Study P01:04-05
`
`1 1l
`
`lr 1 1
`
`‘1
`
`
`
`Table 45. Baseline characteristics (P01:04-05)
`
`NDA 21-272
`UT—I 5 for pulmonary hypertension
`
`—1:” m_Polek W
`Veh
`Veh
`1 1 i
`n=109
`
`1 lr 1 i |1
`
`1111
`
`r 11I
`
`N ,
`44.4
`
`4’
`
`.
`
`
`
`
`
`Systolic blood pressure,
`5Ion
`75.9
`Diastolic blood pressure, Mean
`mmH-1SD 111.1
`
`Mean
`1SD
`
`117.3
`116.9
`
`7
`
`_
`
`”11 > 1 -
`
`l I I
`1,11,15,11 13.
`1.7 1 135 H
`13.9w 13.4
`
`>
`
`The demographics were fairly well balanced across studies and across treatment
`groups. There were however, more males in the 01:05 vehicle group than in any other
`group. The vast majority of subjects were NYHA class 111 subjects (approximately 80%).
`The vast majority of those enrolled were also females approximately 85%). There
`proportion of subjects with primary pulmonary hypertension in the 01:05 study was
`greater than in the 01:04 study. The distribution of these subjects between UT-15 and
`vehicle were, however similar. There were a greater fraction of those enrolled in study
`P01:04 who had their pulmonary hypertension as a consequence of collagen vascular
`disease than in study P01:05.
`
`Those with collagen vascular disease consisted of those with scleroderma (12-treatment,
`l3-vehicle), limited scleroderma (IS-treatment, 7-vehicle); mixed connective tissue
`disease (8otreatment, 9-vehicle); systemic lupus erythematosis (7—treatment, 18-vehicle);
`and overlap syndromes (l-treatment; 2—vehicle). There were relatively more subjects in
`the vehicle group whose etiolog of pulmonary hypertension was a consequence of SLE.
`
`Those defined as having pulmonary hypertension as a consequence of primary disease
`probably consisted of those who had idiopathic pulmonary hypertension as well as
`whose disease was a consequence of anorexogenic drug use.
`
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`-
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`- ... - “1..-“... 1.....- .. ..-.-...._V._. 2.. - .,1.._.- -—— — s»
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`—
`
`-
`
`<-—-
`
`- —
`
`»
`
`
`
`
`
` ‘
`
`
`
`
`
`
`
`11
`
`1 1
`
`rI
`
`Mean
`
`%F
`
`Caucasian
`Black
`Asian
`
`Hispanic
`Other
`
`Primary pulmonary hypertension
`Collagen Vascular
`Cardiac Shunts
`NYHA Class (%)
`
`Duration at current
`
`, months
`Weight, Kg
`
`Height, cm
`
`BSA, m2
`
`Pulse, bpm
`
`I—l—I—un—n
`1
`IV
`Mean
`
`15E
`Mean
`1SD
`Mean
`1SD
`
`1SDZZ00mm:s:1
`
`1SD
`
`. Age}...
`—----—--
`
`
`86%
`86
`5
`6
`
`1 3
`1
`
`59
`30
`22
`16 (14)
`85 (77)
`10 9
`12.1
`
`12.5
`73.8
`119.9
`162.5
`19.9
`1.8
`10.2
`82.4
`112.6
`
`85%
`91
`8
`4
`
`8
`2
`
`61
`25
`27
`10 (9)
`93 (82)
`10 9
`17.2
`
`12.9
`73.3
`121.1
`161.2
`110.5
`1.8
`10.3
`83.5
`112.5
`116.7
`113.8
`
`73.3
`112.0
`
`72%
`1 12
`3
`2
`
`6
`2
`
`77
`1 9
`29
`12 (10)
`107 (86)
`6 5
`19.0
`
`12.4
`72.1
`116.3
`163.4
`19.5
`1.8
`10.2
`81.8
`112.7
`116.3
`116.3
`
`74.3
`110.5
`
`84%
`107
`5
`1
`
`6
`1
`
`73
`16
`31
`15 (13)
`97 (81)
`8 7
`17.8
`
`12.1
`67.6
`118.0
`163.0
`18.5
`1.7
`10.2
`82.1
`111.5
`1 15.5
`114.1
`
`73.4
`111.5
`
`78%
`198
`8
`8
`
`19
`3
`
`136
`49
`5 1
`28 (12)
`192 (81)
`16 7
`15.7
`
`11.8
`72.9
`118.1
`163.0
`19.7
`1.8
`10.2
`82.1
`112.6
`116.8
`116.6
`
`75.1
`110.8
`
`
`85% I
`
`‘
`198
`13
`5
`
`14
`3
`
`134
`4 1
`58
`25 (11)
`190 (82)
`18 8
`17.5
`
`11.8
`70.4
`119.8
`162.1
`19.6
`1.7
`10.2
`82.8
`112.0
`116.1
`114.0
`
`73.3
`111.7
`
`‘
`
`1
`
`1
`‘
`
`‘
`1
`I
`
`.
`
`3
`
`

