Newest Evidence for Tetrahydrocannabinol:Cannabidiol Oromucosal Spray From Postapproval Pragmatic Studies

Abstract

Postapproval studies have an essential role in demonstrating that an intervention is effective and well tolerated during use in daily clinical practice. Numerous large observational and registry studies of tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray have been conducted subsequent to its approval in Europe in 2011. Collectively, these studies provide valuable insight into various aspects of THC:CBD spray during real-world use in patients with multiple sclerosis spasticity, including its long-term effectiveness and tolerability. The Italian Medicines Agency’s web-based registry is the largest observational study of THC:CBD oromucosal spray conducted to date, reporting on more than 1600 patients prescribed THC:CBD spray since it was introduced in Italy in 2013, and further supporting its effectiveness and tolerability profile.

Keywords: :

• multiple sclerosis spasticity
• pragmatic studies
• THC:CBD oromucosal spray

Italian Medicines Agency-ruled web-based e-registry study

The Italian Medicines Agency’s (L’Agenzia Italiana del Farmaco; [AIFA]) web-based e-registry is compulsory for all patients receiving a prescription for tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray in Italy. In order to prescribe THC:CBD oromucosal spray, physicians must complete a web form which ensures that a candidate patient meets the selection criteria as per the approved label: multiple sclerosis (MS) spasticity of at least moderate intensity (Numerical Rating Scale [NRS] score ≥4) and inadequate response to current and ongoing antispasticity medications (e.g., baclofen, tizanidine and others) [1]. Patients with a history of cardiovascular disease or psychiatric disorders, those who are pregnant or planning to become pregnant, or those who are receiving treatment with psychoactive drugs are excluded from prescription. The AIFA e-registry website prospectively collects and stores effectiveness, tolerability and safety data on THC:CBD oromucosal spray for all prescribed patients throughout treatment.

Approximately 18 months after the e-registry was introduced, an independent coordination was organized of 30 large specialized MS centers located across Italy [2]. The aim was to aggregate a large amount of data for analysis in order to facilitate a comprehensive overview of the effect of THC:CBD oromucosal spray in daily practice and minimize biases. The primary outcome measure of interest was evolution in spasticity severity on the 0–10 NRS from baseline to the end of the first month of treatment (trial period), and 3- and 6-month control visits. Other outcomes of interest were reasons for treatment discontinuation, tolerability and daily dose of THC:CBD oromucosal spray. Complementary demographic and clinical information was acquired by retrospective review of patients’ medical charts and patient interview and was entered and stored in a purpose-built ad hoc database.

At the time of analysis, data were available for 1615 patients with MS spasticity who had started treatment with THC:CBD oromucosal spray between 1 January 2014 and 28 February 2015. Mean age of the population was 51 ± 9.5 years and there was a slight female preponderance (52.6%). On average, patients had a long history of disease (mean duration 17.5 ± 8.6 years), significant disability (mean Expanded Disability Status Scale score 6.5 [range: 1.5–9.5]) and severe MS spasticity (mean NRS score 7.5 ± 1.4).

Of 1615 prescribed patients, 1432 (88.7% of the baseline population) reached the end of the first month trial period and were eligible for the early response effectiveness evaluation. Main reasons for exclusion from this analysis were: missing NRS data at baseline (n = 18), discontinued treatment (n = 9), data not available (n = 14) and lost to follow-up (n = 60). At 3 and 6 months after initial prescription of THC:CBD oromucosal spray, 889 patients (55.6%) and 593 patients (37.1%) were eligible for the respective effectiveness evaluations. Main reasons for exclusion from these analyses were: pending clinic visits (164 and 218 patients, respectively) or treatment discontinuation (374 and 76 patients, respectively). Overall, 631 patients (39.5%) discontinued treatment with THC:CBD oromucosal spray during the observation period.

The evolution in MS spasticity severity is shown in Figure 1. At the end of the 4-week trial period, the mean 0–10 NRS score in evaluable patients (n = 1432) decreased from 7.5 at baseline to 5.8, representing a 22.6% improvement. Of these patients, 1010 (62.5% of the baseline population) showed a minimal clinically important difference of ≥20% NRS improvement and 405 (25.1%) had achieved a clinically important difference of ≥30% NRS improvement (Figure 1A). The results were confirmed at the 6-month effectiveness evaluation. Among 593 evaluable patients, the mean 0–10 NRS score was 35.1% lower compared with baseline (from 7.4 to 4.8). In the subgroup with a clinically relevant response to THC:CBD oromucosal spray (n = 252), mean NRS reduction from baseline was 43.4% (from 7.6 to 4.3) (Figure 1B).

Kaplan–Meier survival estimates of time to treatment discontinuation showed that 26.4% (n = 422) of prescribed patients had ended treatment with THC:CBD spray by 6 weeks, with most discontinuations (20.8%; n = 333) occurring within the first 2–4 weeks of treatment [3]. After 6 weeks, most remaining patients continued with treatment (Figure 2).

With regard to tolerability, 18.7% of patients discontinued treatment during the trial period because of adverse events (AEs). AEs reported during this phase were mostly mild to moderate in intensity and transient. The most common AEs (i.e., those with an incidence ≥2.0%) were psychiatric symptoms, fatigue, drowsiness and dizziness (Table 1). Of five serious AEs (0.3% incidence), which comprised two cancer events, and one event each of hypotensive crisis, renal failure and myocardial infarction, none was considered to be treatment related.

