A pilot study of safety, tolerability and pharmacokinetics of cannabidiol therapy in symptomatic kidney failure
Systematic Evaluation of Interventions for Symptom Management In Chronic Kidney Disease – CannaBiDiol (SEISMIC-CBD)
University of Sydney
20 participants
Mar 6, 2023
Interventional
Conditions
Summary
People with kidney failure suffer a variety of symptoms and poor quality of life. Common symptoms include pain, itch, nausea, anorexia, restless legs, difficulty sleeping and fatigue. There are few treatments available, and many symptoms do not respond or go untreated. Cannabinoids, derived from cannabis, have a wide range of therapeutic effects, including showing promise as treatments for pain, itch, and nausea. This makes them promising treatments for some symptoms of kidney failure. Also, cannabinoids are predominantly hepatically metabolized, with the limited available data suggesting their pharmacokinetics may not be substantially affected by reduced kidney function. However, no studies testing these agents in people with kidney failure have been published. The two best studied, and most widely used cannabinoids are tetrahydrocannabinol (THC), which has psychoactive and muscle relaxing actions and may also be analgesic and antiemetic, and cannabidiol (CBD), which has anti-convulsant, anti-inflammatory, and anxiolytic actions. CBD is typically better tolerated and minimises the potentially adverse psychoactive actions of THC. Combined formulations of the two cannabinoids are common in clinical practice. Before embarking on studies of the efficacy of cannabinoids on symptoms in people with kidney failure it is important to first show that they are safe and well tolerated. Hence, the aim of the present study is to determine the safety and tolerability, and pharmacokinetic parameters of cannabinoids in people with kidney failure. The staggered initiation of CBD, is designed to permit assessment of the safety and tolerability of CBD alone, in a manner that minimises the potential for adverse effects in this vulnerable population. The experience gained with this canabidiol will inform the design of future studies.
Eligibility
Inclusion Criteria6
- Adults greater than or equal to 18 years with kidney failure as defined by:
- a. eGFR less than or equal to 15ml/min/1.73m2 (measured by Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] equation) on at least two blood tests within the past three (3) months
- OR
- b. receiving maintenance dialysis (haemodialysis or peritoneal dialysis),
- A score of greater than or equal to 4 on at least one of the following domains of ESASr-Renal: pain, nausea, lack of appetite, itching, problem sleeping, restless legs, tiredness, and
- Participant and treating clinician are willing to perform the study procedures.
Exclusion Criteria15
- Active on the kidney transplant waitlist
- Taking a disqualifying concomitant medication that cannot be ceased during the study period.
- Use of recreational or prescribed cannabis products in the past 4 weeks and unwilling to refrain from using such products for the duration of the present study.
- Unstable mood disorder. Defined as commencing therapy for depression or anxiety (pharmacotherapy or non-pharmacotherapy) within the past 3 months, or in the opinion of the investigator.
- Pregnant or breast-feeding
- Significant hepatic disease, defined as either of the following
- a. Known or suspected cirrhosis (of any degree)
- b. Elevated liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or gamma-glutamyl transferase [GGT]) more than 2x the upper limit of normal on blood tests taken within 3 months of the date of screening.
- Unwilling or unable to follow study procedures
- Unwilling or unable to refrain from driving within 24 hours of receiving THC wafer.
- In the opinion of the treating investigator: death likely within three months
- Taking clopidogrel AND meeting at least ONE of the following conditions in the past (6) months:
- a. Placement of a coronary artery stent
- b. Acute myocardial infarction
- c. Cerebrovascular accident
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Interventions
Participants will be treated with CBD for a total of six (6) weeks. The CBD wafer is commenced from baseline and administered in a participant-led supervised dose escalation phase for the first two (2) weeks. The participants increase the dose until they achieve either a satisfactory degree of relief of symptoms or dose-limiting side effects. This is followed by stable dosing of CBD for a further four (4) weeks (although dose changes are permitted for any reason). Starting dose of CBD - 25mg Increment by which participants can up or down-titrate - 50mg Maximum dose of CBD that participant may self-administer - 300mg Participants may choose not to increase the dose at any point. Decreasing doses is also permitted. Participants will be informed that they may take supplemental doses or increase the dose more rapidly if they wish. It is anticipated that most participants will not reach the highest doses in this schedule. Single doses of 200mg CBD have been given to individuals with eGFR < 30ml/min/1.73m2 (Tayo et al., 2020) and doses up to 6000mg CBD to individuals with normal kidney function (Taylor et al., 2018) with no or few ill effects. Dose titration will occur in weeks 1-2. This is participant-driven, with participants able to increase (or decrease) their doses at their own discretion. They will be advised to gradually escalate the dose until satisfactory relief of symptoms is achieved, and to reduce the dose if side-effects emerge. Participants will record their intake in participant diary. Study staff will be in contact with the patients at least twice per week during these periods, with additional contact to be made if the investigator deems it necessary. Dosing schedule as a guide to dose escalation will be provided to participants. At the end of the study, any unused IMP will be returned and remaining content will be counted so as to allow assessment of adherence to the dosing regimen. This will also allow safe and appropriate destruction.
Locations(1)
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ACTRN12622000383763