`

`Study P01 :04-05
`
`NDA 21-272
`UT-1 5for pulmonary hypertension
`
`Comment. This reviewer does not know if the natural history of pulmonary
`hypertension as a consequence of anorexognic drug use as primary pulmonary
`hypertension are the same. For those with primary pulmonary hypertension secondary
`to anorexogenic use, the ongoing stimulus has been removed. The other causes in
`general (with the exception of repaired congenital shunts) do not have the inciting
`stimulus for pulmonary hypertension terminated.
`
`The number of subjects in each cohort is shown in Table 50. There were very few
`subjects with low exercise capacity in the entire cohort.
`
`A.4.4.2 Disposition of subjects
`
`The flow of subjects through the study is shown in Table 46.
`
`Table 46. Disposition of subjects (P01:04-05)
`
`
`
`Did not complete
`Death
`Deteriorated
`
`Transplant
`Adverse event
`
`A.4.4.3 Oversight Committees
`
`In a supplement dated 3‘ November 2000, United Therapeutics submitted summaries of
`the DSMB meetings. The members of the committee were Drs. Brundage, Harrell,
`, Churchill and Fishman. Reports are available for three meetings 20 July 1999; 18
`October 1999, and 24 November 1999. After the second meeting the DSMB requested
`baseline hemodynamic data and 6-minute walk for analysis at the last meeting. The
`committee requested more information on the nature and treatment of the infusion site
`pain.
`
`With respect to the Steering Committee, there were apparently two steering committees.
`One committee for North American sites and the members were Drs. Barst, Rich,
`Rubin, Crow and Blackburn. A second committee labeled the European Steering
`committee. The members of this committee were Drs Rubin, Simonneau, Galie, Naeiije,
`Crow and Blackburn. Drs Rubin, Crow and Blackburn were inviolved with both
`committees. Meeting dates were as follows: 16 December 1998 (North American), 2
`March 1999 (European), 28 April 1999 (North American), and 7 November 1999 (both
`North American and European)
`
`The only changes to the submitted protocols were made at the 16 December 1998
`meeting. This meeting occurred appraidmately 1 month after the first subject was
`enrolled into study P01:O4 and several days after the first subject enrolled into study
`P01105. The changes were in response to a FDA teleconference call. The changes can
`be summarized as follows. 1) A global QOL in the form of the Minnesota QOL
`questionnaire was added to the assessments at weeks 1, 6, and 12.
`.2) The interim
`
`7’ Subject 04503 developed sepsis secondary to an elective abortion and died while on study drug. The
`database captured this patient as a discontinuation due to AE. This error was discovered afler the data base
`lock.
`
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`

