6.3 Chronic Pulmonary Injury (cont)
`Review of S stems/Illnesses Durin Follow-u in lNO-Ol/ -02
`The INO—Ol/ -02 trials also performed a review of systems at the follow-up visit. Note that while the use of
`home 02 occurred only in the I-NO groups, there was no detectable differences in the occurrence of other pulmonary
`disease. Fewer patients in the l-NO group were reported to have had severe URls.
`
`-
`
`'
`
`
`
`
`
`Table 6.3.6 Pulmonary review of systems for the infants seen in follow-up from the INO-Ul/ -02 trial'.
`Placebo
`l-NO 5 ppm
`l-NO 20 ppm
`l-NO 80 ppm
`Combined l-NO
`
`
`N=36
`N=36
`N=29
`N=31
`N=96
`0 (0%)
`8 (22.2%)
`1 (3.4%)
`5 (16.1%)
`14 (14.6%)
`Home Oxygen
`
`
`
`4.05.0
`111:0.0‘
`3.3113
`3.51.2.5
`Mean age when 02 was
`
`
`
`
`
`
`D/C’d (months) "
`
`
`
`
`
`
`
`5 (13.9%)
`2 (6.5%)
`12 (12.5%)
`7 (19.4%)
`Asthma
`
`
`
`
`
`
`
`4 (11.1%)
`7 (19.4%)
`2 (6.5%)
`13 (13.5%)
`Bronchiolitis
`
`
`
`
`
`
`
`4 (11.1%)
`2 (5.6%)
`2 (6.5%)
`9 (9.4%)
`Bronchitis
`
`
`
`
`
`
`
`
`_
`3 (3.3%)
`3 (8.3%)
`2 (6.5%)
`s (8.3%)
`Pneumonia
`
`
`
`
`
`
`
`
`11 (30.6%)
`Severe um
`a (22.2%)
`6 (19.4%)
`20 (20.8%)
`
`
`
`
`
`
`
`a. Data from NBA vol. 9.3, Tables H.
`b. For infants who received 0, at time of initial discharge.
`
`
`
`3 (10.3%)
`4 (13.8%)
`3 (10.3%)
`3 (10.3%)
`6 (20.7%)
`
`in conclusion, the data regarding the long-term pulmonary toxicity of l-NO is conflicted, and depends on the
`trial data used. In the [NO-01! -02 trial, more infants were taking pulmonary medications at time of follow-up, and
`used 02 after discharge. In the CINRGI trial, the trends for chronic lung injury instead favor l‘NO. NINOS appears to
`be neutral with. respect to the occurrence of chronic pulmonary injury. Whether this scatter is a result of the imprecise
`tools being used to identify pulmonary disease (medicines used, use of 02) or the result of differences in the trials
`(e.g., dose of I-NO, duration of administration, patient populations) simply cannot be determined with any certainty
`in these small datasets. in aggregate, the data do not allow us to conclude that there is either a salutary or adverse
`_ effect of I-NO on chronic pulmonary disease, but
`it also does not exclude the occurrence of either effect
`in
`susceptible (and undefined) populations. Additional information is necessary.
`
`APPEARS THlS WAY
`011 ORIGINAL
`
`NDA 20-845
`Primary Medical Review
`10.99
`'
`_—'—I
`
`7 1
`
`(
`
`

`

`6.4 Acute Neurological Injury
`ClNRGl
`
`The ClNRGl trial collected radiological information about the neurologic changes seen in a subset of the
`papulation. in that subset, a higher fraction 0f the H40 group had abnormal CT scans reported. No difference in the
`rate of abnormal neurologic examinations was detected.
`'
`Table 6.4.1 Discharge neurologic status in the ClNRGl triala.
