PainPhase 1NCT01893424
Bioequivalence Assessment of Oral Administration Vs. Oral Spray of a Cannabinoids (Tetrahydrocannabinol and Cannabidiol)
A Phase 1 study testing Sativex buccal spray and CBD-THC-Piperine-PNL capsule in people with Pain, run by Hadassah Medical Organization at 1 site in Israel.
Trial summary
This project is intended to evaluate self-emulsifying drug delivery system termed Piperine-Pro-Nano-Lipospheres (P-PNL) for enhancing the oral bioavailability of tetrahydrocannabinol (THC) and cannabidiol (CBD).The oral bioavailability of these cannabinoids is hampered by extensive first pass metabolism, resulting in… Read more about this study
- Who is it for?
- Ages 18 to 45 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Pain
- What is being tested?
- Sativex buccal spray and CBD-THC-Piperine-PNL capsule
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteIsrael
- Study dates
- Aug 2013to Jan 2015
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Men 18 through 45 years of age
- Body mass index in the range of: 25 through 30 kg/m2.
- Participants must be able to swallow and absorb oral medications.
- Normal Values Vital Sign Parameters as following: systolic blood pressure 90-139 mmHg, diastolic blood pressure 50-89 mmHg, pulse rate 45-100 bpm, body temperature 36.0-37.5º C.
- Subjects must be able to understand and comply with the requirements of the study (e.g. all medication, dietary, and alcohol restrictions).
- Subjects must provide written informed consent to participate in the study after reading the information and consent form, and after having an opportunity to discuss the study with the investigator.
- Subjects must complete the screening process within 4 weeks prior to the admission visit.
Who cannot join
- Previous participation in an investigational trial involving administration of any investigational compounds within two month prior to the current study.
- Impaired glucose tolerance
- Diabetes mellitus
- Renal disease
- Edema
- Stroke or neurological disorder
Show all 31Show fewer
- Arthritis, joint or tendon abnormalities
- History of asthma
- Hepatic disorder
- History of seizures
- History of psychosis any addictive or other psychiatric disease disorder or a history of any illness that,might confound the results of the study or pose risk by participation in the study.
- History of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) 1 or 2.
- History of cannabis intoxication or dependence.
- Use of the forbidden drugs, substances or foods as follows:
- 14.1 Investigational product (THC or/and CBD ingestion or smoking) within one month preceding the study.
- 14.2 Prescription or non-prescription medication (including herbal, vitamins or dietary supplements) or vaccine within 14 days of the first day of study drug administration or within 5 half-lives before the first day of study drug administration.
- Exceptions are locally acting medications (eg, topical creams), which are not allowed within 5 days of study drug administration, and the occasional use of acetaminophen (up to 3 g/day) and ibuprofen (up to 1200 mg/day).
- 14.3 Consumption of grapefruit, grapefruit juice, Seville oranges, pomelo containing products, within the 14 days prior to study and then throughout the study.
- 14.4 Excessive consumption of alcohol, defined as >3 drinks per day (beer, wine, or distilled spirits), or unwilling to comply with the restricted use of alcohol during the study (48 hours prior to admission and throughout the study)and history of alcoholism.
- Previous surgery on the gastrointestinal tract [including removal of parts of stomach, bowel, liver, gall bladder, or pancreas] or stomach banding).
- Exhausting physical exercise 48 hours prior to drug administration.
- Excessive caffeine and xanthine containing foods and beverages (ie, equivalent to >4 cups brewed coffee per day) from 2 weeks prior to Day -1 and throughout the entire study.
- Those who had donated >0.5 L blood within 30 days of study.
- Abnormal heart function according to the following criteria:
- The subject has a supine pulse rate outside of the range of 40 to 100 bpm (following at least a 10-minute rest) measured at screening or Day -1.
- Supine blood pressure outside of the range of 90 to 139 mm Hg systolic or 50 to 89 mm Hg diastolic (following at least a 10 minute rest) measured at screening or Day-1. 11.
- Clinically significant history of drug allergies (including cannabis extracts, propylene glycol, ethanol, or peppermint oil), drug hypersensitivity or history of idiosyncratic reactions to any drug.
- Presence of mouth ulcerations or any damage of mouth and oral cavity.
