3.6 | Quality of life
Given the complex presentation of the cohort of patients under
investigation, we report the EORTC-QLQ-30 scores (Figure 6) for those
patients diagnosed with breast and prostate cancer with metastasis to
the bone versus those of the whole cohort.
There was an overall improvement from baseline for global health status;
physical functioning; emotional functioning; cognitive functioning;
fatigue; pain; dyspnoea and insomnia (Figure 6). Participants diagnosed
with cancer metastatic to bone reported similar trends to the whole
cohort
(Figure 6). The threshold for clinical significance was only achieved
for emotional functioning, fatigue, dyspnoea, insomnia and appetite
loss.
| Discussion
Quality of life measures in this SAD MAD study met the primary endpoint
of safety and tolerability. The study demonstrated that the
administration of the investigative medicine
(NanaBisTM) was generally safe in a cohort of
chronically ill patients diagnosed with advanced cancers with
intractable pain despite opioid treatment. Moreover, results from
patient-reported outcome questionnaires suggest that patient functioning
(e.g., physical, social, emotional and cognitive) improved clinically
for emotional functioning, fatigue, dyspnea, insomnia and appetite loss.
The water-soluble nanoparticle cannabis formulation has appropriate
pharmacokinetics of cannabinoids for a maintenance analgesic, with peak
plasma concentration in less than an hour and efficacy durable enough to
support dosing every four hours (with multiple dosing). Oromucosal
delivery using 50% ethanol (and propylene glycol) [23] does not
seem to be as effective as the nanoparticle water-soluble spray. For
example, comparing the PK data with that reported for an ethanol-based
Δ9-THC/CBD spray, NanaBisTM achieved an approximate
equivalent AUC(0-t) and Cmax with half
the Δ9-THC/CBD administered dose. The ethanol-based spray (5.4 mg
Δ9-THC/5.4 mg CBD) reported mean AUC(0-t) and
Cmax of 2.99/0.82 ng mL.h−1 and
1.48/0.39 ng mL−1 respectively [23]. A comparison
with half the dose from NanaBisTM 2.5 mg Δ9-THC/2.5 mg
CBD), the calculated means for AUC(0-t) and
Cmax were 2.79/1.46 ng mL.h−1 and
1.58/1.02 ng mL−1 respectively. Furthermore, the
nanoparticle water-soluble delivery technology provided one peak
consistent with mostly mucosal delivery, whereas 50% ethanol provided
two peaks and inconsistent serum levels [23], indicating inefficient
mucosal absorption with substantial swallowing of the medicine and less
effective gastrointestinal absorption. The NanoCelleTMdelivery platform also avoids the local and systemic adverse effects of
ethanol and propylene glycol [29].
There is significant interest in the use of cannabis for the management
of chronic cancer pain or non-cancer pain [30, 31] irrespective of
any adverse outcomes that have been reported. As yet, there is minimal
evidence on the prevalence or predictors for adverse events in people
administered cannabis [32]. In recreational users of cannabis,
coughing fits, anxiety and paranoia were the most common adverse
reactions [32]. In the clinical trial setting, oral,
gastrointestinal or sublingual administered cannabis, was associated
with nausea, fatigue, vertigo/hallucinations, diarrhoea, constipation
and dry mouth [11, 33-36]. In our study, the administration of a
nanoparticle water soluble cannabis-based medicine resulted in mild
drowsiness, fatigue, nausea and vomiting. Drug tolerability was
established at 2-8 sprays, namely 2.5 mg to 10 mg each of Δ9-THC and CBD
every 4 hours, which reported no evidence that the cannabis formulation
increased the risk of serious adverse events. An independent safety
monitoring panel concluded at the end of Stage I of this study, that
there were no safety issues that would impede continued development of
the study’s cannabis-based medicine. The oro-buccal delivered
cannabis-based medicine administered as a water-soluble nanoparticle is
of significant clinical interest given that this formulation was a
self-titrated medicine, that showed preliminary analgesic efficacy in a
subgroup of patients.
There are clearly however, limitations to this study. The sample was
small with an open label pilot design with no comparator that included
only patients with advanced cancer, with intractable pain unrelieved by
opioids. There was a substantial variation in eligible patient cancer
diagnoses that produced a largely heterogenous study group. Furthermore,
patients presented with multiple and overlapping types of pain.
