Study P01:04-05
`
`.
`
`.
`
`‘
`
`NDA 21~272
`U711 5for pulmonary hypertension
`
`Table 96. ECG data (P01:O4—OS)11°
`
`
`ECGstatus
`
`
`
`Normal
`Abnormal
`
`
`
`4521}
`
`
`
`Unknown
`189
`219
`228
`
`194
`207
`Evaluable ECGs N
`227
`230
`
`
`98 (51%)
`89 (43%)
`QTc >440 ms
`78 (34%)
`100 (43%)
`
`
`
`
`
`
`67 (35%)
`68 (33%)
`QRS >100 ms
`63 (28%)
`66 (29%)
`
`
`
`
`
`
`33 (17%)
`22 (l 1%)
`PR >200 ms
`1 9 (8%)
`l 8 (8%)
`
`
`
`
`
`
`1 56 (80%)
`149 (72%)
`Right axis deviationI ’ 1'
`126 (56%)
`1 54 (67%)
`
`
`
`
`
`
`35 (18%)
`35 (l 7%)
`Right atrial enlarge
`37 (16%)
`39 (17%)
`
`
`
`
`
`
`42 (22%)
`44 (2 1%)
`Right ventricular
`38 (l 7%)
`54(23%)
`
`
`
`
`
`
`18 (9%)
`15 (7%)
`hypertrophy
`11 (5%)
`13(6%)
`
`
`
`
`
`
`6(3%)
`6 (3%)
`ST/‘l‘wvave abnormal
`-—--—---
`....-..-
`
`
`
`
`1 (<1%)
`1 (< 1%)
`Nonspecific ST—‘l‘ wave
`
`
`0 (0%)
`3 (1%)
`Specific ST depression
`
`
`
`
`Normal to abnormal
`l (‘<l%)
`4 (2%)
`
`
`
`
`Abnormal to normal
`
`
`Intervals
`Heart rate
`
`
`MeaniSD
`Change
`
`
`
`PR interval
`
`Change
`
`QRS
`
`Change
`
`QT interval
`
`
`
`Comparing UT-15 to vehicle there did not appear to any differences in the effect in ECG
`abnormalities or intervals.
`
`L4.4.9 Summary
`
`This review consists of a description of the protocol and the results of studies P01:04
`and 1301105. The procedures and measurements for both studies were identical. These
`two studies are the pivotal studies that are to support the approval of UT-15 for the
`treatment of pulmonary hypertension, whose etiology is either due to primary disease,
`collagen vascular disease or congenital left to right shunts. Although the individual and
`pooled studies are suggestive of an effect of UT-lS, this reviewer does not feel that the
`results of the studies are sufficient by themselves to support approval.
`
`Subjects who enrolled into these studies were symptomatic pulmonary hypertension
`subjects (NYHA Class ll-IV), despite optimum concurrent therapies. The etiology of the
`pulmonary hypertension could be either primary disease or could be as consequence of
`either collagen vascular disease or left to right congenital shunts.
`
`The primary end point of both studies was the change in walking distance from baseline
`at the end of week 12 in comparing UT-15 to vehicle infusion. For the pivotal analyses
`missing values for those who discontinued were imputed. Those who discontinued
`either because of death, deterioration or adverse events had the worse rank or value
`
`no Data derivedfiom sponsor's tables 14.3.8.1A and 14.3.8.2A.
`
`1" QRSaxl's +90toi180°
`
`G:\N21272.doc
`
`—-—1 63——
`
`1 6:09 Friday, March 09, 2001
`
`Last saved
`
`
`
`

