Study to Assess the Efficacy and Safety of Simtuzumab (GS-6624) in Adults With Idiopathic Pulmonary Fibrosis (IPF) (RAINIER)

• ClinicalTrials.gov Identifier: NCT01769196
• Recruitment Status: Terminated
• First Posted: January 16, 2013
• Results First Posted: April 13, 2017
• Last Update Posted: May 30, 2017
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Idiopathic Pulmonary Fibrosis
• Interventions: Drug: Simtuzumab; Drug: Simtuzumab placebo
• Enrollment: 544

Participant Flow

Recruitment Details	Participants were enrolled at study sites in North America, Europe, and Asia Pacific. The first participant was screened on 31 January 2013. The last study visit occurred on 23 February 2016.
Pre-assignment Details	1250 participants were screened.

Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Period Title: Overall Study
Started	272	272
Completed	0	0
Not Completed	272	272
Reason Not Completed
Adverse Event	24	20
Death	21	26
Investigator Discretion	7	3
Lack of Efficacy	3	2
Progressive disease	11	6
Protocol defined criteria for withdrawal	9	11
Protocol Violation	0	3
Study terminated by sponsor	160	161
Participant never dosed with study drug	1	0
Withdrew consent	36	40

Baseline Characteristics

Arm/Group Title		Simtuzumab	Simtuzumab Placebo	Total
Arm/Group Description		Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week	Total of all reporting groups
Overall Number of Baseline Participants		272	272	544
Baseline Analysis Population Description		Intent-to-Treat (ITT) Analysis Set included all participants who were randomized into the study, and were analyzed according to treatment randomized.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	272 participants	272 participants	544 participants
		67.7 (7.60)	68.5 (7.07)	68.1 (7.34)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	272 participants	272 participants	544 participants
	Female	45 16.5%	47 17.3%	92 16.9%
	Male	227 83.5%	225 82.7%	452 83.1%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	272 participants	272 participants	544 participants
Asian		35 12.9%	36 13.2%	71 13.1%
Black		3 1.1%	3 1.1%	6 1.1%
White		231 84.9%	229 84.2%	460 84.6%
Other		3 1.1%	4 1.5%	7 1.3%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	272 participants	272 participants	544 participants
Hispanic or Latino		5 1.8%	7 2.6%	12 2.2%
Not Hispanic or Latino		267 98.2%	264 97.1%	531 97.6%
Not Permitted		0 0.0%	1 0.4%	1 0.2%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	272 participants	272 participants	544 participants
United States		102 37.5%	106 39.0%	208 38.2%
Korea, Republic of		34 12.5%	35 12.9%	69 12.7%
Spain		11 4.0%	13 4.8%	24 4.4%
Canada		10 3.7%	14 5.1%	24 4.4%
Czech Republic		6 2.2%	6 2.2%	12 2.2%
Belgium		10 3.7%	4 1.5%	14 2.6%
United Kingdom		12 4.4%	21 7.7%	33 6.1%
Poland		15 5.5%	13 4.8%	28 5.1%
Italy		8 2.9%	6 2.2%	14 2.6%
Israel		7 2.6%	5 1.8%	12 2.2%
Australia		11 4.0%	18 6.6%	29 5.3%
France		24 8.8%	12 4.4%	36 6.6%
Germany		22 8.1%	18 6.6%	40 7.4%
Switzerland		0 0.0%	1 0.4%	1 0.2%
Forced vital capacity (FVC) Percent Predicted; Mean (Standard Deviation); Unit of measure: FVC % predicted
	Number Analyzed	272 participants	272 participants	544 participants
		61.4 (12.17)	62.3 (12.22)	61.8 (12.19)
FVC % Predicted Category; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	272 participants	272 participants	544 participants
Mild		37 13.6%	46 16.9%	83 15.3%
Moderate		152 55.9%	150 55.1%	302 55.5%
Severe		83 30.5%	76 27.9%	159 29.2%
Baseline Serum LOXL2; Mean (Standard Deviation); Unit of measure: pg/mL
	Number Analyzed	272 participants	272 participants	544 participants
		89.8 (70.06)	86.7 (51.99)	88.2 (61.48)

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival
Description	Progression free survival (PFS) was defined as the categorical decrease in forced vital capacity (FVC) % predicted (≥ 10% relative decrease in FVC and ≥ 5% absolute decrease in FVC from baseline) with confirmation at a consecutive visit at least 2 weeks later using the same criteria.
Time Frame	Up to 148 weeks