- History of abuse of any drug/chemical.
- Inability to relate to and/or cooperate with the investigators.
- A subject with any other condition, which, in the opinion of the investigator, makes the subject inappropriate for the study.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Bioequivalence Assessment of Oral Administration Vs. Oral Spray of a Cannabinoid Combination (Δ9 -Tetrahydrocannabinol (THC) and Cannabidiol (CBD) In 1:1 Ratio)
This project is intended to evaluate self-emulsifying drug delivery system termed Piperine-Pro-Nano-Lipospheres (P-PNL) for enhancing the oral bioavailability of tetrahydrocannabinol (THC) and cannabidiol (CBD).The oral bioavailability of these cannabinoids is hampered by extensive first pass metabolism, resulting in relative bioavailability of 6%.
The main goal of this study is to evaluate the bioequivalence of THC-CBD P-PNL product for oral administration to Sativex® buccal spray, as measured by AUC 0-24h, Tmax and Cmax.
Read the detailed description
Multiple sclerosis (MS) is a disabling, lifelong disease of the central nervous system. The currently available treatments with analgesic drugs for the management of MS associated pain are limited in their efficacy, and frequently uncontrolled.
The most successful treatment for this MS pain was found to be the use of the combination of Δ 9 -Tetrahydrocannabinol (THC) and Cannabidiol (CBD) in 1:1 ratio. The rationale for the combination of the two cannabinoids was aroused by the reports in the scientific literature that CBD could not only potentiate the therapeutic effects of THC but also diminish the undesirable effects of THC such as anxiety, panic, sedation, dysphonia and tachycardia. Additionally, co-administration of THC and CBD was reported to be safe with no tolerance, abuse or withdrawal effects.
Although therapeutic rationale for the THC and CBD combination was established, an optimal oral dosage form to deliver this cannabinoids combination is not available yet. The reason for that is the marked "first pass" metabolic effect of the cannabinoids in the gastrointestinal tract leading to very limited oral bioavailability of 6%.
In this project we shall utilize our biopharmaceutical experience using an advanced self-emulsifying drug delivery system termed Piperine-Pro-Nano-Lipospheres (P-PNL) for enhancing the oral bioavailability of THC and CBD. P-PNL is an isotropic mixture of a natural alkaloid (piperine) and the active compounds (THC and CBD) in a combination of lipids, surfactants and co-solvent termed the pre-concentrate, which is administered in a soft gelatin capsule. We have shown in pre-clinical investigation that incorporation of THC and CBD into P-PNL is a promising strategy to enhance their oral bioavailability.
Thus, the primary goal of this study: is to evaluate the bioequivalence of the developed THC-CBD P-PNL product for oral administration to Sativex®. This is a currently available product of THC and CBD combination. Sativex® is a solution that has to be administered by spray onto the oromucosal surface to bypass the "first pass" metabolism of the cannabinoids associated with intestinal absorption. SATIVEX® is approved in various countries (i.e. Canada, UK, Spain, New Zealand and Israel-distributed by Neopharm) for a MS pain treatment and in Canada also for cancer pain treatment.
The study will be performed on 12 healthy male volunteers. It will be an open label, cross-over single-arm two sequences study intended to evaluate the pharmacokinetics of THC and CBD. Each volunteer will receive THC:CBD capsule and Sativex® . Both study groups THC-CBD-Piperine-PNL vs. Sativex® will receive identical doses of THC and CBD; 21.6 mg and 20 mg respectively. blood samples will be withdrawn through indwelling cannula from the forearm 30 minutes before (pre-dose) and every 30 minutes interval for the first 4 hours then blood samples will be taken at, 5, 6, 7, 8, 12 and 24 hours after the intake of the study drug. Blood concentration profiles of THC, CBD and their main metabolites:
11-hydroxy-THC, 11-nor-9-carboxy-THC and CBD-glucoronide will be determined in order to calculate the pharmacokinetic parameters of THC and CBD.
