Efficacy & Safety of TD-1473 in Ulcerative Colitis | NCT03758443

ID	Type	Description	Link
2018-002136-24	EudraCT Number

Label	Type	Description	Intervention Names
Active Treatment TD-1473 Dose A	Experimental	Participants will be randomized to receive an oral daily dose of TD-1473. Responders will be re-randomized into the Phase 3 Maintenance portion of the study. Non-responders may participate in an extended induction.	Drug: TD-1473 Dose A
Active Treatment TD-1473 Dose B	Experimental	Participants will be randomized to receive an oral daily dose of TD-1473. Responders will be re-randomized into the Phase 3 Maintenance portion of the study. Non-responders may participate in an extended induction.	Drug: TD-1473 Dose B
Active Treatment TD-1473 Dose C	Experimental	Participants will be randomized to receive an oral daily dose of TD-1473. Responders will be re-randomized into the Phase 3 Maintenance portion of the study. Non-responders may participate in an extended induction.	Drug: TD-1473 Dose C
Placebo	Placebo Comparator	Participants will be randomized to receive an oral daily dose of placebo. Participants who received Placebo (and were non-responders) may move to an extended induction. Subjects who are on placebo will be assigned to active TD-1473 for the extended induction (they will be blinded to dose).	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
TD-1473 Dose A	Drug	See Arm description	Active Treatment TD-1473 Dose A

Measure	Description	Time Frame
Change From Baseline in Total Mayo Score (tMS) at Week 8	Total Mayo Score (tMS) was calculated as the sum of four components: rectal bleeding (0-3), stool frequency (0-3), physician's global assessment (0-3) and Mayo endoscopic subscore (0-3). tMS was reported as a 0-12 point score with 12 reflecting the highest severity.	Baseline to Week 8
Phase 3 Maintenance: Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Maintenance Week (mWeek) 44	Clinical remission by Adapted Mayo score was defined based on Adapted Mayo score components within specific ranges: stool frequency score of 0 or 1, a rectal bleeding subscore of 0 and a Mayo endoscopy subscore of 0 or 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity. Participants with missing Week 44 values were imputed as non-responders.	mWeek 44

Measure	Description	Time Frame
Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Week 8	Clinical remission by Adapted Mayo score was defined based on Adapted Mayo score components within specific ranges: stool frequency score of 0 or 1, a rectal bleeding subscore of 0 and a Mayo endoscopy subscore of 0 or 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity.

Name	Affiliation	Role
Medical Monitor	Theravance Biopharma	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Theravance Biopharma Investigational Site		Chula Vista	California	91911	United States
Theravance Biopharma Investigational Site

ID	Title	Description
FG000	Placebo	Participants were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period. Participants who achieved clinical response by adapted Mayo Score at Week 8 continued to receive blinded placebo in the Maintenance Period. Participants who did not achieve clinical response at Week 8 received 80 mg TD-1473 for 8 weeks in the Extended Induction Period. Participants who achieved clinical response to a total of 8 weeks of TD-1473 induction therapy, either at Week 8 or Week 16, were re-randomized to received placebo; 20 mg, 80 mg, or 200 mg TD-1473 for 44 weeks in the Maintenance Period. Participants who did not achieve clinical response to a total of 8 weeks of TD-1473 induction therapy underwent study exit procedures.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	May 14, 2020	Oct 21, 2022

