The exclusion criteria and ineligibility:
Patients were excluded from participation if they met any of the following: i) demonstrated cognitive impairment or intellectual disability; ii) had a history of primary psychotic disorder, bipolar affective disorder, bipolar disorder with psychotic features, depressive disorder with psychotic features, borderline personality disorder, antisocial personality disorder, or a positive family history (first degree relative) of psychotic disorder or bipolar affective disorder; iii) had any history of allergic or hypersensitivity reaction to any herbal product, including cannabinoids; iv)reported a prior sensitivity reaction to an oro-mucosal administered medicine or supplement (e.g., liposomes); v) had undergone radiotherapy to the mouth or oral cavity; vi) had significant intercurrent medical illnesses that the PI assessed to make them unsafe to be enrolled; especially a history of epilepsy (or a previous history of seizures), or clinically significant hepatic or renal impairment;vii) uncontrolled brain metastases; viii) pregnant or breast feeding; ix) had received epidural analgesia within 48 hours of the baseline assessment; x) had received radiotherapy within two weeks of the initial baseline assessment; xi) were currently receiving levodopa, sildenafil (or any other PDE5s), anticonvulsants and/or cannabinoids, or ketamine.
| Clinical Study Endpoints
Primary Endpoints: consisted of a clinical assessment of safety and tolerability from recorded adverse events/serious adverse events; quality of life scores as measured with The European Organisation for Research and Treatment of Cancer Quality of Life for Cancer Patients Questionnaire (EORTC QLQ-C30-v3) [22]. The minimum threshold for clinical importance for functioning scales scores were: physical functioning, 83; role functioning, 58; social functioning, 71; emotional functioning, 71; cognitive functioning, 75. The minimum threshold for symptom scales scores were: fatigue, 39; pain, 25; nausea/vomiting, 8. The minimum threshold for sleep disturbances scores were: dyspnea, 17; appetite loss, 50; constipation, 50; diarrhea, 17; financial impact, 17. The sensitivities of these thresholds for clinical importance ranged from 0.71 to 0.91 [22].
Furthermore, pharmacokinetic parameters AUC, Cmax, Tmax and bioavailability would be determined.
Secondary endpoints: cannabis treatment analgesic efficacy as assessed by Mean Numerical Pain Rating Scale (NPRS) scores; Mean Brief Pain Inventory scores, Short Form (BPI-SF); Morphine Milligram equivalent (MMeq) doses; rescue analgesia (opioid) doses.
| Study Safety Endpoints
At each visit the incidence and severity of adverse events were recorded. Any clinically significant changes in vital signs or physical examination were reported as adverse events. Clinically relevant changes in concomitant medications, e.g., changes in morphine milligram equivalent doses were also recorded (Supplement 1).
  1. | Statistical Methods
  2. | Sample size
A sample size of n=5 was considered adequate for a limited assessment of the Stage I SAD PK study, which was similar in design to a phase I study that assessed the single and multiple dose PKs and safety and tolerability of an oro-mucosal administered Δ9-THC/CBD spray [23]. Pharmacokinetic parameters were presented as medians within the range of minimum and maximum values.
| Data Analysis:
Analysis of the primary outcome (safety and tolerability) was descriptive. Pharmacokinetic analysis was conducted using a one-compartment open pharmacokinetic model with first order absorption and elimination. The area under the curve (AUC) was calculated using linear extrapolation. The PK analysis included calculating Cmax and Tmax by observation of the concentration-time profile curve; the AUC was calculated from 0 hours to 6 hours using the linear trapezoidal rule; and the half-life (t½) was calculated from the elimination rate constant (kel) which was estimated from the slope of the terminal portion of the log-concentration-time profile.
The limit of detection for all metabolites was 0.1 ng mL−1. For the two secondary efficacy variables (i.e., NPRS pain score and use of breakthrough medication), the Hochberg method [24] was used to test the global hypothesis for a treatment effect on pain [25]. The daily pain NPRS score was calculated as the mean of all the daily assessments. The change in mean NPRS pain scores from baseline (all days in run-in period) to the end of treatment was analysed using analysis of covariance (ANCOVA), with baseline pain as a covariate and grouped study and treatment as factors [26]. The proportions of responders (patients with ≥ 30% improvement from baseline to end of study NPRS and BPI-SF pain scores) was compared. Use of breakthrough medication (during treatment) was recorded. In addition, the change from baseline in mean number of doses of escape medication was analysed using ANCOVA. The EORTC-QLQ-30 was scored according to its scoring manual [27], and differences over time explored using ANOVA. All analyses were conducted in Stata MP V16 for Mac (StataCorp, Texas Station, US).
  1. | Results
  2. | Patient Demographics
Patient demographics and clinical characteristics for both phases of the trial are presented in Table 1. In Stage I there was a predominance of women. The mean age was 65 years, and patients had controlled pain. There was a range of tumor types. In Stage II there was a predominance of women and the median age was 56 years. Again, there was a wide range of tumor types and sites of metastases, however 8 patients (32%) had bone metastases causing pain. There was also a mixture of different types of pain, including patients with multiple types of pain. The most common types of pain, bone origin [8] and neuropathic (11) (Table 1).