Chronic Effects of Effective Oral Cannabidiol Delivery on 24-h Ambulatory Blood Pressure and Vascular Outcomes in Treated and Untreated Hypertension (HYPER-H21-4): Study Protocol for a Randomized, Placebo-Controlled, and Crossover Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Setting
2.2. Eligibility Criteria
2.2.1. Inclusion Criteria
- Documented or measured elevated blood pressure (130/80 to 139/80 mmHg), mild (stage 1) hypertension (140/90 to 159/99 mmHg), or moderate (stage 2) hypertension (160/100 to 179/109 mmHg)
- o
- At least 30 antihypertensive drug-naïve subjects
- o
- At least 30 subjects treated with (1) angiotensin converting enzyme (ACE) inhibitors with or without diuretics or (2) ACE inhibitors with calcium channel blocker with or without diuretics
- Normal or overweight (body mass index 18.5 to <30.0 kg/m2)
- Between the ages of 40–70 years of age
- Post-menopausal women (at least 24 consecutive months in the absence of medications known to induce amenorrhea)
- Undergoing <150 min of moderate-to-vigorous activity per week
- Heterosexually active female subjects of reproductive potential must be on contraception management using at least one of the following methods while taking study drug and for 30 days following the last dose of study drug:
- o
- Barrier method of contraception [condoms (male or female), diaphragm, or cervical cap with spermicide
- o
- Intrauterine device (IUD)
- o
- Hormone-based oral, injectable, or implantable contraceptive
- o
- Bilateral tubal ligation/cauterization
- o
- Surgically sterile (hysterectomy or bilateral oophorectomy) or vasectomized male partner
2.2.2. Exclusion Criteria
- Current smoker or using vapor-based products; or a medical or recreational cannabis user
- Secondary hypertension
- Active malignant disease
- Gout
- History of psychosis and/or depression and/or clinically diagnosed anxiety
- Chronic kidney disease
- Chronic gastrointestinal disease (e.g., irritable bowel syndrome, celiac disease, inflammatory bowel disease, chronic diarrhea) or has had a cholecystectomy in the past
- Current diagnosis or history of any seizure disorder
- Heart failure
- Diabetes mellitus
- Pregnant, breast feeding, or plan to become pregnant
- History of opioid use
- Dual blood pressure therapy other than ACE inhibitors with diuretic or ACE inhibitors with Calcium Channel blocker with or without diuretics (e.g., ACE inhibitors with beta blockers)
- Unwilling or unable to execute the informed consent documentation
- Liver disease, including taking valproate, confirmed on baseline blood biochemistry—exclusion of subjects that have >1.5 upper limit of normal (ULN) for alanine transaminase (ALT) or aspartate transaminase (AST), total bilirubin (TBL) > ULN at baseline determined by local reference population values in Croatia:
- o
- ULN for ALT 48 IU/L
- o
- ULN for AST 38 IU/L
- o
- ULN for TBL 20 μmol/L
- ALT or AST > 3x ULN accompanied by fever, rash, fatigue, nausea, vomiting, right upper quadrant pain or tenderness, and/or eosinophilia (>5%)
- ALT or AST > 5x ULN
- ALT or AST > 3x ULN and TBL > 2x baseline
2.3. Study Arms and Interventions
2.4. Outcome Measures
- Cannabidiol levels in peripheral blood sample.
- Safety (via blood biomarkers, #8 and tolerability (via adverse event reporting).
- Calories burned, total sleep time, number of awakenings—Physical activity and sleep quality (actigraphy) will be monitored via a wrist-based health and fitness tracker FitBit (Fitbit Inc., San Francisco, CA, USA) with a large organic light-emitting diode screen featuring heartrate monitoring and tracking of steps, distance, calories burned, floors climbed, active minutes, and sleep duration. These devices have been well-validated against gold-standard measures with good accuracy [11].
- Pulse wave velocity, augmentation index, and total peripheral resistance measured by Schiller BR-102 plus PWA (Schiller AG, Baar, Switzerland).
- Volume of hippocampus and internal carotid artery blood flow—Volume of hippocampus will be assessed by magnetic resonance imaging (MRI), T1-MPRAGE sequence, whereas blood flow through internal carotid artery will be measured by 1.5T MRI, 4D flow.
- Heart rate variability measured by Schiller medilog®AR Holter recorder (Schiller AG, Baar, Switzerland).
- Cardiovascular risk assessed by tissue levels of advanced glycation end-products (AGEs)—The AGE Reader (DiagnOptics Technologies BV, Groningen, The Netherlands) is a non-invasive monitoring device that uses ultra-violet light to excite autofluorescence in human skin tissue. The autofluorescence reflects tissue levels of AGEs [12]. The measurement of AGEs provides an immediate cardiovascular risk prediction in 12 s. The AGE Reader has been designed for patient-friendly diagnosis; the method is convenient, easy to use, and extensively validated.
- Circulating levels of blood biomarkers—Circulating (steady-state) plasma concentrations of CBD, inflammation (including TNF-alpha, IL-6, IL-10, whole blood count, etc.) and gold-standard biomarkers of plasma nitric oxide (plasma nitrite, s-nitrosothiols, and total nitric oxide) will be measured from peripheral blood sample. Lipids (cholesterol, high- and low-density lipoprotein, and triglycerides), glucose, insulin, HbA1C, renal (creatinine), hepatic (ALT, AST, ALP, GGT, and total bilirubin), drug toxicity (acyl glucuronide), and cardiovascular disease markers (hs-CRP) will also be measured.
