Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000383763
Ethics application status
Approved
Date submitted
12/11/2021
Date registered
4/03/2022
Date last updated
10/05/2024
Date data sharing statement initially provided
4/03/2022
Date results information initially provided
10/05/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot study of safety, tolerability and pharmacokinetics of cannabidiol therapy in symptomatic kidney failure
Scientific title
Systematic Evaluation of Interventions for Symptom Management In Chronic Kidney Disease – CannaBiDiol (SEISMIC-CBD)
Secondary ID [1] 305781 0
Nil known
Universal Trial Number (UTN)
U1111-1271-5512
Trial acronym
SEISMIC-CBD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic symptoms management in chronic kidney disease patients 324287 0
Condition category
Condition code
Renal and Urogenital 321779 321779 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 322179 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 329535 0
Safety: the number of adverse events (of any severity) occurring during the study period. This will be described as the number of events per participant and as the number of participants experiencing at least one adverse event. Adverse events will be categorised by their likely relationship to the study drug, with separate and combined analyses of both.
Timepoint [1] 329535 0
Safety events will be recorded from the first exposure to the investigational product until 28 days following discontinuation. All events will be recorded in the participant’s medical record and entered in the study’s electronic Case Report Form (eCRF), as per instructions in the Study Manual.


Primary outcome [2] 329773 0
Tolerability as indicated by the proportion of participants remaining on treatment at 42 days, this will be determined by telephone interview,
Timepoint [2] 329773 0
The number of participants remaining in the study at 42 days will be assessed.
Secondary outcome [1] 402905 0
Pharmacokinetics analysis will be performed using blood samples collected at day 42. The cannabinoids and metabolites include CBD, CBD, 6-hydroxy-cannabidiol (6-OH-CBD), 7-hydroxy-cannabidiol (7-OH-CBD), 7-carboxy-cannabidiol (7-COOH-CBD)
Timepoint [1] 402905 0
12 participants will have blood samples collected at day 42 for the pharmacokinetics analysis. Participants should be fasted from midnight the preceding evening. Baseline sample will be collected in the morning, prior to administration of any study product due that day. Participants will be allowed to eat and subsequent blood samples will be taken at 1, 2, 3, 4, 6 and 8-hour.
Secondary outcome [2] 407095 0
Edmonton Symptom Assessment System Revised: Renal (ESASr-Renal)
Timepoint [2] 407095 0
Patient reported outcome measure assess on weekly basis from baseline until Week 6. Repeat in Week 10.
Secondary outcome [3] 407096 0
EuroQOL-5 Dimensions (EQ-5D)
Timepoint [3] 407096 0
5-item health-related quality of life instrument asking respondents to report their health status at baseline, Day 21, Day 42 and Day 70.
Secondary outcome [4] 407097 0
Patient Global Impression of Change (PGIC)
Timepoint [4] 407097 0
Validated measure of the patient’s subjective view of their improvement, assess at Day 21 and Day 42
Secondary outcome [5] 407098 0
Patient experience interview
Timepoint [5] 407098 0
All participants will be asked to complete a semi-structured interview at Day 70

Eligibility
Key inclusion criteria
1. 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),
2. 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
3. Participant and treating clinician are willing to perform the study procedures.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Active on the kidney transplant waitlist
2. Taking a disqualifying concomitant medication that cannot be ceased during the study period.
3. 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.
4. 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.
5. Pregnant or breast-feeding
6. 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.
7. Unwilling or unable to follow study procedures
8. Unwilling or unable to refrain from driving within 24 hours of receiving THC wafer.
9. In the opinion of the treating investigator: death likely within three months
10. 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
28/02/2023
Actual
6/03/2023
Date of last participant enrolment
Anticipated
28/06/2024
Actual
23/01/2024
Date of last data collection
Anticipated
1/10/2024
Actual
4/04/2024
Sample size
Target
20
Accrual to date
Final
12
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 21095 0
St George Hospital - Kogarah
Recruitment postcode(s) [1] 35948 0
2217 - Kogarah

Funding & Sponsors
Funding source category [1] 310136 0
University
Name [1] 310136 0
University of Sydney
Country [1] 310136 0
Australia
Funding source category [2] 312765 0
Charities/Societies/Foundations
Name [2] 312765 0
Royal Australasian College of Physicians Foundation (Jacquot Scholarship Award)
Country [2] 312765 0
Australia
Funding source category [3] 312766 0
Commercial sector/Industry
Name [3] 312766 0
In-Kind Support form Ix BioPharma
Country [3] 312766 0
Australia
Funding source category [4] 312767 0
Charities/Societies/Foundations
Name [4] 312767 0
St George and Sutherland Medical Research Foundation
Country [4] 312767 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre, University of Sydney,
Medical Foundation Building
92-94 Parramatta Road, Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 311211 0
None
Name [1] 311211 0
Address [1] 311211 0
Country [1] 311211 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309826 0
South Eastern Sydney Local Health District Human Research Ethics Committee (SESLHD HREC)
Ethics committee address [1] 309826 0
District Executive Unit, Level4
The Sutherland Hospital & Community Health Service
Cnr The Kingsway & Kareena Road
Caringbah NSW 2229
Ethics committee country [1] 309826 0
Australia
Date submitted for ethics approval [1] 309826 0
16/02/2022
Approval date [1] 309826 0
24/02/2022
Ethics approval number [1] 309826 0
2021/ETH11655

Summary
Brief 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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 115518 0
Dr Brendan Smyth
Address 115518 0
Level 5, NHMRC Clinical Trials Centre, The University of Sydney, Medical Foundation Building
92-94 Parramatta Road, Camperdown NSW 2050
Country 115518 0
Australia
Phone 115518 0
+61 411770605
Fax 115518 0
Email 115518 0
brendan.smyth@sydney.edu.au
Contact person for public queries
Name 115519 0
Dr Dr Brendan Smyth/ Ms Aneeka Ratwatte
Address 115519 0
Level 6, NHMRC Clinical Trials Centre, The University of Sydney, Medical Foundation Building 92-94 Parramatta Road, Camperdown NSW 2050
Country 115519 0
Australia
Phone 115519 0
+612 8036 5200
Fax 115519 0
Email 115519 0
seismic-cbd.study@sydney.edu.au
Contact person for scientific queries
Name 115520 0
Dr Brendan Smyth
Address 115520 0
Level 6, NHMRC Clinical Trials Centre, The University of Sydney, Medical Foundation Building 92-94 Parramatta Road, Camperdown NSW 2050
Country 115520 0
Australia
Phone 115520 0
+61 2 8036 5202
Fax 115520 0
Email 115520 0
brendan.smyth@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.