`

`Study P01:04-05
`‘
`
`.
`
`.
`
`'
`
`NBA 21 -272
`UT—I 5for pulmonary hypertension
`
`imputed. Those who discontinued due to adverse events had their last rank or their last
`walk‘distance carried forward.
`..
`,
`
`The primary method of analysis was a non—parametric analysis of the pooled studies.
`The composite of walking distance both studies was pre-specified as pivotal in the
`analysis. The composite of both studies was to be considered demonstrating a benefit
`for UT-15 if either both individual studies were by themselves significant at the p<
`0.049 or if one study was significant (p< 0.049) and the pooled studies had a pwalue of
`less than 0.01.
`
`By the sponsor’s own analysis the study by itself would not be considered successful.
`Neither of the studies demonstrated a pwalue of < 0.049, although their analysis
`demonstrated a p-value of < 0.01 for the pooled studies. The magnitude of the change
`in median walking distance ranged from 2 meters in study P01:04 to 19 meters in study
`POl:05, or between< 1% to a 6% increase in baseline walking distance and a mean
`increase of approximately 3% for the pooled studies.
`
`Dr Lawrence, the FDA statistician, makes a cogent set of arguments, that when a study
`pre-specifies as a' success the composite of several outcomes, the concept of “being
`close” is open to an enormous amount of ambiguity. In the absence of fulfilling the
`prespecified criteria for success all that can be said is that the study did not succeed.
`
`Not only did the sponsor’s analysis not meet the pre-specified criteria for considering
`the studies a success, there was an inherent bias in the statistical approach employed
`in the analysis of the study. There was a clear imbalance in the number of subjects who
`discontinued for adverse events, with nearly all such subjects arising from those treated
`with UT-15. Nearly all such subjects who discontinued due to adverse events had
`infusion site pain/ infusion site reaction as the reason for discontinuation.
`
`There are several consequences that result from this algorithm for irnputing data for
`discontinued subjects. First, those who discontinue due to adverse events could never
`subsequently die, deteriorate or receive transplant. This fraction of subjects, therefore,
`was shielded from the worst imputed outcome values possible in this study.
`
`Second, since nearly all subjects who discontinued in the UT-15 group did so because
`of infusion site pain / reaction. Since infusion site pain was ubiquitous in the UT-lS
`infused subjects, the possibility exists that the discontinuation subjects were suffering
`from infusion site pain in conjunction with a worsening of their disease status.
`
`Third, the process of imputation presupposes the values at early times are reflective of
`the performance at the time of discontinuation. There are clearly subjects whose
`imputed value clearly does not reflect their status at the time of discontinuation.
`Subjects who discontinue for pain, whose discontinuation fell within the time-window of
`an exercise test and who did not undergo further walk testing, the imputed values could
`be disparate with their clinical status at the time of discontinuation.
`
`In order to deal with the inherent biases due to the unequal rates of discontinuation
`adverse events, this reviewer requested three additional analyses. The first analysis
`added the outcomes of three UT-lS and two vehicle subjects who died or were
`transplanted during the lOO-day window defined for the l2-weeks of the study. Since
`these outcomes are really not subjective, the inclusion of these subjects at least partly
`corrects for the imbalance among those who discontinue for adverse events. Including
`the worst outcome for these subjects alters the p-value of the pooled database to 0.02
`and that for the individual studies to >0. 1.
`
`The second analysis includes those, as having a worse outcome, who discontinued for
`adverse events if Flolan was started within one month of discontinuation and within the
`
`window of the study. There were six additional subjects. No subjects were started on
`Flolan either prior to or immediately upon discontinuation of UT-15. Two additional
`
`G:\N21272.doc
`
`—1 64—
`
`Last saved
`16:09 Friday, March 09, 2001
`
`
`
`