Arm/Group Information

ID	Title	Description
BG000	Placebo	Participants were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period. Participants who achieved clinical response by adapted Mayo Score at Week 8 continued to receive blinded placebo in the Maintenance Period. Participants who did not achieve clinical response at Week 8 received 80 mg TD-1473 for 8 weeks in the Extended Induction Period. Participants who achieved clinical response to a total of 8 weeks of TD-1473 induction therapy, either at Week 8 or Week 16, were re-randomized to received placebo; 20 mg, 80 mg, or 200 mg TD-1473 for 44 weeks in the Maintenance Period. Participants who did not achieve clinical response to a total of 8 weeks of TD-1473 induction therapy underwent study exit procedures.
BG001	TD-1473 20 mg	Participants were randomized to receive once-daily administrations of 20 mg TD-1473 for 8 weeks during the Induction Period. Participants who achieved clinical response by adapted Mayo Score at Week 8 continued to receive 20 mg TD-1473 in the Maintenance Period. Participants who did not achieve clinical response at Week 8 continued to receive 20 mg TD-1473 for 8 weeks in the Extended Induction Period. Participants who achieved clinical response to a total of 16 weeks of TD-1473 induction therapy continued to receive 20 mg TD-1473 for 44 weeks in the Maintenance Period. Participants who did not achieve clinical response to a total of 16 weeks of TD-1473 induction therapy underwent study exit procedures.
BG002	TD-1473 80 mg	Participants were randomized to receive once-daily administrations of 80 mg TD-1473 for 8 weeks during the Induction Period. Participants who achieved clinical response by adapted Mayo Score at Week 8 continued to receive 80 mg TD-1473 in the Maintenance Period. Participants who did not achieve clinical response at Week 8 continued to receive 80 mg TD-1473 for 8 weeks in the Extended Induction Period. Participants who achieved clinical response to a total of 16 weeks of TD-1473 induction therapy continued to receive 80 mg TD-1473 for 44 weeks in the Maintenance Period. Participants who did not achieve clinical response to a total of 16 weeks of TD-1473 induction therapy underwent study exit procedures.
BG003	TD-1473 200 mg	Participants were randomized to receive once-daily administrations of 200 mg TD-1473 for 8 weeks during the Induction Period. Participants who achieved clinical response by adapted Mayo Score at Week 8 continued to receive 200 mg TD-1473 in the Maintenance Period. Participants who did not achieve clinical response at Week 8 continued to receive 200 mg TD-1473 for 8 weeks in the Extended Induction Period. Participants who achieved clinical response to a total of 16 weeks of TD-1473 induction therapy continued to receive 200 mg TD-1473 for 44 weeks in the Maintenance Period. Participants who did not achieve clinical response to a total of 16 weeks of TD-1473 induction therapy underwent study exit procedures.
BG004	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Total Mayo Score (tMS) at Week 8

Total Mayo Score (tMS) was calculated as the sum of four components: rectal bleeding (0-3), stool frequency (0-3), physician's global assessment (0-3) and Mayo endoscopic subscore (0-3). tMS was reported as a 0-12 point score with 12 reflecting the highest severity.

Modified Intent-to-Treat (mITT) Analysis Set (Induction Period): Comprised all randomized participants who received at least one dose of study drug.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline to Week 8

ID	Title	Description
OG000	Induction Period: Placebo	Participants were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period.
OG001	Induction Period: TD-1473 20 mg	Participants were randomized to receive once-daily administrations of 20 mg TD-1473 for 8 weeks during the Induction Period.
OG002	Induction Period: TD-1473 80 mg	Participants were randomized to receive once-daily administrations of 80 mg TD-1473 for 8 weeks during the Induction Period.
OG003	Induction Period: TD-1473 200 mg	Participants were randomized to receive once-daily administrations of 200 mg TD-1473 for 8 weeks during the Induction Period.

Units	Counts
Participants	OG00056 OG00154 OG00253 OG003

Title

Denominators

Categories

Title	Measurements
	OG000-1.75± 0.341 OG001-2.02± 0.350 OG002-2.12± 0.351 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Least square estimates, 95% CI, and p-values were obtained by fitting an ANCOVA model with terms for treatment, steroid use at baseline (yes, no) and prior biologic failure (yes, no), and baseline total Mayo score as covariate.	ANCOVA		0.5809		Least Square Mean Difference	-0.27			2-Sided	95	-1.22	0.69					Superiority
OG000 OG002

Primary

Phase 3 Maintenance: Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Maintenance Week (mWeek) 44

Clinical remission by Adapted Mayo score was defined based on Adapted Mayo score components within specific ranges: stool frequency score of 0 or 1, a rectal bleeding subscore of 0 and a Mayo endoscopy subscore of 0 or 1.

The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity.

Participants with missing Week 44 values were imputed as non-responders.

mITT Analysis Set (Maintenance Period): All participants randomized into the Phase 3 Maintenance Study who were also treated. Only participants randomized at least 44 weeks prior to database lock were included.