In this cohort of patients with complex advanced cancers the adverse
events encountered were similar to those commonly reported from other
studies that have administered a cannabis-based medicine [37]; with
the most common being drowsiness, fogginess, fatigue, nausea and
vomiting. The level of emetogenicity in cancer varies based on different
factors and the incidence in this study was 36%. In 8 (32%) patients
that developed nausea, the causal attribution was probably / possible
associated with the administered cannabis-based medicine. In 6 (24%)
patients though, vomiting was concomitantly reported with nausea, with
one patient reporting persistent nausea and vomiting that interrupted
the further administration of the cannabis-based medicine.
Notwithstanding this study of single and multiple cannabis doses that
were oro-buccal administered, demonstrated an overall safety and
tolerance profile.
Various clinical investigations with administered cannabis-based
medicines via the gastrointestinal tract have reported limited
tolerability and efficacy in a variety of indications [38].
Furthermore, the frequency of delivery and the magnitude of exposure to
a drug can also influence the abuse potential and safety profile.
Numerous animal [39-41] and human studies [42-44] have reported
the synergistic analgesic effects of concomitant administration of
opioids and cannabinoids. In our study, patients reported significant
improvement in pain scores over the course of the intervention phase of
the study of approximately 12% (p=0.02). Notwithstanding, all patients
diagnosed with bone metastasis reported a significant reduction in pain
scores at the end of the treatment phase. In participants with a
diagnosis of metastatic breast and prostate cancers (only to bone) had a
highly significant reduction in pain scores (adjusted for rescue
medications) of 33% (unadjusted of 40%) during the escalation and
treatment phases (p<0.01) with minimal mean increases in MMeq
and rescue medications as compared to the cohort overall.
Although this SAD MAD study was not placebo controlled, the improvement
in pain was consistent with a recent systematic and meta-analysis that
concluded that cannabis-based medicines probably increase the number of
people achieving pain relief of 30% or greater compared with placebo.
The pain relief was reversed on cessation of administration of the
investigated medicine. In the metastatic breast and prostate cancer
group cessation of NanaBisTM use resulted in a
decrease in pain relief efficacy of 13%.
5 | Conclusions
This report described a single ascending dose / multiple ascending dose
of a water-soluble
Δ9-THC/CBD nanoparticle formulation administered to advanced cancer
patients with intractable pain as a co-analgesic. The oro-mucosal
administration of this formulation at doses from 2.5 mg to 10 mg per 4
hours of Δ9-THC and CBD (unless asleep) was found to be safe and
tolerable.
There was an overall significant improvement in average NPRS pain scores
over the study treatment period from baseline. There was however a
significant improvement in pain recorded over the treatment period for
all patients diagnosed with bone metastasis. The significant improvement
in average adjusted NPRS pain scores of 33% as recorded for an eligible
subgroup of participants with a diagnosis of breast and prostate cancers
with metastatic disease (only to bone). This may partly be due to the
superior delivery method that the NanoCelleTM platform
of the cannabis-based medicine provides, as well as the cancer pain
subgroup of metastatic bone pain.
Author Contributions: Conceptualisation, SC AJM, LV, SH;
methodology, SC, AJM, BB, LV; formal analysis, BB, LV, AJM;
investigation, SC; resources, SC, LV, SH; data curation, BB, AJM, LV;
writing—original draft preparation, LV, JDH, SH; writing—review and
editing, SC, LV, AJM, BB JDH, DR, SH.; project administration, LV, SH;
funding acquisition, SH. All authors have read and agreed to the
published version of the manuscript
Conflicts of Interest: JDH DR SH and LV are employed by Medlab
Clinical Australia and participate in its cannabis-based medicines
research program. BB is an independent statistician who was funded by
Medlab Clinical Ltd Australia to conduct the statistical analysis.
Acknowledgments: We acknowledge the assistance of Serena Dal
Forno RN, Jillian Bethwaite RN.
Funding: This research was funded by Medlab Clinical Ltd.
Australia.
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Table 1: Patient baseline demographic and clinical
characteristics for Stage I and Stage II.