`

`Study P01 :04—00
`
`:
`
`NBA 21 ~2 72
`UT-1 5for pulmonary hypertension
`
`subjects were started within two weeks of discontinuation of UT—lS and two within one
`month of discontinuation of UT—ls therapy. None of these subjects obviously required
`Flolan at baseline. The immediate use of Flolan upon discontinuation of UT-lS suggests
`that the subject’s status had deteriorated to the point that an optional treatment at
`baseline became a treatment of choice. The p-values for the pooled and individual
`studies when treating those subjects started on Flolan within 1 month of discontinuing
`UT-lS also as worse outcomes shifts the p-value for the pooled studies to 0.082. For
`each of the individual studies the p value was > 0.2.
`
`A third analysis also included all those who were treated with Flolan during the window
`of the study as worse outcomes. In addition, there was one subject whose status at the
`time of continuation appeared to be inconsistent with the imputed measurement from
`week 1. The value for this subject was exclude. The p-values for this analysis for the
`pooled data was >0. 1. The p-values for each of the individual studies were >0.2.
`
`The above three analyses presume that all subjects who discontinued UT-15 therapy
`and received Flolan did so because of the deterioration in their status. Some or all of
`
`these subjects, however, may have been started on Flolan because no other options
`were available. An alternate analysis, performed by the sponsor imposes a last rank
`value for all those who discontinued prematurely, even if the reason was death,
`deterioration or need for transplantation. This analysis removes one source of the bias
`against the placebo in that no subject received a worse outcome. This analysis is
`sponsor's analysis # 4 in this review. The p—value for the pooled studies was 0.01 l and
`that for the individual studies was between 0.07-0.08.
`
`In summary, the study did not succeed by the pre-specified criteria of success. Neither
`study P01:04 or P01:05 was by itself statistically significant by a method of analysis
`that biases results towards [Tr-15 treatment. Other treatments, particularly of those
`who discontinued for adverse events further diminish the positive nature of any results.
`
`Since the primary outcome of the study did not succeed by the pre-specified criteria,
`supportive measures of efficacy are more difficult to interpret. Nevertheless, there is a
`suggestion from the supportive information that UT—lS may have some effect on
`symptoms of pulmonary hypertension. The supportive symptoms were collected only
`among those who completed the study. Those who discontinued for any reason did not
`have any values imputed. In addition, the supportive symptoms were administered by
`the treating physician who might have been aware, based on' the nature of infusion site
`reaction the subject’s treatment.
`
`Subjects showed some improvement in the composite of sixteen signs and symptoms of
`pulmonary hypertension. The metric that was used was a composite of all these
`symptoms. Subjects were assigned a ‘+ 1’ for symptoms present at baseline and absent
`after l2-weeks, and a '-l” for symptoms that went from absent to present. Symptoms
`that were present at baseline and present at end of study, or absent at baseline and
`absent at end of study were assigned a value of ‘0”. The average net change for those
`who completed the study favored UT-lS by + 1 units. The specific symptoms that were
`improved or were less frequently worsened in the UTJS group were dizziness,
`palpitations, orthopnea and chest pain. The most troublesome symptoms of pulmonary
`hypertension, dyspnea and fatigue did not appear to be differentially improved across
`groups.
`
`A second metric that was prospectively collected as a supportive endpoint was the
`dyspnea-fatigue index. This metric consists of three components with values ranging .
`from 0-4. The three components are “magnitude of task”, “magnitude of pace” and
`‘functional impairment”. The higher the value, the less symptomatic the subject. There
`was a net increase of approximately 1.4 units in the overall symptom score among those
`treated with UT-15, approximately equally divided among the three components of this
`metric.
`
`G:\N21272.doc
`
`———1 65—
`
`Last saved
`1 6:09 Friday, March 09, 2001
`
`
`
`