Posted

Count of Participants

Participants

mWeek 44

ID	Title	Description
OG000	Maintenance Period: Placebo	Participants who were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period and achieved clinical response by adapted Mayo Score at Week 8 of the Induction Period continued to receive blinded placebo for 44 weeks in the Maintenance Period.
OG001	Maintenance Period: TD-1473 20 mg	Participants who achieved clinical response to a total of 8 weeks of TD-1473 induction therapy, either at Week 8 or Week 16, and continued to receive 20 mg TD-1473 for 44 weeks in the Maintenance Period.

Secondary

Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Week 8

The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity.

mITT Analysis Set (Induction Period): Comprised all randomized participants who received at least one dose of study drug.

Posted

Count of Participants

Participants

Week 8

ID	Title	Description
OG000	Induction Period: Placebo	Participants were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period.
OG001	Induction Period: TD-1473 20 mg	Participants were randomized to receive once-daily administrations of 20 mg TD-1473 for 8 weeks during the Induction Period.
OG002	Induction Period: TD-1473 80 mg	Participants were randomized to receive once-daily administrations of 80 mg TD-1473 for 8 weeks during the Induction Period.

Secondary

Phase 3 Maintenance: Number of Participants Who Demonstrated a Clinical Response by Adapted Mayo Score Components at mWeek 44

Clinical response was defined as a reduction from baseline in adapted Mayo score of ≥ 2 points and ≥ 30% relative to baseline. It also required ≥ 1 reduction in the rectal bleeding subscore or an absolute subscore ≤ 1.

The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity.

Participants with missing Week 44 values were imputed as non-responders.

Posted

Count of Participants

Participants

Baseline to mWeek 44

ID	Title	Description
OG000	Maintenance Period: Placebo	Participants who were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period and achieved clinical response by adapted Mayo Score at Week 8 of the Induction Period continued to receive blinded placebo for 44 weeks in the Maintenance Period.
OG001	Maintenance Period: TD-1473 20 mg	Participants who achieved clinical response to a total of 8 weeks of TD-1473 induction therapy, either at Week 8 or Week 16, and continued to receive 20 mg TD-1473 for 44 weeks in the Maintenance Period.

Secondary

Phase 3 Maintenance: Number of Participants Who Demonstrated Endoscopic Remission by Adapted Mayo Score Components at mWeek 44

Endoscopic remission was defined as an endoscopic subscore ≤ 1.

Endoscopic subscore was measured using scale of 0-3, where higher numbers reflected greater severity.

Posted

Count of Participants

Participants

mWeek 44

ID	Title	Description
OG000	Maintenance Period: Placebo	Participants who were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period and achieved clinical response by adapted Mayo Score at Week 8 of the Induction Period continued to receive blinded placebo for 44 weeks in the Maintenance Period.
OG001	Maintenance Period: TD-1473 20 mg	Participants who achieved clinical response to a total of 8 weeks of TD-1473 induction therapy, either at Week 8 or Week 16, and continued to receive 20 mg TD-1473 for 44 weeks in the Maintenance Period.
OG002	Maintenance Period: TD-1473 80 mg

Secondary

Phase 3 Maintenance: Number of Participants Who Demonstrated Symptomatic Remission by Adapted Mayo Score Components at mWeek 44

Symptomatic remission was defined as a stool frequency score ≤ 1 and a rectal bleeding subscore of 0.

Stool frequency score and rectal bleeding score were each measured using scale of 0-3, where higher numbers reflected greater severity.

Participants with missing Week 44 values were imputed as non-responders.

Posted

Count of Participants

Participants

mWeek 44

ID	Title	Description
OG000	Maintenance Period: Placebo	Participants who were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period and achieved clinical response by adapted Mayo Score at Week 8 of the Induction Period continued to receive blinded placebo for 44 weeks in the Maintenance Period.
OG001	Maintenance Period: TD-1473 20 mg	Participants who achieved clinical response to a total of 8 weeks of TD-1473 induction therapy, either at Week 8 or Week 16, and continued to receive 20 mg TD-1473 for 44 weeks in the Maintenance Period.
OG002

