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Long Term Safety of Sativex Oromucosal Spray (Sativex®; Nabiximols) as Adjunctive Therapy in Patients With Uncontrolled Persistent Chronic Cancer Related Pain

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ClinicalTrials.gov Identifier: NCT01337089
Recruitment Status : Completed
First Posted : April 18, 2011
Results First Posted : April 23, 2018
Last Update Posted : April 23, 2018
Sponsor:
Collaborator:
Otsuka Pharmaceutical Development & Commercialization, Inc.
Information provided by (Responsible Party):
GW Pharmaceuticals Ltd.

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Pain
Advanced Cancer
Intervention Drug: Nabiximols
Enrollment 660
Recruitment Details Participants enrolled in this study included those who had taken part in studies NCT01262651 (GWCA0958), NCT01361607 (GWCA0962), and NCT01424566 (GWCA1103) and who chose to continue treatment by enrolling in this study, as well as new (de novo) participants who met all inclusion criteria and did not meet any of the exclusion criteria.
Pre-assignment Details For the de novo participants enrolled in this study, a screening visit took place 3 to 14 days prior to enrollment.
Arm/Group Title Nabiximols
Hide Arm/Group Description Nabiximols was self-administered by participants as a 100 microliter (μL) oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 6 months. Nabiximols oromucosal spray contained delta-9-tetrahydrocannabinol (THC) (27 milligram [mg]/milliliter [mL]):cannabidiol (CBD) (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD.
Period Title: Overall Study
Started 660
Received at Least 1 Dose of Study Drug 660
Safety Population 660
Efficacy Dataset 659 [1]
Completed 256
Not Completed 404
Reason Not Completed
Adverse Event             237
Withdrawal by Subject             129
Withdrawal by Investigator             33
Met Withdrawal Criteria             3
Lost to Follow-up             2
[1]
One participant withdrew after administering nabiximols, but no efficacy data were collected.
Arm/Group Title Nabiximols
Hide Arm/Group Description Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 6 months. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD.
Overall Number of Baseline Participants 660
Hide Baseline Analysis Population Description
Safety Population: All participants who received at least 1 dose of nabiximols.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 660 participants
60.2  (11.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 660 participants
Female
313
  47.4%
Male
347
  52.6%
1.Primary Outcome
Title Percent Of Participants With Treatment-emergent Adverse Events
Hide Description Treatment-emergent Adverse Events (TEAEs) were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary version 17.0. A TEAE is defined as an adverse event with an onset after the start of study drug treatment. The percent of participants who experienced one or more TEAEs is reported.
Time Frame Baseline, Day 183
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Population included all participants receiving at least 1 dose of study drug.
Arm/Group Title Nabiximols
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 6 months. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD.
Overall Number of Participants Analyzed 660
Measure Type: Number
Unit of Measure: percent of participants
82.9
2.Secondary Outcome
Title Change From Baseline In Mean NRS Average Pain During The Last Period
Hide Description

Participants indicated the level of pain experienced in the last 24 hours on an 11-point Numerical Rating Scale (NRS), where a score of 0 indicated “no pain” and a score of 10 indicated “pain as bad as you can imagine.” Change in mean NRS average pain was calculated as: Last Period NRS average pain score - Baseline NRS average pain score.

A negative value indicates an improvement in average pain score from Baseline.

Time Frame Baseline, Last Period (Days 156-183) or last 27 days of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Population included all participants receiving at least 1 dose of study drug.
Arm/Group Title Nabiximols
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 6 months. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD.
Overall Number of Participants Analyzed 634
Mean (Standard Deviation)
Unit of Measure: units on a scale
0.0  (1.8)
3.Secondary Outcome
Title Change From Baseline In Mean Sleep Disruption NRS During The Last Period
Hide Description

Participants indicated the level of sleep disruption experienced in the last 24 hours on an 11-point NRS, where a score of 0 indicated “did not disrupt sleep” and a score of 10 indicated “completely disrupted (unable to sleep at all).” Change in mean sleep disruption NRS was calculated as: Last Period sleep disruption NRS score - Baseline sleep disruption NRS score.

