Effect of TAK-954 on Gastrointestinal and Colonic Transit in Diabetic or Idiopathic Gastroparesis Participants

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).

• TAK-954 (Drug): TAK-954 IV infusion.
• Placebo (Drug): TAK-954 placebo-matching IV infusion.

Primary outcomes

• 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 outcomes

• 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.
• 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.
• 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]
• 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]

Sex: All, ages: 18 Years to 65 Years

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).

Participant flow

Outcome results

• Percent Change From Baseline in Half-emptying Time (T1/2) of Gastric Solids (Primary), Mean, percent change: Placebo 3.5 +/- 23.71; TAK-954 0.1 mg -19.8 +/- 14.43; TAK-954 0.3 mg -25.4 +/- 20.90; TAK-954 1 mg -25.7 +/- 23.56 (p 0.0012)
• Colonic Geometric Center (Secondary), Mean, score on a scale: Placebo 0.539 +/- 0.6809; TAK-954 0.1 mg 1.190 +/- 0.9083; TAK-954 0.3 mg 1.737 +/- 1.0302; TAK-954 1 mg 1.148 +/- 0.4138 (p 0.2590)
• Colonic Filling at Hour 6 (Secondary), Mean, percentage of radio-labelled food: Placebo 31.3 +/- 25.38; TAK-954 0.1 mg 55.6 +/- 31.31; TAK-954 0.3 mg 86.4 +/- 19.76; TAK-954 1 mg 75.3 +/- 31.70 (p 0.0436)
• Half-emptying Time (T1/2) of Ascending Colon (Secondary), Median, hours: Placebo 19.1 (2.6 to 36.0); TAK-954 0.1 mg 5.4 (1.9 to 28.8); TAK-954 0.3 mg 6.3 (0.6 to 11.0); TAK-954 1 mg 7.4 (0.9 to 13.6) (p 0.0789)
• AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to t for TAK-954 (Secondary), Mean, h*ng/mL: TAK-954 0.1 mg 8.99 +/- 2.110; TAK-954 0.3 mg 25.79 +/- 8.340; TAK-954 1 mg 83.75 +/- 25.453
• Cmax: Maximum Observed Plasma Concentration for TAK-954 (Secondary), Mean, ng/mL: TAK-954 0.1 mg 1.637 +/- 0.3918; TAK-954 0.3 mg 5.346 +/- 1.5797; TAK-954 1 mg 16.029 +/- 2.9239
• Ctrough: Observed Plasma Concentration at the End of a Dosing Interval (Secondary), Mean, ng/mL: TAK-954 0.1 mg 0.1969 +/- 0.05406; TAK-954 0.3 mg 0.4364 +/- 0.20371; TAK-954 1 mg 1.6817 +/- 0.47072

Adverse events

Time frame: From first dose up to 30 days post last dose (Up to 46 days)

Serious adverse events by term

Other adverse events by term

• Results publication: Chedid V, Brandler J, Arndt K, Vijayvargiya P, Wang XJ, Burton D, Harmsen WS, Siegelman J, Chen C, Chen Y, Almansa C, Dukes G, Camilleri M. Randomised study: effects of the 5-HT4 receptor agonist felcisetrag vs placebo on gut transit in patients with gastroparesis. Aliment Pharmacol Ther. 2021 May;53(9):1010-1020. doi: 10.1111/apt.16304. Epub 2021 Mar 12. PMID 33711180

• Study Protocol (PDF, 2018-12-19)
• Statistical Analysis Plan (PDF, 2018-09-25)

• Medical Director Clinical Science, Study director, Takeda