A Phase 1, Multiple Intravenous Dose Study to Examine Safety, Tolerability, and PK of Intravenous TD-8954, a 5-HT4 Receptor Agonist, in Healthy Subjects

• Sponsor: Theravance Biopharma (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01644240
• Collaborator: (none)
• Enrollment: 16
• Location: 1
• Arms: 3
• Actual Duration (Months): 3
• Patients Per Site Per Month: 5.4

Study Details

Study Description

Brief Summary

This is a single-center, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics (PK) of repeated IV doses of TD-8954 in healthy adults 18 to 45 years of age and healthy elderly subjects 65 to 85 years old. A healthy elderly subject population is included to evaluate the safety, tolerability, and PK of TD-8954 IV. Pharmacodynamic effects on bowel movements will also be evaluated. Screening for all cohorts will be conducted within 21 days before the first dose.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Motility Disorder	Drug: TD-8954; Drug: Placebo - saline	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Intravenous Dose Study to Examine the Safety, Tolerability, and Pharmacokinetics of Intravenous TD-8954, a 5-HT4 Receptor Agonist, in Healthy Subjects
• Actual Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TD-8954 Dose 1	Drug: TD-8954; Intravenous infusion
Placebo Comparator: Placebo	Drug: Placebo - saline; Intravenous infusion
Experimental: TD-8954 Dose 2	Drug: TD-8954; Intravenous infusion

Outcome Measures

Primary Outcome Measures

1. Cmax [Day 1]

   Maximum concentration in plasma following dosing on Day 1

2. Tmax [Day 1]

   Time to maximum plasma concentration

3. t½ [Day 1]

   Time to 50% plasma concentration

4. AUC0-24 [Day 1]

   Area under the plasma concentration time curve through 24 hours after dosing.

5. AUC0-∞ [Day 1]

   Area under the concentration time curve from time 0 to infinity.

6. AUCtau [Day 1]

   Area under the plasma concentration time curve over the dosing interval estimated using the linear trapezoidal rule.

7. Plasma Vz [Day 1]

   Volume of distribution

8. Plasma CL [Day 1]

   Plasma clearance

9. Cmax [Day 5]

   Maximum plasma concentration

10. Tmax [Day 5]

    Time to reach maximum plasma concentration.

11. t½ [Day 5]

    Time to 50% plasma concentration

12. AUC0-24 [Day 5]

    Area under the plasma concentration time curve 24 hours following the last dose.

13. AUC0-∞ [Day 5]

    Area under the plasma concentration time curve from 0 to infinity.

14. AUCtau [Day 5]

    Area under the plasma concentration time curve over the dosing interval estimated using the linear trapezoidal rule.

15. Vss [Day 5]

    Apparent volume of distribution at steady state

16. CLss [Day 5]

    Apparent clearance

Secondary Outcome Measures

1. Number of Subjects With Adverse Events [1 week]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. For Cohorts 1: adult males and females age 18 to 45 years, inclusive; for Cohorts 2 and 3, adult males and females 65 to 85 years of age, inclusive; for Cohort 4, adult males and females 18 to 45 or 65 to 85 years of age, inclusive.

2. Body mass index (BMI)between 18 to 36 kg/m2, inclusive.

3. Average frequency of ≥ 3 bowel movements per week.

Exclusion Criteria:

1. Persistent symptoms of functional GI disorder (such as irritable bowel syndrome, functional constipation, functional dyspepsia, or other symptom-based GI disorders unexplained by a pathologically based disorder) during the 6 months prior to screening, including a history of major surgery of the GI tract, excluding cholecystectomy and appendectomy.

2. History or presence of clinically significant respiratory, GI, renal, hepatic, endocrine, hematological, neurological (including chronic headache, current or prior psychiatric disease/condition, stroke), cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, or dermatological disorders. Subjects with mild, chronic, stable disease (e.g., controlled hypertension, controlled hypercholesterolemia, non insulin-dependent diabetes, osteoarthritis) may be enrolled if the condition is well controlled and not anticipated to interfere with the objectives of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Miami Research Associates	Miami	Florida	United States	33143

Sponsors and Collaborators

• Theravance Biopharma

Investigators

• Study Director: Brett Haumann, SVP, Clinical Development, Theravance Biopharma, US, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Theravance Biopharma
• ClinicalTrials.gov Identifier: NCT01644240
• Other Study ID Numbers: 0095
• First Posted: Jul 19, 2012
• Last Update Posted: Aug 2, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided

Study Results

Participant Flow

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Period Title: Overall Study
STARTED	6	4	6
COMPLETED	6	4	6
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2	Total
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion	Total of all reporting groups
Overall Participants	6	4	6	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.2 (4.92)	37.0 (3.56)	30.2 (5.98)	32.6 (5.49)
Sex: Female, Male (Count of Participants)
Female	2 33.3%	2 50%	3 50%	7 43.8%
Male	4 66.7%	2 50%	3 50%	9 56.3%
Region of Enrollment (Count of Participants)
United States	6 100%	4 100%	6 100%	16 100%

Outcome Measures

1. Primary Outcome

Title	Cmax
Description	Maximum concentration in plasma following dosing on Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Sample size was 6 at all time points with the exception of 0.5 hours for dose 2 where value was considered an outlier and one subject was excluded from the PK analysis resulting in sample size of 5.