- Conditions
- Pain
- Being tested
- Sativex buccal spray, CBD-THC-Piperine-PNL capsule
- Keywords
- Biological Availability, Pharmacokinetics
- Medical subject headings
- Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sativex buccal sprayDrug
Also called Sativex
buccal spray
CBD-THC-Piperine-PNL capsuleDrug
Also called Cannabidiol and dronabinol in ProNanoLiposphere formulation
a capsule containing Cannabidiol and Tetrahydrocannabinol combination
| Study group | Role | What they receive |
|---|---|---|
| Sativex buccal spray | Active comparator | volunteers will receive a single dose of 8 actuations of Sativex® which will be administrated within 1-2 min by the study physician. The dose of THC and CBD to be administered is the following: THC 21.6 mg and CBD 20 mg. Sativex® actuations will be directed sublingually and at the buccal mucosa. Receives: Drug: Sativex buccal spray |
| CBD-THC-Piperine-PNL capsule | Experimental | 12 volunteers will receive a single oral dose of THC:CBD P-PNL capsule with 200 mL of water. The dose of THC and CBD to be administered is the same as in the Sativex arm: THC 21.6 mg and CBD 20 mg. Receives: Drug: CBD-THC-Piperine-PNL capsule |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetic parameters of THC and CBD
Measured: 1 year
Secondary outcomes (1)
exposure to the metabolites of the study drugs
Assessment of the metabolic profile of major THC's and CBD's metabolites:
11-hydroxy-THC, 11-nor-9-carboxy-THC and CBD-glucoronide in healthy volunteers. Plasma metabolites concentrations will be determined using HPLC-MS/MS validated assay. The unit of measure will be provided as ng/ml.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jul 2013 (estimated)
- Study startAug 2013
- Primary completionJan 2014
- Study completionJan 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PainStudies of the same condition, open and under way.
- More trials run by Hadassah Medical OrganizationThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hadassah Medical Organization
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Elyad Davidson, MD, Principal investigator, Director of the pain relief unit in Hadassah Hebrew University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01893424
- Sponsor's protocol ID
- 0658-12-HMO-CTIL
- Status last verified
- Mar 2016
- First submitted
- 16 Jun 2013
- Last updated
- 24 Mar 2016
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 24 Mar 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Bioequivalence Assessment of Oral Administration Vs. Oral Spray of a Cannabinoid Combination (Δ9 -Tetrahydrocannabinol (THC) and Cannabidiol (CBD) In 1:1 Ratio)
- ClinicalTrials.gov ID
- NCT01893424
- Acronym / sponsor ID
- 0658-12-HMO-CTIL
- Conditions
- Pain
- Keywords
- Biological Availability, Pharmacokinetics
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Hadassah Medical OrganizationUniversity, hospital or other
- Study start
- Aug 2013
- Primary completion
- Jan 2014 (actual)
- Study completion
- Jan 2015 (actual)
- First posted
- 9 Jul 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This project is intended to evaluate self-emulsifying drug delivery system termed Piperine-Pro-Nano-Lipospheres (P-PNL) for enhancing the oral bioavailability of tetrahydrocannabinol (THC) and cannabidiol (CBD).The oral bioavailability of these cannabinoids is hampered by extensive first pass metabolism, resulting in relative bioavailability of 6%.
The main goal of this study is to evaluate the bioequivalence of THC-CBD P-PNL product for oral administration to Sativex® buccal spray, as measured by AUC 0-24h, Tmax and Cmax.
Detailed description
Multiple sclerosis (MS) is a disabling, lifelong disease of the central nervous system. The currently available treatments with analgesic drugs for the management of MS associated pain are limited in their efficacy, and frequently uncontrolled.
The most successful treatment for this MS pain was found to be the use of the combination of Δ 9 -Tetrahydrocannabinol (THC) and Cannabidiol (CBD) in 1:1 ratio. The rationale for the combination of the two cannabinoids was aroused by the reports in the scientific literature that CBD could not only potentiate the therapeutic effects of THC but also diminish the undesirable effects of THC such as anxiety, panic, sedation, dysphonia and tachycardia. Additionally, co-administration of THC and CBD was reported to be safe with no tolerance, abuse or withdrawal effects.
Although therapeutic rationale for the THC and CBD combination was established, an optimal oral dosage form to deliver this cannabinoids combination is not available yet. The reason for that is the marked "first pass" metabolic effect of the cannabinoids in the gastrointestinal tract leading to very limited oral bioavailability of 6%.