`Abnormal Head U/S
`
`
`
`
`12/52 (23.1%)
`5/42 (1 1.9%)
`
`
`Abnormal Head CT
`3/34 (23.5)
`12/25 (48.0%)
`
`
`
`
`8/41 (19.5%)
`Abnormal Neurologic Exam
`7/48 (14.6%)
`
`
`
`
`19/89 (21.3%)
`Abnormal CT. U/S or Neurologic Exam
`17/9 (17.5%)
`
`
`a. Data from CINRGI study report, table 67. p Values per sponsor.
`
`NINOS
`
`No differences between treatment groupsin the incidence of seizures or other markers of acute neurologic
`changes were noted in the NINOS trial.
`
`Table 6.4.2 (from 6.0.1.13.1.2) Comparison of specific safety parameters during the NINOS trial'.
`Neurologic Adverse Events
`Placebo Group
`I—NO Group
`-
`(n=121)
`(n=ll4)
`Seizures requiring therapy
`20/122 (17%)
`13/114 (1 1%)
`mum)
`7/7'/(9%)
`
`21/108 (19%)
`16/111 (14%)
`
`
`10/21 (62%)
`9/16 (56%)
`
`
`3/21 (14%)
`0/16 (0%)
`
`8/21 (38%)
`7/16 (44%)
`
`
`3/82 (4%) '
`4/77 (5%)
`
`
`
`
`
`
`
`
`
`
`
`Interventricular hemorrhage (IVH)'
`
`IVH Grade 1
`
`IVH Grade 11
`
`“’11 Grade III-IV
`
`Periventricular leukomalacia
`
`
`
`
`.
`11510-011412
`the end of
`The table below summarizes the results of the specified safety parameters measured at
`hospitalization or 28 days inthe lNO—Ol/ ~02 trial. There were -no significant differences between control and l-NO
`'groups for any of the endpoints. Note that not all subjects have data for a given parameter.
`
`
`
`
`
`-
`4/1 1 (36%)
`
`14/45 (31%)
`
`l-NO
`Combined
`
`
`80 ppm
`I-NO
`7/37 (19%) W
`7/31 (23%)
`16/98 (16%)
`
`
`2/21 (10%)
`7/71 (10%)
`
`0/21 (0%)
`1/71 (2%)
`
`-
`
`
`
`Table 6.4.3 (from 6.0.3.1311) Neurologic disease in lNO-OI/ -02.‘
`Changes in safety endpoints
`Control
`l-NO
`l-NO
`5 ppm
`20 ppm
`5/40 (12%)
`10/35 (23%)
`7/41 (17%)
`Incidence of seizures
`3133670)
`6/29 (21%)
`5/35 (14%)
`Incidence ol'sensorineural hearing 1055
`
`
`3/27 (11%)
`3/23 (13%)
`4/28 (14%)
`Abnormality on cranial ultrasound'
`
`0/27 (0%)
`1/23 (4%)
`1/28 (4%)
`lntracranial hemorrhage or infarct
`
`detected by ultrasound‘
`.
`
`8/19 (42%)
`2/15 (13%)
`9/18 (50%)
`Abnormality on CT or
`
`MRI scan of head'I
`
`
`Interventricular hemorrhage
`2/18 (11%)
`0/15 (0%)
`0/45 (0%)-
`
`0123 (0%)
`0/11 (0%)
`Periventricular hemorrhage
`0/18 (0%)
`0/15 (0%)
`1/23 (5%)
`
`.1/11 (9%)
`2/45 (4%)
`
`
`
`
`
`
`lntracranial hemorrhage‘
`
`1/13 (6%)
`
`2/45 (4%)
`
`
`
`
`
`2/45 (4%)
`Periventricular Ieukomalacia
`0/15 (0%)
`1/23 (5%)
`1/11 (9%)
`0/18 (0%)
`
`
`
`
`
`
`1/45 (2%)
`Extensive cytotoxic edema
`0/15 (0%)
`0/23 (0%)
`1/11 (9%)(
`0/18 (0%)
`
`
`
`
`
`
`
`1/45 (2%
`Subdural hematonra
`0/18 (0%)
`0/15 (0%)
`1/23 (5%)
`0/11 (0%)
`
`a. The Sponsor identified the changes in merhemoglobin and NO; levels, along with overall adverse events, as the most important
`markers.