Outcome Measure Data

Analysis Population Description

ITT Analysis Set

Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description:	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed	272	272
Median (95% Confidence Interval); Unit of Measure: months
	12.6; (11.3 to 14.4)	15.4; (12.6 to 19.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Simtuzumab, Simtuzumab Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The null hypothesis was that there is no difference in PFS between simtuzumab and simtuzumab placebo. The alternative hypothesis was that there is a difference. These hypotheses were evaluated using stratified log-rank test, adjusted for screening post-bronchodilator FVC % predicted, sLOXL2 level categories and concomitant use of pirfenidone or nintedanib (P/N) at time of screening.
Statistical Test of Hypothesis	P-Value	0.329
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.45
	Estimation Comments	Hazard ratio was estimated from Cox regression model adjusted for treatment and stratified for screening post-bronchodilator FVC % predicted, sLOXL2 level categories, and concomitant pirfenidone/nintedanib use at time of screening.

2. Primary Outcome

Title	PFS Among the Participants With sLOXL2 ≥ 50th Percentile
Description	[Not Specified]
Time Frame	Up to 148 weeks

Outcome Measure Data

Analysis Population Description

Participants in the ITT Analysis Set with serum LOXL2 (sLOXL2) ≥ 50th percentile in peripheral blood were analyzed.

Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description:	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed	137	140
Median (95% Confidence Interval); Unit of Measure: months
	11.7; (9.9 to 15.9)	14.3; (10.4 to 19.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Simtuzumab, Simtuzumab Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The null hypothesis was that there is no difference in PFS between simtuzumab and simtuzumab placebo in participants with sLOXL2 ≥ 50th percentile. The alternative hypothesis was that there is a difference. These hypotheses were evaluated using stratified log-rank test, adjusted for screening post-bronchodilator FVC % predicted and concomitant use of pirfenidone or nintedanib (P/N) at time of screening.
Statistical Test of Hypothesis	P-Value	0.851
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.43
	Estimation Comments	Hazard ratio was estimated from Cox regression model adjusted for treatment and stratified for screening post-bronchodilator FVC % predicted and concomitant pirfenidone/nintedanib use at time of screening.

3. Primary Outcome

Title	PFS Among the Participants With sLOXL2 ≥ 75th Percentile
Description	[Not Specified]
Time Frame	Up to 148 weeks

Outcome Measure Data

Analysis Population Description

Participants in the ITT Analysis Set with sLOXL2 ≥ 75th percentile in peripheral blood were analyzed.

Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description:	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed	68	71
Median (95% Confidence Interval); Unit of Measure: months
	11.6; (9.0 to 15.0)	16.9; (7.7 to 21.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Simtuzumab, Simtuzumab Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The null hypothesis was that there is no difference in PFS between simtuzumab and simtuzumab placebo in participants with sLOXL2 ≥ 75th percentile. The alternative hypothesis was that there is a difference. These hypotheses were evaluated using stratified log-rank test, adjusted for screening post-bronchodilator FVC % predicted and concomitant use of pirfenidone or nintedanib (P/N) at time of screening.
Statistical Test of Hypothesis	P-Value	0.475
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.72 to 2.00
	Estimation Comments	Hazard ratio was estimated from Cox regression model adjusted for treatment and stratified for screening post-bronchodilator FVC % predicted and concomitant pirfenidone/nintedanib use at time of screening.

4. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival was defined as the time from randomization date to death that occurred prior to the last dose date plus 30 days.
Time Frame	Up to 151 weeks

Outcome Measure Data

Analysis Population Description

ITT Analysis Set

Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description:	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed	272	272
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA = Not reached due to insufficient number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Simtuzumab, Simtuzumab Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.602
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.61 to 2.37
	Estimation Comments	Hazard ratio was estimated from Cox regression model adjusted for treatment and stratified for screening post-bronchodilator FVC % predicted, sLOXL2 level categories, and concomitant pirfenidone/nintedanib use at time of screening.

5. Secondary Outcome

Title	Overall Survival Among the Participants With sLOXL2 ≥ 50th Percentile
Description	[Not Specified]
Time Frame	Up to 151 weeks

Outcome Measure Data

Analysis Population Description

Participants in the ITT Analysis Set with sLOXL2 ≥ 50th percentile in peripheral blood were analyzed.

Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description:	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed	137	140
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA = Not reached due to insufficient number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Simtuzumab, Simtuzumab Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	The difference in OS between the treatment groups was assessed using the stratified log-rank test, adjusted for screening post-bronchodilator FVC % predicted and concomitant use of pirfenidone or nintedanib (P/N) at time of screening.
Statistical Test of Hypothesis	P-Value	0.988
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.43 to 2.28
	Estimation Comments	Hazard ratio was estimated from Cox regression model adjusted for treatment and stratified for screening post-bronchodilator FVC % predicted and concomitant pirfenidone/nintedanib use at time of screening.

6. Secondary Outcome

Title	Overall Survival Among the Participants With sLOXL2 ≥ 75th Percentile
Description	[Not Specified]
Time Frame	Up to 151 weeks

Outcome Measure Data

Analysis Population Description

Participants in the ITT Analysis Set with sLOXL2 ≥ 75th percentile in peripheral blood were analyzed.

Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description:	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed	68	71
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (19.2 to NA)	NA [1]; (NA to NA)

[1]

NA = Not reached due to insufficient number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Simtuzumab, Simtuzumab Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	The difference in OS between the treatment groups was assessed using the stratified log-rank test, adjusted for screening post-bronchodilator FVC % predicted and concomitant use of pirfenidone or nintedanib (P/N) at time of screening.
Statistical Test of Hypothesis	P-Value	0.925
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.30 to 2.99
	Estimation Comments	Hazard ratio was estimated from Cox regression model adjusted for treatment and stratified for screening post-bronchodilator FVC % predicted and concomitant pirfenidone/nintedanib use at time of screening.

7. Secondary Outcome

Title	Relative Change From Baseline in FVC % Predicted
Description	FVC was defined as the volume of air (liters) that can forcibly be blown out after taking a full breath. FVC % predicted was defined as FVC % of the participant divided by the average FVC % in the population for any person of similar age, sex, and body composition.; Adjusted means were from mixed model repeated measures (MMRM) model with baseline FVC % predicted, sLOXL2 level, concomitant pirfenidone/nintedanib use (never vs. ever), treatment, visit, and treatment-by-visit interaction terms, including all data up to Week 130; The relative change was calculated as 100% * ( value at later time point minus value at baseline ) / value at baseline, with lower values indicating a decrease and higher values indicating an increase.
Time Frame	Weeks 54, 106, and 130

Outcome Measure Data

Analysis Population Description

Participants in the ITT Analysis Set with available data were analyzed. Any participant with available outcome data on baseline or post-baseline was included in the MMRM model, thus all 272 participants in each of the two treatment groups were included in this analysis.

Arm/Group Title		Simtuzumab	Simtuzumab Placebo
Arm/Group Description:		Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed		272	272
Least Squares Mean (Standard Error); Unit of Measure: Percent change in FVC % predicted
Week 54	Number Analyzed	124 participants	117 participants
		-9.20 (0.643)	-8.88 (0.658)
Week 106	Number Analyzed	60 participants	55 participants
		-13.70 (0.883)	-12.16 (0.908)
Week 130	Number Analyzed	10 participants	12 participants
		-18.09 (1.712)	-11.83 (1.600)

8. Secondary Outcome

Title	Definite Acute Exacerbations of IPF Among Adjudicated Respiratory Hospitalizations
Description	[Not Specified]
Time Frame	Up to 148 weeks

Outcome Measure Data

Analysis Population Description

Participants in the ITT Analysis Set with adjudicated respiratory hospitalizations were analyzed.

Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description:	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed	99	84
Measure Type: Count of Participants; Unit of Measure: Participants
	5 5.1%	5 6.0%

9. Secondary Outcome

Title	Number of Adjudicated Respiratory Hospitalizations (ARP) Among Total Hospitalizations
Description	[Not Specified]
Time Frame	Up to 148 weeks

Outcome Measure Data

Analysis Population Description

Participants in ITT Analysis Set with total hospitalizations were analyzed.

Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description:	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed	181	154
Measure Type: Count of Participants; Unit of Measure: Participants
	99 54.7%	84 54.5%

10. Secondary Outcome

Title	Number of Participants Experiencing Adjudicated Respiratory Deaths Among Those With Adjudicated Death
Description	[Not Specified]
Time Frame	Up to 148 weeks

Outcome Measure Data

Analysis Population Description

Participants in the ITT Analysis Set with adjudicated deaths were analyzed.

Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description:	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed	19	17
Measure Type: Count of Participants; Unit of Measure: Participants
	17 89.5%	13 76.5%

11. Secondary Outcome

Title	Absolute Change From Baseline in 6 Minute Walk Distance (6MWD)
Description	Adjusted means were from MMRM model with baseline 6MWD, FVC % predicted, sLOXL2 level, concomitant pirfenidone/nintedanib use (never vs. ever), treatment, visit, and treatment-by-visit interaction terms, including all data up to Week 130.; The absolute change was calculated as value at later time point minus value at baseline, with lower values indicating a decrease and higher values indicating an increase.
Time Frame	Weeks 58, 106, and 130

Outcome Measure Data

Analysis Population Description

Participants in the ITT Analysis Set with available data were analyzed. Any participant with available outcome data on baseline or post-baseline was included in the MMRM model, thus all 272 participants in each of the two treatment groups were included in this analysis.

Arm/Group Title		Simtuzumab	Simtuzumab Placebo
Arm/Group Description:		Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed		272	272
Least Squares Mean (Standard Error); Unit of Measure: Meters
Week 58	Number Analyzed	95 participants	98 participants
		-33.76 (6.617)	-14.70 (6.596)
Week 106	Number Analyzed	44 participants	37 participants
		-37.43 (9.710)	-24.30 (10.318)
Week 130	Number Analyzed	7 participants	9 participants
		-71.20 (19.140)	-31.65 (18.458)

12. Secondary Outcome

Title	Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score
Description	The SGRQ is a disease-specific questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Patients respond to questions about symptoms (frequency & severity) and impact components (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100, with higher scores indicating more limitations.; The absolute change was calculated as value at later time point minus value at baseline, with lower values indicating a decrease and higher values indicating an increase.
Time Frame	Week 58, 106, and 130

Outcome Measure Data

Analysis Population Description

Participants in the ITT Analysis Set with available data were analyzed. Any participant with available outcome data on baseline or post-baseline was included in the MMRM model, thus all 272 participants in each of the two treatment groups were included in this analysis.

Arm/Group Title		Simtuzumab	Simtuzumab Placebo
Arm/Group Description:		Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
Overall Number of Participants Analyzed		272	272
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
Week 58	Number Analyzed	101 participants	104 participants
		6.07 (1.015)	3.62 (1.010)
Week 106	Number Analyzed	48 participants	37 participants
		10.34 (1.425)	6.54 (1.559)
Week 130	Number Analyzed	10 participants	10 participants
		18.10 (2.424)	1.08 (2.473)

