C1inica Study Report
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`
`Figure
`
`PVRI Change From Baseline By Treatment Group Intent-to-Treat
`
`NO PIus 02
`n117
`
`02
`n113
`
`NO
`n113
`
`-a
`
`-0.5
`
`-1
`
`-1.5
`
`-2
`
`-2.5
`
`-3
`
`-3.5
`
`-11
`
`-1.5
`
`-2.9
`
`pO 001 versus baseline
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`Table 15 PVRI Change From Baseline By Treatment Intent-to-Treat
`
`PVRI WU-m2
`
`Baseline room air
`
`Mean
`
`SD
`
`Median
`
`NO FIns 02
`n117
`
`10.8
`
`10.30
`
`7.5
`
`Treatment
`
`02
`n113
`
`10.0
`
`9.65
`
`6.9
`
`NO
`n113
`
`10.3
`
`10.33
`
`6.6
`
`Minimum maximum
`
`0.5 54.0
`
`0.5 47.7
`
`0.9 54.0
`
`Post-treatment
`
`Mean
`
`SD
`
`Median
`
`7.8
`
`8.75
`
`3.6
`
`8.5
`
`8.63
`
`5.5
`
`9.2
`
`10.45
`
`5.6
`
`Minimum maximum
`
`0.0 44.8
`
`0.5 36.5
`
`-6.3 55.3
`
`Change From Baseline
`
`Mean
`
`SD
`
`Median
`
`Minimum maximum
`
`pvaluea
`
`-2.9
`
`4.75
`
`-1.8
`
`-31.2 8.6
`
`0.001
`
`-1.5
`
`3.13
`
`-0.7
`
`-17.6 6.5
`
`0.001
`
`-1.1
`
`3.04
`
`-0.8
`
`-10.0 5.3
`
`0.001
`
`Pairwise comparisons
`NO plus 02 versus 02 pO.OOl
`NO plus 02 versus NO pO.OOl
`02 versus NO pO.l7l
`p-value from Wilcoxen Signed Rank test Only patients with data to determine response at both treatments are
`included in this analysis
`Source Section 14.2.2 Table 6.1.1 and Appendix 16.2.6
`
`Results for the per-protocol population supported those for the intent-to-treat population
`per-protocol population the mean changes from baseline with NO plus 02 02 and NO were -3.8
`p0.001 -1.9 pO.OO1 and -1.1 pO.O25 WUm2 respectively
`
`In the
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`Figure
`
`PS/RI Change From Baseline NO Plus 02 Versus 02 Alone Intent-to-Treat
`
`10
`
`-35
`
`-30
`
`-25
`
`-20
`
`-15
`
`-10
`
`10
`
`I-
`
`-t
`
`tIO02 Treatment
`
`-10
`
`-15
`
`-20
`
`-25
`
`30
`
`-35
`
`-l
`
`-t
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`
`The mean percent changes from baseline in PVRI for the intent-to-treat population Table 16 and
`were -29.6% -15.2% and -15.9% for NO plus 02 02 and NO respectively all
`Figure
`pO.OOl versus baseline
`
`Table 16 PYRI Percent Change From Baseline By Treatment Intent-to-Treat
`
`PYRI WU.m2
`
`Baseline room air
`
`Mean
`
`SD
`
`Median
`
`NO Plus 02
`n117
`
`10.8
`
`10.30
`
`7.5
`
`Treatment
`
`02
`n413
`
`10.0
`
`9.65
`
`6.9
`
`NO
`n113
`
`10.3
`
`10.33
`
`6.6
`
`Minimum maximum
`
`0.5 54.0
`
`0.5 47.7
`
`0.9 54.0
`
`Post-treatment
`
`Mean
`
`SD
`
`Median
`
`7.8
`
`8.75
`
`3.6
`
`8.5
`
`8.63
`
`5.5
`
`9.2
`
`10.45
`
`5.6
`
`Minimum maximum
`
`0.0 44.8
`
`0.5 36.5
`
`-6.3 55.3
`
`Percent Change From
`Baseline
`
`Mean
`
`SD
`
`Median
`
`-29.6
`
`38.74
`
`-30.8
`
`Minimum maximum
`
`-102.7 201.1
`
`p-valu
`
`0.001
`
`-15.2
`
`29.23
`
`-14.8
`
`-73 89.7
`
`0.001
`
`-15.9
`
`43.35
`
`-15.5
`
`-270.7 117.7
`
`0.001
`
`Pairwise comparisons
`NO plus 02 versus 02 pO.00l
`NO plus 02 versus NO p0.002
`02 versus NO p0.91S
`p-value from Wileoxen Signed Rank test Only patients with data to determine response at both treatments are
`included in this analysis
`Source Sectioa 14.2.2 Table 6.1.3 and Appendix 16.2.6
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`Figure
`
`PVRT Percent Change From Baseline by Treatment Intent-to-Treat
`
`NO pIus 02
`N117
`
`02
`N113
`
`NO
`N113
`
`-10
`
`4-
`
`-15
`
`I.
`4-
`
`-20
`
`-25
`
`-30
`
`-35
`
`-15.9
`
`p000l
`
`from
`
`The mean percent changes from baseline in PVRT for the per-protocol population were -26.7%
`0.011 respectively for NO plus 02 02 and NO
`pO.OOl -12.5% p0.001 and -7.8%
`Changes from baseline in PVRI for patients without shunts in both the intent-to-treat and the per-
`protocol populations were generally consistent with those for all patients in the respective
`populations
`Percent changes from baseline in PVRI for patients without shunts in both the intent-to-treat and
`the per-protocol populations were generally consistent with those for all patients in the respective
`populations
`All treatments also significantly decreased PAPm in the intent-to-treat population Table 17
`The mean changes from baseline in PAPm were -7.1 -3.5 and -4.1 mm Hg for NO plus 02 02
`and NO respectively all p0.00l versus baseline
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`Table 17
`
`PAPm Change From Baseline By Treatment Intent-to-Treat
`
`PAPm mm Hg
`
`Baseline room air
`
`Mean
`
`SD
`
`Median
`
`NO Plus 02
`n124
`
`45.3
`
`16.78
`
`41.8
`
`Treatment
`
`02
`n121
`
`44.2
`
`16.30
`
`41.7
`
`NO
`n120
`
`45.0
`
`17.57
`
`40.7
`
`Minimum maximum
`
`17.0 93.0
`
`16.7 88.7
`
`14.0 113.0
`
`Post-treatment
`
`Mean
`
`SD
`
`Median
`
`38.3
`
`16.38
`
`34.7
`
`40.7
`
`14.57
`
`38.7
`
`41.0
`
`17.94
`
`37.2
`
`Minimum maximum
`
`12.7 84.0
`
`26.0 85.0
`
`16.0 89.0
`
`Change From Baseline
`
`Mean
`
`SD
`
`Median
`
`Minimum maximum
`
`pvaJuea
`
`-7.1
`
`8.25
`
`-5.3
`
`-36.0
`
`0.001
`
`-3.5
`
`8.10
`
`-2.3
`
`-37.3 17.7
`
`0.001
`
`-4.1
`
`7.51
`
`-2.8
`
`-50.3 9.0
`
`0.00
`
`Pairwise comparisons
`NO plus 02 versus 02 p0.O0l
`NO plus 02 versus NO pO.OO1
`02 versus NO pO.637
`p-value from Wilcoxen Signed Rank Test Only patients with data to determine response at both treatments are
`included in this analysis
`Source Section 14.2.2 Table 6.2.1 and Appendix 16.2.6
`All treatments also significantly decreased PAPm in the per-protocol population
`The mean
`changes from baseline in PAPm were -7.6 -4.2 and -3.8 mm Hg for NO plus 02 02 and NO
`respectively all pO.OO1 versus baseline
`
`Results for patients without shunts in the intent-to-treat and per-protocol populations generally
`matched those for all patients in the respective populations
`
`Results for the intent-to-treat population indicated no differences among treatments with respect
`to changes from baseline in CO Table 18 The mean changes from baseline in CO were 0.0
`mL/minute for each treatment
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`Table 18 CO Change From Baseline By Treatment Intent-to-Treat
`
`CO mL/minnte
`
`Baseline room air
`
`Mean
`
`SD
`
`Median
`
`NO Plus 02
`n112
`
`2.3
`
`1.43
`
`1.9
`
`Treatment
`
`02
`m109
`
`2.2
`
`1.37
`
`1.9
`
`NO
`n109
`
`2.3
`
`1.35
`
`2.0
`
`Minimum maximum
`
`-2.5 6.8
`
`-2.5 5.9
`
`0.4 6.8
`
`Post-treatment
`
`Mean
`
`SD
`
`Median
`
`Minimum maximum
`
`Change From Baseline
`
`Mean
`
`SD
`
`Median
`
`Minimum maximum
`
`pvaluea
`
`2.2
`
`1.29
`
`2.0
`
`2.2
`
`1.27
`
`1.9
`
`2.4
`
`1.34
`
`2.0
`
`0.2 6.4
`
`0.4 5.1
`
`0.4 7.4
`
`0.0
`
`1.01
`
`-0.1
`
`-5.7 5.1
`
`0.049
`
`0.0
`
`0.70
`
`-0.1
`
`-2.9 4.6
`
`0.132
`
`0.0
`
`0.88
`
`0.0
`
`-5.5 4.5
`
`0.614
`
`Pairwise comparisons
`NO plus 02 versus 02 pO.979
`NO plus 02 versus NO pO.27
`02 versus NO pO.259
`p-value from Wilcoxen Signed Rank Test Only patients with data to determine response at both treatments are
`included in this analysis
`Source Section 14.2.2 Table 5.3.1 and Appendix 16.2.6
`
`Results for the per-protocol population also indicated no differences among treatments with
`to changes from baseline in CO The mean changes from baseline in CO were 0.0
`respect
`raL/minute for each treatment
`
`Results for patients without shunts in the intent-to-treat and per-protocol populations generally
`matched those for all patients in the respective populations
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`Re suits for the intent-to-treat population indicated that treatment with NO plus 02 and 02 alone
`significantly increased SVRI Table 19 The change from baseline for NO plus 02 was 1.4
`WUm2
`0.007 and that for 02 was 1.3 WTJm2
`0.004 The change from baseline in
`SVRI with NO was -0.2 WUm2
`0.889
`
`Table 19
`
`SVR Change From Baseline By Treatment Intent-to-Treat
`
`Wit WiJm2
`
`Baseline room air
`
`Mean
`
`SD
`
`Median
`
`Minimum maximum
`
`Post-treatment
`
`Mean
`
`SD
`
`Median
`
`NO Plus 02
`w409
`
`17.2
`
`8.86
`
`15.9
`
`Treatment
`
`02
`n106
`
`17.6
`
`9.22
`
`16.1
`
`NO
`n106
`
`18.0
`
`8.44
`
`16.2
`
`-7.6 55.6
`
`-7.6 55.6
`
`1.9 44.8
`
`18.7
`
`9.04
`
`17.1
`
`18.9
`
`8.78
`
`17.1
`
`17.8
`
`9.40
`
`15.4
`
`Minimum maximum
`
`3.0 47.4
`
`3.9 43.6
`
`3.3 50.7
`
`Change From Baseline
`
`Mean
`
`SD
`
`Median
`
`1.4
`
`5.94
`
`1.2
`
`1.3
`
`5.16
`
`1.0
`
`-0.2
`
`4.65
`
`0.2
`
`Minimum maximum
`
`-20.5 19.1
`
`-18.1 17.7
`
`-12.5 12.7
`
`p_valnea
`
`0.007
`
`0.004
`
`0.899
`
`Pairwise comparisons
`NO plus 02 versus 02 pO.952
`NO plus 02 versus NO pO.O14
`02 versus NO pO.017
`p-value from Wilcoxen Signed Rank Test Only patients with data to determine response at both treatments are
`included in this analysis
`Source Section 14.2.2 Table 6.4.1 and Appendix 16.2.6
`
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`Results for the per-protocol population supported those for the intent-to-treat population In this
`population treatment with NO plus 02 and 02 alone also significantly increased SYRL The
`change from baseline for NO plus 02 was 1.5 WJm2
`for 02 was 1.4 Wftm2
`0.037 and that
`0.012 The change from baseline in SVRI with NO was 0.3 WUm2
`0.425
`Effects of treatment on CO in patients without shunts in the intcnt-to-treat and per-protocol
`populations were similar to those for all patients in thc respective study populations
`significantly lower PAPm to MAP ratio than 02 alone
`Treatment with NO plus 02 resulted in
`Table 20 These values were 0.60 and 0.64 respectively for NO plus 02 and 02 only
`pcO.OOl
`
`First Table added per request
`Percent Change in Ratio of PYRI to SVIRI by Treatment Intent-to-Treat
`
`Table2Ob from e-mail
`
`Table 20
`
`Ratio PVIRI/SVRI
`
`Baseline
`
`Mean
`
`SD
`
`Median
`
`NO Plus 02
`n408
`
`0.6
`
`0.60
`
`0.5
`
`Treatment
`
`02
`n105
`
`0.5
`
`0.45
`
`0.5
`
`NO
`n106
`
`0.6
`
`0.56
`
`0.4
`
`Minimum Maximum
`
`-L6 4.7
`
`-1.6 1.8
`
`0.0 4.7
`
`Post Treatment
`
`Mean
`
`SD
`
`Median
`
`Minimum
`Maximum
`
`Percent Change from
`Baseline
`
`Mean
`
`SD
`
`Median
`
`Minimum
`Maximum
`
`FYatue
`
`Wilcoxon Signed Rank Test
`Deb to confirm
`Source
`
`0.4
`
`0.31
`
`0.3
`
`0.4
`
`0.31
`
`0.4
`
`0.5
`
`0.46
`
`0.3
`
`0.0 1.3
`
`0.0 1.4
`
`-1.2 2.2
`
`-33.5
`
`36.11
`
`-34.0
`
`-19.3
`
`34.59
`
`-21.3
`
`-6.2
`
`64.04
`
`-13.8
`
`-122.2 140.1
`
`-122.7 93.3
`
`-256.1 294.1
`
`0.001
`
`0.001
`
`0.006
`
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`Table Added Table 20a fr 1ThP
`Table 220
`to SYRI by Treatment Intent-to-Treat
`Change in Ratio of PS/RI
`
`Ratio PVRIJSVHJ
`
`Baseline
`
`Mean
`
`SD
`
`Median
`
`NO Plus 02
`n108
`
`0.6
`
`0.60
`
`0.5
`
`Treatment
`
`02
`n105
`
`0.5
`
`0.45
`
`0.5
`
`NO
`n106
`
`0.6
`
`0.56
`
`0.4
`
`Minimum Maximum
`
`.164.7
`
`-1.6 1.8
`
`0.04.7
`
`Post Treatment
`
`Mean
`
`SD
`
`Median
`
`Minimum
`Maximum
`
`Change from Baseline
`
`Mean
`
`SD
`
`Median
`
`Minimum
`Maximum
`
`PVaIne1
`
`Wilcoxon Signed Rank Test
`Source iDeb to confirm
`
`0.4
`
`0.31
`
`0.3
`
`0.4
`
`0.31
`
`0.4
`
`0.5
`
`0.46
`
`0.3
`
`0.01.3
`
`0.01.4
`
`-1.22.2
`
`-0.2
`
`0.52
`
`-0
`
`-0.1
`
`0.31
`
`-0.1
`
`-0.1
`
`0.54
`
`0.0
`
`-4.4 2.0
`
`-1.6 2.0
`
`-4.4 1.6
`
`0.001
`
`0.001
`
`0.002
`
`There was no difference in the PAPm to MAP ratios for NO plus 02 and 02 alone in the per-
`protocol population This value was 0.71 for both NO plus 02 and 02 only
`0.094
`
`Results for patients without shunts in the intent-to-treat and per-protocol populations were
`consistent with those from all patients in the respective populations
`
`11.4.4
`
`Statistical/Analytical
`
`Issues
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`
`11.4.4.1
`
`Adjustments for Covariates
`
`No adjustments were made for covariates
`
`11.4.4.2 Handling of Dropouts or Missing Data
`There was no imputation of missing data For the tabulations of demographics and efficacy
`statistics patients with missing data were not
`included in the denominator for the calculation of
`any frequency percentages
`
`The denominator for concomitant medications and all adverse events was the total nwnber of
`patients in the treatment group regardless of any missing data
`
`11.4.4.3
`
`Interim Analyses and Data Monitoring
`
`Interim analyses for this study were performed periodically for the Steering Committee to
`review
`
`11.4.4.4 Multicenter Studies
`
`No adjustments
`
`in the data analysis were made with respect
`
`to this variable
`
`11.4.4.5 Multiple Comparisons/Multiplicity
`
`No adjustments for multiple comparisons are necessary The primary efficacy analysis was
`performed on the primary endpoint comparing the two treatment groups of interest Other
`statistical tests to compare other treatment groups and secondary endpoints are provided as
`supportive data only
`
`11.4.4.6
`
`Use of an Efficacy Subset of Patients
`
`Intent-to-treat patients were all patients randomized regardless of actual
`receipt of any treatment
`gas the treatment gas actually received or the appropriateness of their enrollment Efficacy
`analyses were also performed on the per-protocol population since 5% of the patients had
`resistance index PVRI WU.m2 and actually took study
`baseline pulmonary vascular
`The per-protocol population included all patients who took study medication and
`medication
`had baseline PYRI WUm2
`
`11.4.4.7
`
`Active-Control Studies Intended to Show Equivalence
`
`This study had an active comparator but was not
`
`intended to show equivalence
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`
`11.4.4.8
`
`Examination of Subgroups
`
`There was no significant difference in pulmonary vasoreactivity for patients without shunts
`versus the entire study group in either the intent-to-treat or per-protocol populations This was
`also the case for all secondary efficacy variables
`
`11.4.5
`
`Tabulation of Judividual Response Data
`
`be provided
`
`11.4.6
`
`Drug Dose Drug Concentration and Relationship to Respouse
`
`Not applicable
`
`11.4.7
`
`Drug-Drug and Drug-Disease Interactions
`
`Not applicable
`
`11.4.8
`
`By-Patient Displays
`
`be provided
`
`11.4.9
`Efficacy Conclusions
`Results for the primary efficacy variable indicated that for the intent-to-treat population NO plus
`significantly higher pulmonary vasoreactivity response rate 25.7% versus 02
`02 resulted in
`0.019 In addition 17.4% of patients responded only to NO plus 02 versus
`only 14.7%
`6.4% who responded to 02 only
`
`6.6% did not meet the entry criteria for
`considerable proportion of randomized patients
`PVRJ
`per-protocol analysis was perfoniied as well For
`units at baseline For this reason
`each of the pairwise comparisons noted above the treatment effect was of similar or greater
`magnitude and in the same direction as for the ITT population These results were generally not
`statistically significant due to the smaller sample size
`We note that seven patients 6.4% responded to 100% 02 but did not respond to NO 80 ppm
`with 90% 02 which seems illogical These seven patients were reviewed individually
`
`Table 21
`
`Patients that responded only to 100% Oxygen
`
`Pt Number
`
`1004
`
`%A PVRI
`
`02
`
`-58.6%
`
`%j\ P1/RJ
`02NO
`
`-39.9%
`
`%z\ PYRI
`NO
`
`51.7%
`
`Comment
`
`CI -5.2%
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`Pt Number
`
`%L\ PVRI
`
`1015
`
`1026
`
`2007
`
`3006
`
`6005
`
`10003
`
`02
`
`-25.6%
`
`-42.8%
`
`-25.7%
`
`-45.9%
`
`-39.5
`
`-32.6
`
`1NO Therapeutics LLC
`
`Comment
`
`Cl -7.0%
`
`2nd baseline very
`high
`
`Cl -25.91%
`
`ilL P1/RI
`
`1.33
`
`mPAP -19.4%
`
`%A P\TRI
`02N0
`
`-27.3%
`
`-19.2%
`
`-73.3%
`
`48.2%
`
`-55.5
`
`-6.7
`
`%A PyRE
`NO
`
`10.57%
`
`61.5%
`
`-39.6%
`
`117.7
`
`-10.8
`
`10.45%
`
`39.9% reduction in PVRI on the
`5-month-old baby boy with
`Patient 1004 was
`than the 5% limit set by
`combination regimen but dropped the CI by 5.2% greater
`reduction of Cl from 8.65 to 8.11
`the response criteria In absolute terms this was
`L/mIM2 which is within the measurement error of the procedure4
`
`Patient 1015 was an 8.7-year-old girl with
`the CI by 7.0% 1.95 to 1.81 L/mflVl2
`
`27.3% reduction in PYRT but dropped
`
`Patient 1026 was
`
`that had 02 alone in the third treatment
`-month-old baby girl
`the second baseline value for PVRI prior to the 02 alone
`period In this patient
`treatment period was much higher than the initial baseline PVRI 4.525 WUm2 vs
`6.75 WUm2 indicating that the patient was not at baseline when the final PVRI
`value was obtained
`
`Patient 2007 was
`5-month-old baby boy requiring supplemental oxygen at baseline
`large decrease in PVRI and PAP but
`large drop in CI as
`the patient demonstrated
`well without other obvious explanation
`
`6-month-old baby boy with near-normal PVRI at first baseline
`Patient 3006 was
`1.334 WU.m2 this patient had 02 alone in the first
`treatment period In the first
`large percentage drop in PVRI
`followed by
`period there was
`continual rise in
`PyRE accompanied by
`decrease in the CI over the subsequent periods It
`factors or procedural factors
`clear if these changes are related to treatment patient
`
`is not
`
`shunt on supplemental
`Patient 6005 was an 8.6-year-old boy with CFIID without
`decrease in PAPm of
`oxygen at baseline In this ease response criteria require
`20% In this case the reduction in PVRI was 5.5% but the reduction in PAPm was
`19.4% less than the 20% criterion
`
`10.6-year-old boy on supplemental oxygen at baseline This
`Patient 10003 was
`patient met response criteria to 02 alone in the fir st period without
`response to the
`without other obvious explanation
`other treatments in period
`and period
`
`had more than adequate reduction in
`Looking at these patients individually we see that
`of the
`PVRI or PAP to qualify as responders to NO with 02 but missed other elements of the response
`are unexplained There do
`criteria one patient was not at equilibrium during the procedure and
`
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`
`not appear to be commonalities among these patients with regard to center diagnosis age race
`or sequence of treatment None of these patients reported an AE
`There was no significant difference between pulmonary vasoreactivity response rates for NO
`alone versus 02 alone in the intent-to-treat population 23.6% versus 15.1% p0.ll7 although
`numerically more patients were responders with NO alone as compared with 02 alone For this
`comparison 19.8% of patients responded only to NO versus 11.3% for 02 only Comparison of
`results for NO and NO plus 02 in the intent-to-treat population also indicated no significant
`differences in pulmonary vasoreactivity response The response rate for NO was 24.1% and that
`for NO plus 02 was 26.8% p0.6O2 In this comparison 13.9% of patients responded only to
`NO versus 16.7% for NO plus 02
`
`There was no significant difference in pulmonary vasoreactivity among patients with or without
`intubation an indicator of general anesthesia rather than simple
`shunts with or without
`sedation in either the intent-to-treat or per-protocol populations In the intent-to-treat
`population 45.9% of patients with shunts responded versus 46.2% of those without shunts
`pl.000 There was no appreciable difference in response rates by treatment in patients with or
`without shunts Patients with cardiomyopathy as the primary diagnosis seemed to respond more
`often than those with IPAH or CHD but the number of those patients is too small to influence
`the overall results
`
`All treatments significantly decreased PVRI
`In the intent-to-treat population the mean changes
`from baseline with NO pIus 02 02 and NO were -2.9 -1 .5 and -1.1 WUm2 respectively all
`pO.OOI versus baseline The mean percent changes from baseline in PYRI for the intent-to-
`treat population were -29.6% -15.2% and -15.9% for NO plus 02 02 and NO respectively all
`pO.OOl versus baseline
`All treatments also significantly decreased PAPm in the intent-to-treat population
`The mean
`changes from baseline in PAPm were -7.1 -3.5 and -4.1 mm Hg for NO plus 02 02 and NO
`respectively all pO.OO1 versus baseline
`
`in mean changes from baseline in CO
`
`In the intent-to-treat population there were no differences
`0.0 inL/minute for each treatment
`Results for the intent-to-treat population indicated that treatment with NO plus 02 and 02 alone
`significantly increased SVRI The change from baseline for NO plus 02 was 1.4 WIJm2
`pO.0O7 and that for 02 was 1.3 WUm2 pO.OO4 The change from baseline in SVRI with
`inhaled NO
`NO was -0.2 WIJm2 1p0.899 Given the decrease in PAPm this suggests that
`alone or with 02 is selective for the pulmonary vascular bed This is fi.irther
`change in ratio between the PA pressures and the systemic pressures Treatment with NO Pills 02
`signilicamly lower PAPm to MA ratio than 02 alone Thcse values were 0.62 and
`inc in the ratio of PAPm to
`NO plus 02 and 02 only r0.00
`The reduction fron basel
`0.66
`MAP for NO with
`is 7.7% as compared with
`reduction of 10.6% and 7.8% for 07 alone
`and NO alone respcciivcly
`Thus we can conclude that inhaled nitric oxide alone or with
`1R
`INot confirmed
`selective pulmonary vasodilaior
`oxygen is
`
`reflected in the
`
`resulted in
`
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`
`NO Therapeutics LLC
`
`12
`
`SAFETY EVALUATION
`
`12.1
`Extent of Exposure
`Exposure to NO plus 02 NO and 02 is summarized in Table
`The mean durations of exposure
`to NO pius 02 NO and 02 were 15.5 minutes 15.3 minutes and 15.9 minutes respectively
`
`12.2
`
`Adverse Events
`
`12.2.1
`
`Brief Summary of Adverse Events
`
`Seven patients experienced ABs during this study These included cardiac arrest bradyeardia
`low CO output syndrome elevated ST segment on the ECU decreased 02 saturation
`hypotension mouth hemorrhage and PH
`
`12.2.2
`
`Display of Adverse Events
`
`All-causality Adverse Events
`12.2.2.1
`Seven patients experienced ABs during this study Table 22 These included cardiac arrest
`bradycardia low CO output syndrome elevated ST segment on the ECG decreased 02
`saturation hypotension mouth hemorrhage and PET. The numbers of patients and events are too
`small to determine whether risk for AEs differed by diagnosis
`
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`
`Clinical Study Report
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`INO Therapeutics LLC
`
`Table 22
`
`Adverse Events By Diagnosis Safety
`
`System Organ Class/Preferred
`Term
`I%lt
`
`Patients With at Least One AE
`
`_____________
`IPAH
`n2$
`0.0
`
`Cardiac Disorders
`
`Bradyeardia
`
`Cardiac Arrest
`
`Low CO Syndrome
`
`Investigations
`ECG ST Segment Elevation
`
`02 Saturation Decreased
`
`Vascular Disorders
`
`Hypotension
`
`Gastrointestinal Disorders
`
`MouthHemonhage
`
`Respiratory Thoracic and
`Mediastinal Disorders
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`Diagnosis
`
`Cardiomyopathy
`
`n5
`
`20.0
`
`0.0
`
`00.0
`
`00.0
`
`00.0
`
`20.0
`
`20.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`CHD
`n91
`6.6
`
`3.3
`
`22.2
`
`1.1
`
`1.1
`
`2.2
`
`0.0
`
`2.2
`
`1.1
`
`1.1
`
`1.1
`
`1.1
`
`Overall
`n124
`
`5.6
`
`2.4
`
`21.6
`
`0.8
`
`0.8
`
`2.4
`
`0.8
`
`1.6
`
`1.6
`
`1.6
`
`0.8
`
`0.8
`
`00.0
`
`00.0
`
`PH
`1.1
`0.0
`0.0
`0.8
`System organ classes and preferred terms are coded using the MedDRA dictionary Dystem organ classes and
`order of frequency for the Overall column
`patient with multiple
`preferred terms are listed in descending
`occurrences of an AR is counted only once in the AR category
`Source Section 14.3.1 Table 8.1 and Appendix 16.2.7
`
`Adverse events are summarized by diagnosis and age in Table 23 diagnosis and gender in
`Table 24 and diagnosis and race in Table 25 Overall AEs occurred more often in patients
`years of age 6.7% than in those 10 years old 2.9% They also occurred more often in whites
`9.6% versus other races 0.0% Patient gender had no effect on the incidence of adverse
`events 4.8% of males and 6.5% of females experienced at least one AE
`
`10
`
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`
`Table 23
`
`Adverse Events By Diagnosis and Age Safety
`
`System Organ
`Class/Preferred Term
`
`Patients With at Least
`One AE
`
`Cardiac Disorders
`
`Cardiac Arrest
`
`Bradycardia
`
`Low co syndrome
`
`Gastrointestinal
`
`Diagnosis and Age Group
`
`IVAN
`
`Cardiomyopatisy
`
`CIII
`
`Overall
`
`10 years
`n17
`
`10 Years
`
`iwli
`
`10 years
`iw4
`
`10 Years
`iwl
`
`10 years
`n68
`
`10 Years
`n23
`
`10 years
`n89
`
`10 Years
`n35
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`25.0
`
`00
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`7.4
`
`2.9
`
`1.5
`
`1.5
`
`1.5
`
`1.5
`
`4.3
`
`4.3
`
`0.0
`
`4.3
`
`0.0
`
`0.0
`
`6.7
`
`2.2
`
`1.1
`
`1.1
`
`1.1
`
`1.1
`
`2.9
`
`2.9
`
`0.0
`
`2.9
`
`0.0
`
`00.0
`
`Disorders
`
`Mouthllemorrhage
`
`Investigations
`
`ECG ST Segment
`Elevation
`
`02 Saturation Decreased
`
`Respiratory Thoraeie
`and Mediastinal
`
`Disorders
`
`PH
`
`Yasenlar Disorders
`
`0.0
`
`00
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`25.0
`
`25.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`1.5
`
`2.9
`
`0.0
`
`2.9
`
`1.5
`
`1.5
`
`1.5
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`1.1
`
`3.4
`
`1.1
`
`2.2
`
`0.0
`
`.1
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`11.1
`
`2.2
`
`00.0
`
`00.0
`
`Hypotension
`
`0.0
`1.5
`2.2
`0.0
`0.0
`0.0
`0.0
`System organ classes and preferred tenns are coded using the MedD RA dictionary System organ classes and
`order of frequency for the Overall colunm
`patient with multiple
`preferred terms are listed in descending
`of an AlE is counted only once in the AlE category
`occurrences
`Source Section 14.3.1 Table 8.2 and Appendix 16.2.7
`
`0.0
`
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`
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`
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`INO Therapeutics LLC
`
`Table 24
`
`Adverse Events By Diagnosis and Gender Safety
`
`Diagnosis and Gender
`
`IPAH
`
`Cardionsyopathy
`
`CUD
`
`Overall
`
`System Organ
`Class/Preferred Term
`
`Patients With at Least
`One iuo
`
`Cardiac Disorders
`
`Bradycardia
`
`Cardiac Arrest
`
`Low CO Syndrome
`
`Gaatrointeatinal
`
`Male
`n15
`
`0.0
`
`0.0
`
`Female
`n13
`
`0.0
`
`0.0
`
`Male
`n3
`
`0.0
`
`0.0
`
`00.0
`
`00.0
`
`00.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`Female
`
`r2
`
`50.0
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`0.0
`
`Male
`n44
`
`6.8
`
`4.5
`
`12.3
`
`0.0
`
`2.3
`
`2.3
`
`Female
`r47
`
`Male
`n62
`
`Female
`r62
`
`6.4
`
`2.1
`
`12.1
`
`2.1
`
`0.0
`
`0.0
`
`4.8
`
`3.2
`
`1.6
`
`0.0
`
`1.6
`
`1.6
`
`6.5
`
`1.6
`
`1.6
`
`1.6
`
`0.0
`
`0.0
`
`Disord ers
`
`Mouth Hemorrhage
`
`Investigations
`
`ECG ST Segmeot
`Elevation
`
`01 Saturation
`Decreased
`
`Respiratory Thoraeic
`and Nlediastlisal
`
`Disord cr5
`
`PH
`
`Vascular Disorders
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00
`
`0.0
`
`0.0
`
`0.0
`
`50.0
`
`50.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`50.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`2.3
`
`0.0
`
`0.0
`
`0.0
`
`2.3
`
`2.3
`
`0.0
`
`0.0
`43
`
`0.0
`
`1.6
`
`0.0
`
`00.0
`
`4.3
`
`0.0
`
`0.0
`
`0.0
`
`2.1
`
`1.6
`
`1.6
`
`0.0
`
`Hypotcnsion
`
`2.1
`0.0
`0.0
`50.0
`0.0
`0.0
`0.0
`System organ classes and preferred terms are coded using the MedDRA dictionary System organ classes and
`order of frequency for the Overall column
`patient with multiple
`preferred terms are listed in descending
`occurrences of an AE is counted only once in the AId category
`Source Section 14.3.1 Table 8.3 and Appendix 16.2.7
`
`0.0
`
`4.8
`
`1.6
`
`3.2
`
`0.0
`
`0.0
`
`3.2
`
`3.2
`
`Draft V.O.3
`
`58
`
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`
`

`
`Clinical Study Report
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`NO Therapeutics LLC
`
`Table 25
`
`Adverse Events By Diagnosis and Race Safety
`
`WAIT
`
`Carthornyopathy
`
`CHID
`
`Overall
`
`Diagnosis and Race
`
`System Organ
`Class/Preferred Term
`NW
`
`Patients With at Least
`One AE
`
`Cardiac Disorders
`
`Bradycardia
`
`Cardiac Arrest
`
`Low CO Syndrome
`
`Gastrointestinal
`
`White
`n19
`
`All Other
`si9
`
`While
`si3
`
`AIJ Other
`112
`
`0.0
`
`0.0
`
`0.0
`00
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`33.3
`
`0.0
`
`0.0
`
`0.0
`00
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`White
`n51
`
`611.8
`
`5.9
`
`3.9
`
`2.0
`
`2.0
`
`00.0
`
`00.0
`
`00.0
`
`00.0
`
`12.0
`
`00.0
`
`All Other
`n40
`
`Wilsite
`
`xs73
`
`All Other
`n51
`
`0.0
`
`0.0
`
`0.0
`
`00
`
`0.0
`
`9.6
`
`4.1
`
`2.7
`
`1.4
`
`1.4
`
`14
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`Disorders
`
`Mouth Hemorrhage
`
`Investigations
`
`ECG ST Segment
`Elevation
`
`02 Saturation Decreased
`
`Respiratory Thoracic
`and Mediastinal
`
`Disorders
`
`PH
`
`Vasenlar Disorders
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`33.3
`
`33.3
`
`0.0
`
`0.0
`
`0.0
`
`33.3
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`2.0
`
`3.9
`
`0.0
`
`3.9
`
`20
`
`2.0
`
`2.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`1.4
`
`4.1
`
`1.4
`
`2.7
`
`1.4
`
`1.4
`
`2.7
`
`Hypotension
`
`0.0
`2.7
`2.0
`0.0
`0.0
`0.0
`33.3
`System organ classes and preferred terms are coded using the MedDRA dictionary System organ classes and
`preferred terms are listed in descending order of frequency for the Overall column
`patient with multiple
`occurrences of an XE is counted only once in the XE category
`Source Section 14.3.1 Table 8.4 and Appendix 162.7
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`Draft v.0.3
`
`59
`
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`
`

`
`Clinical Study Report
`
`NO Therapeutics LLC
`
`Adverse Events Related to Study Drug
`12.2.2.2
`total of four patients had AEs that were related to study drug Table 26 These events
`included bradycardia low CO syndrome ST segment elevation on the ECG low 02 saturation
`PH and hypotension
`
`Table 26
`
`Adverse Events Related to Study Drug By Diagnosis Safety
`
`System Organ ClassfPreferred
`Term
`r%lt
`
`Patients With at Least One AE
`Related to Study Drug
`
`Cardiac Disorders
`
`Bradycardia
`
`Low CO Syndrome
`
`Investigations
`
`ECG ST Segment Elevation
`
`02 Saturation Decreased
`
`Respiratory Thoracic and
`Mediastiual Disorders
`
`PH
`
`Vascular Disorders
`
`Diagnosis
`
`IPAH
`n28
`
`Cardiomyopathy
`
`n5
`
`ClIP
`n91
`
`Overall
`nt24
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`00.0
`
`0.0
`
`20.0
`
`0.0
`
`0.0
`
`0.0
`
`20.0
`
`20.0
`
`0.0
`
`00.0
`
`00.0
`
`20.0
`
`3.3
`
`2.2
`
`1.1
`
`1.1
`
`1.1
`
`0.0
`
`1.1
`
`3.2
`
`.6
`
`0.8
`
`0.8
`
`.6
`
`0.8
`
`0.8
`
`11.1
`
`10.8
`
`1.1
`
`0.0
`
`0.8
`
`0.8
`
`0.8
`0.0
`0.0
`20.0
`Hypotension
`System organ classes and preferred terms are coded using the MedDRA dictionary System organ classes and
`order of frequency for the Overall column
`patient with multiple
`preferred terms are listed in descending
`of an AE is counted only once in the AE category
`occurrences
`Source Section 14.3.1 Table 10.1 and Appendix 16.2.7
`
`Draft v.0.3
`
`60
`
`Ex. 2014-0314
`
`

`
`Clinical Study Report
`
`INO Therapeutics LLC
`
`Treatment-related AEs are summarized by diagnosis and age in Table 27 Overall treatment-
`10 years of age than in those 10 years old
`related AEs occurred more often in patients
`there were only four treatment-related AEs so any conclusions regarding effects of
`However
`age must be viewed as highly speculative
`
`Table 27 Adverse Events Related to Study Drug By Diagnosis and Age Safety
`
`WAll
`
`Cardioeuyopatlsy
`
`CUD
`
`Overall
`
`Diagnosis
`
`and Age Group
`
`System Organ
`
`ClasslPreferredTernsn
`
`10 years
`n17
`
`10 Years
`n11
`
`510 years
`n4
`
`10 Years
`n1
`
`510 years
`u68
`
`10 Years
`n23
`
`510 years
`iv89
`
`10 Years
`n35
`