In this project we shall utilize our biopharmaceutical experience using an advanced self-emulsifying drug delivery system termed Piperine-Pro-Nano-Lipospheres (P-PNL) for enhancing the oral bioavailability of THC and CBD. P-PNL is an isotropic mixture of a natural alkaloid (piperine) and the active compounds (THC and CBD) in a combination of lipids, surfactants and co-solvent termed the pre-concentrate, which is administered in a soft gelatin capsule. We have shown in pre-clinical investigation that incorporation of THC and CBD into P-PNL is a promising strategy to enhance their oral bioavailability.
Thus, the primary goal of this study: is to evaluate the bioequivalence of the developed THC-CBD P-PNL product for oral administration to Sativex®. This is a currently available product of THC and CBD combination. Sativex® is a solution that has to be administered by spray onto the oromucosal surface to bypass the "first pass" metabolism of the cannabinoids associated with intestinal absorption. SATIVEX® is approved in various countries (i.e. Canada, UK, Spain, New Zealand and Israel-distributed by Neopharm) for a MS pain treatment and in Canada also for cancer pain treatment.
The study will be performed on 12 healthy male volunteers. It will be an open label, cross-over single-arm two sequences study intended to evaluate the pharmacokinetics of THC and CBD. Each volunteer will receive THC:CBD capsule and Sativex® . Both study groups THC-CBD-Piperine-PNL vs. Sativex® will receive identical doses of THC and CBD; 21.6 mg and 20 mg respectively. blood samples will be withdrawn through indwelling cannula from the forearm 30 minutes before (pre-dose) and every 30 minutes interval for the first 4 hours then blood samples will be taken at, 5, 6, 7, 8, 12 and 24 hours after the intake of the study drug. Blood concentration profiles of THC, CBD and their main metabolites:
11-hydroxy-THC, 11-nor-9-carboxy-THC and CBD-glucoronide will be determined in order to calculate the pharmacokinetic parameters of THC and CBD.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sativex buccal spray | Active comparator | Drug: Sativex buccal sprayvolunteers will receive a single dose of 8 actuations of Sativex® which will be administrated within 1-2 min by the study physician. The dose of THC and CBD to be administered is the following: THC 21.6 mg and CBD 20 mg. Sativex® actuations will be directed sublingually and at the buccal mucosa. |
| CBD-THC-Piperine-PNL capsule | Experimental | Drug: CBD-THC-Piperine-PNL capsule12 volunteers will receive a single oral dose of THC:CBD P-PNL capsule with 200 mL of water. The dose of THC and CBD to be administered is the same as in the Sativex arm: THC 21.6 mg and CBD 20 mg. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Men 18 through 45 years of age
- Body mass index in the range of: 25 through 30 kg/m2.
- Participants must be able to swallow and absorb oral medications.
- Normal Values Vital Sign Parameters as following: systolic blood pressure 90-139 mmHg, diastolic blood pressure 50-89 mmHg, pulse rate 45-100 bpm, body temperature 36.0-37.5º C.
- Subjects must be able to understand and comply with the requirements of the study (e.g. all medication, dietary, and alcohol restrictions).
Key exclusion criteria (31 listed)
- Previous participation in an investigational trial involving administration of any investigational compounds within two month prior to the current study.
- Impaired glucose tolerance
- Diabetes mellitus
- Renal disease
- Edema
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sativex buccal sprayAlso: Sativexbuccal spray | Drug | Sativex buccal spray |
| CBD-THC-Piperine-PNL capsuleAlso: Cannabidiol and dronabinol in ProNanoLiposphere formulationa capsule containing Cannabidiol and Tetrahydrocannabinol combination | Drug | CBD-THC-Piperine-PNL capsule |
Primary outcome
Pharmacokinetic parameters of THC and CBD
Time frame: 1 year
1 secondary outcome
exposure to the metabolites of the study drugs
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Mar 2016.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Elyad Davidson, MD principal investigator
Director of the pain relief unit in Hadassah Hebrew University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Sativex buccal spray and CBD-THC-Piperine-PNL capsule in people with Pain, run by Hadassah Medical Organization at 1 site in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pharmacokinetic parameters of THC and CBD (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Mar 2016.