Adverse Events

Time Frame	30 days post last study treatment (up to 148 weeks)
Adverse Event Reporting Description	Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Arm/Group Title	Simtuzumab	Simtuzumab Placebo
Arm/Group Description	Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab placebo administered subcutaneously once a week
All-Cause Mortality
	Simtuzumab	Simtuzumab Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	31/271 (11.44%)	32/272 (11.76%)
Serious Adverse Events
	Simtuzumab	Simtuzumab Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	101/271 (37.27%)	97/272 (35.66%)
Blood and lymphatic system disorders
Anaemia † 1	1/271 (0.37%)	0/272 (0.00%)
Pancytopenia † 1	0/271 (0.00%)	1/272 (0.37%)
Cardiac disorders
Acute myocardial infarction † 1	3/271 (1.11%)	5/272 (1.84%)
Acute right ventricular failure † 1	0/271 (0.00%)	1/272 (0.37%)
Angina pectoris † 1	2/271 (0.74%)	0/272 (0.00%)
Aortic valve stenosis † 1	0/271 (0.00%)	1/272 (0.37%)
Atrial fibrillation † 1	6/271 (2.21%)	1/272 (0.37%)
Atrial flutter † 1	2/271 (0.74%)	0/272 (0.00%)
Cardiac arrest † 1	1/271 (0.37%)	0/272 (0.00%)
Cardiac failure † 1	0/271 (0.00%)	2/272 (0.74%)
Cardiac failure congestive † 1	1/271 (0.37%)	0/272 (0.00%)
Cardio-respiratory arrest † 1	1/271 (0.37%)	0/272 (0.00%)
Cardiomyopathy † 1	1/271 (0.37%)	0/272 (0.00%)
Coronary artery disease † 1	1/271 (0.37%)	3/272 (1.10%)
Coronary artery occlusion † 1	1/271 (0.37%)	1/272 (0.37%)
Myocardial ischaemia † 1	1/271 (0.37%)	0/272 (0.00%)
Pleuropericarditis † 1	1/271 (0.37%)	0/272 (0.00%)
Right ventricular dysfunction † 1	0/271 (0.00%)	1/272 (0.37%)
Right ventricular failure † 1	1/271 (0.37%)	0/272 (0.00%)
Supraventricular tachycardia † 1	2/271 (0.74%)	0/272 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	0/271 (0.00%)	1/272 (0.37%)
Abdominal pain upper † 1	1/271 (0.37%)	0/272 (0.00%)
Colitis ulcerative † 1	1/271 (0.37%)	0/272 (0.00%)
Diverticulum intestinal haemorrhagic † 1	1/271 (0.37%)	0/272 (0.00%)
Gastritis † 1	0/271 (0.00%)	1/272 (0.37%)
Melaena † 1	1/271 (0.37%)	0/272 (0.00%)
Mesenteric venous occlusion † 1	1/271 (0.37%)	0/272 (0.00%)
Oesophageal varices haemorrhage † 1	0/271 (0.00%)	1/272 (0.37%)
Pancreatitis † 1	0/271 (0.00%)	1/272 (0.37%)
Pancreatitis acute † 1	1/271 (0.37%)	2/272 (0.74%)
Rectal haemorrhage † 1	1/271 (0.37%)	0/272 (0.00%)
Small intestinal obstruction † 1	0/271 (0.00%)	1/272 (0.37%)
Upper gastrointestinal haemorrhage † 1	1/271 (0.37%)	0/272 (0.00%)
General disorders
Asthenia † 1	1/271 (0.37%)	2/272 (0.74%)
Chest discomfort † 1	1/271 (0.37%)	0/272 (0.00%)
Chest pain † 1	2/271 (0.74%)	3/272 (1.10%)
Death † 1	1/271 (0.37%)	0/272 (0.00%)
Fatigue † 1	2/271 (0.74%)	0/272 (0.00%)
General physical health deterioration † 1	2/271 (0.74%)	0/272 (0.00%)
Pyrexia † 1	2/271 (0.74%)	0/272 (0.00%)
Hepatobiliary disorders
Cholecystitis † 1	0/271 (0.00%)	2/272 (0.74%)
Cholecystitis acute † 1	4/271 (1.48%)	1/272 (0.37%)
Cholelithiasis † 1	2/271 (0.74%)	0/272 (0.00%)
Hepatic mass † 1	0/271 (0.00%)	1/272 (0.37%)
Hepatic necrosis † 1	0/271 (0.00%)	1/272 (0.37%)
Infections and infestations
Appendicitis † 1	0/271 (0.00%)	1/272 (0.37%)
Bacteraemia † 1	2/271 (0.74%)	0/272 (0.00%)
Bronchitis † 1	2/271 (0.74%)	0/272 (0.00%)
Cellulitis † 1	0/271 (0.00%)	1/272 (0.37%)
Endocarditis † 1	1/271 (0.37%)	0/272 (0.00%)
Furuncle † 1	0/271 (0.00%)	1/272 (0.37%)
Gastroenteritis † 1	1/271 (0.37%)	1/272 (0.37%)
Hepatitis E † 1	0/271 (0.00%)	1/272 (0.37%)
Influenza † 1	1/271 (0.37%)	0/272 (0.00%)
Intervertebral discitis † 1	1/271 (0.37%)	0/272 (0.00%)
Lower respiratory tract infection † 1	0/271 (0.00%)	4/272 (1.47%)
Lung infection † 1	0/271 (0.00%)	1/272 (0.37%)
Mycetoma mycotic † 1	0/271 (0.00%)	1/272 (0.37%)
Oropharyngitis fungal † 1	0/271 (0.00%)	1/272 (0.37%)