A negative value indicates an improvement in sleep disruption score from Baseline.

Time Frame Baseline, Last Period (Days 156-183) or last 27 days of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Population included all participants receiving at least 1 dose of study drug.
Arm/Group Title Nabiximols
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 6 months. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD.
Overall Number of Participants Analyzed 634
Mean (Standard Deviation)
Unit of Measure: units on a scale
0.1  (1.9)
4.Secondary Outcome
Title Patient Satisfaction Questionnaire At Last Visit (Up To Day 183)
Hide Description The Patient Satisfaction Questionnaire (PSQ) was used to assess level of satisfaction of the participant with the study drug, with the markers “extremely satisfied, very satisfied, slightly satisfied, neutral, slightly dissatisfied, very dissatisfied, extremely dissatisfied”. Last visit refers to the last visit that a participant completed the assessment.
Time Frame Last Visit (up to Day 183)
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Population included all participants receiving at least 1 dose of study drug.
Arm/Group Title Nabiximols
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 6 months. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD.
Overall Number of Participants Analyzed 618
Measure Type: Count of Participants
Unit of Measure: Participants
Extremely Satisfied
56
   9.1%
Very Satisfied
230
  37.2%
Slightly Satisfied
185
  29.9%
Neutral
82
  13.3%
Slightly Dissatisfied
33
   5.3%
Very Dissatisfied
22
   3.6%
Extremely Dissatisfied
10
   1.6%
5.Secondary Outcome
Title Change From Baseline In NRS Constipation At Last Visit (Up To Day 183)
Hide Description

Participants indicated level of constipation on an 11-point NRS, where a score of 0 was “no constipation”, and 10 was “constipation as bad as you can imagine.” Last visit refers to the last visit that a participant completed the assessment.

Change in NRS constipation score was calculated as: Last Visit NRS constipation score - Baseline NRS constipation score.

A negative value indicates improvement in condition from Baseline.

