Diabetic Gastroparesis, Idiopathic Gastroparesis
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to evaluate the dose-dependent effects of TAK-954 on gastric emptying time of solids in participants with diabetic or idiopathic gastroparesis assessed by scintigraphy.
Detailed description
The drug being tested in this study is called TAK-954. TAK-954 is a serotonin (5 HT4) receptor agonist and is being tested to treat people who have diabetic or idiopathic gastroparesis and who previously reported delay in stomach emptying. This study will look at the gastric emptying time of solids in people who take TAK-954 or placebo. The study will enroll approximately 41 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): * TAK-954 0.1 mg * TAK-954 0.3 mg * TAK-954 1 mg * Placebo (dummy inactive solution) - this is a solution that looks like the study drug but has no active ingredient. This single center trial will be conducted in the United States. The duration of treatment is 3 days and the overall period of evaluation is up to 28 days. The participants will be contacted by telephone (Days 10 to 14) for follow-up assessment. There will be another follow-up phone call for women of childbearing potential (Days 38 to 43).
Interventions
DRUGPlacebo
TAK-954 placebo-matching IV infusion.
DRUGTAK-954
TAK-954 IV infusion.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Has diabetes mellitus with symptoms of gastroparesis and previously documented gastric emptying delay or previously documented idiopathic gastroparesis in the last 5 years. 2. Has a body mass index (BMI) greater than or equal to (\>=) 16 and less than or equal to (\<=) 40 kilogram per square meter (kg/m\^2) at the Screening Visit.
Exclusion criteria
1. Has glycosylated hemoglobin (HbA1c) greater than (\>) 12 percent (%). 2. Has other structural diseases/conditions that affect the gastrointestinal (GI) system. 3. Are unable to withdraw drugs known to alter GI transit 48 hours prior to the study. 4. Has clinically significant abnormal baseline safety laboratory values. 5. Has preexisting hepatic disease that meets Child-Pugh Class B (moderate; total score 7 to 9 points) or C (severe; total score 10 to 15 points). 6. Are without known preexisting hepatic disease who have 1 or more of the following: * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2 times the upper limit of normal (ULN). * Bilirubin \>1.5 times the ULN unless due to Gilbert's syndrome. * International normalized ratio (INR) \>1.5 unless on anticoagulation therapy. 7. Has QT intervals with Fridericia correction method (QTcF) interval (\>=) 460 millisecond (msec) or with other factors that increase the risk of QT prolongation or arrhythmic events at screening. Note: Participants with bundle branch block and a prolonged QTc interval, or with QTcF between 450 and 460 msec, should be reviewed by the Medical Monitor for potential inclusion. 8. Has second or third degree atrioventricular (AV) block; AV disassociation; \>5 beats of non-sustained VT at a rate \>120 beats per minute (bpm); Electrocardiogram (ECG) changes consistent with acute myocardial ischemia or infarction. 9. Has cardiac history that includes conditions requiring heart rate control (example, atrial fibrillation, atrial flutter, ventricular tachycardia, or other tachyarrhythmias). 10. Has clinical evidence (including physical examination, ECG, clinical laboratory value and review of the medical history) of significant cardiovascular, respiratory, moderate or severe renal insufficiency (creatinine clearance \<=60 mL/min), hematological, neurological, or psychiatric disease, or other disease that interferes with the objectives of the study. 11. If female, are pregnant or lactating or intending to become pregnant before participating in this study, during the study, and 4 to 5 days (5 half-lives) PLUS 30 days after last dose of the study drug; or intending to donate ova during such time period. 12. Are considered by the investigator to be alcoholics not in remission or known substance abusers. Have a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is approximately equivalent to: beer \[354 milliliter per \[mL/\] 12 ounces\], wine \[118 mL/4 ounces\], or distilled spirits \[29.5 mL/1 ounce\] per day).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Half-emptying Time (T1/2) of Gastric Solids | Predose and at multiple time-points post-dose (up to 9 hours) on Day 2 | Half-emptying time (t1/2) of gastric solids is the time for half of the ingested solids or liquids to leave the stomach. Scintigraphy assessments were used to evaluate the gastric emptying of solids following a radio-labelled meal. A negative percent change from baseline indicated improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Colonic Filling at Hour 6 | 6 hours post-radiolabel meal on Day 2 | Colonic filling was estimated as percentage of the radio-labelled meal that reached the colon at Hour 6. |
