Detailed Outcome Data

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Clinical Review Report: Riociguat (Adempas) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2015 Dec.

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Clinical Review Report: Riociguat (Adempas) [Internet].

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APPENDIX 4Detailed Outcome Data

Table 14Subgroup Analyses for Clinical Worsening Events

Subgroup	PATENT-1
Number of Patients with Clinical Worsening, n/N (%)	Placebo Total N = 126	Riociguat 2.5 mg Total N = 254	Riociguat 1.5 mg Total N = 63
Treatment-naive	▬	▬	▬
Pre-treated	▬	▬	▬
Functional class I or II	▬	▬	▬
Functional class III or IV	▬	▬	▬

: Source: Clinical Study Report.¹⁵

Table 15Subgroup Analyses for Change in World Health Organization Functional Class

Subgroup	PATENT-1
Change in WHO Functional Class (Baseline to Last Visit), n (%)	Placeb Total N = 126	Riociguat 2.5 mg Total N = 254	Riociguat 1.5 mg Total N = 63
Treatment-naive	N = 66	N = 123	N = 32
−2	▬	▬	▬
−1	▬	▬	▬
0	▬	▬	▬
+1	▬	▬	▬
+2	▬	▬	▬
+3	▬	▬	▬
Pre-Treated	N = 59	N = 131	N = 31
−2	▬	▬	▬
−1	▬	▬	▬
0	▬	▬	▬
+1	▬	▬	▬
+2	▬	▬	▬
+3	▬	▬	▬
Functional class I or II	N = 64	N = 113	N = 24
−1	▬	▬	▬
0	▬	▬	▬
+1	▬	▬	▬
+2	▬	▬	▬
+3	▬	▬	▬
Functional class III or IV	N = 61	N = 141	N = 39
−2	▬	▬	▬
−1	▬	▬	▬
0	▬	▬	▬
+1	▬	▬	▬
+2	▬	▬	▬

: WHO = World Health Organization.
: Source: Clinical Study Report.¹⁵

Table 16Secondary Efficacy Outcomes

	PATENT-1
Outcome	Placebo N = 126	Riociguat 2.5 mg N = 254	Riociguat 1.5 mg^a N = 63
EQ-5D utility score	N = 124	N = 253	N = 62
Baseline, mean (SD)	0.68 (0.24)	0.68 (0.24)	▬
Change from baseline to week 12, mean (SD)	−0.03 (0.30)	0.03 (0.24)	0.08 (0.31)
Least squares MD (95% CI) versus placebo	--	0.06 (0.01 to 0.11)	NR
P value		0.07^a	NS
EQ-5D VAS score	N = 123	N = 250	N = 62
Baseline, mean (SD)	▬	▬	▬
Change from baseline to week 12, mean (SD)	−1.4 ▬	3.6 ▬	6.1 ▬
Least squares MD (95% CI) versus placebo	--	▬	▬
P value		▬	▬
LPH score	N = 122	N = 247	N = 62
Baseline, mean (SD)	42 (23)	42 (22)	43 (23)
Change from baseline to week 12, mean (SD)	0.4 (18.2)	−6 (18)	−10 (21)
Least squares MD (95% CI) versus placebo	--	−6 (−10 to −3)	NR
P value		NS^c	NS
Borg CR10 score	N = 126	N = 254	N = 63
Baseline, mean (SD)	3.9 (2.5)	3.9 (2.2)	▬
Change from baseline to week 12, mean (SD)	0.1 (2.1)	−0.4 (1.7)	−0.3 (1.5)
Least squares MD (95% CI) versus placebo	--	NR	NR
P value		0.002	NS
PVR (dyn∙s∙cm^-5)	N = 107	N = 232	N = 58
Baseline, mean (SD)	834 (477)	791 (453)	848 (548)
Change from baseline to week 12, mean (SD)	−9 (317)	−223 (260)	−168 (320)
Least squares MD (95% CI) versus placebo	--	−226 (−281 to −170)	NR
P value		< 0.0001	< 0.0001
NT-proBNP (pg/ml)	N = 106	N = 228	N = 54
Baseline, mean (SD)	1,228 (1,77	1,027 (1,799)	1,190 (1,405)
Change from baseline to week 12, mean (SD)	232 (1,011)	−198 (1,721)	−472 (913)
Least squares MD (95% CI) versus placebo	--	−432 (−782 to −82)	NR
P value		< 0.001	< 0.0001

: CI = confidence interval; EQ-5D = EuroQol 5-Dimensions Questionnaire; LPH = Living with Pulmonary Hypertension questionnaire; MD = mean difference; NR = not reported; NS = not statistically significant; NT-proBNP = N-terminal pro-brain natriuretic peptide; PVR = pulmonary vascular resistance; SD = standard deviation; VAS = visual analogue scale.
a: Statistical testing based on post-hoc data from the FDA Medical Review.
b: Based on the stratified Wilcoxon test.
c: Not statistically significant due to failure to achieve statistical significance in a prior outcome in the hierarchical testing procedure.
: Source: Ghofrani 2013, ¹⁴ Clinical Study Report,¹⁵ FDA Medical Review.¹¹

Table 17Subgroup Analyses for EQ-5D Utility Score

Subgroup	PATENT-1
EQ-5D Utility Score	Placebo Total N = 126	Riociguat 2.5 mg Total N = 254	Riociguat 1.5 mg Total N = 63
Treatment-naive	N = 64	N = 123	N = 32
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬
Pre-Treated	N = 60	N = 130	N = 30
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬
Functional class I or II	N = 63	N = 113	N = 24
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬
Functional class III or IV	N = 60	N = 140	N = 38
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬

: EQ-5D = EuroQol 5-Dimensions Questionnaire; SD = standard deviation.
: Source: Clinical Study Report.¹⁵

Table 18Subgroup Analyses for Six-Minute Walk Distance Test

Subgroup	PATENT-1
6MWD, m	Placebo Total N = 126	Riociguat 2.5 mg Total N = 254	Riociguat 1.5 mg Total N = 63
Treatment-naive	N = 66	N = 123	N = 32
Baseline, mean (SD)	360 (80)	370 (66)	347 (72)
Change from baseline to week 12, mean (SD)	−6 (88)	32 (74)	49 (47)
Least squares MD (95% CI) versus placebo		38 (14 to 62)	55 (22 to 89)
Pre-treated	N = 60	N = 131	N = 31
Baseline, mean (SD)	376 (68)	353 (69)	380 (57)
Change from baseline to week 12, mean (SD)	−5 (83)	27 (58)	12 (100)
Least squares MD (95% CI) versus placebo		36 (15 to 56)	17 (−22 to 56)
Treatment group by prior treatment interaction term P value		▬	▬
Functional class I or II	N = 64	N = 113	N = 24
Baseline, mean (SD)	▬	▬	▬
Change from baseline to week 12, mean (SD)	18 (63)	▬	▬
Least squares MD (95% CI) versus placebo		12 (−8 to 32)	17 (−12 to 45)
Functional class III or IV	N = 61	N = 141	N = 39
Baseline, mean (SD)	▬	▬	▬
Change from baseline to week 12, mean (SD)	−30 (99)	▬	▬
Least squares MD (95% CI) versus placebo		60 (36 to 83)	59 (19 to 99)
Treatment group by functional class interaction term P value		▬	▬

: 6MWD = six-minute walk distance; CI = confidence interval; m = metres; MD = mean difference; SD = standard deviation.
: Source: Clinical Study Report,¹⁵ FDA Medical Review.¹¹

Table 19Subgroup Analyses for Living with Pulmonary Hypertension Questionnaire Total Score

Subgroup	PATENT-1
LPH Total Score	Placebo Total N = 126	Riociguat 2.5 mg Total N = 254	Riociguat 1.5 mg Total N = 63
Treatment-naive	N = 65	N = 120	N = 32
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬
Pre-Treated	N = 57	N = 127	N = 30
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬
Functional class I or II	N = 62	N = 110	N = 24
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬
Functional class III or IV	N = 59	N = 137	N = 38
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬

: LPH = Living with Pulmonary Hypertension questionnaire; SD = standard deviation.
: Source: Clinical Study Report.¹⁵

Table 20Subgroup Analyses for Borg CR10 Score

Subgroup	PATENT-1
Borg CR10 Scale	Placebo Total N = 126	Riociguat 2.5 mg Total N = 254	Riociguat 1.5 mg Total N = 63
Treatment-naive	N = 66	N = 123	N = 32
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬
Pre-Treated	N = 60	N = 131	N = 31
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬
Functional class I or II	N = 64	N = 113	N = 24
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬
Functional class III or IV	N = 61	N = 141	N = 39
Baseline, mean (SD)	▬	▬	▬
Change from baseline to last visit, mean (SD)	▬	▬	▬

: SD = standard deviation.
: Source: Clinical Study Report.¹⁵

Table 21Exploratory Outcomes

	PATENT-1
	Placebo N = 126	Riociguat 2.5 mg N = 254	Riociguat 1.5 mg N = 63
mPAP (mm Hg)	N = 109	N = 235	▬
Baseline, mean (SD)	48.9 (15.2)	47.1 (14.8)	▬
Change from baseline to week 12, mean (SD)	−0.5 (9.4)	−3.9 (7.8)	▬
Least squares MD (95% CI) versus placebo		−3.8 (−5.6 to −2.1)	▬
P value		NS^a	NS^b
Cardiac Index (L/min/m²)	N = 108	N = 233	▬
Baseline, mean (SD)	▬	▬	▬
Change from baseline to week 12, mean (SD)	−0.02 (0.6)	0.54 (0.6)	▬
Least squares MD (95% CI) versus placebo		0.56 (0.44 to 0.69)	▬
P value		NS^a	NR
Supplemental Oxygen Therapy	N = 126	N = 254	N = 63
Prior therapy, n (%)	22 (18)	47 (19)	16 (25)
Concomitant therapy, n (%)	24 (19)	50 (20)	18 (29)
New concomitant therapy, n (%)	6 (5)	9 (4)	5 (8)

: CI = confidence interval; MD = mean difference; mPAP = mean pulmonary artery pressure; NR = not reported; NS = not statistically significant; SD = standard deviation.
a: Outcome was outside the statistical hierarchy and thus is considered not statistically significant.
b: Statistically significant differences were reported by the FDA based on post-hoc analyses. These outcomes were exploratory and outside the statistical hierarchy.
: Source: Ghofrani 2013, ¹⁴ Clinical Study Report,¹⁵ FDA Medical Review.¹¹

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Clinical Review Report: Riociguat (Adempas) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2015 Dec. APPENDIX 4, Detailed Outcome Data.
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