Dyspepsia, Gastroparesis
Conditions
Brief summary
Researchers are looking at the effects of a cannabidiol medication on stomach function in people with gastroparesis (a paralyzed stomach) and people with dyspepsia (an upset stomach caused by improper functioning of the stomach's muscles or nerves).
Interventions
DRUGCannabidiol
Cannabidiol and the matching placebo solution (excipients alone) will be provided in identical 100ml amber glass bottles. At the end of the treatment period, the treatment solutions will be tapered (10% volume each day) over 10 days. In accordance with Food and Drug Administration guidance, prior to starting treatment and at end of 1 month treatment, we shall obtain serum transaminases (alanine and aspartate) and total bilirubin levels. These tests will also be performed if patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine); if such features develop the treatment will be interrupted or discontinued.
OTHERplacebo
Cannabidiol and the matching placebo solution (excipients alone) will be provided in identical 100ml amber glass bottles. At the end of the treatment period, the treatment solutions will be tapered (10% volume each day) over 10 days. In accordance with Food and Drug Administration guidance, prior to starting treatment and at end of 1 month treatment, we shall obtain serum transaminases (alanine and aspartate) and total bilirubin levels. These tests will also be performed if patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine); if such features develop the treatment will be interrupted or discontinued.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients with gastroparesis or functional dyspepsia (FD) * Age 18-70 years * Patients will be identified from among Mayo Clinic patients. * Patients will have symptoms consistent with gastroparesis based on a national guideline for gastroparesis (symptoms plus delayed gastric emptying of solids). Patients with Rome IV criteria for postprandial distress syndrome (a subset of functional dyspepsia) will be selected based on gastric emptying of solids which is NOT delayed, in addition to standard FD criteria: * Symptoms fulfilled for the last 3 months with onset greater than 6 months before diagnosis: * One or more symptoms being bothersome: postprandial fullness, early satiation, epigastric pain or burning * Must include one or both of the following at least 3 days per week: bothersome postprandial fullness (i.e., severe enough to impact on usual activities) or bothersome early satiation (i.e., severe enough to prevent finishing a regular-size meal) * No evidence of organic, systemic, or metabolic disease to explain the symptoms on routine investigations. * Participants will have previously undergone test of gastric emptying of solids using the standardized Mayo Clinic scintigraphic method * Ability to provide informed consent * Absence of other diseases (structural or metabolic) which could interfere with interpretation of the study results * Body mass index of 18-35 kg/m2 * Several medication classes, particularly those affecting gastrointestinal transit or motor functions, will be excluded, including GLP-1 receptor or amylin agonists in patients with diabetes mellitus. Stable doses of thyroid replacement, estrogen replacement, low-dose aspirin for cardioprotection, and birth control (but with adequate backup contraception, as drug interactions with birth control have not been conducted for secretin PAM) are
Exclusion criteria
* Patients with current H. pylori infection will be excluded. * Pregnancy or lactation * Rapid metabolizers for CYP3A4 or CYP2C19 \[estimated prevalence of 17% and 18% respectively * based on literature review will be excluded since this could impact assessment of effects of cannabidiol * Patients with abnormal baseline liver transaminases (any value above UNL), since up to 3-fold, dose-related elevations of liver transaminases (ALT and/or AST) occur in 13% of treated patients (vs. 1% placebo); * Hypersensitivity to cannabidiol or any of the ingredients in EPIDIOLEX * Concomitant use of valproate, central nervous system (CNS) depressants and alcohol, other hepatotoxic drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gastric Emptying Half-time (T1/2) of Solids | 4 weeks | Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Gastric emptying (GE t 1/2) was measured by scintigraphy and defined as the time required for 50% of the radiolabeled tracer to empty from the stomach. |
| Gastric Emptying Lag Time (T-lag) of Solids | 4 weeks | Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Gastric emptying lag time (GE t-lag) was measured by scintigraphy and defined as the amount of time the radioactive meal was in the stomach before starting to empty into the small bowel. |
| Fasting Gastric Volume | 4 weeks | Gastric fasting volume was measured prior to a meal of 300 mL standardized radio-labeled Ensure drink using an intravenous injection of Technetium Tc-99m pertechnetate and noninvasive single photon emission-computed tomography (SPECT). |
| Gastric Accommodation | 4 weeks | Gastric accommodation was measured 15 minutes after ingestion of 300 mL standardized radio-labeled Ensure drink using an intravenous injection of Technetium Tc-99m pertechnetate and noninvasive single photon emission-computed tomography (SPECT). |
| Satiation Volume to Fullness | 4 weeks | Thirty (30) minutes after ingesting the meal of 300 mL radio-labeled Ensure drink, an additional Ensure drink was ingested at a constant rate of 30 mL/min. Participants recorded their sensations every 5 minutes using a numeric scale from 0 to 5, with level 0 being no symptoms, level 3 corresponding to fullness sensation after a typical meal, and level 5 corresponding to the MTV (maximum or unbearable fullness/satiation). Nutrient intake was stopped when subjects reach a score of 5. |