| Half-emptying Time (T1/2) of Ascending Colon | Predose and at multiple time-points post-dose (up to 25 hours) on Days 1, 2 and 3 | T1/2 of ascending colon emptying was estimated by analysis of proportionate emptying over time of counts from the colon. Scintigraphy assessments were used to evaluate the emptying of solids or liquids from ascending colon following a radio-labelled meal. |
| Colonic Geometric Center | 4, 24, and 48 hours post-radiolabeled meal on Day 2 | The scintigraphic method was used to measure colonic geometric center following a radio-labelled meal. The geometric center (GC) was the weighted average of counts in the different colonic regions, where 0= no radioactivity in the colon and if radioactivity was detected in the colon, 1=all isotope was in the ascending colon and 5=all isotope was in the stool; a high GC indicated faster colonic transit. |
| Cmax: Maximum Observed Plasma Concentration for TAK-954 | Predose and at multiple time-points post-dose (up to 25 hours) on Days 1, 2 and 3 | — |
| Ctrough: Observed Plasma Concentration at the End of a Dosing Interval | At multiple time-points post-dose, up to 9 hours on Day 2 and up to 25 hours on Day 3 | — |
| AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 | Predose and at multiple time-points post-dose (up to 25 hours) on Days 1, 2 and 3 | — |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in the United States from 02 January 2018 to 12 July 2019.
Pre-assignment details
Participants with a diagnosis of diabetic or idiopathic gastroparesis were enrolled and randomized in 1:1:1:1 ratio to receive TAK-954 0.1 mg, 0.3 mg, 1 mg or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo TAK-954 placebo-matching, 60-minute infusion, IV, once daily on Days 1 to 3. | 10 |
| TAK-954 0.1 mg TAK-954 0.1 mg, 60-minute infusion, IV, once daily on Days 1 to 3. | 10 |
| TAK-954 0.3 mg TAK-954 0.3 mg, 60-minute infusion, IV, once daily on Days 1 to 3. | 9 |
| TAK-954 1 mg TAK-954 1 mg, 60-minute infusion, IV, once daily on Days 1 to 3. | 7 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | TAK-954 0.1 mg | TAK-954 0.3 mg | TAK-954 1 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 46.2 years STANDARD_DEVIATION 15.67 | 46.8 years STANDARD_DEVIATION 12.45 | 42.3 years STANDARD_DEVIATION 11.82 | 40.3 years STANDARD_DEVIATION 8.75 | 44.3 years STANDARD_DEVIATION 12.45 |
| Body Mass Index (BMI) | 24.8 kg/m^2 STANDARD_DEVIATION 4.88 | 28.4 kg/m^2 STANDARD_DEVIATION 5.5 | 27.7 kg/m^2 STANDARD_DEVIATION 5.44 | 22.6 kg/m^2 STANDARD_DEVIATION 3.15 | 26.1 kg/m^2 STANDARD_DEVIATION 5.24 |
| Disease History Diabetic Gastroparesis | 3 Participants | 3 Participants | 6 Participants | 2 Participants | 14 Participants |
| Disease History Idiopathic Gastroparesis | 7 Participants | 7 Participants | 3 Participants | 5 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 9 Participants | 9 Participants | 7 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Height | 166.2 cm STANDARD_DEVIATION 9.37 | 160.7 cm STANDARD_DEVIATION 7.27 | 165.7 cm STANDARD_DEVIATION 5.92 | 166.3 cm STANDARD_DEVIATION 7.57 | 164.6 cm STANDARD_DEVIATION 7.74 |
| Race/Ethnicity, Customized White | 10 Participants | 10 Participants | 9 Participants | 7 Participants | 36 Participants |
| Sex: Female, Male Female | 8 Participants | 10 Participants | 7 Participants | 5 Participants | 30 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 6 Participants |
| Weight | 68.3 kg STANDARD_DEVIATION 15.05 | 73.4 kg STANDARD_DEVIATION 14.57 | 76.5 kg STANDARD_DEVIATION 17.97 | 62.5 kg STANDARD_DEVIATION 9.22 | 70.6 kg STANDARD_DEVIATION 15.07 |
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 / 10 | 0 / 10 | 0 / 9 | 0 / 7 |
| other Total, other adverse events | 6 / 10 | 5 / 10 | 6 / 9 | 6 / 7 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 9 | 1 / 7 |
Outcome results
Primary
Percent Change From Baseline in Half-emptying Time (T1/2) of Gastric Solids
Half-emptying time (t1/2) of gastric solids is the time for half of the ingested solids or liquids to leave the stomach. Scintigraphy assessments were used to evaluate the gastric emptying of solids following a radio-labelled meal. A negative percent change from baseline indicated improvement.
