Study P01 :04-05
`
`‘
`
`NBA 21 -272
`UT-I 5 for pulmonary hypertension
`
`Table 76. Hemodynamic results (P01:04—05)"’1
`
`i l i1 I V
`
`i I
`
`ri i
`
`l i
`
`i
`
`i iill iii i 1a:5% > iil
`
`\l
`
`Week 12 chm?”
`iIi ii l1
`
`4 l 1l l 1
`
`<0.001 ‘
`
`.1. H- y—
`195
`-0.510.4
`194
`0.110.04
`193
`1.810.6
`
`199
`-2.710.8
`199
`.-2.210.6
`199
`-2.310.5
`163
`-3.510.6
`
`1 75
`-0. 110.3
`
`198
`-2.311.1
`198
`-1.810.9
`197
`-1.710.9
`175
`-3.511.0
`181
`2.0108
`194
`-0.610.3
`
`
`
`215
`- 111
`21 1
`1 .4103
`209
`~0. 110.04
`208
`-0.610.5
`
`215
`0.3109
`2 15
`0610.6
`215
`0710.6
`187
`1 210.6
`
`199
`0910.4
`
`2 14
`-0.410.8
`214
`-0.410.1
`21 1
`- 1 .010.9
`190
`-O.810.9
`l 82
`-1 .410.7
`205
`-0.410.3
`
`234
`8211
`23 l
`1 010.4
`' 232
`2.210.05
`23 l
`2810.7
`
`228
`8211
`228
`1010.4
`225
`2.410.06
`222
`3010.9
`
`235
`9511.5
`
`235
`4010.8
`235
`6011 .0
`203
`2510.9
`
`225
`9.3102
`
`234
`12111.3
`234
`7410.8
`234
`9110.9
`2 1 9
`3911 .0
`215
`6010.8
`227
`1910.3
`
`231
`9611.6
`23 1
`4311.0
`231
`6211.2
`204
`2711.0
`
`217
`9.5102
`
`230
`11911.1
`230
`7210.9
`229
`9010.9
`21 1
`3811 . 1
`2 1 5
`6210.7
`225
`1910.3
`
`
`
`
`
`
`
`mean1$E
`
`N m
`
`ean1SE
`
`mean1SE
`
`mean1SE
`
`N
`mean1SE
`
`N
`meaniSE
`
`Nm
`
`eaniSE
`
`N m
`
`ean18E
`
`N
`mean1$E
`
`N
`Ba
`
`an1SE
`
`N m
`
`eaniSE
`
`mean1SE
`
`N
`mean1SE
`N
`mean1SE
`Z
`mean1SE
`
`
`
`rate ‘
`
`0"’U
`Right atrial pressure
`mml-lg
`Cardiac index
`L/ min / m2
`Stroke index
`
`L/ beat/ m2
`Pulmonary systolic
`mml—l 1
`
`Pulmonary diastolic
`33
`:
`
`Pulmonary mean
`BBI
`Pulm vasc resis index
`
`mml-l /L/min/m2
`Pulmonary cap wedge
`mml-l:
`
`Systemic systolic
`mml-l ;
`
`Systemic diastolic
`mmHg
`Systemic mean
`BB:1:
`
`Syst vasc resis index
`mmH 1 /L/min/m2
`Mixed venous oxygen
`%
`
`Respiration rate
`min-1
`
`
`
`
`
`
`
`
`
`
`<0.001
`
`<0.001
`
`0.02
`
`<0.001
`
`0.08
`
`0.08
`
`03
`
`
`
`
`
`
`<0.001 .
`
`<0.2
`
`
`
`The table indicates that for this truncated population (i.e. completers), there were
`modest decreases in right atrial pressures, pulmonary artery pressures (mean,
`systolic and diastolic) and pulmonary vascular resistance. Cardiac index, stroke
`index and mixed venous oxygenation were increased.
`
`APPEARS ““8 W“
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`’0' The p-ualue is based on the treatment effect of the ANCOVA with baseline and treatment as the couan'ates.
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`Study P01:04-01>
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`,
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`NBA 21 -272
`UT—I 5 for pulmonary hypertension
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`
`
`Onlreatmen
`
`ZOAOGOEIWIZBA
`
`AOGOEDIWIZOMDA
`
`SAPD
`
`3“”
`
`SAPM 33"”
`
`Figure 15. Hemodynamics scatter plots (P01:04-05)
`Reviewers' analysis. Baseline and week-12 hemodynamic data are plotted for subjects
`on vehicle (P, square) and 01-15 (A, triangle). Marginal box-and—whiskers plots
`compare the distributions in the treatment groups at baseline and at 12 weeks.
`Panes are (HR) heart rate, (PAPD) pulmonary artery diastolic pressure, (PAP!)
`pulmonary artery mean pressure, (PAPS) pulmonary artery systolic pressure, (PCWP)
`pulmonary capillary wedge pressure, (RAP) right atrial pressure, (SAPD) systemic
`diastolic pressure, (SAW) systemic mean pressure, and (SAPS) systemic systolic
`pressure.
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`Ontreatmen
`
`Ontreatmen
`
`0ntreatmen
`
`Ontreatmen
`
`Ontreatmen
`
`0ntreatmen
`
`'40
`
`so 801001me
`
`HR
`
`Basel'ne
`
`s.-
`
`3E.
`
`-
`
`.33c
`0
`
`0 501(1)]me
`
`PAPS
`
`33““
`
`

`

`Study I 01:04-05
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`,
`
`’
`‘
`
`NDA 21-272
`UT-I 5for pulmonary hypertension
`
`The effect on hemodynamics, though statistically significant is in general small and of
`uncertain consequence. For cardiac index the net change (assuming that the data for
`those measured is consistent with thewhole group) there was a net increase of 7.6%.
`There was an approximately 5% (3 mm Hg) decrease in mean pulmonary artery
`pressure. There was an approximately 18% decrease in pulmonary vascular resistance.
`
`The sponsor was requested to analyze whether there was a correlation between
`hemodynamics (change in and % change in C1, PVR or PAPm) and walking distance,
`dyspnea fatigue rating or Borg-score. Among these 18 analyses only the correlation
`between PVR and walk distance was nominally significant (by Spearman-Rank
`correlation). Change in mixed venous oxygenation was correlated with walk and
`dyspnea fatigue index. The % change in mixed venous oxygenation was correlated with
`walk distance and dyspnea-fatigue index.
`
`Egen saturation
`
`Although prespecified as a secondary end~point, this metric was not measured. In fact it
`did not appear that this metric was collected. With the exception of those who were on
`oxygen, during catheterization, no oxygen saturation data was captured.
`
`Other end points
`
`The following end points are often considered in drugs for use in subjects with CHF due
`to left-sided systolic dysfunction. The outcomes would be reasonable to consider for
`subjects with pulmonary hypertension. They were not prespecified as end-points for
`these studies.
`
`Mortality
`
`There did not appear to be a signal that mortality was altered by UT—15. There were a
`total of 19 subject who died during the course of the study. Nine in the UT-lS and ten
`in the vehicle group. Death occurred on treatment day (mean + SD) 42 1 26 for UT-15
`and on day 49 1 35 for vehicle.
`,
`
`Of these deaths, six UT-15 (#4017, #9006, #10002, #23002, #51007, and #55005) and
`seven vehicle (#9012, #10001, #15003, #16003, #60006, #60015 and #65004) were
`listed as deaths. Four subjects, two in the UT.15 (subjects #54005 and #58001) and
`one vehicle subject (#65011) were listed as having deteriorated, these subjects died after
`the assessment of deterioration. There were two subjects, one UT-15 (#4503) and one
`vehicle (#52006) subject who were listed as adverse events who died. One subject in the
`vehicle group (#16006) was listed as having completed (the subject had the last cardiac
`catheterization) but died during the hospitalization.
`
`Hospitalizations
`
`This data was culled from Table 14.3.4.1, p 5609. That section of the submission
`contained narratives of all serious adverse events. These narratives should have
`
`captured all hospitalizations. There was no difference in the number of subjects
`hospitalized in comparing UT-15 to vehicle. There were 40 vehicle subjects and 38 UT-
`15 subjects who were hospitalized or had their duration of hospitalization increased.
`Capsular summaries for those hospitalized are available under safety. Two of the .
`vehicle subjects who were hospitalized had actually inadvertently received UT-15 at the
`time of event that caused hospitalization.
`
`With respect to the number of subjects who were hospitalized for cardiovascular events
`or worsening of pulmonary hypertension, any analysis would be highly subjective. This
`reviewer, however, counted those who died or appeared to be hospitalized for
`cardiovascular diseases as 25 in the vehicle group and 22 in the UT-15 group. Check
`marks next to the number in Table 82 on page 138 reflect this reviewer’s judgement as
`to what was considered as a cardiovascular event.
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`btudy P01:04-05
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`.
`
`NBA 21 -2 72
`UT—1 5for pulmonary hypertension
`
`Need for medication chagges
`
`With respect to subjects who required either pressor support or flolan, this reviewer
`counted 12 UT- 15 subjects and 13 vehicle subjects who required pressors or flolan
`during the course of the study. Among those who were treated with pressors three
`vehicle subjects and no UT—15 subjects received flolan early on (day 2) of treatment for
`short duration (1 day). It seems that flolan in these subjects was used as a provocative
`test for pulmonary vascular responsiveness and not to treat worsening of status.
`Excluding these three subjects suggest l2 UT-15 and 10 vehicle subjects required
`inotropic or prostaglandin support during the study. There did not appear to be any
`differences in the need of pressors or flolan or pressors among the two treatments.
`
`This reviewer also explored the need or increase of medications used for pulmonary
`hypertension. The data was contained in sponsor’s Listing 16.2.4.7 of the NDA. This
`was not a pre-specified analysis, but has been used as support of medications that have
`been approved for the treatment of left-sided failure. Since this reviewer tabulated the
`data by hand and not by querying the database, the analysis is only be considered an
`approximation.
`
`The metric used was the number of subjects who received treatment with an additional
`drug used to treat pulmonary hypertension or had one of these ongoing medications
`increased at the end of treatment relative to baseline. The drug classes that were
`considered in this analysis were those that might be increased in subjects whose
`pulmonary hypertension status was worsening. The drugs included loop diuretics,
`calcium channel blockers, vasodilators (including hydralazine, clonidine, nitrates), ACE
`inhibitors or angiotensin II blockers, oxygen, flolan, pressors, steroids, digoxin,
`aldactone or non-loop diuretics. Topical steroids used for the treatment of infusion site
`pain were not included in the sponsor’s listing but captured in a subsequent listing
`16.2.4.8. These topical steroids were not included in this count. This reviewer also did ‘
`not consider changes in antithrombotics (e.g. coumadin and its derivatives, heparin) or
`antiplatelet drugs (e.g. ticlopidine) as a reflection of worsening disease but rather as
`responses to changing lNR.
`
`Based on this analysis, there were 165/233 subjects (70.8%) of those in the UT-lS
`group and 163/ 266 (69.1%) of the vehicle group who did not receive new medications
`and did not have baseline medications increased in doses (these patients could have
`medications changed i.e. decreased but were not counted). There did not appear to be
`an overwhelming signal that subject’s status was sufficiently altered to require less
`concurrent medications.
`
`Concomitant medications by class of drug, at the end of study and at screening are
`shown in table below (derived from sponsor’s Table 1 1.2.2. 12 and 11.4.5). There were
`slight increases in the number of subjects treated with each category of drug for both
`treatments. There were far more subjects treated with anticoagulants at the end of the
`study than at baseline-screening. Other classes of drugs were only slightly increased
`over baseline. There were more subjects on vehicle versus UT-15 subjects taking
`diuretics at the end of the study relative to baseline (28 versus 20), calcium channel
`blockers (4 versus 3), other vasodilators (0 versus 6) and digoxin (1 1 versus 9).
`
`PPEARS nus WAY
`A on omemu
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`Study 1001:04-043
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`‘
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`'
`
`NDA 21-272
`UT—1 5for pulmonary hypertension
`
`Table 77. Medication changes (P01:O4—05)
`
`Arpoloq:
`
`2.1,,
`
`_.
`
`,
`
`Anticoagulants
`
`Calcium channel
`blockers
`
`Other
`vasodilators
`
`Digoxin
`
`Diuretics
`
`Baseline
`Treatment
`
`Baseline
`Treatment
`
`Baseline
`Treatment
`
`, Baseline
`Treatment
`
`Baseline
`Tremam ,, ,
`
`58 (52)
`94 85
`
`50 (45)
`52 49
`
`19 (17)
`24 22
`
`30 (27)
`35 32
`
`54 (49)
`
`61 (54)
`95 84
`
`49 (43)
`50 44
`
`18 (16)
`18 16
`
`34 (30)
`41 36
`
`69 (6 1 )
`
`88 (82)
`116 92
`
`48 (38)
`49 39
`
`16 (13)
`17 14
`
`29 (23)
`33 26
`
`75 (60)
`
`88 (73)
`104 87
`
`160 (68)
`210 89
`
`149 (64) ‘
`199 85
`
`48 (40)
`51 43
`
`15 913)
`15 13
`
`22 (18)
`26 22
`
`57 (56)
`
`98 (42)
`101 43
`
`35 (15
`41 17
`
`59 (25)
`68 29
`
`97 (42)
`101 43
`
`33 (14)
`33 14
`
`56 (24)
`67 29
`
`1 29 (55)
`157
`
`l 36 (58)
`156
`
`Change in NYHA classification
`
`This parameter was not measured after baseline. No change in subject NYHA status
`was available.
`
`Dose response
`
`There was no formal dose-response data available. Since subjects were forced titrated
`based on symptom improvement as well as tolerance to drug, any dose~related data is
`confounded by duration of time in the study. Dose response data could theoretically be
`defined by the walking effect at a given infusion rate of drug.
`
`The relationship of infusion rate and walking distance at week 12 is shown in Figure
`16. Both vehicle (P) and UT-15 (A) have positive non-zero slope effects. The intercepts of
`the two drugs differ. The intercept for vehicle is negative and significantly different from
`baseline.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`APPEARS THIS WAY
`on ORIGINAL
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`

`

`Study P01:04-05
`
`,
`
`NDA 21 «272
`UT-1 5 for pulmonary hypertension
`
`m
`
`Figure 16. Change from baseline. in walking distance (feet) by dose (studies P01:04, P01:05).
`P=Vehicle; Asaetive treatment. Data derived from dataaets for both studies combined,
`tables RANDCODE, WALK, and ODRUO. Horizontal line marks no change from
`baseline.
`
`The data from the figure above were fitted to a straight line (linear least squares
`procedure) using JMP. The resulting fitted parameters and their confidence limits are
`shown in Table 78.
`
`Table 78. Pit of change in walking distance (feet) by dose to y=m*DOSE+b.
`
`
`_ 55:27 m- aceisz mm-
`
`
`
`
`
`Subggug analysis based on baseline status
`
`Dr. Lawrence, the FDA statistician analyzed the time-dependent effect of the various
`cohorts that were enrolled in this study .A linear mixed-effect model was used here as
`an exploratory analysis in order to see the treatment effect over time. This model
`assumes that those subjects who discontinued early, regardless of the reason for
`discontinuation, would have walking distances similar to those subjects who completed
`the study. Missing data can be predicted based on the performance of other subjects
`that have similar characteristics to the one with missing data.
`'
`
`Since each subject would theoretically have three measurements post-baseline, Dr
`Lawrence modeled the change from baseline as a quadratic function of time. The
`specific linear model that was used contained fixed-effects for treatment group, baseline
`distance walked, etiology, vasodilator use among secondary PH subjects, and time as a
`quadratic function. In addition, all two-way interactions between treatment group and
`the other variables as well as the two—way interactions between stratification (etiolog/
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`Study P01 :04-05
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`'
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`
`NDA 21-272
`UT—1 5for pulmonary hypertension
`
`vasodilator use) and time were included in the model. There were random effects for
`the intercept, slope, and the quadratic term for time. The strategy was to specify a
`complex model and let the data decide which terms were important. The curves for
`each stratification level at the average baseline walking distance are shown in Figure 13
`on page 1 19.
`
`From Figure 13, it appears that at Week 1, subjects in all strata in the vehicle group
`improved walking distance by an average of about 10 meters. Over the course of the
`trial, there was a gradual deterioration in the performance of all subjects, independent
`of origin. In the UT-15 group, the change at Week 1 was about 15 m in the SPH (no
`vasodilator) subgroup and about 20 m in the other two subgroups, but over the course
`of the trial, the improvement was maintained or increased slightly.
`
`M2
`
`Pharmacokinetic measurements were collected on Days 2, week 1, week 6 and week 12.
`The kinetic data was not attached to this study report but was submitted separately as
`a biopharmaceutical report.
`
`Tolerance
`
`There is no information submitted that any effect of UTolS lasts more than the 12-week
`duration of this study. No randomized withdrawal information of the study was
`performed to convincingly demonstrate a persistent drug effect. The concern that there
`may be tolerance arises from the large increase in dose of UT-lS in going from week 1 to
`week 6 or week 12 and the minimal change in walking distances over these dose
`increases. The doses are graphically displayed in Figure 12 on page 90. There were a
`greater than 4-fold increase in dose in going from the end of weekl 1.2 ng/ kg/ min to
`week 6 (5.9 ng/ kg/ min). There was minimal change, however, in walking distance
`during the same period of time.
`
`There does not appear to be adequate information available from pre-clinical, animal
`and biopharm data to rule out a potential of diminishing effect of long duration of UT-
`15 treatment. Mechanism of tolerance may include
`
`o A decrease in the availability after long duration of infusion i.e. fibrosis at'
`the infusion site may limit availability. Because infusion sites were rotated
`frequently, this is not likely.
`
`o Metabolites may be produced that act in a counter-regulatory manner to the
`effect of UT—15 (the metabolic profile as well as the half—fife of the known
`metabolites as well as the potential for the existence of uncharacterized
`metabolites remain a possibility.
`
`0 Down regulation of receptors or de-linking of receptors from regulatory
`proteins may have occurred.
`
`54.4.8 Safety
`
`A.4A.8.1 Exposure
`
`There were a total of 469 subjects who were randomized and received at least one dose
`of drug/vehicle. The mean (iSD) duration of exposure for those treated with UTo15 was
`81.06 i 17.1 days and for vehicle it was 82.83 i 14.1 Days. There were 31 UT-15 and
`16 vehicle subjects who were treated for less than 72 days (the lower limit of the
`window for the 12-week visit). Subjects were exposed to UT—lS for a total of 18,887
`subject x days (51.75 subject it years) and to vehicle for 19,547 subject it days (53.55
`V subject it years). Exposure to vehicle was therefore 3.5% greater than that of UT—15 The
`mean dose of UT-lS/vehicle are shown in Figure 12 on page 103.
`
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`Study P01 :04-05
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`J
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`:
`
`NBA 21 -272
`UT-J 5for pulmonary hypertension
`
`The distribution of infusion rates for UT-15 and vehicle subjects are shown in Table 79.
`Approximately 50% of those treated with vehicle received doses of >20 ng/ kg/ min. For
`the UT—15 treated subjects the median dose was 9.3 ng/ kg/ min.
`
`Table 79. Distribution of doses by week (P01:04-05)
`Week 8
`
`
`
`More vehicle subjects were titrated upward and more UT—15 subjects were down titrated
`during the course of the study (Table 80). It should be noted that when doses were
`decreased, the usual reason was for either infusion site pain /reaction. There was no
`fixed dose decrease that was to occur in response to infusion site pain supervened.
`Trivial dose changes were often implemented as a consequence of infusion site pain.
`The reasons for dose decreases are shown in Table 81.
`
`Table 80. Increase: and decreases in dose (P01:04-05)1°2
`
`
`-_‘
`
`
`
`
`
`
`Week 5-8 “—
`
`
`
`
`
`
`Vomitm-
`
`' n53-" -I7 " ifl" 9 4
`'_-Ims1m€aunl''
`—m- 3113 —m
`—IIBJI 1113
`mm-
`m- 7 4
`
`‘
`
`Of the treated subjects who had dose reduction, 57 of the 64 UT—15 subjects with
`infusion site pain and 26 of the 31 subjects with infusion site reaction. For UT-IS
`infusion site pain and infusion site reaction were first noted at doses of 0- <2.5 '
`ng/ kg/ min. Only six subjects had the onset of pain and 4 subjects with infusion site
`reaction had the onset of symptoms at doses > 2.5 ng/kg/ min.
`
`Approximately 65% of those treated with UT-IS complained of infusion site pain by the
`end of the first week of treatment. The percentage increased to approzdmately 90%
`complained of pain by the end of week 3. Nearly all subjects had infusion site pain by
`the end of week 12.
`
`The fraction of subjects treated with opiates by the end of week 1 was 4%. This fraction
`increased to approximately 12% by the end of week 3 and 28% by the end of the study.
`The fraction of subjects treated with anti~inilammatory drugs was 16% at the end of
`week land increased to 28% at the end of week 3 and 44 % by the end of the 12-week
`
`"’9 Sponsor’s Table 12.1.2A
`
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`Study P01:04—05
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`UT~1 5 for pulmonary hypertension
`
`study. The fraction of UT-15 who received either opiates opr anti-inflammatory drugs
`was 16% by the end of week 1, 32% by the end of week 3 and 52% by the end of the
`study.
`"
`
`It is, however, unclear whether the need for pain medication was continuous and
`therefore a necessary component of treatment or the pain medication as taken only on a
`PRN basis and therefore only an intermittent nuisance. Based on discussions with the
`sponsor, patients were offered a prescription and compliance and use of the pain
`medication was not further followed.
`
`AAA-.83 Deaths
`
`There were a total of 19 deaths in or around the study. Nine of these deaths in people
`randomized to UT-lS and ten to vehicle. Subjects who died were: # 04/4017;
`#0514503; #04/9006; #04/ 10002; #04/23002; #05/ 51007; #05154005; #05/55005;
`and #0515800] in the UT-15 group and 04/9012; #04/ 10001; #04/15003; #04/ 16003;
`#04116006; #05l52006; #05/60006; #05 / 60015; #05 / 65004; #05165011 in the
`vehicle group. The underlined subjects discontinued for reasons other than death but
`died during the l2-week window of the study. Capsular summaries are available in
`Table 82 below which contains the list of all subjects hospitalized.
`
`A.4.4.8.3 Dropouts] diecontinuati one
`
`There were 20 dropouts for adverse events or withdrawal of consent in the UT— 15 group.
`One additional subject #4503 was listed as a dropout but died of sepsis.
`
`A.4.4.8.4 Hospitalizations or prolongation of hospitalization:
`
`There were 38 and 40 subjects, randomized to UT-15 and vehicle, respectively who were
`either hospitalized or whose hospitalization was prolonged. Two vehicle subjects were
`inadvertently administered UT~15 and were hospitalized after the cross-over while
`treated with active drug. Capsular summaries for those that were hospitalized,
`deteriorated or died are shown in Table 82.
`
`APPEARS “"8 WAY
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`APPEARS nus WAY
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`ou ORIGINAL
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`Study FUIIU4-Ub
`
`NDA 21-272
`UT-l 5for pulmonary hypertension
`
`Table 82. Capsular summaries for those who died, were hospitalized or whose hospitalization was
`prolonged (Pill:04-05)
`
`Description
`
`Thiswasa37- year old Caucas1an female w1thpulmonaryhypertensron
`NYHA Class III status. She was hospitalized for an allergic reaction to Bactrim,
`rescribed for a UTl.
`
`This was a 35.year old Caucasian Female with pulmonary hypertension and systemic
`sclerosis and NYHA class ll]. Concomitant medications included furosemide, isradipine,
`-
`'
`-
`- usitive stools.
`
`This was a 38-year old Caucasian female subject with pulmonary hypertension and SLE
`.
`-italized for -neumococcal menin;itis.
`This was a 32-year old Caucasian female with primary pulmonary hypertension and
`NYHA Class Ill status. She was hospitalized on day 21 of the study for worsened heart
`This was a 36-year old Hispanic female with primary pulmonary hypertension and NYl-lA i
`Class III status. The subject became septic status post a medical termination of
`1
`pregnancy. The subject treated with antibiotics but subsequently died.
`
`Subject!”
`Arm
`Eirent
`
`404/2019
`UT-15
`
`04/2022
`111215
`
`04/ 3009
`UT- 1 5
`
`O4 /401 7
`UT— 1 5
`death
`
`05/ 4503
`UT— 1 5
`ADR
`Pt died
`
`04 / 5003
`UT~ 1 5
`
`04/5009
`ur-15
`ADR
`
`04/7004
`UT-15
`ADR
`
`04/9001
`UT—lS
`
`04/9002
`‘ UT- 1 5
`
`
`
`This was a 71.year old Caucasian female with pulmonary hypertension and limited
`scleroderma and NYHA Class IV. Concomitant medications included digoxin, enalapril
`and warfarin. She was hospitalized for diarrhea, rectal bleeding and vomiting. Warfarin
`was withheld and the sub'ect was reh drated.
`
`This was a 51-year old Caucasian female with pulmonary hypertension and a congenital
`systemic to pulmonary shunt and NYHA Class III status. She was hospitalized on day 2
`(one-day post—catheterization) for a right groin hematoma and a collection of blood in the ,
`- lvis. The sub‘ect was not takin- anticoa-
`lants at the time of the event.
`
`This was a 44-year old Caucasian female with pulmonary hypertension and a congenital
`systemic to pulmonary shunt. She was NYHA Class II. The subject was hospitalized
`twice, once for hemoptysis and a possible upper lobe infiltrate (on day 35) once again for
`hemoptysis (on day 43). Endobronchial embolization was performed. Concomitant
`medications included digoxin and furosemide. Coumadin was stopped on the day of the
`first event.
`
`This was a 30-year old Caucasian female with pulmonary hypertension and mixed
`connective tissue disease and NYHA Class III who was admitted to the hospital for
`nausea, vomiting dehydration and hyponatremia (serum sodium 126). The subject was
`,a'ven iv fluids and recovered.
`This was a 61-year old Caucasian female with pulmonary hypertension and mixed
`connective tissue disease who was admitted because of diarrhea, pancytopenia
`(Hemoglobin '- 8.9 g/dL; platelets 44 x 103 /uL; WBC = 3,74 x 103/uL) and hyponatremia
`(Na+ -= 117 mEq/L). She had recently been treated with cyclophosphamide. She was
`treated with fluid restrictions, electrolytes, dobutamine, prednisone and platelet and
`RBC transfusions. She recovered.
`
`This was a 29—year old Caucasian female with pulmonary hypertension and a congenital
`systemic to pulmonary shunt (atrial septal defect) and NYHA Class 111 status. She
`developed lightheadedness and bilateral loss of vision on day 2. A paradoxical embolism
`was suspected. The study drug was stopped. The next day the drug was commenced,
`New symptoms (facial droop and dysarthria) were noted. Angiography and thrombolysis
`were undertaken and a birds nest filter placed to intercept any emboli from the lower
`limbs The subject subsequently suffered seizures, with increased intracranial pressure.
`The sub'ect deteriorated to brain death and subse-
`This was a 53-year old Caucasian female subject with primary pulmonary hypertension
`_ NYHAClassIll. The subect was hos'. fl .,
`.
`_
`chiatnc d1sturbance
`
`’03 1/indicates non-fatal events the reviewer assess as cardiovascular in nature.
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`Study P01:04-05
`
`.
`
`i
`
`NDA 21 -272
`UT-I 5 for pulmonary hypertension
`
`
`
`04/ 12007
`UT-15
`
`04/ 13001
`UT~15
`
`04 / 23002
`UT-15
`death
`
`05/ 24505
`UT-lS
`
`
`
`
`
`3
`
`i3lfilx
`
`
`
`7 Study/7
`Subjectl°3
`Arm
`
`
`
`Th1s was a 40—year old Caucasxan female with pulmonary hypertension ass66iated with
`;
`
`”64i1666é
`
`UT- 1 5
`
`mixed connective tissue disease and NYHA Class IV status. The subject was hospitalized
`death
`on study day 57 with worsening right heart failure. Her condition deteriorated and she
`
`
`
`suffered an arrh mia and died.
`
`
`04/10006
`This was a 46 year old Caucasian male with a history of primary pulmonary
`
`
`UT-15
`hypertension and NYHA Class III The subject was hospitalized on day 22 for altered
`
`
`renal function (BUN was 99mcreasing to l 15, Creatinine was 1. 7 and increased to 2.5
`
`
`mg/dL). The subject was hydrated with correction of the BUN (to 85mg/ d1.) The subject
`
`
`
`
`was aain hos vitalized on da s 38 and a ain on da 57 for fluid overload.
`404/ 12002 This was a 71 year old Caucasian female with a history of primary pulmonary
`
`
`
`UT-IS
`hypertension and NYHA Class 111 status. The subject sustained a CVA on day 52 of
`treatment but continued on thera 9 .
`
`
`This was a 70-year old Caucasian female with primary pulmonary hypertension and
`
`NYHA Class III status. The subject was hospitalized on day 86 for a pneumothorax post
`
`
`l2-week catheter-ization.
`This was a 58-year Caucasian female with primary pulmonary hypertension and NYHA
`
`
`
`
`Class lll status. The subject administered an excess of UT- 15 (a bolus of 1.5 mL or
`
`
`approximately 1500 ng). The subject had severe pain at the infusion site and removed
`
`
`the subcutaneous catheter. The symptoms, upon arriving at the emergency room,
`
`
`
`
`consisted of vomitin , headache, neck ache and 1e aim. The stud dru_ was restarted.
`
`1/04/ 14005 This was a 40-year old Caucasian female with a history of pulmonary hypertension and a
`
`
`
`
`UT-15
`congenital systemic to pulmonary shunt and NYHA Class 111. After the 12-week
`catheterization the subject developed increasing dyspnea, chest pain and left shoulder
`
`
`pain and was hypoxemic. She was treated with supplemental oxygen improved over the
`
`
`
`
`
`next two da 3 and was dischar ed.
`04/ 14009 This was a 36-year old Hispanic female with pulmonary hypertension associated with a
`
`
`
`
`UT-15
`congenital systemic to pulmonary shunt. She was treated with digoxin, oxygen and
`
`
`warfarin. After heavy menstrual bleeding she was seen in the ER on day 69 with a
`complaint of lightheadedness and dyspnea. Her hemoglobin was 7.3 g/dL, the INR was
`
`
`
`
`1.43. She was again hospitalized on day 79 with a diagnosis of acute right heart failure.
`
`
`
`-en and diuretics.
`
`05/ 14501
`This was a 41-year old Caucasian female with primary pulmonary hypertension and
`
`
`
`
`
`UT-15
`NYl-lA Class III status. The subject was hospitalized on day 48 an episode of acute
`
`
`1405/21501
`This was a 36~year old Hispanic female subject with primary pulmonary hypertension an
`
`Lnuis
`
`NYl-lA Class III. The subject was hospitalized because she was hypoxemic associated with
`
`
`drome. She recovered.
`an acute flu s
`
`
`
`This was a lS-year old Native American female with pulmonary hypertension and a
`
`congenital systemic to pulmonary shunt and NYHA Class II status. The subject was
`found comatose, pulseless and hardly breathing. Attempted resuscitation was
`unsuccessful and the sub'ect died.
`This was a 49-year old Caucasian female with pulmonary hypertension as a consequence
`
`of a congenital systemic to pulmonary shunt. She was NYHA Class 111. She was
`
`hos-italized on da 55 for deh dration.
`This was a 52 year old Caucasian female with pulmonary hypertension and limited
`
`
`scleroderrna and NYHA Class IV. The subject had a syncopal episode at cardiac
`
`catheterization on da 85 of the stud . The event was attributed to a vasova_al event.
`
`
`
`
`
`
`
`
`
`
`05/50015
`UT-lS
`
`
`
`3/05/ 50023 This was a 37—year old Caucasian female with a history of pulmonary hypertension
`
`3 UT-15
`associated with mixed connective tissue disease and NYHA Class IV status. The subject
`
`
`had her hospitalization duration increased because of supraventricular tachycardia. On
`
`
`day 3 of treatment. The subject was again hospitalized on day 70 and 76 for worsening
`
`
`
`heart failure and uain at the infusion site.
`
`
`
`
`
`05/51007
`This was a 28-year old Caucasian female with a history of primary pulmonary
`
`hypertension and NYHA Class 111 status. The subject had a syncopal episode at the time
`
`
`o cathetenzation for week 12. Thesub'ect had an e-isode of bradcardia with lossof
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`Study P01 :04-05
`
`NDA 21-272
`UT—I 5for pulmonary hypertension
`
`‘
`and subsequently developed electromechanical dissociation and died. Autopsy revealed
`severe pulmonary hypertension with cor pulmonale. Inflammatory changes were noted in g
`the m ocardium.
`‘
`
`405/ 52001
`UT-lS
`
`This was a 40-year old Caucasian male with primary pulmonary hypertension and NYHA 1
`Class III. The subject developed a recurrent event of atrial flutter and was treated with
`amiodarone.
`
`05/53020
`UT-15
`
`05/ 53001
`UT.15
`
`This was a 48—year old Caucasian female with pulmonary hypertension and a congenital
`systemic to pulmonary shunt and NYHA Class III. The subject complained of asthenia.
`The asthenia was attributed to malfunction of the infusion pump. The subject was
`admitted to the hos-ital for -um re-air on da 17 and a in on 26.
`This was a 61—year old Caucasian female with primary pulmonary hypertension and
`NYHA Class lll status. The subject was taking acenocoumarol and furosemide. The
`subject developed an episode of melena. The lNR at the time was 4.0. The hemoglobin
`was 4.9 g/dL. The subject received three units of packed red blood cells. At gastroscopy
`an active area of hemorrha 'c astritis was noted.
`‘ 405 / 53022 This was a 42-year old Caucasian male with a history of primary pulmonary
`UT-15
`hypertension and NYHA Class III. The subject was hospitalized on day 28 for worsening
`deteriorate
`heart failure. Because of intolerable site pain in conjunction with the worsening of heart
`failure the sub'ect was started on iv flolan.
`
`
`
`;
`;
`é
`
`'g
`‘2
`
`L
`
`g
`
`i
`
`
`
`‘105/ 54005 This was a 20-year old Caucasian female with pulmonary hypertension and a congenital
`UT-15
`systemic to pulmonary shunt and NYHA Class III status. The subject was admitted to the
`deteriorate
`hospital on day 43 for worsening hypoxemia and unstable hemodynamics. The subject
`was suspected of having had a pulmonary embolism (the subject was not on any
`anticoagulant at the time of enrollment because of a history of menorrhagia). No
`ventilation-perfusion scan was performed. The subject had two cardio-respiratory arrests
`and died.
`
`405/ 54014 This was a 44 -year old Caucasian female with pulmonary hypertension and a congenital
`UT-lS
`systemic to pulmonary shunt. The subject was admitted to the hospital with asthenia
`and increasing dyspnea. The subject was diagnosed with adrenal insufficiency and was
`treated with intravenous then oral h drocortisone.
`
`‘
`
`‘
`
`05/ 55005
`UT-15
`death
`
`This was a 32-year old Caucasian female with a history of primary pulmonary
`hypertension and NYHA Class IV. The subject had an ep