`

`Study P01 :04-05
`
`’
`
`NDA 21-272
`UT-I 5for pulmonary hypertension
`
`The quality of life metric was the Minnesota living with heart failure questionnaire. This
`questionnaire consists of 21 questions and is divided in to 4 domains. This QOL.
`questionnaire was validated among subjects with CHF and not pulmonary
`hypertension, though the questions and limitation are somewhat similar among groups.
`The questionnaire is often analyzed as a global and three subcategories, physical,
`economical and emotional dimension. This questionnaire was not apparently
`administered to all subjects. Overall there was no global signal for this questionnaire.
`The global QOL did not differ between the two treatments. The physical dimension,
`however, was statistically favored the UT-lS group.
`
`Each subject was asked to rank his or her degree of breathlessness after each six-
`minute walk by the Borg-dyspnea scale. This metric ranged from 1‘10. The higher
`numbers suggest greater degrees of shortness of breath. The exercise coordinator
`performed this task and consequently is more likely to have been shielded from telltale
`adverse events that would indicate the specific treatment. Both the pooled studies and
`each of the individual studies were highly significant in improvement (p<0.01) of this
`metric. The magnitude was approximately 0.8 units.
`
`It does not appear that UT-lS altered the natural course of pulmonary hypertension.
`Deaths, hospitalizations, hospitalizations for cardiovascular reasons or need for new or
`increases in medications or need for inotropic or Flolan during the 12-week study did
`not apparently differ between the two treatments. These metrics, however, were not
`prespecified as end—points, but are often collected and may served as convincing
`endpoints of benefit.
`
`There were a total of 19 subjects who died during the window of the study. Ten of these
`subjects were in the vehicle group and nine in the UT-lS group.
`
`Hospitalizations were equivalent in both groups. There were 40 subjects who were
`hospitalized or had their hospitalizations prolonged among the vehicle group and 38
`among the UT-15 group. No of those hospitalized among those randomized to vehicle
`were hospitalized after accidentally crossed-over and while treated with UT-15. The
`investigators at the various study sites did not adjudicate cause-specific
`hospitalizations. This reviewer, based on the capsular summaries found 22 of those
`treated with LIT-15 and 25 of those treated with vehicle had their hospitalizations
`prolonged or required hospitalization as a consequence of cardiovascular or pulmonary
`hypertension related.
`'
`
`Subjects who status deteriorates may require new medications or increase in doses of
`ongoing medications. A difference in the need to alter medications may suggest a benefit
`of a given treatment. For the purposes of this assessment the following drug classes
`were considered: loop diuretics, calcium channel blockers, vasodilators (including
`hydralazine, clonidine, nitrates), ACE inhibitors or angiotensin ll blockers, oxygen,
`Flolan, pressors, steroids, digoxin, aldactone or non—loop diuretics.
`
`There was no difference in the number of subjects who required Flolan or inotropic
`support. This reviewer counted 12 subjects in the UT-lS group and 10 in the vehicle
`group that required either Flolan or inotropes. There were an additional 3 subject, all in
`the vehicle group that received flolan early in the course of the study, that suggested
`the infusion was a provocative test for vascular responsiveness and not a treatment for
`disease decompensation. These three subjects were excluded from the above count.
`
`Among those who completed the study, there was a modest improvement in
`catheterized hemodynamics. Right atrial pressures, pulmonary artery pressures (mean,
`systolic and diastolic) and pulmonary vascular resistance were decreased. Cardiac
`index, stroke index and mixed venous oxygenation were increased. The effect on
`
`G:\N21272.doc
`
`»
`
`Last saved
`
`-—1 66—
`
`16:09 Friday, March 09, 2001
`
`

`

`Study P01:04-05
`
`.
`
`.
`
`NDA 21-272
`UT-1 5 for pulmonary hypertension
`
`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 the Whole ’group) there was a net increase of 7.6%. There
`was an approximately 5% (3 mm‘l-lg) decrease in mean pulmonary artery pressure.
`There was an approximately 18% decrease in pulmonary vascular resistance. Changes
`in CI, PAPm or M did not convincingly correlate with any benefit. The only consistent
`hemodynamic parameter with a positive correlation was SVOz.
`
`Dosing was predicated on improving symptoms of pulmonary hypertension while
`minimizing excessive pharmacologic effect or infusion related adverse events. Itis
`therefore not possible to define either the initial, optimal or an appropriate dose range
`of use for UT-lS based on the data from this study.
`
`Despite nearly an order of magnitude increase in mean infusion rate, there was minimal
`increase in walking distance among those treated with UT—lS. The observed differences
`more reflect a worsening of the distance walked by the vehicle group than by an
`improvement among those taking larger and larger infusions of UT—15. There was no
`randomized withdrawal to ascertain a persistent (or any) benefit of UT-15. In fact among
`the hand-full of subjects who discontinued UTolS acutely, no evidence of rebound was
`described.
`
`With respect to safety, the duration of exposure was 81 days for those in the UT-15
`group and 83 days for those treated with vehicle. The number of deaths and
`hospitalizations were equivalent between the two treatments. More UT—15 treated
`subjects than vehicle subjects had adverse events listed as severe in intensity (62%
`versus 20%). The vast majority of the difference reflects the irritating effect of active
`drug infusion.
`
`Two subjects in the UT—15 group had episodes of hemolytic anemia. One subject
`discontinued treatment and the other subject continued on a lower dose of therapy.
`One additional subject had pancytopenia that the sponsor attributed to previous
`cyclophosphamide treatment. She continued on therapy. It does not appear that UT-lS
`is causative of these events since two of the three subjects continued on therapy.
`
`The most frequent adverse events among those treated with UT-IS were also related to
`the “skin and appendage” system (94% versus 67%). The most frequently reported
`events were “infusion site pain” or “infusion site reaction”, 85% and 83% of those
`enrolled, respectively, the corresponding numbers among those treated with vehicle
`were 27% and 27%, respectively. ‘Gastrointestinal” symptoms were more frequent in
`the UT-15 than vehicle group (45% versus 32%), predominantly “diarrhea” (25% versus
`15%) and “nausea” (22% versus 18%). Adverse events associated with the “nervous”
`system were more frequent in the UT-15 group than vehicle (30% versus 22%), with the
`most common adverse event described as vasodilation (11% versus 5%). Adverse events
`associated with “Metabolic and Nutritional” system had more events in the UT-lS group
`than vehicle (20 versus 13 %). The most frequent increase was in edema (9% versus
`3%).
`
`“Chest pain” (9% versus 4%), ‘dyspnea’ (8% versus 3%), “cough” (8% versus 3%); and
`“infusion site bleeding” (44% versus 34%) was more frequent in the vehicle group than
`in the UT-15 group.
`
`With respect to laboratory and hematology, group mean difference existed for: total
`bilirubin, LDH, BUN, hemoglobin, hematocrit and white blood cell count were all
`decreased relative to vehicle group. Platelet counts were increased in UT-15 relative to
`vehicle. Hypokalemia was noted in five patients treated with UT-lS and none with
`vehicle.
`
`ECG intervals did not apparently differ among groups.
`
`G:\N21272.doc
`
`—-1 67—
`
`Last saved
`16:09 Friday, March 09, 2001
`
`