| Satiation Maximum Tolerated Volume (MTV) | 4 weeks | Thirty (30) minutes after ingesting the meal of 300 mL radio-labeled Ensure drink, an additional Ensure drink was ingested at a constant rate of 30 mL/min. Participants recorded their sensations every 5 minutes using a numeric scale from 0 to 5, with level 0 being no symptoms, level 3 corresponding to fullness sensation after a typical meal, and level 5 corresponding to the MTV (maximum or unbearable fullness/satiation). Nutrient intake was stopped when subjects reach a score of 5. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Weekly Global Symptom Assessment | 4 weeks | The number of functional dyspepsia participants who confirmed adequate relief of dyspepsia symptoms, based on the self-reporting question In the past 7 days have you had adequate relief of your upper abdominal pain or discomfort?. |
| Average Daily Vomiting Episodes in Gastroparesis | 4 weeks | The average daily number of vomiting episodes in gastroparesis was measured by participants self-reporting responses to the question In the past 24 hours how many episodes of vomiting did you have? |
| Mean Daily Symptom Score in Functional Dyspepsia | 4 weeks | Self-reported daily symptom diaries assessed 3 symptoms of functional dyspepsia: (1) upper abdominal pain, (2) nausea, and (3) bloating or distension. Each symptom was scored from 0-4, where 0=none, 1= very mild, 2=mild, 3=moderate, and 4=severe. The responses were averaged together to provide an overall symptom score, which ranged from 0-4, where a higher score reflects worse symptoms. |
| Mean Daily Epigastric Pain in Functional Dyspepsia | 4 weeks | Mean daily epigastric pain in functional dyspepsia participants as measured by the question How much did you suffer from pain in your stomach area today?. The score is based on 5 point scale ranging from 0 (not at all) to 5 (extremely) where a higher score reflects more pain. |
| Quality of Life in Functional Dyspepsia | 4 weeks | The Nepean Dyspepsia Index (NDI) is used to assess functional dyspepsia quality of life. NDI scores are summarized as overall quality of life based on 5 subscales: interference, knowledge/control, eating/drinking, sleep disturbance, work/study. There are two questions per subscale for a total of 10 questions. Each question is ranked from 0-4, where 0 is 'not at all' and 4 is 'extremely'. The results from each question are added together to generate a total index score of 0 to 40. A lower score reflects no to little impact functional dyspepsia has on on quality of life while a higher score reflects significant impact functional dyspepsia has on quality of life. |
| Aggregate Symptom Score | 4 weeks | Postprandial symptoms of fullness, nausea, bloating, and pain were measured 30min after the satiation drink test using 100mm horizontal visual analog scales, with the words none and worst ever anchored at each end. Scores for each symptom were added to calculate the aggregate symptom score, which ranged from 0-400, where a lower score reflected mild symptoms and a higher score reflected more severe symptoms. |
| Overall Severity in Gastroparesis | 4 weeks | Overall severity in gastroparesis was self-measured daily by asking the question In thinking about your gastroparesis disorder, what was the overall severity of your gastroparesis symptoms today (during the past 24 hours)? The responses were ranked as 0 (none), 1 (mild), 2 (moderate), 3 (severe) and 4 (very severe). Scores range from 0-4, where 0 reflects little to no severity of symptoms and 4 reflects severe symptoms. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Functional Dyspepsia - Cannabidiol Cannabidiol will be administered to participants with functional dyspepsia orally twice daily in equally divided doses starting at 2.5mg/kg per day and increasing by 2.5 to 5.0mg/kg every other day until the target dose of 20mg/kg is reached. | 25 |
| Functional Dyspepsia - Placebo Placebo will be administered to participants with functional dyspepsia orally twice daily in equally divided doses starting at 2.5mg/kg per day and increasing by 2.5 to 5.0mg/kg every other day until the target dose of 20mg/kg is reached. | 23 |
| Gastroparesis - Canabidiol Cannabidiol will be administered to participants with gastroparesis orally twice daily in equally divided doses starting at 2.5mg/kg per day and increasing by 2.5 to 5.0mg/kg every other day until the target dose of 20mg/kg is reached. | 21 |
| Gastroparesis - Placebo Placebo will be administered to participants with gastroparesis orally twice daily in equally divided doses starting at 2.5mg/kg per day and increasing by 2.5 to 5.0mg/kg every other day until the target dose of 20mg/kg is reached. | 23 |
| Total | 92 |
Baseline characteristics
| Characteristic | Functional Dyspepsia - Cannabidiol | Total | Gastroparesis - Placebo | Gastroparesis - Canabidiol | Functional Dyspepsia - Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 34.5 years | 37.0 years | 44.0 years | 44.0 years | 35.0 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 23 Participants | 88 Participants | 23 Participants | 21 Participants | 21 Participants |
| Region of Enrollment United States | 25 participants | 92 participants | 23 participants | 21 participants | 23 participants |
| Sex: Female, Male Female | 19 Participants | 75 Participants | 20 Participants | 19 Participants | 17 Participants |
| Sex: Female, Male Male | 6 Participants | 17 Participants | 3 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 23 | 0 / 21 | 0 / 23 |
| other Total, other adverse events | 11 / 25 | 8 / 23 | 19 / 21 | 10 / 23 |
| serious Total, serious adverse events | 0 / 25 | 0 / 23 | 2 / 21 | 0 / 23 |
Outcome results
Primary
Fasting Gastric Volume
Gastric fasting volume was measured prior to a meal of 300 mL standardized radio-labeled Ensure drink using an intravenous injection of Technetium Tc-99m pertechnetate and noninvasive single photon emission-computed tomography (SPECT).