Time frame: Predose and at multiple time-points post-dose (up to 9 hours) on Day 2
Population: Full analysis set included all randomized participants who received at least 1 dose of study drug. Overall number of participants analyzed is number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Half-emptying Time (T1/2) of Gastric Solids | 3.5 percent change | Standard Deviation 23.71 |
| TAK-954 0.1 mg | Percent Change From Baseline in Half-emptying Time (T1/2) of Gastric Solids | -19.8 percent change | Standard Deviation 14.43 |
| TAK-954 0.3 mg | Percent Change From Baseline in Half-emptying Time (T1/2) of Gastric Solids | -25.4 percent change | Standard Deviation 20.9 |
| TAK-954 1 mg | Percent Change From Baseline in Half-emptying Time (T1/2) of Gastric Solids | -25.7 percent change | Standard Deviation 23.56 |
p-value: 0.001295% CI: [-41.757, -9.858]ANCOVA
p-value: 0.001895% CI: [-45.224, -9.813]ANCOVA
p-value: <0.000195% CI: [-59.616, -23.902]ANCOVA
Secondary
AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954
Time frame: Predose and at multiple time-points post-dose (up to 25 hours) on Days 1, 2 and 3
Population: Pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of study drug and had sufficient blood sampling to allow for PK evaluation. Number analyzed is the number of participants with evaluable data at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 | Day 2 | 12.16 h*ng/mL | Standard Deviation 3.033 |
| Placebo | AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 | Day 1 | 8.99 h*ng/mL | Standard Deviation 2.11 |
| Placebo | AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 | Day 3 | 15.72 h*ng/mL | Standard Deviation 3.387 |
| TAK-954 0.1 mg | AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 | Day 2 | 33.94 h*ng/mL | Standard Deviation 9.249 |
| TAK-954 0.1 mg | AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 | Day 1 | 25.79 h*ng/mL | Standard Deviation 8.34 |
| TAK-954 0.1 mg | AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 | Day 3 | 39.34 h*ng/mL | Standard Deviation 12.699 |
| TAK-954 0.3 mg | AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 | Day 1 | 83.75 h*ng/mL | Standard Deviation 25.453 |
| TAK-954 0.3 mg | AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 | Day 3 | 125.88 h*ng/mL | Standard Deviation 34.586 |
| TAK-954 0.3 mg | AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 | Day 2 | 109.86 h*ng/mL | Standard Deviation 31.009 |
Secondary
Cmax: Maximum Observed Plasma Concentration for TAK-954
Time frame: Predose and at multiple time-points post-dose (up to 25 hours) on Days 1, 2 and 3
Population: PK analysis set included all participants who received at least 1 dose of study drug and had sufficient blood sampling to allow for PK evaluation. Number analyzed is the number of participants with evaluable data at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Cmax: Maximum Observed Plasma Concentration for TAK-954 | Day 2 | 1.687 ng/mL | Standard Deviation 0.4227 |
| Placebo | Cmax: Maximum Observed Plasma Concentration for TAK-954 | Day 1 | 1.637 ng/mL | Standard Deviation 0.3918 |
| Placebo | Cmax: Maximum Observed Plasma Concentration for TAK-954 | Day 3 | 1.705 ng/mL | Standard Deviation 0.3297 |
| TAK-954 0.1 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 | Day 2 | 5.821 ng/mL | Standard Deviation 1.9447 |
| TAK-954 0.1 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 | Day 1 | 5.346 ng/mL | Standard Deviation 1.5797 |
| TAK-954 0.1 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 | Day 3 | 5.056 ng/mL | Standard Deviation 1.543 |
| TAK-954 0.3 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 | Day 1 | 16.029 ng/mL | Standard Deviation 2.9239 |
| TAK-954 0.3 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 | Day 3 | 17.700 ng/mL | Standard Deviation 7.1544 |
| TAK-954 0.3 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 | Day 2 | 15.517 ng/mL | Standard Deviation 3.707 |
Secondary
Colonic Filling at Hour 6
Colonic filling was estimated as percentage of the radio-labelled meal that reached the colon at Hour 6.