`

`Study P01:04-05
`
`r
`
`,
`
`i
`
`NDA 21-272
`UT-I 5for pulmonary hypertension
`
`Vital signs were poorly followed. Blood pressure was only recorded for the initial
`infusion day. The dose of UT-IS, however, was very low and consequently allows no
`assurance that hemodynamics was not effected by credible infusion rates of UT-15.
`There were, however, 29 subjects treated with UT—15 who had their dose decreased for
`excessive pharmacologic effect, with no further description as to the specifics of the
`event.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`G:\N21272.doc
`
`7
`
`-—1 68—-
`
`Last saved
`16:09 Friday, March 09, 2001
`
`

`

`Reviews of individual studies
`Study P01 :07
`
`.-
`
`'
`
`NDA 21-272
`UT-1 5for pulmonary hypertension
`
`. A.5 Study P01:07: A bio availability study of KIT-15 administered
`subcutaneously versus intravenously in healthy volunteers.
`
`A.5.1 Sites and investigators
`
`P01:07 was conducted at a single site in the United States.
`
`Table 97. Investigators (P01:O7).
`
`
`
`[E- PPD Develo- merit, West Austin Texas
`
`
`
`A.5.2 Background
`
`Initial protocol submitted: N /A
`
`Protocol amendments:
`
`None.
`
`Subject enmllment:
`
`6.4.99 to 6.24.99
`
`A.5.3 Study design
`
`This single-center, open-label, non—randomized Phase I trial examined the
`pharmacokinetics and safety of single IV doses of UT-lS administered either by IV or
`subcutaneous routes. Healthy volunteers were given the drug at a rate of 15 ng/ kg/ min
`IV or SQ for 150 minutes, during which time samples for pharmacoldnetic assessment
`were obtained. The patients were also monitored for safety using serum chemistries,
`CBC, ECG monitoring and vital signs. The IV and SQ periods were separated by a 5 to
`7-day washout period.
`
`A.5.3.1 Objectives
`To assess the safety pharmacokinetics of a single IV and SQ dose of UT-lSin healthy
`volunteers.
`
`A.5.3.2 Number of subjects] ran domization
`Fifteen patients were to be enrolled in the study.
`
`A.5.3.3 Inclusion] exclusion criteria
`
`Healthy volunteers were enrolled in the trial. Women were to be of non-child-bearing
`potential; subjects of child—bearing potential had to have a negative serum pregnancy
`test prior to study entry.
`
`A.5.3.4 Dosage] administration
`
`Healthy volunteers were given the drug at a rate of 15 ng/ kg/ min IV or SQ for 150
`minutes.
`
`A.5.3.5 Duration/ adjustment of therapy
`
`Therapy was not adjusted for any individuals enrolled in the trial.
`
`55.3.6 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. 2.22.
`
`L533? Statistical consideration s
`
`The statistics in the trial were observational in nature.
`
`A.5.4 Results
`
`Fifteen patients (7 female, 8 male) were enrolled in the trial and completed the infusion
`of both IV and SQ UT-lS.
`
`G:\N21272.doc
`
`—1 69——
`
`Last saved
`1 6:09 Friday, March 09, 2001
`
`
`
`