`Study P01 :04-05
`
`NDA 21-272
`UT-I 5for pulmonary hypertension
`
`efficacy assessment was dropped. 3) The last value carried forth approach was used. 4)
`The Ultrafast CT was incorporated to rule out thromboembolic disease. These changes
`were incorporated in the protocol by Amendment #3.
`
`11.4.4.4 Conduct
`
`_
`
`There were 60 subjects whose were stratified inaccurately. Thirty-one of these subjects
`were vehicle treated subjects and 29 were UT-lS treated subjects. The specifics are
`shown in Table 47 below:
`
`
`
`a
`
`
`
`
`i
`x
`Table 47. Mistakes in stratification (P01:04-05)
`
`
`
`l1
`
`”fwd:
`
`Stratified as low exercise capacity and no vasodilator use—really high exercise
`ca -aci
`and es vasodilator use
`
`Stratified as high exercise capacity and vasodilator use—really low exercise
`ca - 2 ci
`and no vasodilator use
`
`Stratified as primary pulmonary disease with vasodilator use—really secondary
`nulmona
`h p rtension with no vasodilator use
`Stratified as vasodilator use—mean no vasodilator use
`
`
`p Stratified as no vasodilator use—real] vasodilator use
`
`
`
`There was no overwhelming bias in the errors in of stratification. The mlTT considers
`subjects with appropriate stratification. The pITT analysis considers these subjects as
`randomized.
`
`Blinding. By protocol, the treatment was blinded to both the physician and subject. An
`additional barrier to unblinding was included. The physician who performed the
`exercise distance test was not the physician who was in charge of the subject’s care.
`Other metrics, particularly the dyspnea—fatigue index, however, were performed (and
`often completed) by the treating physician.
`
`' Blinding, however, was not perfect. At the end of the 12-week period the blind of each
`._ subject was broken to facilitate treatment into long term therapy. Common drug-related
`adverse events would rapidly be associated with a given treatment, certainly after the
`subject’s treatment was unblinded.
`
`A second and related compromise to the blind of this study is that subjects who were
`treated with active drug were more likely to have infusion site pain/ infusion site
`reaction. Furthermore, the intensity and severity of such pain, much more frequently
`required concomitant medications including narcotics and anti-inflammatory drugs
`among UT—15 subjects than those treated with vehicle. The onset of such pain was early
`during the course of treatment. It is, therefore, unclear to what extent measurements
`performed by the treating physician was compromised by the potential unblinding.
`
`Major assessments of those enrolled may have been by an investigator who had a good
`idea as to the randomized therapy. Most notably, assessments of signs and symptoms
`of CHF, quality of life measurements, as well as certain important classifications such
`as the reason for discontinuations were perhaps biased by the knowledge of treatment.
`
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`
`‘ “N '
`fl
`‘
`seconda
`disease—real
`Stratified as orim .
`disease—real!
`-rima
`Stratified as second :
`Stratified as low exercise—ream hih exercise
`Stratified as hi,
`exercise—{call
`low exercise
`Stratified as hi
`exercise but exercise exceeds u . - r limits allowed
`Mia-stratified as low exercise capacity and secondary pulmonary hypertension
`and vasodilator use—in reality high exercise capacity, primary disease and no
`vasodilator use
`'
`
`oulmon .
`--ulmon
`
`h p rtension
`h ‘0 'rtension
`
`\
`
`
`
`
`

