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Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes.

ABSTRACT: Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long-term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash-out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with ?(9) -tetrahydrocannabinol and cannabidiol (THC/CBD) oromucosal spray in patients with multiple sclerosis (MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo-allocated patients. The overall mean therapeutic gain of THC/CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27-point improvement on the spasticity 0-10 Numerical Rating Scale (NRS; ~-20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid-based medications are being investigated.

SUBMITTER: Di Marzo V

PROVIDER: S-EPMC6495119 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes.

Di Marzo Vincenzo V Centonze Diego D

CNS neuroscience & therapeutics 20141204 3

Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long-term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash-out period, it is difficult to show further improvements and thus large therapeutic gains versus plac ...[more]

PMID: 25475413

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Project description:INTRODUCTION:Stroke is the most disabling neurological disorder and often causes spasticity. Transmucosal cannabinoids (tetrahydrocannabinol and cannabidiol (THC:CBD), Sativex) is currently available to treat spasticity-associated symptoms in patients with multiple sclerosis. Cannabinoids are being considered useful also in the treatment of pain, nausea and epilepsy, but may bear and increased risk for cardiovascular events. Spasticity is often assessed with subjective and clinical rating scales, which are unable to measure the increased excitability of the monosynaptic reflex, considered the hallmark of spasticity. The neurophysiological assessment of the stretch reflex provides a precise and objective method to measure spasticity. We propose a novel study to understand if Sativex could be useful in reducing spasticity in stroke survivors and investigating tolerability and safety by accurate cardiovascular monitoring. METHODS AND ANALYSIS:We will recruit 50 patients with spasticity following stroke to take THC:CBD in a double-blind placebo-controlled cross-over study. Spasticity will be assessed with a numeric rating scale for spasticity, the modified Ashworth scale and with the electromyographical recording of the stretch reflex. The cardiovascular risk will be assessed prior to inclusion. Blood pressure, heart rate, number of daily spasms, bladder function, sleep disruption and adverse events will be monitored throughout the study. A mixed-model analysis of variance will be used to compare the stretch reflex amplitude between the time points; semiquantitative measures will be compared using the Mann-Whitney test (THC:CBD vs placebo) and Wilcoxon test (baseline vs treatment). ETHICS AND DISSEMINATION:The study was registered on the EudraCT database with number 2016-001034-10 and approved by both the Italian Medicines Agency (Agenzia Italiana del Farmaco) and local Ethics Committee 'Comitato Etico Regionale della Liguria'. Data will be made anonymous and uploaded to a open access repository. Results will be disseminated by presentations at national and international conferences and by publication in journals of clinical neuroscience and neurology.

Project description:ABSTRACT:This Phase I study aimed to assess the potential drug-drug interactions (pharmacokinetic [PK] and safety profile) of ?9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex (®), nabiximols) in combination with cytochrome P450 (CYP450) inducer (rifampicin) or inhibitors (ketoconazole or omeprazole). Thirty-six healthy male subjects were divided into three groups of 12, and then randomized to one of two treatment sequences per group. Subjects received four sprays of THC/CBD (10.8/10 mg) alongside single doses of the CYP3A and 2C19 inducer rifampicin (600 mg), CYP3A inhibitor ketoconazole (400 mg) or CYP2C19 inhibitor omeprazole (40 mg). Plasma samples were analyzed for CBD, THC and its metabolite 11-hydroxy-THC (11-OH-THC). A single dose of four sprays of THC/CBD spray (10.8/10 mg) following repeated doses of rifampicin (600 mg) reduced the Cmax and AUC of all analytes. Cmax reduced from 2.94 to 1.88 ng/mL (-36%), 1.03 to 0.50 ng/mL (-52%) and 3.38 to 0.45 ng/mL (-87%) for THC, CBD and 11-OH-THC, respectively compared to single dose administration of THC/CBD spray alone. Ketoconazole co-administration with THC/CBD spray had the opposite effect, increasing the Cmax of the respective analytes from 2.65 to 3.36 ng/mL (+27%), 0.66 to 1.25 ng/mL (+89%) and 3.59 to 10.92 ng/mL (+204%). No significant deviations in Cmax or AUC for any analyte were observed when THC/CBD spray was co-administered with omeprazole. THC/CBD spray was well tolerated by the study subjects both alone and in combination with rifampicin, ketoconazole and omeprazole. Evaluation of the PKs of THC/CBD spray alone and in combination with CYP450 inhibitors/inducers suggests that all analytes are substrates for the isoenzyme CYP3A4, but not CYP2C19. On the basis of our findings, there is likely to be little impact on other drugs metabolized by CYP enzymes on the PK parameters of THC/CBD spray, but potential effects should be taken into consideration when co-administering THC/CBD spray with compounds which share the CYP3A4 pathway such as rifampicin or ketoconazole. TRIALS REGISTRATION:NCT01323465.

Project description:BackgroundTreatment of spasticity poses a major challenge in amyotrophic lateral sclerosis (ALS) patient management. Delta-9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (THC:CBD), approved for the treatment of spasticity in multiple sclerosis, serves as a complementary off-label treatment option in ALS-related spasticity. However, few structured data are available on THC:CBD in the treatment of spasticity in ALS.MethodA retrospective mono-centric cohort study was realised in 32 patients that meet the following criteria: 1) diagnosis of ALS, 2) ALS-related spasticity; 3) treatment with THC:CBD. Spasticity was rated using the Numeric Rating Scale (NRS). Patient's experience with THC:CBD was assessed using the net promoter score (NPS) and treatment satisfaction questionnaire for medication (TSMQ-9) as captured through telephone survey or online assessment.ResultsThe mean dose THC:CBD were 5.5 daily actuations (range?<?1 to 20). Three subgroups of patients were identified: 1) high-dose daily use (? 7 daily actuations, 34%, n?=?11), 2) low-dose daily use (<?7 daily actuations, 50%, n?=?16), 3) infrequent use (<?1 daily actuation, 16%, n?=?5). Overall NPS was +?4.9 (values above 0 express a positive recommendation to fellow patients). Remarkably, patients with moderate to severe spasticity (NRS???4) reported a high recommendation rate (NPS: +?29) in contrast to patients with mild spasticity (NRS?<?4; NPS: -?44). For the three main domains of TSQM-9 high mean satisfaction levels were found (maximum value 100): effectiveness 70.5 (±22.3), convenience 76.6 (±23.3) and global satisfaction 75.0 (±24.7).ConclusionTHC:CBD is used in a wide dose range suggesting that the drug was applied on the basis of individual patients' needs and preferences. Contributing to this notion, moderate to severe spasticity was associated with an elevated number of daily THC:CBD actuations and stronger recommendation rate (NPS) as compared to patients with mild spasticity. Overall, treatment satisfaction (TSQM-9) was high. The results suggest that THC:CBD may serve as a valuable addition in the spectrum of symptomatic therapy in ALS. However, prospective studies and head-to-head comparisons to other spasticity medications are of interest to further explore the effectiveness of THC:CBD in the management of spasticity, and other ALS-related symptoms.

Project description:IntroductionChemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV.Methods and analysisThe current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5?mg) capsules or placebo capsules three times a day on day -1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day -1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients.Ethics and disseminationThe protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.Drug supplyTilray.Protocol version2.0, 9 June 2017.Trial registration numberANZCTR12616001036404; Pre-results.

Dataset Information

Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes.

Publications

Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes.

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