Time Frame Baseline, Last Visit (up to Day 183)
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Population included all participants receiving at least 1 dose of study drug.
Arm/Group Title Nabiximols
Hide Arm/Group Description:
Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 6 months. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD.
Overall Number of Participants Analyzed 619
Mean (Standard Deviation)
Unit of Measure: units on a scale
-0.1  (2.5)
Time Frame Up to Day 197 post-enrollment
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Nabiximols
Hide Arm/Group Description Nabiximols was self-administered by participants as a 100 μL oromucosal spray in the morning and evening, up to a maximum of 10 sprays per day, for 6 months. Nabiximols oromucosal spray contained THC (27 mg/mL):CBD (25 mg/mL), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Each 100 μL actuation delivered 2.7 mg THC and 2.5 mg CBD.
All-Cause Mortality
Nabiximols
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Nabiximols
Affected / at Risk (%)
Total   301/660 (45.61%) 
Blood and lymphatic system disorders   
Anaemia  1  8/660 (1.21%) 
Anaemia Of Malignant Disease  1  1/660 (0.15%) 
Febrile Neutropenia  1  1/660 (0.15%) 
Neutropenia  1  1/660 (0.15%) 
Cardiac disorders   
Angina Pectoris  1  1/660 (0.15%) 
Atrial Fibrillation  1  1/660 (0.15%) 
Cardiopulmonary Failure  1  1/660 (0.15%) 
Myocardial Infarction  1  3/660 (0.45%) 
Congenital, familial and genetic disorders   
Pyloric Stenosis  1  1/660 (0.15%) 
Ear and labyrinth disorders   
Deafness Neurosensory  1  1/660 (0.15%) 
Vertigo  1  1/660 (0.15%) 
Endocrine disorders   
Adrenal Insufficiency  1  1/660 (0.15%) 
Eye disorders   
Blindness  1  1/660 (0.15%) 
Gastrointestinal disorders   
Nausea  1  6/660 (0.91%) 
Vomiting  1  7/660 (1.06%) 
Abdominal Pain  1  4/660 (0.61%) 
Abdominal Pain Upper  1  1/660 (0.15%) 
Gastritis  1  1/660 (0.15%) 
Gastritis Erosive  1  1/660 (0.15%) 
Haematemesis  1  1/660 (0.15%) 
Ileus  1  2/660 (0.30%) 
Intestinal Obstruction  1  1/660 (0.15%) 
Mechanical Ileus  1  1/660 (0.15%) 
Proctalgia  1  1/660 (0.15%) 
Small Intestinal Obstruction  1  2/660 (0.30%) 
Tongue Haemorrhage  1  1/660 (0.15%) 
General disorders   
Chest Pain  1  4/660 (0.61%) 
Device Occlusion  1  1/660 (0.15%) 
General Physical Health Deterioration  1  1/660 (0.15%) 
Local Swelling  1  1/660 (0.15%) 
Pain  1  6/660 (0.91%) 
Pyrexia  1  3/660 (0.45%) 
Infections and infestations   
Gastroenteritis  1  2/660 (0.30%) 
Urinary Tract Infection  1  1/660 (0.15%) 
Bacteraemia  1  1/660 (0.15%) 
Bronchitis  1  1/660 (0.15%) 
Catheter Site Infection  1  1/660 (0.15%) 
Cellulitis  1  2/660 (0.30%) 
Clostridium Difficile Colitis  1  1/660 (0.15%) 
Diverticulitis  1  1/660 (0.15%) 
Herpes Zoster  1  1/660 (0.15%) 
Klebsiella Sepsis  1  1/660 (0.15%) 
Lobar Pneumonia  1  1/660 (0.15%) 
Lower Respiratory Tract Infection  1  4/660 (0.61%) 
Pelvic Abscess  1  1/660 (0.15%) 
Pneumonia  1  6/660 (0.91%) 
Pseudomembranous Colitis  1  1/660 (0.15%) 
Respiratory Tract Infection  1  1/660 (0.15%) 
Sepsis  1  3/660 (0.45%) 
Sinusitis  1  1/660 (0.15%) 
Staphylococcal Bacteraemia  1  1/660 (0.15%) 
Staphylococcal Sepsis  1  1/660 (0.15%) 
Subacute Endocarditis  1  1/660 (0.15%) 
Viral Infection  1  1/660 (0.15%) 
Injury, poisoning and procedural complications   
Accidental Overdose  1  1/660 (0.15%) 
Fall  1  5/660 (0.76%) 
Femur Fracture  1  1/660 (0.15%) 
Gastrointestinal Stoma Complication  1  1/660 (0.15%) 
Joint Dislocation  1  1/660 (0.15%) 
Procedural Headache  1  2/660 (0.30%) 
Radiation Oesophagitis  1  1/660 (0.15%) 
Shunt Occlusion  1  1/660 (0.15%) 
Stoma Complication  1  1/660 (0.15%) 
Metabolism and nutrition disorders   
Cachexia  1  1/660 (0.15%) 
Dehydration  1  4/660 (0.61%) 
Diabetes Mellitus  1  1/660 (0.15%) 
Hypokalaemia  1  1/660 (0.15%) 