`b. Only those infants who had a normal cranial ultrasound at the start ofthe bird and an ultrasound at the end ofthe trial are included.
`c. Category includes one subject with suspected white matter hemorrhage, one grade one germinal matrix hemorrhage. and one infarct,
`detected by ultrasound. Only subjects with normal baseline ultrasound were included.
`d. Abnormalities detected at any time during the hospitalimtion. No baseline scans are available in most cases. making it difficult to
`date the onset of thelabnormality.
`'
`-
`e. Category includes parietal lobe. posterior fossa and frontal lobe hemorrhages.
`'
`
`I
`
`The [NOSG trial did not collect information about neurological injury.
`
`In conclusion. the data do not suggest an effect of l-NO on the incidence of neurologic injury during the
`initial hospitalization when l-NO was administered.
`
`NDA 20-845
`Primary Medical Review
`10.99
`'
`
`72
`
`'
`
`

`

`6.5 Chronic Neurological Injury
`it is essential to remember that the
`In this discussion, and in the discuSSion of chronic pulmonary injury,
`degree at” follow—up for each of the trials was <90% 'for almost all endpoint, and <50% for some endpoints of interest.
`This will be apparent by comparing the numbers in the denominators of the results with the number of patients
`enrolled in each of the trials. This obviously introduces potential biases (both positive and negative) in the
`interpretation of the results.
`
`CINRGI
`
`The ClNRGI trial collected 6- and 12-month data from a fraction of the population. Recall that there were 89
`infants in the control group and 97 in the l-NO group. The results are of limited interpretabilit'y.
`'
`
`Table 6.5.1 Six-month follow-up data from the CINRGI trial”.
`
`
`——me-
`Abnormal Neurologie Exam-.6 Month
`7/33 (18.4%)
`9/32 (28.1%)
`
`
`Abnormal Neurologic Exam- 12 Month
`0/24 (0%)
`3f20 (15.0%)
`a. Data from ClNRGl study report. table 38-39.
`
`NINOS
`
`NINOS enrolled 121 placebo patients and 114 I-NO patients. No significant differences were detected with
`regard to any chronic neurologic abnormalities in the NINOS trial. In data not shown here, assessments of mental
`development (Bayley’s), psychomotor development and audiology were similar in both treatment groups. A lowor
`incidence of seizures at follow-up was noted in the I-NO group.
`
`Table 6.5.2 Neurologic diagnoses for the subjects with long-term FM in the NINOS trial'.
`Control
`l—NO
`N=88
`N=85
`Normal
`69 (79.3%)
`66 (77.6%)
`Global hypotonia
`3 (3.4%)
`0 (0%)
`
`
`
`
`Monoplegia
`2 (2.3%)
`2 (2.4%)
`
`
`
`
`Diplegia
`'
`3. (3.4%)
`2 (2.4%)
`
`
`
`
`Hemiplegia-right side
`. 1 (1.1%)
`2 (2.4%)
`
`
`
`
`Quadraplegia
`s (5.7%)
`4'(4'.7%)
`
`
`
`
`Truncal hypotonia
`.
`. 401.6%)
`4 (4.7%)
`
`
`
`a. Data from NDA vol. 11.1, Table 52.
`
`_
`
`Table 6.5.3 Cerebral palsy and seizures in the subjects with long-term F/U inthe NINOS trial'.
`Control
`
`I-NO_-
`
`
`Cerebral palsy present
`Mild or Moderate Cerebral Palsy
`
`'
`Severe Cerebral Palsy
`
`
`"'3‘“ .--1'I“-
`,
`Seizures present €43”?!
`”3"”.
`
`
`a. Data from NDA vol. “.1, Table 53.
`
`9 (10.3%)
`401.6%)
`5 (5.7%)
`
`.
