Single Ascending Doses of Kratom in Healthy Nondependent Adults With Opioid Experience

Study Overview
=================
Brief Summary
-----------------
Kratom (Mitragyna speciosa) is a plant often used to self-treat conditions such as pain, coughing, diarrhea, anxiety and depression, opioid use disorder, and opioid withdrawal. Due to limited data availability, the goal of this clinical trial is to learn about safety, pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body) of Kratom in adult recreational polydrug users with opioid experience.

Detailed Description
-----------------
This is a phase I, single-dose, randomized, adaptive, double-blind, placebo-controlled, single ascending dose (SAD), sequential group study in adult recreational polydrug users with opioid experience performed at a single study center. This study will consist of five cohorts. Forty subjects are planned to participate. Eight subjects will participate in each cohort. Within each cohort, 6 subjects will be randomized to receive Kratom and 2 subjects will be randomized to receive placebo. Each subject will be involved in the study for up to approximately 37 days (including screening).

Official Title
-----------------
Adaptive Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Single Ascending Doses of Kratom in Healthy, Nondependent, Adult Recreational Polydrug Users With Opioid Experience

Conditions
-----------------
Safety, Pharmacokinetics, Pharmacodynamics

Intervention / Treatment
-----------------
* Drug: Kratom
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of signed and dated informed consent form (ICF) Stated willingness to comply with all study procedures and availability for the duration of the study Healthy adult male or female Current nondependent, polydrug recreational user who has used opioid drugs for recreational (nontherapeutic) purposes (i.e., for psychoactive effects) and has a history of recreational use of at least 2 or more of any of the perception-altering (e.g., lysergic acid diethylamide [LSD], kratom, cannabis, dronabinol, ketamine, phencyclidine [PCP], dextromethorphan, 3,4 methylenedioxymethamphetamine [MDMA], mescaline, psilocybin, tryptamine derivatives or ring-substituted amphetamines with perception altering effects) or stimulant (e.g., cocaine, amphetamine, methamphetamine, methylphenidate, methcathinone, and other synthetic cathinones) drugs If male, meets one of the following criteria: Is able to procreate and agrees to use one of the accepted contraceptive regimens and not to donate sperm from study drug administration to at least 90 days after study drug administration. An acceptable method of contraception includes one of the following: Abstinence from heterosexual intercourse Double-barrier method (e.g., male condom with spermicide or male condom with a vaginal spermicide [gel, foam, or suppository]) Or Is unable to procreate; defined as surgically sterile (i.e., has undergone a vasectomy at least 180 days prior to study drug administration) If female, meets one of the following criteria: Is of childbearing potential and agrees to use an acceptable contraceptive method. Acceptable contraceptive methods include: a1. Abstinence from heterosexual intercourse from the Screening visit through to at least 30 days after study drug administration a2. One of the following contraceptive methods, used from at least 28 days prior to the Screening visit through to at least 30 days after study drug administration: Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal birth control products, or transdermal patch) Intrauterine device (with or without hormones) Male partner vasectomized at least 6 months prior to the Screening visit a3. One of the following double-barrier contraceptive methods, used from the Screening visit through to at least 30 days study drug administration: Male condom plus spermicide Diaphragm plus spermicide Cervical cap plus spermicide Is of non-childbearing potential, defined as surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation), or is in a postmenopausal state (i.e., at least 1 year without menses without an alternative medical condition prior to the Screening visit and follicle stimulating hormone levels ≥ 40 mIU/mL at Screening) Body mass index (BMI) within 18.0 kg/m2 to 34.0 kg/m2, inclusively at Screening Minimum weight of 50.0 kg at Screening Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination (including vital signs, oxygen saturation [SpO2], and respiratory rate) and/or ECG, as determined by an Investigator Exclusion Criteria: Difficulty swallowing capsules Female who is lactating Female who is pregnant according to the pregnancy test at Screening or prior to study drug administration Male with female partner who is pregnant, lactating, or planning to become pregnant during this study or within 90 days after study drug administration History of significant hypersensitivity to kratom or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs Presence or history of significant gastrointestinal, liver or kidney disease, or surgery that may affect drug bioavailability with the exception of cholecystectomy that is permitted at the discretion of an Investigator History of significant hepatic, renal, cardiovascular, pulmonary, hematologic, neurological, psychiatric, gastrointestinal, endocrine, immunologic, ophthalmologic, or dermatologic disease Presence of any significant respiratory illness or presence or history of chronic respiratory disease (e.g., upper respiratory illness, sleep apnea, emphysema, asthma) at Screening (subjects with acute respiratory illness may be rescheduled upon resolution at the discretion of an Investigator) History of substance or alcohol moderate to severe use disorder (excluding nicotine and caffeine) within the past 2 years, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) Is a heavy smoker (> 20 cigarettes per day) and/or is unable to abstain from smoking or unable to abstain from the use of prohibited nicotine-containing products for at least 1 hour before and 8 hours after study drug administration (including e-cigarettes, pipes, cigars, chewing tobacco, nicotine topical patches, nicotine gum, or nicotine lozenges) Regularly consumes excessive amounts of caffeine or xanthines, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day History of suicidal behavior within 2 years of Screening, showing suicidal tendency as per the C-SSRS administered at Screening, or is currently at risk of suicide in the opinion of an Investigator Presence of clinically significant ECG abnormalities at the Screening visit, as defined by medical judgment. Note: QT corrected according to Fridericia's formula (QTcF) interval of > 450 msec in male subjects or > 470 msec in female subjects will be exclusionary. The ECG may be repeated once for confirmatory purposes if the initial value obtained exceeds the limits specified. Estimated glomerular filtration rate (eGFR) ≤ 60 mL/min as calculated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation Any clinically significant illness in the 28 days prior to study drug administration Use of any prescription drugs (with the exception of hormonal contraceptives or hormone replacement therapy) in the 28 days prior to study drug administration, that in the opinion of an Investigator would put into question the status of the participant as healthy Use of St. John's wort in the 28 days prior to study drug administration Positive test result for alcohol and/or drugs of abuse at admission (prior to study drug administration). Subjects with positive results at admission may be rescheduled at the discretion of an Investigator. If tetrahydrocannabinol (THC) is positive at admission a cannabis intoxication evaluation will be done by an Investigator and subjects may be permitted to continue in the study at the discretion of an Investigator. Other positive test results should be reviewed to determine if the subject may be rescheduled, in the opinion of the investigator. Positive screening results to HIV Ag/Ab combo, hepatitis B surface antigen or hepatitis C virus tests Any other clinically significant abnormalities in laboratory test results at Screening that would, in the opinion of an Investigator, increase the subject's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data Inclusion in a previous group for this clinical study Intake of kratom in the 14 days prior to study drug administration Intake of an Investigational Product (IP) in the 28 days prior to study drug administration Donation of plasma in the 7 days prior to study drug administration Donation of 1 unit of blood to American Red Cross or equivalent organization or donation of over 500 mL of blood in the 56 days prior to study drug administration Subject cannot eat dairy and/or is lactose intolerant Is, in the opinion of an Investigator or designee, considered unsuitable or unlikely to comply with the study protocol for any reason

