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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 Δ(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.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.

    Source

    CNS neuroscience & therapeutics 21:3 2015 Mar pg 215-21

    MeSH

    Cannabidiol
    Clinical Trials as Topic
    Dronabinol
    Humans
    Multiple Sclerosis
    Muscle Spasticity
    Neuromuscular Agents
    Oral Sprays
    Placebo Effect

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Review

    Language

    eng

    PubMed ID

    25475413

    Citation

    Di Marzo, Vincenzo, and Diego Centonze. "Placebo Effects in a Multiple Sclerosis Spasticity Enriched Clinical Trial With the Oromucosal Cannabinoid Spray (THC/CBD): Dimension and Possible Causes." CNS Neuroscience & Therapeutics, vol. 21, no. 3, 2015, pp. 215-21.
    Di Marzo V, Centonze D. Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes. CNS Neurosci Ther. 2015;21(3):215-21.
    Di Marzo, V., & Centonze, D. (2015). Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes. CNS Neuroscience & Therapeutics, 21(3), pp. 215-21. doi:10.1111/cns.12358.
    Di Marzo V, Centonze D. Placebo Effects in a Multiple Sclerosis Spasticity Enriched Clinical Trial With the Oromucosal Cannabinoid Spray (THC/CBD): Dimension and Possible Causes. CNS Neurosci Ther. 2015;21(3):215-21. PubMed PMID: 25475413.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes. AU - Di Marzo,Vincenzo, AU - Centonze,Diego, Y1 - 2014/12/04/ PY - 2014/08/07/received PY - 2014/10/21/revised PY - 2014/10/22/accepted PY - 2014/12/6/entrez PY - 2014/12/6/pubmed PY - 2015/12/15/medline KW - Endocannabinoid system KW - Multiple sclerosis KW - Placebo KW - Spasticity KW - Δ9-tetrahydrocannabinol and cannabidiol SP - 215 EP - 21 JF - CNS neuroscience & therapeutics JO - CNS Neurosci Ther VL - 21 IS - 3 N2 - 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 Δ(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. SN - 1755-5949 UR - https://www.unboundmedicine.com/medline/citation/25475413/Placebo_effects_in_a_multiple_sclerosis_spasticity_enriched_clinical_trial_with_the_oromucosal_cannabinoid_spray__THC/CBD_:_dimension_and_possible_causes_ L2 - https://doi.org/10.1111/cns.12358 DB - PRIME DP - Unbound Medicine ER -