`

`
`
`Were in violation of inclusion criteria for diagnosis of
`pulmonary hypertension the appropriate
`hemod
`amic . : rameters
`
`Were in violation of exclusion of criteria for portal
`hypertension, history of left sided disease, other
`diseases (i.e. sickle cell anemia, schistosomiasis),
`musculoskeletal disorder that could alter
`ambulation, or exercise distance between 40-450 m.
`
`Received any prostaglandin (or analogs) therapy for 7
`da s of the week l2—exercise test
`
`
`
`
`
`Study P01:O4-05
`
`NBA 21 -272
`UT—l 5for pulmonary hypertension
`
`Protocol violations. The sponsor cites the following criteria as major deviations. There
`were relatively few subjects who deviated from protocol.
`
`Table 48. Protocol deviations (P01.04-05)”
`
`J
`
`Subjects whoreceived the incorrect treatmentfor any
`-art of the treatment - riod
`
`treatment - riod
`
`
`
`Pooled
`\ l r1
`5tr
`
`.L
`
`
`-_II
`
`
`
`
`
`
`
`Other protocol violatons considered on an individual
`basis prior to unblinding (received rescue therapy”,
`
`,,interstitial lun- disease”.
`p
`
`
`A.4.4.5 Definitions of subject co horts used in analyses“
`
`The “Pure Intent-to Treat” [or QI’I‘T”| ls defined as all subjects randomized in either
`study. Subjects are counted to the group to which they were randomized, regardless of
`the treatment they were actually given, or whether any study drug was given atall. All
`original stratification information used in the randomization procedure is used,
`regardless of whether it was later found to be incorrect.
`
`The “Modified Intent‘to Treat” or (“mlT'I‘”| population is the same as the “plT'l‘” .
`population except that subjects who did not receive either study drug medication were
`excluded from the analysis. In addition, the efficacy data for any subject who was
`inadvertently given the alternative treatment during the trial (i.e. crossed over) due to
`errors in resupply of study medication was censored at the time of cross—over (by not
`having data after cross-over included in the analysis). Incorrect stratification data was '
`corrected for this cohort.
`
`The “Per-Protocol” population was defined as all subjects in either study who actually
`receiving study drug for at least 8 weeks and who had baseline and week 12 exercise
`test assessments or discontinued due to death, transplantation or clinical deterioration.
`This population excluded subject with major protocol violations, and those who were
`not receiving study drug during their Week l2-exercise test due to premature
`discontinuation. Subjects were counted as being in the group corresponding to the
`treatment they actually received at the start of the dosing period. Subjects who crossed-
`
`” Sponsor's analysis.
`
`5’ These are the same subjects who received the wrong treatment.
`
`3’ Two subjects on vehicle.
`
`’3 One subject on UT-15.
`
`’4 Volume 33A, page 6365.
`
`G:\N212 72. doc
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`

`Study P01:04-05
`
`UT] 5for pulmonary hypertension
`
`NDA 21-272
`
`over to the alternative treatment during the trial were excluded from this cohort.
`Subjects with the following protocol violations were excluded from this cohort:
`
`Subjects who violate inclusion criteria #3 and #6.That is, subjects who do
`not satisfy the criteria for the diagnosis of pulmonary hypertension and
`exclude left sided cardiac dysfunction.
`
`Subjects who violate exclusion criteria #9, #10, #11 and #12. That is those
`with portal hypertension, a history of left sided disease, a history of other
`diseases (i.e. sickle cell anemia, schistosomiasis), Musculoskeletal disorder
`that could alter ambulation or who had an exercise distance outside the
`
`range of 40—450 meters at baseline.
`Subjects who are treated with prostaglandin or their analogues for
`pulmonary hypertension.
`
`'
`
`Subjects who are treated with chronic or inhaled medications to treat
`pulmonary hypertension.
`
`Other protocol violations
`
`The ‘Safeg; Population" is defined as all subjects in either study who actually receiving
`study drug, and all subjects will be counted as being in the group corresponding to the
`treatment that they actually received. If a subject received UT-15 at any point during
`the study, they will be counted in that treatment group.
`
`Comment. Subjects who are inadvertently treated with UT- 15 should also be included
`in the denominator of the vehicle group. These subjects were only included in the UT-15
`group. The denominator of the vehicle group and consequently, the rate of adverse
`events was mildly inflated in the vehicle group.
`The specifics of the cohorts are shown in Table 49.
`
`APPEARS THIS WAY
`0" ORIGINAL
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`16:09 Friday, March 09, 2001
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`Last saved
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`.. v..-_e..c_..-...._.....,.‘. www... '...._ ,_.. ., ..
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`..
`
`