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1, 1 g of Kratom<br>A total of 6 subjects will receive an oral single dose administration of the active product | Drug: Kratom<br>* Single administration thirty minutes after the start of a high-fat breakfast<br>|
| Experimental: Cohort 2, 2 g of Kratom<br>A total of 6 subjects will receive an oral single dose administration of the active product | Drug: Kratom<br>* Single administration thirty minutes after the start of a high-fat breakfast<br>|
| Experimental: Cohort 3, 4 g of Kratom<br>A total of 6 subjects will receive an oral single dose administration of the active product | Drug: Kratom<br>* Single administration thirty minutes after the start of a high-fat breakfast<br>|
| Experimental: Cohort 4, 6 g of Kratom<br>A total of 6 subjects will receive an oral single dose administration of the active product | Drug: Kratom<br>* Single administration thirty minutes after the start of a high-fat breakfast<br>|
| Experimental: Cohort 5, 8 g of Kratom<br>A total of 6 subjects will receive an oral single dose administration of the active product | Drug: Kratom<br>* Single administration thirty minutes after the start of a high-fat breakfast<br>|
| Placebo Comparator: Placebo<br>A total of 2 subjects per cohort will receive an oral single dose administration of placebo | Drug: Placebo<br>* Single administration thirty minutes after the start of a high-fat breakfast<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | For purposes of monitoring safety, treatment-emergent adverse events (AEs) will be graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. | Day 1 through Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration | Cmax (ng/mL) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | 
| Time of maximum observed concentration | Tmax (hours) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | 
| Area under the concentration time curve from time zero to the time of last quantifiable concentration (AUC0-T) | AUC0-T (ng*h/mL) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | 
| Area under the concentration time curve extrapolated to infinity | AUC0-inf (ng*h/mL) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | 
| Dose-normalized Cmax calculated at Cmax / Dose | Cmax/D (ng/mL/mg) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | 
| Dose-normalized AUC0-T calculated as AUC0-T / Dose | AUC0-T/D (ng*h/mL/mg) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | 
| Dose-normalized AUC0-inf calculated as AUC0-inf / Dose | AUC0-inf/D (ng*h/mL/mg) will be evaluated for: mitragynine, 7 hydroxy-mitragynine, paynantheine, speciogynine, and speciociliatine | 0, 0.25, 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 hours post-dose | 
| Maximum effect for Drug Liking | Maximum (peak) effect (Emax) for Drug Liking assessed on a bipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as strong disliking (score = 0), neither like nor dislike (score = 50) to strong liking (score = 100). | 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose | 
| Maximum effect for Overall Drug Liking | Maximum (peak) effect (Emax) for Overall Drug Liking assessed on a bipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as strong disliking (score = 0), neither like nor dislike (score = 50) to strong liking (score = 100). | 12 and 24 hours postdose | 
| Maximum effect for Take Drug Again | Maximum (peak) effect (Emax) for Take Drug Again assessed on a bipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as definitely would not (score = 0), neither would nor would not (score = 50) to definitely would (score = 100). | 12 and 24 hours postdose | 
| Maximum effect for High | Maximum (peak) effect (Emax) for High assessed on an unipolar (0 to 100 points) visual analog scale (VAS). Anchors will be presented using text such as not at all (score = 0) to extremely (score = 100). | Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Kratom, Mitragynine, Botanical substance, Single Ascending Dose