Osteomyelitis † 1	1/271 (0.37%)	0/272 (0.00%)
Pneumonia † 1	16/271 (5.90%)	18/272 (6.62%)
Pneumonia klebsiella † 1	0/271 (0.00%)	1/272 (0.37%)
Pulmonary tuberculosis † 1	1/271 (0.37%)	0/272 (0.00%)
Pyelonephritis † 1	0/271 (0.00%)	1/272 (0.37%)
Respiratory moniliasis † 1	0/271 (0.00%)	1/272 (0.37%)
Respiratory syncytial virus infection † 1	0/271 (0.00%)	1/272 (0.37%)
Respiratory tract infection † 1	0/271 (0.00%)	3/272 (1.10%)
Sepsis † 1	1/271 (0.37%)	1/272 (0.37%)
Upper respiratory tract infection † 1	1/271 (0.37%)	1/272 (0.37%)
Urinary tract infection † 1	3/271 (1.11%)	0/272 (0.00%)
Urosepsis † 1	1/271 (0.37%)	0/272 (0.00%)
Injury, poisoning and procedural complications
Contusion † 1	0/271 (0.00%)	1/272 (0.37%)
Femur fracture † 1	1/271 (0.37%)	0/272 (0.00%)
Ligament sprain † 1	0/271 (0.00%)	1/272 (0.37%)
Post procedural stroke † 1	0/271 (0.00%)	1/272 (0.37%)
Rib fracture † 1	0/271 (0.00%)	1/272 (0.37%)
Spinal compression fracture † 1	0/271 (0.00%)	1/272 (0.37%)
Investigations
Blood creatinine increased † 1	1/271 (0.37%)	0/272 (0.00%)
Blood urea increased † 1	1/271 (0.37%)	0/272 (0.00%)
Ejection fraction decreased † 1	0/271 (0.00%)	1/272 (0.37%)
International normalised ratio increased † 1	1/271 (0.37%)	0/272 (0.00%)
Metabolism and nutrition disorders
Diabetic ketoacidosis † 1	0/271 (0.00%)	1/272 (0.37%)
Type 2 diabetes mellitus † 1	0/271 (0.00%)	1/272 (0.37%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion † 1	0/271 (0.00%)	1/272 (0.37%)
Musculoskeletal chest pain † 1	0/271 (0.00%)	1/272 (0.37%)
Rheumatoid arthritis † 1	1/271 (0.37%)	0/272 (0.00%)
Rotator cuff syndrome † 1	1/271 (0.37%)	1/272 (0.37%)
Spinal column stenosis † 1	1/271 (0.37%)	0/272 (0.00%)
Spondylolysis † 1	0/271 (0.00%)	1/272 (0.37%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma † 1	1/271 (0.37%)	0/272 (0.00%)
Bronchioloalveolar carcinoma † 1	0/271 (0.00%)	1/272 (0.37%)
Colon cancer † 1	0/271 (0.00%)	1/272 (0.37%)
Gastrointestinal carcinoma † 1	0/271 (0.00%)	1/272 (0.37%)
Lung cancer metastatic † 1	1/271 (0.37%)	0/272 (0.00%)
Lung neoplasm malignant † 1	1/271 (0.37%)	1/272 (0.37%)
Malignant melanoma † 1	0/271 (0.00%)	1/272 (0.37%)
Metastases to liver † 1	0/271 (0.00%)	1/272 (0.37%)
Metastases to lung † 1	0/271 (0.00%)	1/272 (0.37%)
Non-small cell lung cancer † 1	1/271 (0.37%)	0/272 (0.00%)
Oesophageal carcinoma † 1	0/271 (0.00%)	1/272 (0.37%)
Squamous cell carcinoma of lung † 1	1/271 (0.37%)	1/272 (0.37%)
Squamous cell carcinoma of the tongue † 1	1/271 (0.37%)	0/272 (0.00%)
Nervous system disorders
Amnesia † 1	1/271 (0.37%)	0/272 (0.00%)
Carotid artery stenosis † 1	0/271 (0.00%)	1/272 (0.37%)
Chronic inflammatory demyelinating polyradiculoneuropathy † 1	0/271 (0.00%)	1/272 (0.37%)
Dizziness † 1	1/271 (0.37%)	0/272 (0.00%)
Facial paresis † 1	0/271 (0.00%)	1/272 (0.37%)
Hypoaesthesia † 1	0/271 (0.00%)	1/272 (0.37%)
Ischaemic stroke † 1	0/271 (0.00%)	1/272 (0.37%)
Polyneuropathy † 1	1/271 (0.37%)	0/272 (0.00%)
Presyncope † 1	0/271 (0.00%)	1/272 (0.37%)
Seizure † 1	0/271 (0.00%)	1/272 (0.37%)
Syncope † 1	2/271 (0.74%)	2/272 (0.74%)
Transient ischaemic attack † 1	2/271 (0.74%)	2/272 (0.74%)
VIth nerve paralysis † 1	0/271 (0.00%)	1/272 (0.37%)
Renal and urinary disorders
Acute kidney injury † 1	1/271 (0.37%)	0/272 (0.00%)
Calculus urinary † 1	0/271 (0.00%)	1/272 (0.37%)
Glomerulonephritis † 1	1/271 (0.37%)	0/272 (0.00%)
Goodpasture's syndrome † 1	1/271 (0.37%)	0/272 (0.00%)
Haematuria † 1	0/271 (0.00%)	1/272 (0.37%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	6/271 (2.21%)	1/272 (0.37%)
Cough † 1	1/271 (0.37%)	1/272 (0.37%)
Dyspnoea † 1	10/271 (3.69%)	7/272 (2.57%)
Dyspnoea exertional † 1	0/271 (0.00%)	1/272 (0.37%)
Haemoptysis † 1	0/271 (0.00%)	1/272 (0.37%)
Hypoxia † 1	3/271 (1.11%)	2/272 (0.74%)