`

`Study P01:04-05
`
`NDA 21-2 72
`UT-l 5 for pulmonary hypertension
`
`Table 49. Cohorts analyzed (P01:04-05)
`
`—-nn--m- Per-otocol m-
`Randomized manually to correct
`Included
`Included
`Included
`Included
`treatment
`
`Included:
`Randomized manually, received
`. Efficacy
`incorrect treatment weeks 7-12
`
`
`censored at
`
`week 6
`
`Included:
`Included:
`Incorrect stratification information
`
`
`
`Stratification
`Stratification
`
`
`information
`information
`
`
`corrected
`not corrected
`
`Excluded
`
`Included
`
`Included:
`Stratification
`information
`corrected
`
`
`
`Included:
`Stratification
`information
`corrected
`
`Included m Excluded
`Included
`Excluded
`
`Included
`
`Excluded
`
`Excluded
`
`Included
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`site
`
`Received dru;s for < 8 weeks
`Subjects who did not have the
`diagnosis of pulmonary
`hypertension or did not have the
`- uuisite hemod
`amics
`
`
`
`
`
`Subjects who had Portal
`hypertension, left sided failure,
`other diseases that cauSe
`
`pulmonary hypertension,
`musculoskeletal disorders or 6-
`
`minute walk outside 50-450 m
`Subjects with premature
`discontinuations aside of death,
`
`
`
`
`
`
`
`
`‘
`‘
`
`‘
`1
`
`The distribution of subjects by stratification cohort is shown in Table 50.
`
`Table 50. Subjects by stratification cohort (P01:04-05)
`
`
`
`There were few subjects with low exercise performance. Slighly more than half the
`subjects were stratified as primary pulmonary hypertension with high exercise
`performance.
`
`Concomitant symptoms at baseline are shown in Table 51. The most common
`symptoms at baseline were dyspnea on exertion, exercise intolerance and‘fatigue. The
`remaining symptoms are listed in approximate decreasing frequency.
`
`‘5 Primary or secondary pulmonary hypertension; high or low exercise capacity; receiving or not receiving
`uasodilators.
`
`G:\N21272.doc
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`-—100——
`
`16:09 Friday, March 09, 2001
`
`Last saved
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`.fi- “NV ~__...._-
`
`.
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`.t ......._,.-. ._.-..'.-,- "V.-....._.e--.
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`
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`
`

`

`Study P01:04-05
`
`NDA 21 -272
`U711 5for pulmonary hypertension
`
`>
`Table 51. Symptom: at baseline (P01:04-05)
`u
`
`1
`
`A
`
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`
`
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`
`Baseline medications. Baseline classes of medications are shown in Table 52. The
`vast majority of subjects were on some class of medications at baseline. The proportion
`of subjects in both groups on each class of medication was similar. Approximately 2/3
`of those enrolled was anti-coagulated at baseline. Loop diuretics were used in
`approximately 45% of those enrolled. Steroids were actually infrequently used (< 10% of
`those enrolled] despite the 90 subjects whose etiology of pulmonary hypertension was
`due to collagen vascular disease.
`
`
`
`A.4.4.6 Dosing
`
`The dose level of UT-15 (or vehicle) was predicated on increasing the dose of drug to a
`point where signs and symptoms of pulmonary hypertension are improved, balanced
`against any dose-related adverse event profile of the drugs. The dose of drug (or vehicle)
`
`G:\N21272.doc
`
`’
`
`Last saved
`
`—1 01——
`
`1 6:09 Friday, March 09, 2001
`
`
`
`