`
`
`10 (l 1.9%)
`5 (6.0%)
`
`5 (6.0%)
`
`“4f(4.'7%)“‘.'3‘ "
`
`
`
`
`
`IND-011412
`
`-
`
`The INO-Ol/ -02 trial collected data on the use ofanticonvulsants at the end of 1 year follow-up for the 41
`placebo and 104 l-NO patients. Few infants were using antieonvulsanm at the time of follow-up—-two individuals in
`the l-NO 20 ppm group.
`'
`
`
`
`
`Table 6.5.4 Post-discharge medications at the one-year follow—up visit in the INO-Ol/ —02 trial'.
`Placebo
`l-NO 5 ppm
`I—NO 20 ppm
`I-NO 80 ppm
`Combined l-NO
`N=36
`N=36
`N=29
`N=31
`N=96
`«0%)
`more)
`26.9%)
`atom
`mm)
`a. Data from NDA vol. 9.3, Tables 9.
`
`
`
`
`
`
`NDA 26-845
`Primary Medical Review
`10.99
`-
`
`73
`
`

`

`-
`
`.
`6.5 Chronic Neurological Injury (cont)
`Review of S stems/illnesses Durin Follow-u in INO-OI/ -02
`A review of systems performed at the follow-up visit found relatively few problems. The respiratory ROS is
`summarized separately. The occurrence of abnormalities in the neurologic Review of Systems is summarized below.
`Reports of strabismus were more common in the I-NO groups.
`
`
`
`
`l-NO 80 ppm
`
`
`N=3l
`
`
`
`
`
`Strahism"§..-L~;ef .1..‘«3:'.).l-..;.-;-:: gillféw“
`
`
`
`402.9%)
`,-;r1(1,t.5%)
`
`
`
`Hearing problems
`3 (8.3%)
`
`
`
`
`
`I (3.2%)
`9 (9.4%)
`
`
`6 (20.7%)
` s (13:99.)
`Speech problems
`4 (11.1%)
`
`
`
`
`
`4 (12.9%)
`15 (15.6%)
`a. Data from NDA vol. 93, Tables l0.
`
`,
`
`-
`
`Combined [-NO
`N=96
`
`The sponsor also collected data on the occurrence of seizures in the follow-up population. The only infants
`with seizures were in the 29 ppm and 80 ppm l-NO groups. There Were, however, no differences noted in the
`incidence of abnormal neurologic examinations at 1 year.
`'
`
`Table 6.5.6 Incidence of seizures and neurologic abnormalities at follow—up in the INO-Ol/ -02 trial'.
`
`
`_- "“5"”
`-
`N=96
`N=31
`N=29
`N=36
`
`:o (0%» 1- :s——m—
`403.8%)
`
`mafia-ima—
`Neurologic Abnormalities
`
`
`
`on Physical Exam
`
`
`
`
`
`
`
`74 (77.l%)
`None
`28 (77.8%)
`3| (86.1%)
`20 (69.0%)
`
`
`
`
`
`4 (4.2%)
`Mild
`3 (8.3%)
`l (2.8%)
`2 (6.9%)
`
`
`
`
`
`
`5 (17.2%)
`l3 (13.5%)
`3 (8.3%)
`Moderate
`4 (11.1%)
`
`
`
`
`5 (5.2%)
`Missing
`1 (2.8%)
`l (2.8%)
`2 (6.9%)
`
`
`
`
`a. Data from NDA vol. 9.3, Table 16.
`
`
`
`
`
`23 (74.2%)
`
`l (3.2%)
`
`
`5 (16.1%)
`
`2 (6.5%)
`
`
`N=36
`
`
`
`
`
`
`
`
`in data not shown here (see lNO—Ol/ -02 update elsewhere in this document), the incidence of
`Finally,
`abnormalities in mental development, psychomotor development and andiologywere assessed at follow-up. No
`worrisome patterns were evident in the data obtained from those patients with available follow-up.
