Cooperative Agreement to Support a Human Abuse Potential Study of Botanical Kratom (U01 Clinical Trial Required)

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An estimated 1.7 million Americans aged 12 and older used kratom in 2021, according to the Substance Abuse and Mental Health Services Administration’s National Survey on Drug Use and Health. FDA has warned consumers about the use of Kratom (Mitragyna speciosa), a plant indigenous to Southeast Asia. Kratom alkaloids have demonstrated both affinity and activity at mu opioid receptors, receptor sites known to be associated with abuse. Although Kratom use is prevalent, to date, clinical evaluations of abuse potential have not been performed. This research proposal describes a human abuse potential (HAP) study of botanical Kratom. This HAP study will help researchers, scientists, individuals using or considering the use of kratom, and the broader public health community because it will generate important findings related to the safety profile of kratom. The primary objective(s) of the HAP study are to characterize the abuse potential and subjective effects of botanical Kratom. Importantly, FDA currently has a pilot, dose-finding and safety study of botanical Kratom. The pilot study is expected to provide critical information for conducting the HAP study, including information on the Kratom dose, the botanical supply provider, and content for the Investigational New Drug (IND) application (e.g., safety information and chemistry manufacturing and controls (CMC) data). Interested parties are expected to be able to fulfill all the requirements of the IND submission. The study should adhere to the design principles outlined in the guidance for industry: "Assessment of Abuse Potential of Drugs." As described in the guidance, the study should be conducted in a human pharmacology laboratory and can be performed in either an inpatient or outpatient setting. On-site safety measures should be described in addition to subject discharge criteria. The HAP study should be performed in nondependent subjects with a history of recreational drug use, including opioids and botanical kratom. Applicants are expected to provide a statistical analysis plan including a power analysis to justify their proposed sample size. Typically, HAP studies consist of a screening phase, qualification phase, treatment phase, and follow-up visit. During the qualification phase, subjects are administered placebo and a dose of the positive control and evaluated using a bipolar drug liking visual analog scale (VAS) ranging from 0-100. During the qualification phase, the placebo response should be between 40-60 points while the positive control should produce a score outside of the placebo range and with a difference of at least 15 points greater than placebo. A naloxone challenge phase may be implemented prior to the qualification phase to rule out physical dependence. The treatment phase should be a within-subject, randomized, double-blind, placebo and active controlled study. Two to three doses of a positive control should be employed along with three doses of botanical Kratom to establish a dose-response curve. Selection of the doses of botanical Kratom and the positive control for the treatment phase can be made in conjunction with FDA utilizing data from FDA's pilot dose-ranging study of botanical Kratom. The oral route of administration (using encapsulated botanical Kratom) is expected for the HAP study. Appropriate washout period(s) should be used between sessions. Maximum response (i.e., Emax) on VAS assessments of "drug liking" should be the primary outcome measure. Other measures such as "high," "sedation," and willingness to take the drug again should also be assessed. Novel measures of reinforcement (e.g., behavioral economic measures and/or willingness to pay for drug) may be considered in consultation with FDA. Assessments should be performed at the appropriate timepoints after drug and Kratom administration (e.g., Tmax). Safety and physiological measurements (e.g., pupillometry) should also be implemented. The expected outcome from performing the HAP study is a detailed study report describing the methodology, conclusions, and interpretation of the HAP study results.