`

`Study P01 :04—05
`
`‘
`
`NDA 21-272
`UT-1 5 for pulmonary hypertension
`
`was increased if the signs and symptoms of pulmonary hypertension were not improved
`or if the subject’s clinical condition deteriorated.
`
`The dose of drug (vehicle) was not to be increased or was to be decreased if there were
`any of the following:
`
`0 Changes in hemodynamics, vital signs, or clinical signs or symptoms (e.g.
`lightheadedness).
`'
`
`- Onset of an adverse experience associated with study drug (headache,
`nausea, emesis. restlessness and anxiety, or
`
`0
`
`Pain at the infusion site (either new onset or worsening of pain).
`
`The mean infusion rates for both vehicle and UT-15 are shown in Figure l 1. At the end
`of the period the infusion rate of UT-lS (mean iSD) was 9.3 i 5.4 ug/ kg/ min and that
`for vehicle was 19. 1 :t 4.8 pg/ kg/ min. The lower doses of U-15 reflects the limitation
`imposed by the onset of adverse events or excessive pharmacological effect or UT-lS
`and should not be construed as demonstrating a benefit of UT-15 in ameliorating the
`
`N
`
`—- Vehicle
`
`+ UT-15
`
`WeekinStudy
`
`0300
`
`4.3—3.3; h
`
`E E\ U
`
`)
`
`) 5G*
`iU
`
`0
`(C
`n:
`
`23456789101112
`
`More vehicle subjects were titrated upward than UT-15 subjects (Figure 12). The greater
`number of such subjects could either reflect the greater need for increased dosing (i.e. a
`measure of increased benefit for UT-15) or conversely the marginal tolerance of the UT-
`15 dose so that further dose increases were not well tolerated. More UT—15 subjects
`required dose reductions than vehicle subjects. Sponsor’s Listing 16.2.5.3 only lists the
`reason for dose changes. The usual reasons for downward change was due to pain at
`the infusion sites. No reason was listed for not increasing the dose.
`
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`Study P01 :04-05
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`NDA 21-2 72
`UT-I 5for pulmonary hypertension
`
`
`
`return. (hangs: in
`
`time my
`
`'
`
`' ”
`
`
`
`Adverse events limiting dose. Infusion with UT-15 was less well tolerated than
`vehicle. Based on the data in Listing 16.2.5.3, ninety-five UT-15 subjects had dose
`reductions at least once for either infusion site pain or infusion site reaction. An
`additional twenty-nine had the dose reduced due to excessive pharmacologic function.
`For those treated with vehicle there was one subject who had the dose decreased due to
`adverse events related to infusion site pain or reaction and three for excessive
`pharmacologic effect.
`
`The sponsor also supplies concomitant medications that were required to mitigate pain
`(redness, bruising, burning or pain). Of the subjects treated with UT-15, 207/ 233
`(89%) with data available required some medications for infusion site reaction (pain or
`erythema). Only 35 / 237 vehicle subjects (15%) required medication for infusion site
`reactions. The medications, which were used to treat these symptoms, ranged from
`narcotics, anti-inflammatory oral agents to topical steroids, astringents and irritants.
`More UT~15 required opiate antagonists than vehicle subjects (68 versus 3). There
`were more subjects treated with UT-lS who required some form of anti-inflammatory
`medication than those treated with vehicle (13 1 versus 8).
`
`There were more subjects who discontinued from active treatment than from vehicle. Of
`the 233 subjects who were randomized to active UT-15, 33 discontinued prior to the
`
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`.,.. .
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`