`
`in conclusion, the data available do not reveal a clear pattern of long-term neurologic adverse outcomes
`following l-NO therapy. In data not shown here, assessments of mental development (Bayley’s), psychomotor
`development and audiology were similar in both treatment groups from the INO-Ol/ -02 and NINOS trial follow—up
`data (sections 4.1 and 4.2 of this review).
`.
`The increased incidence of seizures reported in the lNO-Dl/ -02 trial
`is countered by their decreased
`incidence in the l-NO group ofNFNOS. The increased frequency of strabismus was only assessed in the lNO-Ol/ -02,
`and is difficult to interpret with the small numbers of patients. There is a striking increase in strabismus relative to
`placebo in both the 20 and 80 ppm groups, however. raising the possibility of an adverse effect. Further data are
`needed to address the issue of strabismus following l-NO use.
`-
`
`NDA 20-845
`Primary Medical Review
`l0.99
`.
`
`
`74
`
`

`

`6.6 Laboratory Abnormalities
`a. increased Methemoa:lobin and N03 concentrations
`
`CINRGI
`
`CINRGI had a maximum dose of 20 ppm l-NO‘for the first 4 hours, after which time the infants were
`reduced to 5 ppm as tolerated.
`
`Elevated Methemoglobin levels
`- Two infants in the l-NO group had methemoglobinemia >4% during the treatment period (1.9% of the infants
`exposed to l-NO). No control
`infant had elevatedmethemoglobin. The l-NO group also had a higher mean -
`methemoglobin level during the treatment period on average, when compared with the control group (p = 0.001 per
`sponsor).
`'
`'
`
`Elevated N02 Levels
`No infant in Either treatment group developed NO; levels >5 ppm during the study. Likewise, there was no
`significant difference between the two treatment groups with regard to the changes in mean NO; levels during the
`treatment period (p=0.83).
`
`NlNOS
`NINOS used an in'ttial dose of 20 ppm l-NO. if the infant failed to respond with an increase in PaOz, the l-
`NO could be increased to 80 ppm.
`'
`e
`
`Elevated Methemoglobin levels
`A total of i 1 subjects (4 controls, 7 l-NO) had their study gas decreased because their methemoglobin levels
`Were >5%. All continued on study gas at lower flow rate. No subject was discontinued because of N02 >7 ppm or
`methemoglobin >10%.
`
`A Table 6.6.1 (from 6.0.l.l3.2b.l) Peak Metherno lobin levels from the NINOS trial.
`g
`
`
`Changes in safety endpoints'
`Combined l-NO
`
`
`Peak methemoglobin level during first 12 hours
`
`ofstudy gas
`
`Peak methemoglobin level at any time
`
`Peak methemoglobin level at any time
`
`0.0 - 1.0%
`1.1-2.0
`
`2.1—30
`
`3.1-5.0
`
`5.1 to 10
`
`Peak methemoglobin level at any time,
`excluding 8 subjects who received
`
`
`
`
`
`<0.00]
`
`
`
`
`2.4il.8%
`
`
`
`
`
`
`52“ l2 (46%)
`lSlll0(l4%)
`(0.001
`
`
`49/ll2 (44%)
`49fll0(45%)
`
`
`
`6/112 (5%)
`.23/ll0(21%)
`
`
`
`4/ll2(4%)
`lZ/llO(ll%)
`
`
`
`l/ll2(l%)
`Il/ll0(|0°/n)
`
`
`
`
`
`wrong study gas
`Elevated NO; Levels
`Only one individual had a N0; level >7.0 % during the trial ( subject _#A08 from center 55). The level was
`9.1, and the subject underwent a successful wean of study gas.