Idiopathic pulmonary fibrosis † 1	31/271 (11.44%)	35/272 (12.87%)
Interstitial lung disease † 1	0/271 (0.00%)	1/272 (0.37%)
Lung disorder † 1	0/271 (0.00%)	1/272 (0.37%)
Nasal polyps † 1	1/271 (0.37%)	0/272 (0.00%)
Pleural effusion † 1	0/271 (0.00%)	1/272 (0.37%)
Pleurisy † 1	1/271 (0.37%)	0/272 (0.00%)
Pneumothorax † 1	2/271 (0.74%)	3/272 (1.10%)
Pulmonary alveolar haemorrhage † 1	1/271 (0.37%)	0/272 (0.00%)
Pulmonary embolism † 1	1/271 (0.37%)	3/272 (1.10%)
Pulmonary fibrosis † 1	3/271 (1.11%)	0/272 (0.00%)
Pulmonary hypertension † 1	1/271 (0.37%)	0/272 (0.00%)
Pulmonary oedema † 1	1/271 (0.37%)	0/272 (0.00%)
Respiratory disorder † 1	1/271 (0.37%)	0/272 (0.00%)
Respiratory distress † 1	1/271 (0.37%)	1/272 (0.37%)
Respiratory failure † 1	5/271 (1.85%)	4/272 (1.47%)
Tachypnoea † 1	1/271 (0.37%)	0/272 (0.00%)
Skin and subcutaneous tissue disorders
Diabetic foot † 1	0/271 (0.00%)	1/272 (0.37%)
Vascular disorders
Aortic stenosis † 1	2/271 (0.74%)	1/272 (0.37%)
Circulatory collapse † 1	0/271 (0.00%)	1/272 (0.37%)
Deep vein thrombosis † 1	1/271 (0.37%)	1/272 (0.37%)
Femoral artery occlusion † 1	0/271 (0.00%)	1/272 (0.37%)
Hypertension † 1	1/271 (0.37%)	0/272 (0.00%)
Peripheral ischaemia † 1	0/271 (0.00%)	1/272 (0.37%)
Peripheral vascular disorder † 1	0/271 (0.00%)	1/272 (0.37%)
Vasculitis † 1	1/271 (0.37%)	0/272 (0.00%)
1 Term from vocabulary, MedDRA 18.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Simtuzumab	Simtuzumab Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	237/271 (87.45%)	246/272 (90.44%)
Gastrointestinal disorders
Constipation † 1	16/271 (5.90%)	13/272 (4.78%)
Diarrhoea † 1	44/271 (16.24%)	47/272 (17.28%)
Gastrooesophageal reflux disease † 1	21/271 (7.75%)	22/272 (8.09%)
Nausea † 1	33/271 (12.18%)	35/272 (12.87%)
General disorders
Asthenia † 1	15/271 (5.54%)	17/272 (6.25%)
Chest pain † 1	18/271 (6.64%)	16/272 (5.88%)
Fatigue † 1	49/271 (18.08%)	48/272 (17.65%)
Injection site bruising † 1	17/271 (6.27%)	10/272 (3.68%)
Oedema peripheral † 1	21/271 (7.75%)	12/272 (4.41%)
Pyrexia † 1	21/271 (7.75%)	12/272 (4.41%)
Infections and infestations
Bronchitis † 1	32/271 (11.81%)	39/272 (14.34%)
Lower respiratory tract infection † 1	8/271 (2.95%)	15/272 (5.51%)
Nasopharyngitis † 1	36/271 (13.28%)	43/272 (15.81%)
Respiratory tract infection † 1	14/271 (5.17%)	17/272 (6.25%)
Sinusitis † 1	16/271 (5.90%)	14/272 (5.15%)
Upper respiratory tract infection † 1	57/271 (21.03%)	57/272 (20.96%)
Investigations
Weight decreased † 1	25/271 (9.23%)	24/272 (8.82%)
Metabolism and nutrition disorders
Decreased appetite † 1	29/271 (10.70%)	34/272 (12.50%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	35/271 (12.92%)	22/272 (8.09%)
Back pain † 1	27/271 (9.96%)	28/272 (10.29%)
Pain in extremity † 1	9/271 (3.32%)	14/272 (5.15%)
Nervous system disorders
Dizziness † 1	31/271 (11.44%)	26/272 (9.56%)
Headache † 1	32/271 (11.81%)	35/272 (12.87%)
Psychiatric disorders
Depression † 1	14/271 (5.17%)	12/272 (4.41%)
Insomnia † 1	15/271 (5.54%)	17/272 (6.25%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	102/271 (37.64%)	93/272 (34.19%)
Dyspnoea † 1	98/271 (36.16%)	73/272 (26.84%)
Dyspnoea exertional † 1	30/271 (11.07%)	29/272 (10.66%)
Epistaxis † 1	16/271 (5.90%)	9/272 (3.31%)
Idiopathic pulmonary fibrosis † 1	33/271 (12.18%)	27/272 (9.93%)
Oropharyngeal pain † 1	16/271 (5.90%)	15/272 (5.51%)
Productive cough † 1	22/271 (8.12%)	18/272 (6.62%)
Rhinorrhoea † 1	19/271 (7.01%)	15/272 (5.51%)
Sputum increased † 1	14/271 (5.17%)	4/272 (1.47%)
Skin and subcutaneous tissue disorders
Pruritus † 1	17/271 (6.27%)	8/272 (2.94%)
Rash † 1	22/271 (8.12%)	21/272 (7.72%)
Vascular disorders
Hypertension † 1	15/271 (5.54%)	12/272 (4.41%)
1 Term from vocabulary, MedDRA 18.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met:

