 (25.12)

Adverse Events

Time Frame	All adverse events occurring from during the extension study (up to 1049 days) were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected.
Adverse Event Reporting Description	All adverse events occurring during the study were reported on the running logs at the back of the study case report form.
Arm/Group Title	GW-1000-02
Arm/Group Description	Contains THC (27 mg/ml) and CBD (25 mg/ml). Subjects received study medication delivered in 100 μl actuations by a pump action oromucosal spray. Maximum permitted dose was eight actuations in any three hour period and 48 actuations (THC 130 mg:CBD 120 mg) in 24 hours
All Cause Mortality
	GW-1000-02
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	GW-1000-02
	Affected / at Risk (%)	# Events
Total	23/137 (16.8%)
Blood and lymphatic system disorders
Lymphadenopathy	1/137 (0.7%)
Cardiac disorders
Atrial Fibrillation	1/137 (0.7%)
Gastrointestinal disorders
Vomiting NOS	2/137 (1.5%)
Diarrhoea NOS	1/137 (0.7%)
General disorders
Fall	1/137 (0.7%)
Oedema Peripheral	1/137 (0.7%)
Weakness	1/137 (0.7%)
Hepatobiliary disorders
Biliary Cirrhosis Primary	1/137 (0.7%)
Infections and infestations
Urinary Tract Infection Not Otherwise Specified (NOS)	4/137 (2.9%)
Pneumonia NOS	1/137 (0.7%)
Bone infection NOS	1/137 (0.7%)
Cellulitis	1/137 (0.7%)
Injury, poisoning and procedural complications
Femur Fracture	1/137 (0.7%)
Lower Limb Fracture NOS	1/137 (0.7%)
Head Injury	1/137 (0.7%)
Metabolism and nutrition disorders
Dehydration	1/137 (0.7%)
Hyperglycaemia NOS	1/137 (0.7%)
Musculoskeletal and connective tissue disorders
Muscle Spasms	2/137 (1.5%)
Muscle Weakness NOS	2/137 (1.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer Metastatic	1/137 (0.7%)
Breast Cancer NOS	1/137 (0.7%)
Lung Cancer Stage Unspecified (excl metastatic tumours to lung)	1/137 (0.7%)
Nervous system disorders
Multiple Sclerosis Relapse	3/137 (2.2%)
Balance Impaired NOS	2/137 (1.5%)
Convulsions NOS	1/137 (0.7%)
Hypotonia	1/137 (0.7%)
Psychiatric disorders
Panic Attack	1/137 (0.7%)
Psychotic Disorder NOS	1/137 (0.7%)
Respiratory, thoracic and mediastinal disorders
Pleurisy	1/137 (0.7%)
Skin and subcutaneous tissue disorders
Decubitus Ulcer	2/137 (1.5%)
Vascular disorders
Deep Vein Thrombosis NOS	1/137 (0.7%)
Other (Not Including Serious) Adverse Events
	GW-1000-02
	Affected / at Risk (%)	# Events
Total	127/137 (92.7%)
Gastrointestinal disorders
ORAL PAIN	32/137 (23.4%)
DIARRHOEA NOS	27/137 (19.7%)
NAUSEA	24/137 (17.5%)
VOMITING NOS	16/137 (11.7%)
GLOSSODYNIA	15/137 (10.9%)
ORAL MUCOSAL DISORDER	15/137 (10.9%)
CONSTIPATION	12/137 (8.8%)
DRY MOUTH	11/137 (8%)
ORAL DISCOMFORT	9/137 (6.6%)
MOUTH ULCERATION	8/137 (5.8%)
DYSPEPSIA	7/137 (5.1%)
LOOSE STOOLS	7/137 (5.1%)
TOOTHACHE	7/137 (5.1%)
TOOTH DISCOLOURATION	6/137 (4.4%)
General disorders
FALL	21/137 (15.3%)
FATIGUE	16/137 (11.7%)
WEAKNESS	11/137 (8%)
LETHARGY	10/137 (7.3%)
APPLICATION SITE IRRITATION	9/137 (6.6%)
APPLICATION SITE PAIN	6/137 (4.4%)
MALAISE	6/137 (4.4%)
FEELING ABNORMAL	5/137 (3.6%)
Infections and infestations
URINARY TRACT INFECTION NOS	56/137 (40.9%)
NASOPHARYNGITIS	37/137 (27%)
LOWER RESPIRATORY TRACT INFECTION NOS	13/137 (9.5%)
TOOTH CARIES NOS	9/137 (6.6%)
BACTERIAL INFECTION NOS	8/137 (5.8%)
BLADDER INFECTION NOS	6/137 (4.4%)
VAGINAL CANDIDIASIS	6/137 (4.4%)
VIRAL INFECTION NOS	5/137 (3.6%)
Investigations
WEIGHT DECREASED	13/137 (9.5%)
GAMMA-GLUTAMYLTRANSFERASE INCREASED	10/137 (7.3%)
Metabolism and nutrition disorders
ANOREXIA	7/137 (5.1%)
Musculoskeletal and connective tissue disorders
PAIN IN LIMB	17/137 (12.4%)
MUSCLE WEAKNESS NOS	13/137 (9.5%)
ARTHRALGIA	12/137 (8.8%)
BACK PAIN	10/137 (7.3%)
MUSCLE SPASMS	7/137 (5.1%)
JOINT SWELLING	5/137 (3.6%)
MYALGIA	5/137 (3.6%)
PERIPHERAL SWELLING	5/137 (3.6%)
Nervous system disorders
DIZZINESS	30/137 (21.9%)
HEADACHE NOS	23/137 (16.8%)
BALANCE IMPAIRED NOS	21/137 (15.3%)
MULTIPLE SCLEROSIS AGGRAVATED	16/137 (11.7%)
DYSGEUSIA	13/137 (9.5%)
MULTIPLE SCLEROSIS RELAPSE	12/137 (8.8%)
DISTURBANCE IN ATTENTION	9/137 (6.6%)
SOMNOLENCE	9/137 (6.6%)
SYNCOPE	9/137 (6.6%)
MEMORY IMPAIRMENT	6/137 (4.4%)
Psychiatric disorders
SHORT-TERM MEMORY LOSS	9/137 (6.6%)
DEPRESSED MOOD	7/137 (5.1%)
DISORIENTATION	6/137 (4.4%)
INSOMNIA	5/137 (3.6%)
Respiratory, thoracic and mediastinal disorders
PHARYNGITIS	8/137 (5.8%)
THROAT IRRITATION	5/137 (3.6%)
Skin and subcutaneous tissue disorders
CONTUSION	12/137 (8.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GW will coordinate the dissemination of data from this study and may solicit input and assistance from the principal investigator. All publications, for example manuscripts, abstracts, oral/slide presentations or book chapters based on this study, must be submitted to GW for corporate review before release.