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Induction Period: Placebo	Participants who were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period.	61	4	61	7	61
EG001	Induction Period: TD-1473 20 mg	Participants who were randomized to receive once-daily administrations of 20 mg TD-1473 for 8 weeks during the Induction Period. Participants who did not achieve clinical response at Week 8 continued to receive 20 mg TD-1473 for 8 weeks in the Extended Induction Period.	61	4	61	11	61
EG002	Induction Period: TD-1473 80 mg	Participants who were randomized to receive once-daily administrations of 80 mg TD-1473 for 8 weeks during the Induction Period. Participants who did not achieve clinical response at Week 8 continued to receive 80 mg TD-1473 for 8 weeks in the Extended Induction Period.	59	2	59	9	59
EG003	Induction Period: Placebo to TD-1473 80 mg	Participants who were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period. Participants who did not achieve clinical response at Week 8 received 80 mg TD-1473 for 8 weeks in the Extended Induction Period.	42	3	42	4	42
EG004	Induction Period: TD-1473 200 mg	Participants who were randomized to receive once-daily administrations of 200 mg TD-1473 for 8 weeks during the Induction Period. Participants who did not achieve clinical response at Week 8 continued to receive 200 mg TD-1473 for 8 weeks in the Extended Induction Period.	58	4	58	14	58
EG005	Maintenance Period: Placebo	Participants who were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period and achieved clinical response by adapted Mayo Score at Week 8 of the Induction Period continued to receive blinded placebo for 44 weeks in the Maintenance Period.	29	1	29	6	29
EG006	Maintenance Period: TD-1473 20 mg	Participants who achieved clinical response to a total of 8 weeks of TD-1473 induction therapy, either at Week 8 or Week 16, and were re-randomized to 20 mg TD-1473 for 44 weeks in the Maintenance Period.	31	2	31	14	31
EG007	Maintenance Period: TD-1473 80 mg	Participants who achieved clinical response to a total of 8 weeks of TD-1473 induction therapy, either at Week 8 or Week 16, and were re-randomized to 80 mg TD-1473 for 44 weeks in the Maintenance Period.	25	2	25	5	25
EG008	Maintenance Period: TD-1473 200 mg	Participants who achieved clinical response to a total of 8 weeks of TD-1473 induction therapy, either at Week 8 or Week 16, and were re-randomized to 200 mg TD-1473 for 44 weeks in the Maintenance Period.	22	1	22	1	22

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Colitis ulcerative	Gastrointestinal disorders	MedDRA (24.1)	Systematic Assessment	EG0002 affected61 at risk EG0013 affected61 at risk EG0021 affected59 at risk EG0031 affected42 at risk EG0042 affected58 at risk EG0050 affected29 at risk EG0060 affected31 at risk EG0071 affected25 at risk EG0081 affected22 at risk
Atrial fibrillation	Cardiac disorders	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0010 affected61 at risk EG0020 affected59 at risk EG003
Angina pectoris	Cardiac disorders	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0010 affected61 at risk EG0020 affected59 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0010 affected61 at risk EG0020 affected59 at risk EG003
Rhabdomyolysis	Musculoskeletal and connective tissue disorders	MedDRA (24.1)	Systematic Assessment	EG0001 affected61 at risk EG0010 affected61 at risk EG0020 affected59 at risk EG003
Cytomegalovirus colitis	Infections and infestations	MedDRA (24.1)	Systematic Assessment	EG0001 affected61 at risk EG0010 affected61 at risk EG0020 affected59 at risk EG003
Liver abscess	Infections and infestations	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0011 affected61 at risk EG0020 affected59 at risk EG003
Large intestine operation	Surgical and medical procedures	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0010 affected61 at risk EG0021 affected59 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0010 affected61 at risk EG0020 affected59 at risk EG003
Adenocarcinoma of colon	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0011 affected61 at risk EG0020 affected59 at risk EG003
Tubulointerstitial nephritis	Renal and urinary disorders	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0010 affected61 at risk EG0020 affected59 at risk EG003
Urethral stenosis	Renal and urinary disorders	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0010 affected61 at risk EG0020 affected59 at risk EG003
Joint injury	Injury, poisoning and procedural complications	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0010 affected61 at risk EG0020 affected59 at risk EG003
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (24.1)	Systematic Assessment	EG0000 affected61 at risk EG0010 affected61 at risk EG0020 affected59 at risk EG003

ID	Term
D003093	Colitis, Ulcerative
D015212	Inflammatory Bowel Diseases

ID	Term
D003092	Colitis
D005759	Gastroenteritis
D005767	Gastrointestinal Diseases
D004066	Digestive System Diseases
D003108	Colonic Diseases
D007410	Intestinal Diseases