- Outcomes assessed using questionnaires:
- Salt intake measured by Big life sodium calculator [13]
- Sleepiness measured by Epworth sleepiness scale [14]
- Geriatric depression measured by Geriatric depression scale-short form [15]
- Physical activity measured by Global Physical Activity Questionnaire (Total weekly Metabolic equivalent of task (MET)-min is calculated in a following manner: (Minutes engaged in moderate-intensity activity each week X 4 MET) + (Minutes engaged in vigorous-intensity activity each week X 8 MET) [16]
- Memory measured by Memory Complaint Questionnaire [17]
- Sleep quality measured by Pittsburgh sleep quality index [18]
- Perceived stress measured by Perceived stress scale [19]
- General health measured by Short form-36 (SF-36) [20]
- Anxiety measured by State-Trait Anxiety Inventory [21]
- Obstructive sleep apnea risk measured by STOP-BANG [22]
- Depression measured by Beck’s Depression Inventory [23]
- Mediterranean diet serving score [24]
2.5. Laboratory Visits
2.6. Sample Size Calculation
2.7. Adverse Events
2.8. Data Collection and Management
2.9. Statistical Analysis Plan
3. Rationale for Conducting the Trial
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Randomization Group | Dose Period 1 (2.5 Weeks) | Dose Period 2 (2.5 Weeks) |
---|---|---|
DehydraTECH2.0 CBD | ≤75 kg: CBD, 225 mg/day | <100 kg: CBD, 375 mg/day |
75 mg morning (1 capsule) | 75 mg morning (1 capsule) | |
75 mg afternoon (1 capsule) | 150 mg afternoon (2 capsules) | |
75 mg bedtime (1 capsule) | 150 mg bedtime (2 capsules) | |
>75 kg: CBD, 300 mg/day | ≥100 kg: CBD, 450 mg/day | |
75 mg morning (1 capsule) | 150 mg morning (2 capsules) | |
75 mg afternoon (1 capsule) | 150 mg afternoon (2 capsules) | |
150 mg bedtime (2 capsules) | 150 mg bedtime (2 capsules) | |
Placebo | Placebo, number of capsules matched to active treatment based on body weight | Placebo, number of capsules matched to active treatment based on body weight |
Assessment Measure | Screening | First Set of Visits | Washout | Second Set of Visits | ||||
---|---|---|---|---|---|---|---|---|
Timing of visit (weeks) | 0 | 2.5 | 5 | 0 | 2.5 | 5 | ||
Anthropometry and medical history | ||||||||
Medical history | ✓ | |||||||
Demographics and health history | ✓ | |||||||
Eligibility screening questionnaire | ✓ | |||||||
Anthropometrics and vital signs | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |
Bioelectrical impedance analysis | ✓ | ✓ | ||||||
Indices of cardiovascular health | ||||||||
24-h ambulatory blood pressure | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||
24-h ambulatory ECG | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||
Pulse wave analysis | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||
AGE Reader | ✓ | |||||||
Brain structure and function (MRI) | ✓ | ✓ | ✓ | ✓ | ||||
Blood work and urine analysis | ||||||||
Blood biomarkers | ✓ | ✓ | ✓ | ✓ | ||||
Liver transaminases | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |
Cannabidiol in urine | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||
Sleep, health and physical activity | ||||||||
Actigraphy | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||
Sleep quality | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||
Questionnaires | ||||||||
Big life sodium calculator | ✓ | ✓ | ✓ | ✓ | ||||
Epworth Sleepiness Scale | ✓ | ✓ | ✓ | ✓ | ||||
Geriatric Depression Scale | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||
Global Physical Activity Questionnaire | ✓ | |||||||
Memory Assessment Clinic-Q | ✓ | ✓ | ||||||
Mediterranean Diet Serving Score | ✓ | |||||||
Pittsburgh Sleep Quality Index | ✓ | |||||||
Perceived Stress Scale | ✓ | ✓ | ✓ | ✓ | ||||
Short Form-36 | ✓ | ✓ | ✓ | ✓ | ||||
State-Trait Anxiety Inventory | ✓ | ✓ | ✓ | ✓ | ||||
STOP-Bang | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||
Beck’s Depression Inventory | ✓ |
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Kumric, M.; Bozic, J.; Dujic, G.; Vrdoljak, J.; Dujic, Z. Chronic Effects of Effective Oral Cannabidiol Delivery on 24-h Ambulatory Blood Pressure and Vascular Outcomes in Treated and Untreated Hypertension (HYPER-H21-4): Study Protocol for a Randomized, Placebo-Controlled, and Crossover Study. J. Pers. Med. 2022, 12, 1037. https://doi.org/10.3390/jpm12071037
Kumric M, Bozic J, Dujic G, Vrdoljak J, Dujic Z. Chronic Effects of Effective Oral Cannabidiol Delivery on 24-h Ambulatory Blood Pressure and Vascular Outcomes in Treated and Untreated Hypertension (HYPER-H21-4): Study Protocol for a Randomized, Placebo-Controlled, and Crossover Study. Journal of Personalized Medicine. 2022; 12(7):1037. https://doi.org/10.3390/jpm12071037
Chicago/Turabian StyleKumric, Marko, Josko Bozic, Goran Dujic, Josip Vrdoljak, and Zeljko Dujic. 2022. "Chronic Effects of Effective Oral Cannabidiol Delivery on 24-h Ambulatory Blood Pressure and Vascular Outcomes in Treated and Untreated Hypertension (HYPER-H21-4): Study Protocol for a Randomized, Placebo-Controlled, and Crossover Study" Journal of Personalized Medicine 12, no. 7: 1037. https://doi.org/10.3390/jpm12071037