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Fasting Gastric Volume | 179.0 mL |
| Functional Dyspepsia - Placebo | Fasting Gastric Volume | 214.5 mL |
| Gastroparesis - Canabidiol | Fasting Gastric Volume | 235.6 mL |
| Gastroparesis - Placebo | Fasting Gastric Volume | 220.3 mL |
Primary
Gastric Accommodation
Gastric accommodation was measured 15 minutes after ingestion of 300 mL standardized radio-labeled Ensure drink using an intravenous injection of Technetium Tc-99m pertechnetate and noninvasive single photon emission-computed tomography (SPECT).
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Gastric Accommodation | 410.2 mL |
| Functional Dyspepsia - Placebo | Gastric Accommodation | 417.5 mL |
| Gastroparesis - Canabidiol | Gastric Accommodation | 440.6 mL |
| Gastroparesis - Placebo | Gastric Accommodation | 415.5 mL |
Primary
Gastric Emptying Half-time (T1/2) of Solids
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Gastric emptying (GE t 1/2) was measured by scintigraphy and defined as the time required for 50% of the radiolabeled tracer to empty from the stomach.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Gastric Emptying Half-time (T1/2) of Solids | 128.7 minutes |
| Functional Dyspepsia - Placebo | Gastric Emptying Half-time (T1/2) of Solids | 125.8 minutes |
| Gastroparesis - Canabidiol | Gastric Emptying Half-time (T1/2) of Solids | 246.4 minutes |
| Gastroparesis - Placebo | Gastric Emptying Half-time (T1/2) of Solids | 198.4 minutes |
Primary
Gastric Emptying Lag Time (T-lag) of Solids
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Gastric emptying lag time (GE t-lag) was measured by scintigraphy and defined as the amount of time the radioactive meal was in the stomach before starting to empty into the small bowel.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Gastric Emptying Lag Time (T-lag) of Solids | 46.0 minutes |
| Functional Dyspepsia - Placebo | Gastric Emptying Lag Time (T-lag) of Solids | 52.1 minutes |
| Gastroparesis - Canabidiol | Gastric Emptying Lag Time (T-lag) of Solids | 83.0 minutes |
| Gastroparesis - Placebo | Gastric Emptying Lag Time (T-lag) of Solids | 60.8 minutes |
Primary
Satiation Maximum Tolerated Volume (MTV)
Thirty (30) minutes after ingesting the meal of 300 mL radio-labeled Ensure drink, an additional Ensure drink was ingested at a constant rate of 30 mL/min. Participants recorded their sensations every 5 minutes using a numeric scale from 0 to 5, with level 0 being no symptoms, level 3 corresponding to fullness sensation after a typical meal, and level 5 corresponding to the MTV (maximum or unbearable fullness/satiation). Nutrient intake was stopped when subjects reach a score of 5.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Satiation Maximum Tolerated Volume (MTV) | 808.8 mL |
| Functional Dyspepsia - Placebo | Satiation Maximum Tolerated Volume (MTV) | 871.0 mL |
| Gastroparesis - Canabidiol | Satiation Maximum Tolerated Volume (MTV) | 1061.6 mL |
| Gastroparesis - Placebo | Satiation Maximum Tolerated Volume (MTV) | 812.7 mL |
Primary
Satiation Volume to Fullness
Thirty (30) minutes after ingesting the meal of 300 mL radio-labeled Ensure drink, an additional Ensure drink was ingested at a constant rate of 30 mL/min. Participants recorded their sensations every 5 minutes using a numeric scale from 0 to 5, with level 0 being no symptoms, level 3 corresponding to fullness sensation after a typical meal, and level 5 corresponding to the MTV (maximum or unbearable fullness/satiation). Nutrient intake was stopped when subjects reach a score of 5.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Satiation Volume to Fullness | 373.3 mL |
| Functional Dyspepsia - Placebo | Satiation Volume to Fullness | 622.1 mL |
| Gastroparesis - Canabidiol | Satiation Volume to Fullness | 682.6 mL |
| Gastroparesis - Placebo | Satiation Volume to Fullness | 638.2 mL |
Secondary
Aggregate Symptom Score
Postprandial symptoms of fullness, nausea, bloating, and pain were measured 30min after the satiation drink test using 100mm horizontal visual analog scales, with the words none and worst ever anchored at each end. Scores for each symptom were added to calculate the aggregate symptom score, which ranged from 0-400, where a lower score reflected mild symptoms and a higher score reflected more severe symptoms.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Aggregate Symptom Score | 182.5 score on a scale |
| Functional Dyspepsia - Placebo | Aggregate Symptom Score | 219.0 score on a scale |
| Gastroparesis - Canabidiol | Aggregate Symptom Score | 243.0 score on a scale |
| Gastroparesis - Placebo | Aggregate Symptom Score | 264.5 score on a scale |
Secondary
Average Daily Vomiting Episodes in Gastroparesis
The average daily number of vomiting episodes in gastroparesis was measured by participants self-reporting responses to the question In the past 24 hours how many episodes of vomiting did you have?