`

`Reviews of individual studies
`Study P01 :07
`
`A.5.4.1 Efficacy
`
`.
`
`+
`
`4
`
`NBA 21 -272
`UT-l 5for pulmonary hypertension
`
`No efficacy data of clear relevance to the approvability of subcutaneous UT-lS for
`pulmonary hypertension were obtained in this small study. During the period of
`infusion there was no significant changes in any hemodynamic parameters per the
`sponsor. The pharmacokinetic analyses from the study will be discussed elsewhere by
`Drs. Nguyenand Gobburu.
`
`15.4.2 Safety
`
`There were no deaths reported in the study, and no SAEs during the IV or SQ infusions.
`The most common AEs reported were dizziness and heachache, which were more
`common in the IV formulation than following the SQ formulation. Injection site pain
`was more common in the SQ dosing.
`
`A.5.5 Summary .
`
`$55.1 Efficacy summary
`
`Study P01:07 studied the acute effects of IV and SQ UT-15 in normal volunteers. No
`acute hemodynamic changes were detected for either formulation.
`
`A.5.5.2 Safety summary
`
`The adverse events identified in this open-label study are similar to those reported in
`other small trials of IV and SQ UT-lS.
`
`A.5.5.3 Reviewer's conclusions
`
`No new safety concerns were identified in this study.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`APPEARS THIS WAY
`0" ORIGINAL
`
`G:\N21272.doc
`
`—1 70—
`
`Last saved
`16:09 Friday, March 09, 2001
`
`

`

`Reviews of individual studies
`Study P01 :08
`
`’
`
`NDA 21—272
`UT-l 5for pulmonary hypertension
`
`A.6 Study P01:08: A study to evaluate the effects of acetaminophen on
`the pharmacokinetics of UT-15 in healthy Volunteers.
`
`A.6.1 Sites and investigators
`
`P01:08 was conducted at a single site in the United States.
`
`Table 98. Investigators (P01:08).
`
`PPD Develo-enm ,tWes Autins Texas
`
`'1‘. Hunt,M.D.,
`
`A.6.2 Background
`
`Initial protocol submitted: N/A
`
`Protocol amendments:
`
`None.
`
`Subject enrollment:
`
`8.3.99 ta 9.20.99
`
`A.6.3 Study design
`
`This singleocenter, open-label, non-randomized Phase 1 trial examined the effect of
`acetaminophen an the pharmacokinetics and safety of SQ UT-lS. Healthy volunteers
`were administered UT-lS, 15 ng/ kg] min SQ for 6 hours in two dosing intervals
`separated by a 7 day washout period.
`In the first period, patients were given
`acetaminophen starting 25 hours before start of UT-15 and continuing through period
`of infusion
`
`L6.3.1 Objectives
`
`1. To assess the effect of oral acetaminophen on the pharmacokinctics of SQ UT-lS in
`healthy volunteers.
`
`$6.32 Number of subjects] randomization
`
`Twenty-nine (29) patients were to be enrolled in the study and 26 completed.
`
`A.6.3.3 Inclusion] exclusion criteria
`
`Healthy volunteers were enrolled in the trial. Women were to be ofnon-child- .
`bearing potential; subjects of child-bearing potential had to have a negative serum
`pregnancy test prior to study entry.
`56.3.4 Dosage] administration
`
`See trial design for details.
`
`A.6.3.5 Duration] adjustment of therapy
`
`Therapy was not adjusted for any individuals enrolled in the trial. TWO individuals were
`discontinued for drug-related reasons: one for pump failure (for SQ administration) and
`the other following vomiting of a dose of acetaminophen.
`
`A.6.3.6 Safety and efficacy endp oints measured g
`
`A listing of the measurements made during the trial can be found in the trial study
`report: NDA 21-272, vol. 2.22.
`
`$6.33! Statistical considerations
`
`The statistics in the trial were observational in nature.
`
`A.6.4 Results
`
`Nonty-nine (29) patients, 17 females and 12 males, were to be enrolled in the study
`and 26 completed. One person withdrew consent, one discontinued for pump failure (for
`SQ administration) and the other following vomiting of a dose of acetaminophen.
`
`G:\N21272.dac
`
`-1 71—-
`
`Last saved
`16:46 Friday, March 09, 2001
`
`,
`
`.
`
`.....
`
`l.._._ -... ._-w-.v,.¢r.'...._......‘..__...
`
`..__..__._...,._.
`
`
`
`