Time frame: 6 hours post-radiolabel meal on Day 2
Population: Full analysis set included all randomized participants who received at least 1 dose of study drug. Overall number of participants analyzed is number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Colonic Filling at Hour 6 | 31.3 percentage of radio-labelled food | Standard Deviation 25.38 |
| TAK-954 0.1 mg | Colonic Filling at Hour 6 | 55.6 percentage of radio-labelled food | Standard Deviation 31.31 |
| TAK-954 0.3 mg | Colonic Filling at Hour 6 | 86.4 percentage of radio-labelled food | Standard Deviation 19.76 |
| TAK-954 1 mg | Colonic Filling at Hour 6 | 75.3 percentage of radio-labelled food | Standard Deviation 31.7 |
p-value: 0.043695% CI: [0.799, 65.439]ANCOVA
p-value: 0.000795% CI: [23.555, 92.396]ANCOVA
p-value: 0.013495% CI: [8.249, 80.629]ANCOVA
Secondary
Colonic Geometric Center
The scintigraphic method was used to measure colonic geometric center following a radio-labelled meal. The geometric center (GC) was the weighted average of counts in the different colonic regions, where 0= no radioactivity in the colon and if radioactivity was detected in the colon, 1=all isotope was in the ascending colon and 5=all isotope was in the stool; a high GC indicated faster colonic transit.
Time frame: 4, 24, and 48 hours post-radiolabeled meal on Day 2
Population: Full analysis set included all randomized participants who received at least 1 dose of study drug. Number analyzed is the number of participants with evaluable data at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Colonic Geometric Center | Colonic Transit at 4 Hours, Day 2 | 0.539 score on a scale | Standard Deviation 0.6809 |
| Placebo | Colonic Geometric Center | Colonic Transit at 24 Hours, Day 2 | 1.965 score on a scale | Standard Deviation 1.2964 |
| Placebo | Colonic Geometric Center | Colonic Transit at 48 Hours, Day 2 | 3.323 score on a scale | Standard Deviation 1.2948 |
| TAK-954 0.1 mg | Colonic Geometric Center | Colonic Transit at 24 Hours, Day 2 | 3.792 score on a scale | Standard Deviation 1.1441 |
| TAK-954 0.1 mg | Colonic Geometric Center | Colonic Transit at 4 Hours, Day 2 | 1.190 score on a scale | Standard Deviation 0.9083 |
| TAK-954 0.1 mg | Colonic Geometric Center | Colonic Transit at 48 Hours, Day 2 | 4.406 score on a scale | Standard Deviation 1.1169 |
| TAK-954 0.3 mg | Colonic Geometric Center | Colonic Transit at 24 Hours, Day 2 | 3.468 score on a scale | Standard Deviation 1.3252 |
| TAK-954 0.3 mg | Colonic Geometric Center | Colonic Transit at 48 Hours, Day 2 | 4.550 score on a scale | Standard Deviation 0.9004 |
| TAK-954 0.3 mg | Colonic Geometric Center | Colonic Transit at 4 Hours, Day 2 | 1.737 score on a scale | Standard Deviation 1.0302 |
| TAK-954 1 mg | Colonic Geometric Center | Colonic Transit at 48 Hours, Day 2 | 3.792 score on a scale | Standard Deviation 1.0382 |
| TAK-954 1 mg | Colonic Geometric Center | Colonic Transit at 24 Hours, Day 2 | 2.978 score on a scale | Standard Deviation 1.1382 |
| TAK-954 1 mg | Colonic Geometric Center | Colonic Transit at 4 Hours, Day 2 | 1.148 score on a scale | Standard Deviation 0.4138 |
