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).
- | Statistical Methods
- | 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).
- | Results
- | 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).