`Study P01 :04-05
`
`NDA 21-272
`UT—I 5 for pulmonary hypertension
`
`week~12 end point (see Figure 1.2). Eighteen of these subjects discontinued due to
`adverse events. Seventeen of these subjects had some degree of pain as the attributed
`reason for discontinuation. Among the 237 subjects who received vehicle, there were
`15 subjects who did not complete the 12—week study period. None of these subjects
`discontinued for site pain.
`
`In summary, UT—15 infusion causes complications at the infusion site at a much
`greater frequency and greater intensity than vehicle infusion and consequently, these
`subjects required more frequent and more intense treatment for this pain. This
`asymmetry of infusion pain across treatments has some consequences. It is quite likely
`that the investigator had a good idea which subject was receiving active drug and which
`was receiving vehicle.
`
`Since a blinded, designated, investigator supervised the pivotal six-minute walk, this
`reviewer does not believe this measurement was compromised. The more frequent pain
`in the UT-lS infusion group, however, may have compromised the analysis of this
`metric in a subtler way. Since subjects who discontinued for worsening heart failure are
`assigned the worst outcomes, whereas those who discontinued for adverse event are
`given their last observation carried forward, the attribution of a cause of
`discontinuation is intimately alters the imputed value that was used in the pivotal
`analysis.
`
`The implications of the much more frequent infusion pain can be considered by the
`following example. Consider two subjects, one treated with UT-15 and one treated with
`vehicle that had exactly the same disease course. Both subjects had early and
`persistent deterioration. The subject treated with UT-ls has some infusion site pain,
`perhaps even severe in nature. Neither subject was feeling particularly better with
`respect to their underlying pulmonary hypertension. In fact, these subjects may have
`been feeling worse. Only the UT-15 subject had the concomitant infusion-site pain and
`discontinued early. Both subjects eventually went on to die, receive transplant or
`deteriorate by the criteria of the study. However, only the vehicle subject was treated as
`the worst outcome. The UT-15 subject who died, deteriorated or was transplanted early
`was censored and the last observation carried forward. The last observation may have
`been distant to the time of discontinuation and might not have captured the entirety or
`even a substantial portion of the status of the subject at the time of the event. Although
`the study planned to perform exercise measurements on all subjects at l2—weeks, even
`among those who discontinued, in general, this measurement was not performed.
`Subjects did not have their status at the end of the study i.e. for 84 days with a window
`of 71- 100 days, with regards to deterioration, death or transplantation ascertained.
`
`If one accepts the possibility that those who ostensibly discontinued for infusion site
`pain also potentially had a component of worsening disease, then the six minute walk
`that uses a last observation carried forward analysis produces a more optimistic
`outcome particularly for the treatment group. The consequence of this asymmetry in
`adverse events is explored in conjunction with the reviewer’s analysis (see section xxxx).
`
`A.4.4.7 Efficacy
`
`A.4A.7.1 Walking distance
`
`Baseline measurements. The baseline walk-distance (per sponsor) for study 01:04 and
`01:05 are shown in Table 53. The distances are relatively consistent across studies. It
`should be appreciated that a reasonable walking distance for a healthy individual,
`assuming a 20-minute mile would be approximately 480 meters. Subjects with high
`baseline measurements, therefore, had modest upside potential. The analysis treated
`baseline—walking distance as a monotonic covariate and consequently did not correct for
`differences in exercise performance at the extremes of baseline measurements.
`
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`

`

`Study P01 :04-05
`
`NDA 21-272
`UT—l 5for pulmonary hypertension
`
`Table 53. Baseline walking distance (P01:04-05)
`
`
`
`
`
`
`— 901m
`
`
`
`
`_A-_“, ._
`
`
`_
`
`N125
`
`.
`
`
`
`4
`
`
`
`
`25-75 urcentile
`
`272-377
`
`264-390
`
`P-valem ,.
`
`
`272-377
`i
`1
`
`w
`
`270-396
`lww w w !
`
`272-397
`
`264—395
`
`
`
`Effect of UT-15 on six-minute walk. The sponsor performed a multitude of analyses
`of the six-minute walk data. There is a general consistency across all analyses. Neither
`of the two studies by themselves was statistically significant by most of these analyses.
`The p~value for the pooled studies as performed by the sponsor was, in general, less
`than p<0.01, but never so overwhelming as to be <0.00125. As such, even by the
`sponsor’s own rules or by the criteria usually proposed by this Division this study could
`not be considered as sufficient for drug approval.
`
`There were, moreover, ambiguities in the statistical plan as proposed by the sponsor,
`Dr. Lawrence, the FDA statistician reanalyzed the data by treating the data consistent
`with the protocol but different to that as performed by the sponsor.
`
`This reviewer performed an alternate set of analyses. The starting point of these
`analyses revolved around the asymmetry of the study design. The default algorithm for
`assigning a walk distance for subjects who discontinue without a l2.week walk is
`shown in Table l. 19. Those subjects who discontinued due to adverse events had their
`last observation imputed. Those who discontinued either due to death, transplantation
`or deterioration were treated as a worse outcome. For the non-parametric analysis
`those who discontinued due to death, deterioration or transplantation were assigned a
`worst rank, in the non-parametric analysis they were assigned a walking distance of
`zero feet.
`'
`-
`
`There are several consequences to the imbalance in discontinuations. First, those who
`discontinue due to adverse events could never receive a worst outcome whereas those
`
`who were in the vehicle group could potentially receive the worst outcome due to death,
`transplantation or deterioration. Second, it is unclear to what extent the attribution of
`a discontinuation would be preferentially assigned to infusion related problems as
`opposed to deterioration of status. Third, the imputed value could be so distant to the
`time of discontinuation that it inaccurately reflects the status at the time of
`discontinuation. The imputed value would be clearly inaccurate. Lastly, the
`asymmetric use of medications that may alter hemodynamics could also bias any
`interpretation of the results.
`
`Since there were many more subjects in the UT-lS group who were discontinued due to
`ADRs, these subjects could never receive the worst outcome. The analyses performed by
`this reviewer attempt, in a stepwise manner, to test the consequence of the asymmetry
`in discontinuations.
`
`The first analysis performed by this reviewer consists of imputing a worse value to those
`who died, were transplanted during the window of the study (till day 100). These
`outcomes are not subjective and corrections could easily be performed. The second
`analysis treated those deaths, transplantation as worst outcomes but also added those
`who were started on flolan within a month of discontinuing UT-15 and within the 100—
`day window of the study as worst outcomes. This analysis was based on the
`assumption was that those who were relatively rapidly started on flolan had some
`deterioration in status that transformed the optional need for flolan at baseline to the
`treatment of choice. A third analysis also treated as worst outcomes all those who were
`
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`