`
`' Table 6.6.2 (from 6.0.].13.2a.l) Peak NO; levels in ppm from the Nl'NOS trial.-
`
`Changes in safety endpoints m- Combined l-NO ‘
`
`
`
`Peal-t NO; level during first 12 hours
`0.11:0.3
`0.65:0.9
`‘
`
`
`ofstudy gas
`
`
`
`
`Peak N0, level at any time
`
`
` level at any time
`Peak N01
`
`
`
`
`
`
`98/ l0] (97%)
`0.0'— 1.0
`
`
`
`
`3/l01 (3%)
`1.1-3.0
`
`
`
`
`'0/101 (0%)
`3.1 -5;0
`
`
`
`
`0/10l (0%)
`5.1-7.0
`
`
`
`
`0/10l (0%)
`7.] to 10
`
`
`
`
`‘
`Peak N01 level at any time, excluding
`
`
`8 subjects who received wrong study gas
`
`
`
`0. Leo 3 m
`
`<0.00l
`
`
`
`
`<0.00[
`
`85/1 IO (77%)
`2l1110(l9%)
`'2/110 (2%)
`l/ll0(l%)
`l/ll0(l%)
`
`NDA 20-845
`Primary Medical Review
`l0.99
`.
`
`
`75
`
`'
`
`

`

`6.6 Laboratory Abnormalities (cont)
`lNO-Oll —02
`‘
`1NO-0i/ -02 randomized the treatment group to receive 5, 20 or 80 ppm 1-NO.
`
`Methemoelobin levels
`The avarage methemogIObin level was >l% at any time only in the 80 ppm l-NO group. After 12 hours of
`exposure to 80 ppm l-NO, the mean methemoglobin level peaked at 5.08:2.32%.
`The average time to after starting l-NO to the development of elevated methemoglobin was l0.4i9.5 hours
`overall, but only 3 subjects developed elevated .methemoglobin levels >10 hours after starting the l-NO. This is
`reflected in the median time to peak methemoglobin level, which was 8 hours. The l-NO was discontinued in four of
`the subjects and reduced and ultimately discontinued in the other 9 subjects.
`in the lNO-01/-02 trial, the average peak methemoglobin level was significantly higher in the 80 ppm l-NO
`group. After 12 hours of exposure to 80 ppm l-NO, the mean methemoglobin level peaked at 5.08:2.32%. '
`
`Table 6.6.3 (from 6.0.1.1321). 1) Peak methemoglobin levels from the INO-Ol/ -02 trial (not all subjects had
`data available).
`
`
`
`
`0.7t0.4_2
`
`0.89i0.88
`
`1.161069
`
`
`
`@-
`
`Combined
`I-NO
`2.57:2.8
`
`5.77t2.8
`Peak methemoglobin level
`at any time
`
`
`Peak methemoglobin level
`
`at any time .
`
`
`
`0.0 - 1.0%
`31/40 (78%)
`28/40 (70%)
`18/36 (50%)
`0/37 (0%)
`46/1 13 (41%)
`
`
`
`
`
`1.1 - 2.0
`9/40 (22%)
`11/40 (28%)
`17/36 (47%)
`2/37 (5%)
`30/1 13 (26%)
`
`
`
`
`
`2.1 - 30
`0/40 (0%)
`0/40 (0%)
`0/36 (0%)
`4/37 ( l 1%)
`4/ 1 l3 (4%)
`
`
`
`
`
`3.1 ~ 5.0
`0/40 (0%)
`0/40 (0%)
`1/36 (2%)
`9/37 (24%)
`10/1 l3 (9%)
`
`
`
`
`
`5.1 to 10
`0/36 (0%)
`18/37 (49%)
`0/40 (0%)
`1/40 (2%)
`19/113 (17%)
`
`
`
`
`
`0/40 (0%)
`0/40 (0%)
`2/37 (5%)
`0/36 (0%)
`>100
`2/113 (2%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Mean NO; levels in the 1N0-01/-02 trial.
`in the [NO-0H -02 trial, the average NO; level was >l% at any time only in the 80 ppm l-NO group. The
`large majority of subjects in‘the l-NO group had peak N02 concentrations >3.0 ppm. Note, however, that the peak
`N02 concentration for the 80 ppm group was significantly higher overall, and 7/9 subjects who had NO; levels >30
`at any time during the trial were in the 80 ppm group.