Comparison: Colonic Transit at 4 Hours, Day 2p-value: 0.25995% CI: [-0.364, 1.795]ANCOVA
Comparison: Colonic Transit at 4 Hours, Day 2p-value: 0.02895% CI: [0.119, 2.418]ANCOVA
Comparison: Colonic Transit at 4 Hours, Day 2p-value: 0.688295% CI: [-0.757, 1.66]ANCOVA
Comparison: Colonic Transit at 24 Hours, Day 2p-value: 0.006295% CI: [0.493, 3.25]ANCOVA
Comparison: Colonic Transit at 24 Hours, Day 2p-value: 0.14995% CI: [-0.327, 2.717]ANCOVA
Comparison: Colonic Transit at 24 Hours, Day 2p-value: 0.628595% CI: [-0.931, 2.2]ANCOVA
Comparison: Colonic Transit at 48 Hours, Day 2p-value: 0.035895% CI: [0.073, 2.501]ANCOVA
Comparison: Colonic Transit at 48 Hours, Day 2p-value: 0.04395% CI: [0.035, 2.621]ANCOVA
Comparison: Colonic Transit at 48 Hours, Day 2p-value: 0.941995% CI: [-1.107, 1.611]ANCOVA
Secondary
Ctrough: Observed Plasma Concentration at the End of a Dosing Interval
Time frame: At multiple time-points post-dose, up to 9 hours on Day 2 and up to 25 hours on Day 3
Population: PK analysis set included all participants who received at least 1 dose of study drug and had sufficient blood sampling to allow for PK evaluation. Number analyzed is the number of participants with evaluable data at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Ctrough: Observed Plasma Concentration at the End of a Dosing Interval | Day 2 | 0.1969 ng/mL | Standard Deviation 0.05406 |
| Placebo | Ctrough: Observed Plasma Concentration at the End of a Dosing Interval | Day 3 | 0.2854 ng/mL | Standard Deviation 0.10319 |
| TAK-954 0.1 mg | Ctrough: Observed Plasma Concentration at the End of a Dosing Interval | Day 2 | 0.4364 ng/mL | Standard Deviation 0.20371 |
| TAK-954 0.1 mg | Ctrough: Observed Plasma Concentration at the End of a Dosing Interval | Day 3 | 0.6392 ng/mL | Standard Deviation 0.26371 |
| TAK-954 0.3 mg | Ctrough: Observed Plasma Concentration at the End of a Dosing Interval | Day 2 | 1.6817 ng/mL | Standard Deviation 0.47072 |
| TAK-954 0.3 mg | Ctrough: Observed Plasma Concentration at the End of a Dosing Interval | Day 3 | 2.2620 ng/mL | Standard Deviation 0.40493 |
Secondary
Half-emptying Time (T1/2) of Ascending Colon
T1/2 of ascending colon emptying was estimated by analysis of proportionate emptying over time of counts from the colon. Scintigraphy assessments were used to evaluate the emptying of solids or liquids from ascending colon following a radio-labelled meal.
Time frame: Predose and at multiple time-points post-dose (up to 25 hours) on Days 1, 2 and 3
Population: Full analysis set included all randomized participants who received at least 1 dose of study drug. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Half-emptying Time (T1/2) of Ascending Colon | 19.1 hours |
| TAK-954 0.1 mg | Half-emptying Time (T1/2) of Ascending Colon | 5.4 hours |
| TAK-954 0.3 mg | Half-emptying Time (T1/2) of Ascending Colon | 6.3 hours |
| TAK-954 1 mg | Half-emptying Time (T1/2) of Ascending Colon | 7.4 hours |
p-value: 0.078995% CI: [-21.507, 0.96]ANCOVA
p-value: 0.02795% CI: [-25.242, -1.314]ANCOVA
p-value: 0.07595% CI: [-24.206, 0.952]ANCOVA