E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pain in patients with advanced cancer who have inadequate analgesia even with optimized chronic opioid therapy. |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058019 |
E.1.2 | Term | Cancer pain |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of Sativex, compared with placebo, when used as an adjunctive measure, in relieving uncontrolled persistent chronic pain (not breakthrough pain) in patients with advanced cancer, who have inadequate analgesia even with optimized chronic opioid therapy. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of Sativex compared with placebo on:
• Secondary measures of pain
• Sleep disruption
• Constipation
• Opioid consumption
• Change in general function
• Treatment failure
To evaluate the safety and tolerability of Sativex compared with placebo through the following assessments:
• Adverse Events (AE)
• Survival
• Suicidal Tendencies (Columbia Suicide Severity Rating Scale - C-SSRS)
• Clinical laboratory tests
• Vital signs |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Annex 1, Version 4, Dated 19 Jan 2015 - Objectives: To assess exposure to Sativex at steady state in patients on a stable self-titrated dose regimen of Sativex and to evaluate the sources of variability in dose-concentration relationship between patients.
Protocol Annex 2, Version 1, Dated 14 March 2013 - Objectives: The purpose of this Annex is to describe the methodology for identifying and evaluating clinical trial adverse event data through systematic categorization, tabulation, and analysis which can illuminate an abuse potential signal.
Protocol Annex 3, Version 1, Dated 16 April 2013 – Objectives: The purpose of this Annex is to describe the methodology for the assessment of potential physical dependence and withdrawal effects as well as to allow for the inclusion of a ‘Health Service Utilization’ Questionnaire.
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E.3 | Principal inclusion criteria |
Patients meeting the following criteria will be considered suitable to enter into the Eligibility Period for this study at Visit 1:
• Willing and able to give written informed consent.
• The patient is at least 18 years of age or older.
• The patient has advanced cancer.
• The patient has a clinical diagnosis of cancer related pain, which is not wholly alleviated with his or her current optimized opioid treatment.
• The patient is receiving an optimized maintenance dose of Step III opioid therapy, preferably with a sustained release preparation, but also allowing a regular maintenance dose of around the clock use of immediate release preparations.
• The patient is receiving a daily maintenance dose Step III opioid therapy of less than or equal to a total daily opioid dose of 500 mg/day of morphine equivalence (including maintenance and break-through opioids).
• The patient is using no more than one type of break-through opioid analgesia.
• The patient is willing to continue to take their maintenance opioid therapy at the same daily dose, throughout the duration of the study where possible.
• Willing and able to comply with all study requirements.
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E.4 | Principal exclusion criteria |
The patient may not enter the study if ANY of the following apply:
• Have any planned clinical interventions that would affect their pain (e.g., chemotherapy or radiation therapy where, in the clinical judgment of the investigator, these would be expected to affect pain).
• The patient is currently using or has used cannabis or cannabinoid based medications within 30 days of study entry and is 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 substance abuse/dependence disorder (including opiate abuse/dependence prior to the diagnosis of cancer), current heavy alcohol consumption (more than 60g of pure alcohol per day for men, and more than 40g of pure alcohol per day for women), current use of an illicit drug or current non prescribed use of any prescription drug.
• Has poorly controlled epilepsy or recurrent seizures (i.e., one or more seizure during the last year).
• Any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP.
• Has experienced myocardial infarction or clinically significant cardiac dysfunction within the last 12 months or has a cardiac disorder that, in the opinion of the investigator would put the patient at risk of a clinically significant arrhythmia or myocardial infarction.
• Has significantly impaired renal function as evidenced by a creatinine clearance lower than 40 mL/min at Visit 1.
• Has significantly impaired hepatic function at Visit 1 (ALT >5X upper limit of normal (ULN) or bilirubin (TBL) > 2X ULN). If the ALT or AST >3X ULN and the TBL >2X ULN (or INR >1.5), this patient should not enter the study.
• Female patients of child-bearing potential and male patients whose partner is of child-bearing potential, unless willing to ensure that they or their partner use effective contraception, for example, oral contraception, double barrier, intra-uterine device, during the study and for three months thereafter (however, a male condom should not be used in conjunction with a female condom as this may not prove effective).
• Female patient who is pregnant, lactating or planning pregnancy during the course of the study and for three months thereafter.
• Patients who have received a non-approved IMP within 30 days of Visit 1.
• Any other significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, or may influence the result of the study, or the patient's ability to participate in the study.
• Travel outside the country of residence planned during the study.
• Patients previously enrolled into Part A of this study or any other Sativex clinical trial for Cancer Pain.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the mean change from baseline to the end of treatment in NRS average pain score. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The last 4 days of IMP treatment in Part B. |
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E.5.2 | Secondary end point(s) |
The following key secondary endpoints will have their Type I error controlled by a hierarchical testing procedure:
• Percent improvement from the eligibility period to the end of treatment in NRS average pain score.
• Change from baseline in mean NRS worst pain.
• Change from baseline in mean Sleep Disruption NRS.
The remaining secondary efficacy endpoints are:
• Subject (patient) Global Impression of Change (SGIC).
• Patient Satisfaction Questionnaire (PSQ).
• Change from baseline in mean total opioid (morphine equivalence) use.
• Change from baseline in mean daily maintenance dose opioid (morphine equivalence) use.
• Change from baseline in mean break-through opioid usage (morphine equivalence) use.
• Change from baseline in constipation NRS.
• Physician Global Impression of Change in general function (PGIC).
• Time to withdrawal for any reason during Part B.
• Withdrawal from Part B due to lack of efficacy. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The diary data based end of treatment values will be calculated using the same rules as for the primary endpoint – i.e. last 4 days of IMP treatment in Part B. The other end of treatment values will use the Visit 5 assessment data. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 64 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Bulgaria |
Germany |
Hungary |
India |
Israel |
Italy |
Korea, Republic of |
Lithuania |
Poland |
Romania |
Spain |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |