Reviews of individual studies
`Study P01:01
`
`'
`
`'
`
`'
`
`NDA 21-272
`UT-I 5for pulmonary hypertension
`
`Table 14. Baseline hemodynamie parameters (P01:Ol)“
`
`
`
`_3i4_8117‘
`
`Emm—'7 - '
`
`I—--E!-—
`
`
`
`
`_——
`
`
`
`
`
`
`
`
`Table 15 below summarizes the change from baseline for the same parameters. There
`was a consistent acute eflect to increase cardiac index (CI) and decrease pulmonary
`vascular resistance index (PVRI). No clear dose-related effect on any of the measured
`parameters was demonstrated.
`
`Table 15. Change from baseline in hemodynamie parameters (P01:01P°
`
`mm—
`R1
`tAtrial Press (mini-lg)
`Cardiac Index
`
`svm (mmHg/L-min-m2
`
`FM“
`"TD“
`n=14
`
`urn
`3:14
`
`mint
`1:1
`
`415% ‘
`+8:t2%
`+1o:3%
`o39111%
`-1916%
`-1016%
`+26il2% +27117%
`+32i~9%
`-1.6:2% 0.513%
`-9:3%
`-2215%
`«17% -2019%
`-8.518%
`-6110%
`
`-26i5%
`
`
`
`SVO/WZP)
`
`7
`
`7
`
`7
`
`.
`
`7
`
`+815% )
`
`Hemodynamic changes during washout. Patients were followed for 120 minutes after
`discontinuation of UT—lS with hemodynamic measurements. During that period the
`hemodynamic changes seen during UT—lS did not return to baseline.(see table 14.2.3 in
`study report for details). No patient had rebound pulmonary hypertension during the
`120 minutes after UT- 15 discontinuation.
`
`Maximum tolerated dose: of LIT-15. The table below summarizes the MTD of UT-15
`for the patients who completed the initial UT-lS infusions, as well as the patients who
`completed the maintenance phase of the UT-lS infusion. The four subjects who
`discontinued were receiving different doses of UT-15. However, most of the patients at
`the higher doses of UT-lS were either discontinued or had to have their dose reduced.
`
`“ Datafrom NDA vol. 2.16, table 11.4.1A.
`’9 Mixed venous 02 saturation.
`
`”DatafmmNDA vol. 2.16, table 11.4.1C.
`
`2’ Marbnally tolerated dose
`
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`Reviews of individual studies
`Study P01 :01
`
`.
`
`'
`
`NDA 21-272
`UT-1 5 for pulmonary hypertension
`
`4
`
`
`
`
`Table 16. Dosing ofUT-IS “1:01)”
`
`Initiation of
`maintenance
`
`‘ICompletlon of
`maintenance
`
`Completion
`without dose
`
`
`
`
`
`
`
`
`
`
`
`‘
`s W "duct“
`__—__-
`mun-—
`—--_-‘
`mun"
`I_—-——-
`E_-—_-_
`
`. 51.4.5 Safety
`
`The overall event rates for adverse events, serious adverse events, discontinuations, and
`deaths are shown below. The number of subjects with any SAE and subject
`discontinuations due to AEs are shown in Table. 17.
`
`Table 17. Disposition of subjects (P01:01P3
`
`III
`
`_nitited01115 H 7
`
`Com deted initial infusion m
`Discontinued with adverse event '-
`Serious adverse event
`u
`
`
`
`A.1.4.5.1 Comparisons of defined safety endpoints
`
`Due to the small sample size, no formal comparisons are performed.
`
`A.1.4.5.2 Comments on specific safety parameters
`
`Deaths. There were no deaths reported for subjects in the trial.
`
`Serious adverse events. No SAEs occurred during the administration of study drug.
`
`Adverse events. Table 18 below summarizes the reported AEs.
`
`Table 18. Subjects with adverse events on KIT-15 (P01:01).34
`ll %
`
`A
`
`Hedach'fl '
`Infusion site reaction
`Flushin ;
`Nausea
`
`1352% ‘
`4 16%
`32%
`16%
`
`Dizziness
`
`,
`
`,
`
`Discontinuation. There were four discontinuations during the maintenance phase of
`the UT-IS infusion. Three of these were for nausea, headache and or vomiting. The
`fourth patient experienced pulmonary hypertension and is detailed below.
`
`Subject 02005 hadfour SAES: pulmonary hypertmion, atelectasis, bronchitis andpneumonia.
`
`aDatafrom NDA vol. 2.16, table 12.1.3.
`
`3’ Data from NDA 21 -272, vol. 2.16, section 12.1.3.
`
`3" Data from NBA 21 -272, table 12.2.2.2B.
`
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`Kemews a] maunduat studies
`Study P01 :01
`
`g
`
`f
`
`,
`
`NDA 21-272
`UT-1 5for pulmonary hypertension
`
`This 12—year old girl with Class III CHF was hospitalizedfor evaluation. At baseline her
`pulmonary pressures were 152/68, mean I 02 mmHg, exceeding her systemic arterial BP (mean 8]
`mmHg). Following initiation of UT-15 her cardiac output and systemic pressure rose, and her
`pulmonary pressuresfell. She achieved a dose of UT-l5 of80 ng/kg/min, where she had a dose-
`Iimiting side efikct ofagitation and ratlessness. She was then entered into the maintenance phase
`at 69 ng/kg/min. Afler 35 minutes her PAP rose abruptly to 218/147 and arterial saturation fell to
`75%. Treatment was stopped, and patient received milrinone and 03 with slow resolution ofthe
`elevated PAP. The investigatorsfelt that her cardiac Ieft-to~right shunt, along with her agitation,
`contributed to the pulmonary hypertensive crisis.
`
`Effects on ECG. Review of the summary data from the ECGs collected during the trial
`showed no pattern of QT prolongation independent of heart rate. See NDA vol. 2.18,
`table 16.2.8.4 for details.
`
`A.1.5 Summary
`
`A.1.5.1 Efficacy summary
`
`Study P01:01 measured the acute hemodynamic effects of UT-lS in patients with
`Primary Pulmonary Hypertension. Samples were also collected for pharmacokinetic
`assessments. The changes measured in this opendabel trial were consistent with an
`acute effect of UT-lS on pulmonary vascular pressures, leading to an improvement in
`cardiac index. The pharmacokinetic assessment will be performed by other reviewers.
`
`$1.53 Safety summary
`
`There were no new safety concerns identified in this small study. One potentially useful
`observation was that no evidence for rebound hypertension was seen in the 120
`minutes following UT-lS discontinuation.
`
`A.1.5.3 Reviewer”: conclusions
`
`This small study of the acute effects of UT-15 on central hemodynamics found data
`consistent with an acute effect of UT—IS to cause pulmonary vascular dilatation. No
`clear dose-relationship for this effect was demonstrated. Doses higher than 10 ng/ kg
`were not tolerated without dose reduction in this short-term trial, most commonly due
`to headaches, nausea and / or vomiting. No new safety concerns emerged from this small
`trial.
`
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`Study ml:02
`
`'
`
`UT-I 5forpulmonary hypertension
`
`A.2 Study P01:02: A dose-range-finding study comparing intravenous and
`subcutaneous ISAUBI (UT-15) in NYHA Class III]IV patients with primary
`pulmonary hypertension.
`.
`'
`
`41.2.1 Sites and Investigators
`
`P01:02 was conducted at 10 sites in the United States. The investigators are shown in
`Table 19.
`
`Table 19. Investigators (”1:02)
`
`
`fifiififi
`
`.w
`
`
`O7
`
`David Badesch MD
`lvan Robbins MD
`Victor Ta -son MD
`Adaani Frost MD
`
`Sean Gaine MB
`Rob Barst MD
`Smart Rich, MD
`Bruce Brundae M
`
`Michael MGcoon M
`
`
`
`
`
`Robert Boure, MD .
`
`A.2.2 Background
`
`Initial protocol submitted: 6.18.97
`
`Protocol amendments:
`
`one
`
`Amendment #1, submitted on 12.22.97, enrolled 7 additional patients to Cohort 11
`following the completion of Cohort lll. Cohort III (20 ng/ kg/ min SQ dose), was deemed
`the maximum tolerated acute dose by the sponsor. The enrollment of seven additional
`patients to Cohort 1] resulted in a total of 13 patients completing the 10 ng/ kg/ min
`dose.
`
`Subject enrollment:
`
`10.4.97 to 1.27.98
`
`Case report form cutoff:
`
`4.29.94
`
`A.2.3 Study design
`
`In this multi-centcr, parallel, sequential, open-label dose-escalation trial, eligible
`patients underwent cardiac catheterization and then entered a treatment phase, which
`consisted of four segments: (a) an IV UT-lS 75-minute Dosing Segment, (b) an IV UT—15
`150 minute Washout Segment, (c) a subcutaneous (SQ) UT-lS ISO-minute Dosing
`Segment (see below for doses), and (d) a SQ UT-lS ISO—minute Washout Segment.
`
`During the subcutaneous (SQ) period of the trial, subjects received IV dosing at 10
`ng/ kg/ min followed by one of three SQ doses:
`
`1) 5 ng/ kg/ min (n-=6 subjects)
`
`2) 10 ng/kg/min (nsl3 subjects), or
`
`3) 20 ng/ kg/ min (n=6 subjects).
`
`The primary goals of the trial were to collect safety, hemodynamic and pharmacokinetic
`data on the use of SQ UT-15 in pulmonary hypertension.
`
`_
`_
`$23.1 Objectives
`To characterize the pharmacokinetic profile of subcutaneous (SQ) administration of UT-
`15 in patients with severe primary pulmonary hypertension (PPl-l).
`
`$2.33 Number of subjects] ran domisation
`Twenty-five (25) patients with pulmonary hypertension were enrolled into the study: 6
`each at the 5 and 20 ng/kg/min dose and 13 at the 10 ng/kg/min dose.
`
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`Renews ofindim'dual studies
`Study P01:02
`
`,.
`
`.-
`
`NDA 21-272
`‘
`UT-I 5for pulmonary hypertension
`
`A.2.3.3 Inclusion] exclusion criteria
`
`Inclusion criteria (must be present] ,
`
`2 12 years of age;
`
`Females must be post-menopausal or surgically sterile, or if female of child
`bearing potential, had a negative pregnancy test;
`
`had a diagnosis of severe, symptomatic PPl-l and were classified NYHA Class
`III or [V at Screening/ Baseline;
`
`had a chest radiograph consistent with the diagnosis of PPH performed
`within the previous six months;
`
`, had pulmonary function tests consistent with the diagnosis of PPl-l
`performed within the previous year;
`
`had a pulmonary ventilation / perfusion scan or pulmonary angiography
`performed since the onset of symptoms with results consistent with the
`diagnosis of PPH;
`
`had an echocardiogram within previous year consistent with the diagnosis of
`PPH, specifically: evidence of right ventricular hypertrophy or dilation,
`evidence of normal left ventricular function, and absence of mitral valve
`stenosis;
`
`had a cardiac catheterization at Baseline consistent with the diagnosis of
`PPl-l, specifically:
`
`PAPm 2 25 mmHg, and PCWP or a left ventricular end diastolic pressure
`5 15 mml—lg, and PVR > 3 mml-Ig/ L/ min, and absence of congenital heart
`disease (including atrial septal defect, ventricular septal defect, partial
`anomalous pulmonary venous drainage, but presence of a patent
`foramen ovalc would not exclude a patient);
`
`had indicated willingness to participate by signing an informed consent
`form.
`
`Exclusion criteria (may not be present)
`
`had a new type of chronic therapy (e.g., a different category of oral
`vasodilator, a diuretic, digoxin) for PPH added within the last month,
`excepting anticoagulants;
`
`had any PPl-l medication, excepting anticoagulants, discontinued within the
`last week;
`
`had any disease known to cause secondary pulmonary hypertension (e.g.,
`obstructive lung disease, collagen vascular disease, parasitic disease
`affecting the pulmonary system, sickle cell anemia, mitral valve stenosis,
`portal hypertension, or human immunodeficiency virus infection); or
`
`were currently receiving an investigational drug or have participated in
`investigational drug study within the past 30 days;
`
`52.3.4 Dosage] administration
`
`UT-15 was administered IV or via sub-cutaneous infusion placed in the abdominal wall.
`After right-heart catheterization and baseline hemodynamic parameters, subjects
`received IV dosing at 10 ng/ kg/ min min followed by a SC dose of
`
`1) 5 ng/kg/ min (n=6 subjects)
`
`G:\N2 1 2 72. doc
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`Last saved
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`

`Kemews a] mammal studies
`Study P01:02
`
`.
`
`3
`
`'7'
`
`NBA 21-2 72
`UT-I 5for pulmonary hypertension
`
`2) 10 ng/kg/min (n=l3 subjects), or
`
`3) 20 ng/kg/min (n=6 subjects),
`
`Concomitant medications. Drugs routinely used for PPH patients, including calcium
`channel blockers, digoxin, diuretics, anticoagulants and oxygen were provided by the
`hospital pharmacy and administered as deemed appropriate by each investigator.
`Prostacyclin analogues were not allowed as therapy.
`
`$2.3.5 Duration] adjustment of therapy
`
`Study drug was administered in hospital, and where patients remained throughout the
`drug administration and for 24 hours thereafter.
`
`$23.6 Safety and efficacy endp oints measured
`
`A listing of the measurements made during the trial can be found in the trial study
`report: NDA 21-272, vol. 2.19. Invasive hemodynamic measurements were made
`during the period of the infusions and at the end of the washout period along with
`pharmacokinetic sampling and routine vital signs. After washout and through the first
`24 hours vital signs and ECGs were collected every 8 hours.
`
`$2.3.7 Statistical considerations
`
`The statistics in the trial were observational in nature given the small numbers with the
`exception of the pharmacokinetic assessments. These pharmacoldnetic analyses are
`discussed in a separate review by Nhi Nyugen, Ph.D. and Joga Gobburu, Ph.D.
`
`A.2.4 Results
`
`$2.4.1 Subject demographics & baseline characteristics
`
`The majority of the patients in the trial were white (72%) and female (80%), with a mean
`age of 40 and a mean duration since diagnosis of PPl-l of 0.9 years. The majority (19/25)
`were NYHA Class III and the remainder NYHA Class IV. The reader is referred to the
`
`study report for additional demographics. '
`
`$2.4.2 Disposition of subjects
`
`Of the 25 patients enrolled, 10 patients had to terminate either the 75-minute iv
`infusion or the 150~minute SQ infusion prematurely due to intolerability or technical
`problems. Hence, only 15 patients completed both the iv and SQ infusions in their
`entirety.
`.
`
`Subject selection. No information is available about subject selection in protocol
`P0 1 :02 .
`
`Protocol violations & deviations. Patient 04002 received 20 ng/ kg/ min due to staff
`error. His course will be discussed in the safety section of this review.
`
`Concomitant therapies. Given the short duration of the trial no concomitant
`medications were used during the administration of the study drug.
`
`$2.43 Pharmacokinetics analyses
`
`The pharmacokinetic results from the trial are reviewed elsewhere by Drs. Nguyenand
`Gobburu. The sponsor estimated the half-life of subcutaneous UT-lS at between 55 to
`117 minutes, and the half~life for the N form of UT-15 as 25 to 42 minutes.
`
`$2.4.4 Hemodynamic changes
`
`Table 20 below summarizes the hemodynamic changes from baseline for the IV and SC
`administration of UT-lS. Baseline is taken as the last value before starting the infusion,
`either following baseline hemodynamics (for the IV) or at the end of the 150 minute
`washout period (for the SC). The data from patient 04002 are not included here. Of the
`25 patients enrolled, 10 patients had to terminate either the 75-minute iv infusion or
`
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`

`newewo VJ uuLtULuuLu atuulsa
`Study P01 :02
`
`.
`
`IVUA 21-2/2
`U711 5 for pulmonary hypertension
`
`the ISO-minute SQ infusion prematurely due to intolerability or technical problems (see
`Safety below). Hence, only 15 patients completed both the iv and SQ infusions in their
`entirety (and have data available for inclusion into Table 20 below).
`
`Table 20. Baseline hemody'naxnie parameters (POI:OZP5
`
`mam-— 8512
`
`
`
`
`v1-51
`
`i
`
`1‘»0°
`
`102:2
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`
`Table 21 below summarizes the change from baseline for the same parameters. There
`was a consistent acute effect to increase cardiac index (Cl) and decrease pulmonary
`vascular resistance index (PVRI). No clear dose-related effect on any of the measured
`parameters was demonstrated.
`
`Table 21. Change from baseline hemodynamic parameters (POROZP?
`
`-E—
`
`m_-_—-
`
`
`
`
`
`
`
`—_———
`
`
`
`
`
`
`
`
`
`
`
`Rebound hypertension. No evidence of rebound hypertension was seen during the
`150 minutes following the discontinuation of UT- 15. The vasodilatation persisted to the
`150 minute timepoint following discontinuation of UT-lS, limiting the usefulness of this
`data in ruling out a rebound phenomenon. Data for the 10 ng/ kg/ min dose group is
`shown below as representative. .
`
`
`
`”Datafiom NDA vol. 2.19, table 11.4.1A.
`“Mixed venous Qsatwution.
`
`”Datafi'om NDA ml. 2.19, table 11.4.1C.
`
`G:\N21272.doe
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`

`Reviews of tndtmaual studies ‘
`Study P01 :02
`
`',
`
`'f
`
`NDA 21 -2 72
`UT—J 5for pulmonary hypertension
`
`Table 22. Baseline, peak, and end-of-washout hemodynamie parameters (P01:02P'
`
`
`W‘Mh“
`
`
`
`_'7 ' '
`
`
`
`
`
`
`
`'7
`
`67.3
`
`, 31. ,,
`
`p
`
`
`
`ndof
`
`’
`
`,
`
`588
`
`225
`
`83
`
`
`
`5.2.4.5 Safety
`
`The overall event rates for adverse events, serious adverse events, discontinuations, and
`deaths are shown below. The number of subjects with any SAE and subject
`discontinuations due to AEs were
`
`Table 23. Disposition of subjects (”1:02P
`
`- m». a, ‘
`
`Deaths“
`
`'
`Initiated UT-ls
`Com -leted 150 min infusion
`Discontinued with adverse event
`Serious adverse event”
`
`7
`
`A.2.4.5.1 comparisons of defined safety endpoints
`Due to the small sample size, no formal comparisons are performed.
`
`A.2.4.5.2 Comments on specific safety parameters
`
`Deaths. No deaths occurred within three days of discontinuation from the trial.
`
`Subject 02005 completed the trial without problems, and remained in the hospitalfor a Hickman
`catheter to be placedfor Flolan initiation. Afler placement ofthe Hickman, the patient remained
`in the hospital, and wasfimnd cyanotic andpulseless that night. FIoIan was not initiated.
`
`Subject 04004 with PPH (NYHA Class 11]) completed the trial without complications and then
`received a Hickman to start Flolan. Flolan was initiated without dtfliculty at a dose of4
`ng/kg/min. The patient was readmitted the next day with worsening CHF and had a bradycardic
`then asystolic arrest and died.
`
`Serious adverse events. No SAEs occurred during the administration of study drug.
`
`Adverse events. Table 24 below summarizes the reported AEs.
`
`2'Datafrom NDA vol. 2.19, table 11.4.1.5and 16.2.6.1. Shownforthe SO 10 ng/kg/min group.
`
`”Datafrom NDA 21-272, table 12.1.1.4 and narratives.
`
`”OneSAEocauredbeforeinitiaubnof‘mfiisionofsmdydrug.
`
`3' Two deaths occurred 8 hours and 3 days afier dismissalfrom the study. See section belowfor details.
`
`G:\N212 72. doc
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`
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`Study P01 :02
`
`.
`'
`
`"
`
`nu“ 21-4 14
`UT-l 5for pulmonary hypertension
`
`
`
`ECGs and vital signs. No effect of UT-15 on ECG parameters, including the QT
`interval, was seen. See vol. 2.21, table 16.2.8.4 for details. Following administration of
`UT-lS the heart rate rose by a mean of 3.3 bpm, and the mean blood pressure fell by
`6.8/8.7 mml—ig (table 16.2.8.3).
`
`A.2.5 Summary
`
`A.2.5.1 Efficacy summary
`
`Study PO]:O2 measured the acute hemodynamic effects of UT-lS in patients with
`Primary Pulmonary Hypertension. Samples were also collected for pharmacokinetic
`assessments. The changes measured in this open-label trial were consistent with an
`acute effect of UT-15 on pulmonary vascular pressures, leading to an improvement in
`cardiac index. The pharmacokinetic/ pharmacodynamic assessment will be performed
`by other reviewers.
`
`A.2.5.2 Safety summary
`
`There were no new safety concerns identified in this small study. One observation was
`that no evidence for rebound hypertension was seen in the 150 minutes following UT-lS
`discontinuation. Unfortunately, the fact that vasodilatation persisted for the period of
`measurement limits the usefulness of this observation.
`
`The two deaths occurring so shortly after completion of the trial are of concern,
`especially the death that occurred the night after completion, before Flolan was
`initiated. While no evidence implicating the drug exists, the timing raises concerns
`about changes that occurred following discontinuation of UT-lS such as hemodynamic
`changes or shifts in fluids or electrolytes.
`
`A.2.5.3 Reviewer’s conclusions
`
`This small study of the acute effects of UT-15 on central hemodynamics found data
`consistent with an acute effect of UT-15 to cause pulmonary vascular dilatation. No
`clear dose-relationship for this effect was demonstrated. No new safety concerns were
`identified, but two deaths occurred soon after drug discontinuation. These deaths will
`be considered in the context of the integrated safety summary elsewhere.
`
`PPEARS nus WAY
`A on ORlGlNAL
`
`3’ Data from NDA 21 -272, table 12.22.28.
`
`G:\N21272. doc
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`

`J\leva UJ LlLulUluLl-UL vluulvv
`
`Study P01 :03
`
`UT-I 5 for pulmonary hypertension
`
`JVUA AI'Z /.4
`
`A.3 Study P01:03: A mu lticenter, double-blind, randomized, parallel
`comparison of the safety and efficacy of chronic subcutaneous UT—15 plus
`conventional therapy to conventional therapy in patients with severe
`primary pulmonary hypertension: an 8-week study.
`
`A.3.1 Sites and investigators
`
`P01:03 was conducted at 5 sites in the United States. The investigators are shown in
`Table 25.
`
`Table 25. Investigators (P01:03).
`
`"
`
`
`
`MB '
`Rob Barst, MD
`Stuart Rich, MD
`Ronald Oudiz, MD &
`Shelle Sha-iro, MD
`
`ROW“ 511-”: MD
`
`A.3.2 Background
`
`Initial protocol submitted: 2.25.98
`
`Protocol amendments:
`
`4.21.98 and 6.16.98
`
`Amendment #1 (4.21.98) reduced the number of pharmacokinetic blood samples
`collected.
`
`Amendment #2 (6.16.98) lowered the starting dose (i.e., from 5 ng/ kg/ min to 2.5
`ng/ kg/ min or below) and the in—hospital dose increment from 5 ng/ kg/ min to 2.5 or 5
`ng/ kg/ min. This change resulted in a reduction in the maximum achievable closes at
`the end of Week 1 through Week 8 of the Treatment Phase
`
`These changes resulted in a lower number of UT—ls concentration values per patient for
`pharmacokinetic analysis, resulting in a less precise pharmacokinetic analysis.
`
`Subject enrollment:
`
`4.23.98 to 10.7.98
`
`Case report form cutoff:
`
`4.29.94
`
`The safety and efficacy results of the study were presented at the 1999 European
`Congress of Cardiology and published in abstract form”.
`
`A.3.3 Study design
`
`Eligible patients were randomized (2:1) to receive conventional therapy plus a
`continuous subcutaneous infusion of UT—15 or conventional therapy plus a continuous
`subcutaneous infusion of placebo for an 8—week infusion period. During the Treatment
`Phase, in addition to efficacy measurement (exercise capacity) and assessment of
`clinical signs and symptoms of the disease at scheduled visits (Weeks 1, 4 and 8), blood
`samples were collected for pharmacokinetic analysis. Hemodynamic and symptom
`assessments were not available to the individual who conducted the primary efficacy
`analysis [6—minute walk). Similarly, the walk results were only known by an
`independent exercise administrator.
`
`33 McLaughlin V, Barst R, Rich 8, et al. Eflicacy and safety of UT-l 5, a prostacydin analogue, for primary
`pulmonary hypertension. Eur Heart J 1999; 20 (Abstr Suppl):486.
`
`G:\N21272.doc
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`

`KCUlCLUS OJ Inawluual szuales
`Study P01 :03
`
`._
`
`;
`
`NUA 21-2/2
`UT-I 5for pulmonary hypertension
`
`A.3.3. 1' Objectives
`
`1) The primary objective of this study was to assess the safety of continuous
`subcutaneous infusion of UT—lS in an outpatient environment to patients with primary
`pulmonary hypertension (PPH).
`
`2) The secondary objective of this study was to characterize the pharmacokinetic
`disposition of chronic, subcutaneous administration of UT-15 in this patient
`population.
`
`' 3) Exercise, hemodynamics and symptoms of disease were monitored, including
`invasive hemodynamic measurements were made at baseline and week 8.
`
`The primary efficacy end—point was exercise capacity (6—minute walk) at weeks 1, 4 and
`8. Additional efficacy measurements included changes in the signs and symptoms of
`pulmonary. hypertension and heart failure, including the Borg Dyspnea Scale and the
`Dyspnea-Fatigue Rating.
`
`Pharmacokinetic evaluation focused on the plasma UT-lS concentration versus time
`profiles in individual patients.
`
`A.3.3.2 Number of subjects] randomization
`
`Twenty—six (26) patients with PPH were enrolled into the study: 17 received UT—15, 9
`received placebo.
`
`$3.33 Inclusion] exclusion criteria
`
`Inclusion criteria (must be present)
`
`0
`
`o
`
`0
`
`I
`
`0
`
`0
`
`0
`
`28 years of age;
`
`If female, be physiologically incapable of child bearing or practicing an
`acceptable method of birth control;
`
`have a diagnosis of severe, symptomatic PPH and remain NYHA Class III or
`IV despite the use of chronic oral vasodilators for at least one month;
`
`have a chest radiograph consistent with the diagnosis of PPl-I performed
`within the previous six months;
`
`have pulmonary function tests consistent with the diagnosis of PPH
`performed within the previous year;
`
`have a ventilation perfusion scan or pulmonary angiography consistent with
`the diagnosis of PPH;
`
`have an echocardiogram within previous year consistent with the diagnosis
`of PPH, specifically: evidence of right ventricular hypertrophyor dilation,
`evidence of normal left ventricular function, and absence of mitral valve
`stenosis;
`
`0
`
`have hemodynamics consistent with PPH, specifically:
`
`-
`
`o
`
`o
`
`PAPm 2 25 mmHg, and
`
`PCWP or a left ventricular end diastolic pressure 5 15 mmHg, and
`
`PVR > 3 mmHg/L/min, and
`
`0 Absence of congenital heart disease (atrial septal defect, ventricular septal
`defect, partial anomalous pulmonary venous drainage);
`
`0
`
`be mentally and physically capable of learning to administer study drug
`using an infusion pump and a subcutaneous access;
`
`G:\N21272.doc
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`UT-I 5for pulmonary hypertension
`
`0
`
`signed informed consent.
`
`Exclusion criteria (may not be present)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`be pregnant (women of childbearing potential must have a negative
`pregnancy test);
`
`have a new type of chronic therapy (other than anti-coagulation) for PPl-l
`added within the last month;
`
`have any oral PPH medication excepting anticoagulants discontinued within
`the last week;
`
`received any chronic prostaglandin or prostaglandin analogue therapy (IV or
`inhaled) within the past 30 days;
`
`have any disease known to cause secondary pulmonary hypertension (e.g.,
`obstructive lung disease, collagen vascular disease, parasitic disease
`affecting the pulmonary system, sickle cell anemia, mitral valve stenosis,
`portal hypertension, HIV);
`
`have a musculoskeletal disorder (e.g., arthritis, artificial leg, etc.) or any
`other disease which could limit ambulation, or be connected to a machine
`which was not portable;
`
`have a baseline exercise capacity of less than‘50 meters or greater than 450
`meters walked in six minutes;
`
`be receiving an investigational drug or have participated in investigational
`drug study within the past 30 days;
`
`have the presence of any physiological condition which contraindicates the
`administration of UT—15.
`
`A.3.3.4 Dosage] administration
`
`UT-15 or placebo was administered via sub—cutaneous infusion. Of the 17 patients
`randomized to receive UT-15, only one patient received a starting dose of 5 ng/kg/ min.
`Fifteen 15 patients received a starting dose of 2.5 ng/ kg/ min and one patient received a
`starting dose of 1 ng/ kg/ min.
`
`Study drug was administered subcutaneously using a positive pressure .M
`w infusion pump. The subcutaneous catheter was placed in the
`abdominal wall of patients, and the infusion site was moved, if needed, at the discretion
`of the investigator. There was to be no washout period between changes in UT-15
`infusion rates (doses).
`
`The original starting dose was to by 5 ng/ kg/ min, but the protocol was amended to a
`starting dose of 2.5 ng/kg/min.
`
`Concomitant medications. Short-terms (<5 days) of therapy with other agents to treat
`CHF were permitted with the exception of prostacyclin (Flolan) and its analogues. All
`other agents were permitted in both treatment groups.
`
`Duration / adjustment of therapy
`
`Study drug was started in hospital, and where patients remained for the first week to
`assure stabilization. Study drug was up-titrated weekly to maximum tolerated dose. If a
`dose was not tolerated, it could be decreased to the maximum tolerated dose for each
`patient.
`
`G:\N21272.doc
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`

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`A.3.3.5 Safety and efficacy endp oints measured
`
`Table 26. Timetable for clinical observations and lab measurements (P01:03)34
`Treteatmn
`
`
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`3‘ Data from table 9.5.1 from P01 :03 Clinical Study Report.
`
`35 See Clinical report for P01 :03, section 9.5.2. 1 for list of labs measured.
`
`’6 Evaluation ofPPH signs and symptoms was conducted for each study patient at Baseline and Weeks 1, 4,
`and 8. To ensure consistency, these parameters were evaluated by the same physician for a given patient
`throughout the study. The following relevant PPH signs and symptoms were assessed as present or absent;
`severity, extent or grade was evaluated as shown:
`
`
`
`Dyspna attest
`
`
`
`Insular venous distention ll 45 degrees (extent)
`
`
`
`
`
`
`
`For each patient at Weeks 1, 4, and 8, each parameter was assigned a change score as follows:
`
`Wm...
`
`mmmwwm
`
`WWW»
`
`mm.
`
`
`
`
`
`A composite change score for each assessment period (Week 1, Week 4, or Week 8) was calculated for each
`patient by adding change scores ofthe individual signs and symptoms.
`
`37 The Dyspnea-Fatigue Rating was assessed at Baseline and Weeks 1, 4, and 8 by study staff that were
`responsible for patient care. This clinical index of dyspnea and fatigue consists of three components, each rated
`on a scale of 0 to 4 (worst to best), for magnitude of the task that evokes dyspnea orfatigue, the amplitude of
`the pace (or effort) with which the task is performed, and the associated functional impairment in general
`activities. The ratings for each component are added to form an aggregate score, which can rangefrom 0 (for the
`worst condition) to 12 (for the best).
`
`The ratings for the three components of the Dyspnea-Fatigue Rating are:
`
`1. Magnitude of task (at normal pace):
`
`4 Extraordinary. Becomes short ofbreath orfatigued (hereafter called 'symptomatic’) only with
`extraordinary activity such as carrying very heavy loads on level ground, lighter loads uphill or running. No
`symptoms with ordinary tasks.
`
`3 Hajor. Becomes symptomatic only with such major activities as walking up a steep hill, climbing more
`than threeflights of stairs or carrying a moderate load on the level.
`
`2 Moderate. Becomes symptomatic with moderate or average tasks such as walking up a gradual hill,
`climbing less than three flights ofstairs or carrying a light load on level ground.
`
`1 Light. Becomes symptomatic with light activities, such as walla'ng on the level, washing or standing.
`
`G:\N21272. doc
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`16:09 Friday, March 09, 2001
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`Last saved
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`
`
`
`
`
`
`The six-minute walk was assessed along a level, limited-access corridor with a
`minimum length of 33 meters. The test area was marked with gradations to permit
`distance calculation of partial laps. At a given center, the walk test was to be conducted
`by the same test administrator, who was otherwise uninvolved in the study or care of
`the study patients and was blinded to the treatment assignment.
`
`A.3.3.6 Statistical considerations
`
`Power. Trial P01:03 had limited enrollment, and was conducted to provide safety data
`and to characterize the pharmacokinetics of UT-lS. In addition, the sponsor used it to
`provide estimates of between—treatment changes (and associated variances) of exercise
`
`0 None. Symptomatic at rest, while sitting or lying down.
`
`2. Magnitude ofpace:
`
`4 Extraordinary. Essentially all conceivable physical tasks are Manned at normal pace.
`
`3 Major. Major tasks, as defined earlier, are performed at a reduced pace, taking longer to complete. Less
`strenuous tasks can be done at normal pace.
`
`2 Moderate. Moderate tasks, as defined earlier, are performed at a reduced pace, taking longer to complete.
`Light tasks can be done at normal pace.
`
`1 Light. Light tasks are done at a reduced pace.
`
`0 None. Symptomatic at rest.
`
`3. Functional impairment:
`
`4 None. Can carry out usual activities and occupation (if employed before onset ofPPH) without symptoms.
`
`3 Slight. Distinct impairment in at least one activity but no activities completely abandoned. A change in
`activity may have occurred at work or in other activities, but the change is slight or is not clearly caused by
`shortness of breath orfatigue.
`
`2 Moderate. Patient ha