• The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or
• The study has been completed at all study sites for at least 2 years

Results Point of Contact

• Name/Title: Clinical Trial Disclosures
• Organization: Gilead Sciences
• EMail: ClinicalTrialDisclosures@gilead.com

Publications of Results:

Humphries SM, O'Riordan TG, Zhang JJ, Bayly S, Sood R, Hayden A, Lynch DA; Relationship Baseline Fibrosis Score to Lung Function in A Clinical Trial Population with Idiopathic Pulmonary Fibrosis. ATS International Conference, 2016 May 13-18, San Francisco CA.

Raghu G, Brown K, Collard H, Lederer D, Martinez F, Noble P, Song JW, Wells A, Whelan T, Moreau E, Patterson S, Bayly S, Chien J, Zhang J, O'Riordan T; Simtuzumab in Idiopathic Pulmonary Fibrosis: Results of a Randomized Clinical Trial. ERS Congress, 2016 September 3-7, London, UK.

Raghu G, Brown KK, Collard HR, Lederer DJ, Martinez FJ, Noble PW, Song JW, Wells AU, Whalen TP, Lambert L, Chien JW, Zhang JJ, O'Riordan TG; Simtuzumab in Idiopathic Pulmonary Fibrosis (IPF): Baseline Demographic and Lung Function Data from a Clinical Trial. ATS International Conference, 2016 May 13-18, San Francisco CA.

Other Publications:

Raghu G, Brown KK, Collard HR, Cottin V, Gibson KF, Kaner RJ, Lederer DJ, Martinez FJ, Noble PW, Song JW, Wells AU, Whelan TP, Wuyts W, Moreau E, Patterson SD, Smith V, Bayly S, Chien JW, Gong Q, Zhang JJ, O'Riordan TG. Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. Lancet Respir Med. 2017 Jan;5(1):22-32. doi: 10.1016/S2213-2600(16)30421-0. Epub 2016 Dec 7.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01769196
• Other Study ID Numbers: GS-US-322-0207; 2012-001571-36 ( EudraCT Number )
• First Submitted: January 14, 2013
• First Posted: January 16, 2013
• Results First Submitted: February 22, 2017
• Results First Posted: April 13, 2017
• Last Update Posted: May 30, 2017