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	5
Mean (Standard Deviation) [pg/mL]	6920 (2120)	1200 (275)

2. Primary Outcome

Title	Tmax
Description	Time to maximum plasma concentration
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	5
Median (Full Range) [hours]	0.983	0.887

3. Primary Outcome

Title	t½
Description	Time to 50% plasma concentration
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Subjects did not meet extrapolation criteria and were not included in the analysis.

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	3	0	1
Mean (Standard Deviation) [hours]	10.3 (1.22)	8.77

4. Primary Outcome

Title	AUC0-24
Description	Area under the plasma concentration time curve through 24 hours after dosing.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	3	0	1
Mean (Standard Deviation) [pg*hr/mL]	41500 (2740)	12800

5. Primary Outcome

Title	AUC0-∞
Description	Area under the concentration time curve from time 0 to infinity.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	3	0	1
Mean (Standard Deviation) [pg*hr/mL]	50600 (5440)	15300

6. Primary Outcome

Title	AUCtau
Description	Area under the plasma concentration time curve over the dosing interval estimated using the linear trapezoidal rule.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	5
Mean (Standard Deviation) [pg*hr/mL]	37600 (7070)	8180 (2610)

7. Primary Outcome

Title	Plasma Vz
Description	Volume of distribution
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	3	0	1
Mean (Standard Deviation) [Liters]	147 (9.37)	82.8

8. Primary Outcome

Title	Plasma CL
Description	Plasma clearance
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	3	0	1
Mean (Standard Deviation) [L/hr]	9.95 (1.03)	6.55

9. Primary Outcome

Title	Cmax
Description	Maximum plasma concentration
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	6
Mean (Standard Deviation) [pg/mL]	7070 (1550)	7600 (1650)

10. Secondary Outcome

Title	Number of Subjects With Adverse Events
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	4	6
Number [participants]	5 83.3%	1 25%	2 33.3%

11. Primary Outcome

Title	Tmax
Description	Time to reach maximum plasma concentration.
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	6
Median (Full Range) [hours]	0.983	0.983

12. Primary Outcome

Title	t½
Description	Time to 50% plasma concentration
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	6
Mean (Standard Deviation) [hours]	18.0 (3.18)	18.9 (3.47)

13. Primary Outcome

Title	AUC0-24
Description	Area under the plasma concentration time curve 24 hours following the last dose.
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	6
Mean (Standard Deviation) [pg*hr/mL]	51000 (9310)	63300 (11800)

14. Primary Outcome

Title	AUC0-∞
Description	Area under the plasma concentration time curve from 0 to infinity.
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	6
Mean (Standard Deviation) [pg*hr/mL]	80400 (15700)	102000 (12300)

15. Primary Outcome

Title	AUCtau
Description	Area under the plasma concentration time curve over the dosing interval estimated using the linear trapezoidal rule.
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	6
Mean (Standard Deviation) [pg*hr/mL]	68700 (12700)	86300 (12800)

16. Primary Outcome

Title	Vss
Description	Apparent volume of distribution at steady state
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	6
Mean (Standard Deviation) [L]	225 (68.1)	194 (60.4)

17. Primary Outcome

Title	CLss
Description	Apparent clearance
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TD-8954 Dose 1	Placebo	TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion	Placebo - saline: Intravenous infusion	TD-8954: Intravenous infusion
Measure Participants	6	0	6
Mean (Standard Deviation) [L/hr]	10.1 (2.00)	8.11 (1.34)

Adverse Events

Arm/Group Title	TD-8954 Dose 1		Placebo		TD-8954 Dose 2
Arm/Group Description	TD-8954: Intravenous infusion		Placebo - saline: Intravenous infusion		TD-8954: Intravenous infusion
All Cause Mortality
	TD-8954 Dose 1		Placebo		TD-8954 Dose 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	TD-8954 Dose 1		Placebo		TD-8954 Dose 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/4 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	TD-8954 Dose 1		Placebo		TD-8954 Dose 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		1/4 (25%)		2/6 (33.3%)
Cardiac disorders
Tachycardia	1/6 (16.7%)	1	0/4 (0%)	0	0/6 (0%)	0
Gastrointestinal disorders
Abdominal Pain	1/6 (16.7%)	1	0/4 (0%)	0	0/6 (0%)	0
Diarrhoea	1/6 (16.7%)	1	0/4 (0%)	0	0/6 (0%)	0
General disorders
Infusion Site Extravasation	1/6 (16.7%)	1	0/4 (0%)	0	0/6 (0%)	0
Investigations
Transaminases Increased	1/6 (16.7%)	1	1/4 (25%)	1	0/6 (0%)	0
Nervous system disorders
Headache	4/6 (66.7%)	4	0/4 (0%)	0	1/6 (16.7%)	1
Dizziness Postural	2/6 (33.3%)	2	0/4 (0%)	0	1/6 (16.7%)	1

Limitations/Caveats

Early termination leading to small numbers of subjects analyzed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The PI may communicate the trial results generated by the PI, but only after the first publication or presentation of the combined study results generated by all participating sites. The Sponsor can then review trial results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The Sponsor cannot require changes to the communication and cannot extend the embargo.