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Average Daily Vomiting Episodes in Gastroparesis | 0.0 vomiting episodes/day |
| Functional Dyspepsia - Placebo | Average Daily Vomiting Episodes in Gastroparesis | 0.2 vomiting episodes/day |
Secondary
Mean Daily Epigastric Pain in Functional Dyspepsia
Mean daily epigastric pain in functional dyspepsia participants as measured by the question How much did you suffer from pain in your stomach area today?. The score is based on 5 point scale ranging from 0 (not at all) to 5 (extremely) where a higher score reflects more pain.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Mean Daily Epigastric Pain in Functional Dyspepsia | 0.7 score on a scale |
| Functional Dyspepsia - Placebo | Mean Daily Epigastric Pain in Functional Dyspepsia | 0.8 score on a scale |
Secondary
Mean Daily Symptom Score in Functional Dyspepsia
Self-reported daily symptom diaries assessed 3 symptoms of functional dyspepsia: (1) upper abdominal pain, (2) nausea, and (3) bloating or distension. Each symptom was scored from 0-4, where 0=none, 1= very mild, 2=mild, 3=moderate, and 4=severe. The responses were averaged together to provide an overall symptom score, which ranged from 0-4, where a higher score reflects worse symptoms.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Mean Daily Symptom Score in Functional Dyspepsia | 1.2 score on a scale |
| Functional Dyspepsia - Placebo | Mean Daily Symptom Score in Functional Dyspepsia | 1.1 score on a scale |
Secondary
Overall Severity in Gastroparesis
Overall severity in gastroparesis was self-measured daily by asking the question In thinking about your gastroparesis disorder, what was the overall severity of your gastroparesis symptoms today (during the past 24 hours)? The responses were ranked as 0 (none), 1 (mild), 2 (moderate), 3 (severe) and 4 (very severe). Scores range from 0-4, where 0 reflects little to no severity of symptoms and 4 reflects severe symptoms.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Overall Severity in Gastroparesis | 1.8 score on a scale |
| Functional Dyspepsia - Placebo | Overall Severity in Gastroparesis | 1.6 score on a scale |
Secondary
Quality of Life in Functional Dyspepsia
The Nepean Dyspepsia Index (NDI) is used to assess functional dyspepsia quality of life. NDI scores are summarized as overall quality of life based on 5 subscales: interference, knowledge/control, eating/drinking, sleep disturbance, work/study. There are two questions per subscale for a total of 10 questions. Each question is ranked from 0-4, where 0 is 'not at all' and 4 is 'extremely'. The results from each question are added together to generate a total index score of 0 to 40. A lower score reflects no to little impact functional dyspepsia has on on quality of life while a higher score reflects significant impact functional dyspepsia has on quality of life.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Quality of Life in Functional Dyspepsia | 4.4 score on a scale |
| Functional Dyspepsia - Placebo | Quality of Life in Functional Dyspepsia | 3.6 score on a scale |
Secondary
Weekly Global Symptom Assessment
The number of functional dyspepsia participants who confirmed adequate relief of dyspepsia symptoms, based on the self-reporting question In the past 7 days have you had adequate relief of your upper abdominal pain or discomfort?.
Time frame: 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Functional Dyspepsia - Cannabidiol | Weekly Global Symptom Assessment | 12 Participants |
| Functional Dyspepsia - Placebo | Weekly Global Symptom Assessment | 11 Participants |