`

`Reviews of individual studies
`Study P01 :08
`
`A.6.4.1 Efficacy
`
`_
`'
`
`I'
`
`NDA 21~2 72
`UT-1 5for pulmonary hypertension
`
`No efficacy data of clear relevance to the efficacy of subcutaneous UT-15 for pulmonary
`hypertension were obtained in this small study. During the period of infusion there was
`no significant changes in any hemodynamic parameters per the sponsor. The
`pharmacokinetic analyses from the study will be discussed elsewhere by Drs. Nguyen
`and Gobburu.
`
`$6.43 Safety
`
`There were no deaths reported in the study, and no SAEs during the UT~15 infusions.
`The most common AEs reported were heachache (59%) and nausea (38%).
`
`A.6.5 Summary
`
`A.6.5.1 Efficacy summary
`
`Study P01:08 studied the acute effects of acetaminophen on the phannacokinetics of
`UT-lS. No acute hemodynamic changes were reported. The pharmacoldnetics will be
`discussed in other reviews, but the sponsor reported no effect of acetaminophen on UT-
`15 pharmacokinetics.
`
`A.6.5.2 Safety summary
`
`The adverse events identified in this open-label study are similar to those reported in
`other small trials of SQ UT-15. The three discontinuations were unrelated to UT—lS
`adverse effects.
`
`A.6.5.3 Reviewer'e conclusions
`
`No new safety concerns were identified in this study.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`G:\N21272.doc
`
`-—1 72——
`
`Last saved
`16:46 Friday, March 09, 2001
`
`
`
`

`

`Reviews of individual studies
`‘ Study P01 :09
`
`V
`
`,
`
`,
`’
`
`NDA 21-272
`UT—l 5for pulmonary hypertension
`
`A.7 Study P01:09: A chronic, dose-escalation study of the
`pharmacolrinetics of UT-15 administered by continuous subcutaneous
`infusion in healthy volunteers.
`
`A.7.1 Sites and investigators
`
`P01:09 was conducted at a single site in the United States.
`
`Table 99. Investigators (”1:09).
`
`
`
`I 1‘. Hunt, M.D., PhD.
`
`PPD Devel-moent West Austin Texas
`
`
`‘
`
`A.7.2 Background
`
`Initial protocol submitted: N /A
`
`Protocol amendments:
`
`None
`
`Subject enrollment:
`
`7.15.99 to 8.28.99
`
`A.7.3 Study design
`
`This single—center, open-label, non-randomized, dose-escalation Phase I trial examined
`the pharmacokinetics of UT-lS administered via SQ infusion for 28 days. Healthy
`volunteers received UT-15, starting at a dose of 2.5 ng/ kg] min for 7 days. Doses were
`increased at 7 day intervals to 5, 10 and 15 ng/ kg] min respectively for periods 2, 3 and
`4. Serial plasma samples were collected for PK as well as clinical chemistries, CBC and
`coagulation parameters. Additional samples for PK were collected after discontinuation
`of UT-ls.
`
`A.7.3.1 Objectives
`
`.
`
`1. To assess the chronic pharmacokinetics of UT-lS administered by continuous 28-
`day SQ infusion.
`
`2. To assess the safety and tolerability of chronic SQ UT-IS infusion in healthy
`volunteers.
`
`A.7.3.2 Number of subjects] randomization
`
`Fourteen (14) patients were to be enrolled in the study. Six subjects completed the trial;
`8 others discontinued due to infusion site pain.
`
`A.7.3.3 Inclusion] exclusion criteria
`
`Healthy volunteers were enrolled in the trial. Women were to be of non-child-
`bearing potential; subjects of child-bearing potential had to have a negative serum
`pregnancy test prior to study entry.
`A.7.3.4 Dosage] administration
`
`See tn'al design for details.
`
`A.7.3.5 Duration] adjustment of therapy
`
`Dose of UTJS was adjusted as detailed in the study design section above. Study lasted
`for 28 days.
`
`5.31.3.6 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. 2.22.
`57.3.7 Statistical consideration s
`
`The statistics in the trial were observational in nature.
`
`G:\N21272.doc
`mm. ,..
`....
`a
`. _.,.
`....
`
`.
`
`..__ ,..-._- -.,....._.._ ...~.._._.....-..
`
`,
`
`—1 73—
`
`16:46 Friday, March 09, 2001
`
`-
`
`Last saved
`
`