Table 1. Adverse events leading to discontinuation of tetrahydrocannabinol:cannabidiol oromucosal spray among L’Agenzia Italiana del Farmaco-ruled e-registry patients who completed the trial period (n = 1432).

Adverse event	n (%)
Cognitive disturbances	9 (0.6)
Psychiatric symptoms	46 (3.2)
Fatigue	36 (2.5)
Drowsiness	32 (2.2)
Dizziness	30 (2.0)
Gastrointestinal symptoms	21 (1.4)
Mouth discomfort	10 (0.7)
Allergic reaction	2 (0.2)
Other neurological symptoms	16 (1.2)
Not available	100 (7.0)

Reproduced with permission from [2].

The mean dose of THC:CBD oromucosal spray was consistently between 6 and 7 sprays/day at all evaluation timepoints (1, 3 and 6 months) indicating no abuse, and an individualized dosing approach was observed. Meaningful MS spasticity NRS reduction occurred soon after treatment initiation and, in treatment responders, was maintained over time despite a lower mean dose of THC:CBD oromucosal spray and greater dose flexibility relative to that in the pivotal Phase III trial [4].

The findings of this e-registry study are particularly relevant in view of the significant level of baseline impairment in the patient cohort as regards disease history, disability (Expanded Disability Status Scale) and MS spasticity severity (NRS).

Figure 1. Mean 0–10 numerical rating scale score evolution from baseline to:

(A) end of trial period (T1) and (B) 6 months of treatment (T3) with THC:CBD oromucosal spray. ^†73% of 811 patients with the possibility of reaching the T3 visit on the analysis date.

Reproduced with permission from [2].

Figure 2. Kaplan–Meier survival estimate of time to treatment failure with tetrahydrocannabinol:cannabidiol oromucosal spray in the Italian Medicine Agency’s web-based e-registry study.

Reproduced with permission from [3].

Clinical interpretation

Numerous observational and registry studies of THC:CBD oromucosal spray have been conducted since its approval in Europe in 2011 (Table 2) [2,5–14]. Of these, the AIFA-ruled web-based e-registry is the largest observational study of THC:CBD oromucosal spray to date, reporting on more than 1600 patients prescribed the medication since it was introduced in Italy in 2013 [2].

Table 2. Key features of observational and registry studies of tetrahydrocannabinol:cannabidiol oromucosal spray.

Year of publication	Study title	Sample	Design	Duration	Country	Status	Ref.
2013	Survey of activities of daily living	159	Retrospective	1 year	UK	Completed	[5]
2013	Long-term follow-up	146	Prospective	1 year	UK	Completed	[6]
2013	Spanish registry	207	Prospective	1 year	Spain	Completed	[7]
2014	MOVE 2 Germany	355	Prospective	3 months	Germany	Completed	[8]
2015	Driving ability	33	Prospective	1 month	Germany	Completed	[9]
2015	Spasticity and mobility	20	Prospective	1 month	Italy	Completed	[10]
2016	MOVE 2 Italy	433	Prospective	3 months	Italy	Completed	[11]
2016	UK and German registries	941	Retrospective	>2 years	UK and Germany	Completed	[12]
2016	Italian registry	1615	Prospective	6 months	Italy	Ongoing	[2]
2017	Muscle ultrasonography	55	Prospective	1 month	Italy	Part 2 ongoing	[13]
2018	TASTE	52	Prospective	1 month	Italy	Completed	[14]
TOTAL:		4016

The AIFA e-registry confirms and extends the results reported previously with THC:CBD oromucosal spray in observational studies [8,11] and registry studies [7,12], permitting some general conclusions to be drawn. THC:CBD oromucosal spray is effective and well tolerated in managing resistant MS spasticity in daily clinical practice, including patients with a long disease history and severe baseline MS spasticity. As such, THC:CBD oromucosal spray addresses an unmet need in a relevant proportion of the MS population. Careful adherence to the trial period is useful to identify patients with a meaningful initial response to treatment. Patients with insufficient benefit and/or poor tolerability to THC:CBD oromucosal spray typically discontinue treatment within the first few weeks, limiting exposure to those patients most likely to benefit. Accumulating experience with THC:CBD oromucosal spray in daily practice suggests that, on average, a dose of 6–7 sprays/day provides effective symptomatic relief of MS spasticity. THC:CBD oromucosal spray has a solid tolerability profile in both the short and long term. Throughout an estimated 100,000 patient-years of exposure to THC:CBD oromucosal spray worldwide (as at October 2018), no new safety concerns have been reported beyond its known safety profile and no risks related to use of herbal cannabis (e.g., abuse, diversion) have emerged. Thus, patients with moderate-to-severe resistant MS spasticity who respond to, and are able to tolerate, THC:CBD oromucosal spray can expect to experience clinically relevant and prolonged symptomatic relief of MS spasticity. As the AIFA e-registry is ongoing, the next analysis is expected to report on approximately 1000 patients in Italy who will have reached 18 months of treatment with THC:CBD oromucosal spray.

Acknowledgments

The article is based on a symposium presented at ECTRIMS 2018 in Berlin, Germany.

Financial & competing interests disclosure

F Patti has received funds/fees for speaking and advisory board activities from Almirall, Bayer, Biogen, Merck Serono, Novartis, Sanofi-Genzyme and Teva; has received research grants from the Italian MS Foundation (FISM), Italian Ministry of Research and University (MIUR) and University of Catania. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was provided by Content Ed Net (Madrid, Spain) with funding from Almirall SA (Barcelona, Spain).