Hyponatraemia  1  1/660 (0.15%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  1/660 (0.15%) 
Back Pain  1  2/660 (0.30%) 
Muscular Weakness  1  1/660 (0.15%) 
Osteonecrosis  1  1/660 (0.15%) 
Pathological Fracture  1  4/660 (0.61%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Neoplasm Progression  1  209/660 (31.67%) 
Breast Cancer Metastatic  1  1/660 (0.15%) 
Cancer Pain  1  4/660 (0.61%) 
Lung Adenocarcinoma  1  1/660 (0.15%) 
Lung Neoplasm Malignant  1  1/660 (0.15%) 
Metastases To Bone  1  1/660 (0.15%) 
Metastases To Central Nervous System  1  3/660 (0.45%) 
Metastases To Liver  1  1/660 (0.15%) 
Metastases To Spine  1  1/660 (0.15%) 
Metastatic Neoplasm  1  1/660 (0.15%) 
Ovarian Cancer  1  1/313 (0.32%) 
Plasma Cell Myeloma  1  2/660 (0.30%) 
Squamous Cell Carcinoma Of Skin  1  1/660 (0.15%) 
Tumour Haemorrhage  1  1/660 (0.15%) 
Nervous system disorders   
Spinal Cord Compression  1  3/660 (0.45%) 
Altered State Of Consciousness  1  1/660 (0.15%) 
Balance Disorder  1  1/660 (0.15%) 
Carotid Artery Stenosis  1  1/660 (0.15%) 
Cerebral Infarction  1  1/660 (0.15%) 
Cerebrovascular Accident  1  3/660 (0.45%) 
Grand Mal Convulsion  1  1/660 (0.15%) 
Dementia With Lewy Bodies  1  1/660 (0.15%) 
Dizziness  1  2/660 (0.30%) 
Encephalopathy  1  1/660 (0.15%) 
Epilepsy  1  1/660 (0.15%) 
Posterior Reversible Encephalopathy Syndrome  1  2/660 (0.30%) 
Syncope  1  1/660 (0.15%) 
Tremor  1  1/660 (0.15%) 
Convulsion  1  2/660 (0.30%) 
Psychiatric disorders   
Agitation  1  1/660 (0.15%) 
Completed Suicide  1  1/660 (0.15%) 
Depression  1  1/660 (0.15%) 
Disorientation  1  4/660 (0.61%) 
Mental Status Changes  1  2/660 (0.30%) 
Suicide Attempt  1  1/660 (0.15%) 
Renal and urinary disorders   
Renal Failure Acute  1  1/660 (0.15%) 
Urinary Retention  1  5/660 (0.76%) 
Urinary Tract Obstruction  1  1/660 (0.15%) 
Reproductive system and breast disorders   
Genital Haemorrhage  1  1/660 (0.15%) 
Vaginal Fistula  1  1/313 (0.32%) 
Respiratory, thoracic and mediastinal disorders   
Dyspnoea  1  5/660 (0.76%) 
Chronic Obstructive Pulmonary Disease  1  3/660 (0.45%) 
Hypoxia  1  1/660 (0.15%) 
Pleural Effusion  1  2/660 (0.30%) 
Pulmonary Embolism  1  1/660 (0.15%) 
Respiratory Failure  1  3/660 (0.45%) 
Skin and subcutaneous tissue disorders   
Acute Febrile Neutrophilic Dermatosis  1  1/660 (0.15%) 
Dry Gangrene  1  1/660 (0.15%) 
Vascular disorders   
Deep Vein Thrombosis  1  4/660 (0.61%) 
Haemorrhage  1  1/660 (0.15%) 
Hypertension  1  1/660 (0.15%) 
Hypotension  1  1/660 (0.15%) 
Inferior Vena Caval Occlusion  1  1/660 (0.15%) 
Venous Thrombosis Limb  1  1/660 (0.15%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Nabiximols
Affected / at Risk (%)
Total   291/660 (44.09%) 
Blood and lymphatic system disorders   
Anaemia  1  39/660 (5.91%) 
Gastrointestinal disorders   
Nausea  1  86/660 (13.03%) 
Vomiting  1  59/660 (8.94%) 
Constipation  1  44/660 (6.67%) 
Diarrhoea  1  41/660 (6.21%) 
General disorders   
Fatigue  1  35/660 (5.30%) 
Asthenia  1  50/660 (7.58%) 
Metabolism and nutrition disorders   
Decreased Appetite  1  49/660 (7.42%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Neoplasm Progression  1  41/660 (6.21%) 
Nervous system disorders   
Dizziness  1  51/660 (7.73%) 
Somnolence  1  38/660 (5.76%) 
Respiratory, thoracic and mediastinal disorders   
Dyspnoea  1  37/660 (5.61%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Medical Enquiries
Organization: GW Pharmaceuticals Ltd.
Responsible Party: GW Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier: NCT01337089     History of Changes
Other Study ID Numbers: GWCA0999
2009-016529-32 ( EudraCT Number )
First Submitted: April 12, 2011
First Posted: April 18, 2011
Results First Submitted: March 23, 2018
Results First Posted: April 23, 2018
Last Update Posted: April 23, 2018