`Patients With al Least
`One AF Related to Stssdy
`Drug
`
`Cardiac Disorders
`
`I3radycardia
`
`Low CO syndrome
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`2.9
`
`1.5
`
`0.0
`
`1.5
`
`25.0
`
`0.0
`
`0.0
`
`0.0
`
`25.0
`
`4.3
`
`3.4
`
`4.3
`
`4.3
`
`0.0
`
`0.0
`
`.1
`
`0.0
`
`1.1
`
`2.9
`
`2.9
`
`2.9
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`Investigations
`
`ECc5T5eginent
`
`02 saturation Decreased
`
`Respiratory Thoracic
`and Mediastinal
`
`Disorders
`
`PH
`
`vascular Disorders
`
`00.0
`
`00.0
`
`0.0
`
`00.0
`
`00.0
`
`00.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`00
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`1.5
`
`0.0
`
`1.5
`
`1.5
`
`11.5
`
`0.0
`
`25.0
`
`0.0
`
`0.0
`
`00.0
`
`25.0
`
`2.2
`
`1.1
`
`1.1
`
`1.1
`
`11.1
`
`1.1
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`Hypotension
`
`1.1
`0.0
`0.0
`0.0
`0.0
`00.0
`25.0
`System organ classes and preferred terms are coded using the MedDRA dictionary System organ classes and
`preferred terms are listed in descending order of frequency for the Overall column
`patient with multiple
`occurrences of an AE is counted only once in the AE category
`Source Section 14.3.1 Table 01.2 and Appendix 16.2.7
`
`Draft v.0.3
`
`Ex. 2014-0315
`
`

`
`Clinical Study Report
`
`INO Therapeutics LLC
`
`Treatment-related AEs are summarized by diagnosis and gender in Table 28 Two treatment-
`related AEs occurred in males 3.2% and two in females 3.2%
`
`Table 28 Adverse Events Related to Study Drug by Diagnosis and Gender Safety
`
`IPAII
`
`Cardiomyopathy
`
`CHD
`
`Overalj
`
`Diagnosis
`
`and Gender
`
`System Organ
`Class/Preferred Term
`
`a_
`
`Patients With at Least
`One AE Related to
`Study Drug
`
`Cardiac Disorders
`
`Bradycardia
`
`Low CO Syndrome
`
`Investigations
`
`Male
`n15
`
`0.0
`
`0.0
`
`0.0
`00
`
`Female
`n13
`
`00
`
`0.0
`000
`
`0.0
`
`Male
`n3
`
`Female
`
`u2
`
`Male
`n44
`
`Female
`n47
`
`Male
`n62
`
`Female
`n62
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`50.0
`
`0.0
`00
`00
`
`50.0
`
`4.5
`
`4.5
`
`2.3
`
`2.3
`
`2.1
`
`0.0
`
`0.0
`
`0.0
`
`32
`
`3.2
`
`1.6
`
`1.6
`
`3.2
`
`00
`00
`
`0.0
`
`3.2
`
`FCC ST Segment
`
`Decreased
`
`Respiratory Thoracic
`and Mediastinal
`
`Disorders
`
`PH
`
`Vascular Disorders
`
`0.0
`
`00
`
`0.0
`
`00
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`50.0
`
`0.0
`
`0.0
`
`0.0
`
`50.0
`
`0.0
`
`0.0
`
`0.0
`
`2.3
`
`2.3
`
`0.0
`
`2.1
`
`0.0
`
`2.1
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`16
`
`1.6
`
`0.0
`
`Hypotension
`
`0.0
`0.0
`0.0
`00.0
`0.0
`50.0
`0.0
`System organ classes and preferred terms are coded using the MedDRA dictionary System organ classes and
`preferred terms are listed in descending order of frequency for the Overall column
`patient with multiple
`occurrences of an AE is counted only once in the AE category
`Source Section 14.3.1 Table 10.3 and Appendix 16.2.7
`
`1.6
`
`1.6
`
`0.0
`
`0.0
`
`1.6
`
`1.6
`
`Draft v.0.3
`
`62
`
`Ex. 2014-0316
`
`

`
`Clinical Study Report
`
`NO Therapeutics LLC
`
`Treatment-related AEs are summarized by diagnosis and race in Table 29 All four treatment-
`related AEs occurred in whites 5.5%
`
`Table 30 Adverse Events Related to Study Drug By Diagnosis and Race Safety
`
`System Organ
`Class/Preferred Term
`
`Patients With at Least
`One AE Related to Study
`Drug
`
`Cardiac Disorders
`
`Bradycardia
`
`Low CO Syndrome
`
`White
`n19
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`Diagnosis and Rare
`
`WAH
`
`Cardiomyopathy
`
`CR11
`
`Overall
`
`Mi Other
`r9
`
`White
`n3
`
`All other
`
`n2
`
`White
`nSl
`
`All Other
`
`n40
`
`White
`n73
`
`AJJ Other
`
`ieSl
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`33.3
`
`0.0
`
`5.9
`
`0.0
`
`1- 5.5
`
`00.0
`
`00.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`33.3
`
`3.9
`
`2.0
`
`2.0
`
`2.0
`
`00.0
`
`22.7
`
`0.0
`
`0.0
`
`0.0
`
`1.4
`
`1.4
`27
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`Investigations
`
`i2ins
`
`ment
`
`02 Saturation Decreased
`
`Respiratory Thoracic
`and Mediastinal
`
`Disorders
`
`PH
`
`Vascular Disorders
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`33.3
`
`0.0
`
`0.0
`
`00.0
`
`33.3
`
`2.0
`
`2.1
`
`12.0
`
`00.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`1.4
`
`1.4
`
`1.4
`
`1.4
`
`1.4
`
`Hypoteosion
`
`0.0
`1.4
`0.0
`0.0
`0.0
`0.0
`33.3
`System organ classes and preferred terms are coded using the MedDRA dictionary System organ classes and
`patient with multiple
`preferred terms are listed in descending order of frequency for the Overall column-
`occurrences of an AE is counted only once in the AE category
`Source Section 14.3.1 Table 10.4 and Appendix 16.2.7
`
`0.0
`
`0.0
`
`0.0
`
`00.0
`
`0.0
`
`0.0
`
`12