`

`Reviews of individual studies
`Study P01 :09
`
`.
`
`p
`
`.
`'
`
`4
`
`A.7.4 Results
`
`NDA 21-2 72
`,
`UT-I 5for pulmonary hypertension
`
`Fourteen (14) patients were to be enrolled in the study. Six subjects completed the trial;
`8 others discontinued due to infusion site pain.
`
`A.7.4.1 Emcaey
`
`No efficacy data of clear relevance to the approvability of subcutaneous UT-15 for
`pulmonary hypertension were obtained in this small study. During the period of
`infusion there was no significant changes in any hemodynamic parameters per the
`sponsor. The pharmacokinetic analyses from the study will be discussed elsewhere by
`Drs. Nguyenand Gobburu. The sponsor concluded that the trial demonstrated linear
`pharmacokinetics over the range of doses studied in the trial, with an apparent
`elimination half-life for the 15 ng/kg/min dose of 2.93 hours.
`
`$74.2 Safety
`
`There were no deaths reported in the study, and no SAEs during the UT-lS infusions.
`The most common AEs reported were injection site pain (13/14 subjects), headache
`(11/14), nausea (7/14) and dizziness (7/ 14). Blood pressure and other vital signs did
`not change significantly from baseline in the patients. ECG evaluation did not find any
`significant changes from baseline.
`
`A.7.5 Summary
`
`A.7.5.1 Efficacy summary
`
`Study P01:09 studied the pharmacokinetics of UT~15 during chronic SQ infusion. No
`hemodynamic changes during the 28 day study were seen. The pharmacoln’netics will
`be discussed in other reviews.
`
`A.7.5.2 Safety summary
`The adverse events identified in this open-label study are similar to those reported in
`other long-term trials of UT—lS, especially the prominent occurrence of site pain, which
`lead to the discontinuation of 8 of the 14 enrolled subjects.
`
`$15.3 Reviewer's conclusions
`
`No new safety concerns were identified in this study.
`
`APPEARS nus WAY
`0N ORIGINAL
`
`G:\N21272. doc
`
`—1 74-—
`
`16:46 Friday, March 09, 2001
`
`Last saved
`
`

`

`Reviews of individual studies
`Study P01:1 0
`‘
`
`7
`
`_‘
`'
`
`NBA 21-2 72
`UT-J 5for pulmonary hypertension
`
`A.8 Study P01:10: A sin gle-center, open-label, mass balance, urinary
`metabolite profiling, and safety study of 14C-UT-15 following an 8-hour
`- subcutaneous infusion in six normal healthy male subjects.
`
`A.8.1 Sites and investigators
`
`P01:10 was conducted at a single site in the United States.
`
`Table 100. Investigators (P01:10).
`
`
`
`,,
`
`
`m Russell M. D1xon,M.D.
`
`7
`
`7 Canoe Madison Wi
`
`
`
`A.8.2 Background
`
`Initial protocol submitted: N] A
`Protocol amendments:
`None
`
`Subject enrollment:
`
`1.6.00 to 1.16.00
`
`A.8.3 Study design
`
`This single—center, open-label, non-randomized, Phase I trial examined the metabolic
`fate of l4C-labeled UT-l5 in healthy male volunteers. Each subject received a single 8-
`hour infusion (SQ) of l4C—UT-15 at a rate of 15 ng/kg/min. Vital signs, clinical labs,
`ECGs and adverse events were monitored throughout the trial and at its conclusion.
`
`$83.1 Objectives
`
`1. To characterize whole blood and plasma radioactivity of l4C-UT-15 following an 8-
`hour subcutaneous infusion in normal healthy male volunteers.
`
`2. To characterize the urinary and fecal excretion of radioactivity following an 8-hour
`SQ infusion of UT-lS.
`
`3. To evaluate the safety of UT-lS under the same conditions.
`
`4. To examine the pattern of urinary metabolites following the 8-hour SQ
`administration of LIT-15.
`
`A.8.3.2 Number of subjects] randomization
`
`Six patients were to be enrolled in the study. Six subjects completed the study.
`
`$8.33 Inclusion] exclu