`Study P01 :04-05
`
`UT-1 5 for pulmonary hypertension
`
`NBA 21 -2 72
`
`started on flolan during the 100-day window of the study whether they were started
`within a month or after a month of stopping. Lastly, there was an occasional subject
`whose status was clearly worse than the LOCF value would imply. In general, the LOCF
`was at a time point distant to when the subject discontinued. It seemed counter—
`intuitive to impute a very favorable value where the course was clearly downhill. These
`subjects were censored without the positive walking distance imputed.
`
`By either Dr. Lawrence’s or this reviewer’s analyses, the p~value for the pooled studies
`exceeds p>0.01.
`
`Table 54. Imputation rules for subjects without s week 12 walk (”1:04-05)
`
`
`
`
`
`Death within l2-weeks;
`excluding accidents or death
`unrelated to disease or
`stud
`
`Clinical decompensation
`within 12 weeks; excluding
`accidents or death unrelated
`to disease or stud
`
`
`
`rank of zero
`
`Lowest standardized
`rank of zero
`
` asee pslu 77
`
`standardized
`rank of zero
`
`worst observed
`
`change
`
`standardized
`rank of zero
`
`Lowest
`standardized
`rank of zero
`
`Regression
`A- roach’
`
`Regression
`A - -roach'
`
`Regression
`A - oroach*
`
`Regression
`A- -roah* _
`
`Baseline plus
`worst observed
`
`change
`
`Baseline plus
`worst observed
`Chane
`Regression
`A - -roach‘
`
`Regression
`A . oroach‘
`
`Regression
`A . -roach*
`
`Regression
`. _- roach‘
`
`Transplantation
`
`Last standardized
`rank of zero
`
`0 Meters
`
`AE (survivor, week 12)
`
`Accidents or death unrelated Last standardized
`to disease or stud
`rank carried forward
`Last standardized
`rank carried forward
`Last standardized
`rank carried forward
`Last standardized
`
`Lost to Follow-up (survivor,
`Week 12
`Consent withdrawn
`sum» week 12
`
`raced forward .
`
`LOCF
`
`LOCF
`
`LOCF
`
`LOCF
`
`Sponsor’s analysis #1
`
`Database: Pooled studies P01:04 and P01:05.
`
`Type of Analysis: Non-parametric analysis of covariance (covariates included: baseline
`distance walked, center, etiology of pulmonary hypertension (primary versus secondary)
`and vasodilator use at baseline. Later added a covariate was use of steroids to treat
`
`primary pulmonary hypertension).
`
`Population: mITT.
`
`Subjects excluded: One subject with no post baseline measurement (UT-15, pt#
`10507), one subject who withdrew before receiving any dose (vehicle; pt # 07501) and
`three UT—15 subjects were excluded (#05010; #08008 and #66006) because of the
`absence of other subjects in their stratification cel