`
`Table 6.6.4 (from 6.0.3.13.2a.1) Peak NO; levels in ppm from the 1N0-01/-02 trial.
`
`
`
`Changes in safety endpoints —m I-NO 20 ppm
`l-NO 80 ppm
`
`
`
`Mean peak N01 level at any time
`0.59t0.8
`0.53i.73
`
`
`
`Peak NO2 level at any time (ppm)
`
`
`
`
`34/41 (83%)
`32/42 (76%)
`0.0 - 1.0
`0/37 (0%)
`
`
`
`
`6/41 (15%)
`8/42 (19%)
`1.] -3.0
`29/37 (78%)
`
`
`
`
`
`
`2/42 (5%)
`1/41 (1%)
`3.0- 5.0
`4/37 (11%)
`
`
`
`
`
`0/41 (0%)
`0/41 (0%)
`3/37 (8%)
`5.1 - 7.0
`.
`
`
`
`
`
`
`0 (0%)
`0/41 (0%)
`7.1 to 10
`0/41 (0%)
`
`
`
`
`
`
`30/35 (86%)
`4/35 (1 1%)
`1/35 (1%)
`0/35 (0%)
`0/35 (0%)
`
`_
`
`NDA 20-845
`Primary Medical Review
`-
`10.99
`
`76
`
`

`

`6.6 Laboratory Abnormalities (cont)
`IN OSG
`
`INOSG administered l-NO at a dose of 80 ppm.
`
`NO; levels
`No information on NO; levels was submitted as part of the NDA from the INOSG trial.
`
`Methemoglobin levels
`Peak methemoglobin levels averaged 3.8:t4.(l during the first twelve hours of therapy, and 5.3i5.8 at any
`time during the trial for the subjects in the l-NO group with available data.
`Three of the infants Who received l-NO had peak methemoglobin levels >5% during the trial.
`
`Table 6.6.5 (fiom 6.0.2.13.2b.l) Peak Methemogiobin levels from the INOSG trial.
`Changes in safety endpoints
`Combined l-NO
`
`Peal-t methemoglobin level during first 12 hours
`18:4,!) (n= ll)
`
`'
`of study gas
`Peak methemoglobin level at any time —m-
`
`
`Peak methemoglobin level at any time'
`
`
`
`
`2/1] (18%)
`0.0 - 1.0%
`NIA
`
`
`2/” (18%)
`1.1- 211
`N/A
`
`
`
`2/11 08%)
`2.1- 4.0
`N/A
`
`
`
`5/1] (45%)
`>4_0
`NIA
`3. Eleven of 16 subjects who received l-NO, and none of the control subjects, have data.
`
`NIA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-
`
`the incidence of both methemoglobinemia and elevated N02 concentrations is markedly
`In conclusion,
`increased in the 80 ppm groups of the lNO-Ol/ -02 trial and increased NO; was seen in the I-NO group of the [N080
`trial. ln‘distinction, in the three trials using 20 ppm, 15/243 (6.2%) infants on l-NO had a methemoglobin level >3.0%,
`the majority of them in the NINOS trial, following increase in I-NO from 20 to 80 ppm . The incidence of elevated
`N02 levels in the 20 ppm group was 30443 (0.1%) of the infants, much lower than the rate at 80 ppm I-NO. This
`result should be put in context with the efficacy data from the NINOS trial (see original NDA submission, vol. 2.14,
`page 92). Per the sponsor’s analysis, an individual who failed torespond to l-NO 20 ppm was also failed to respond to
`80 ppm. No data are available about the effect of doses between 20 and 80 ppm in the same population. These data
`argue for the use of no more than 20 ppm for two reasons: I) use of 80 ppm is associated with undesirable side-
`effects, and 2) infant who do not have improved oxygenation on 20 ppm are unlikely to respond to 80 ppm.
`
`APPEARS THlS WAY
`0N ORIGINAL
`
`NDA 20-845
`Primary Medical Review
`10.99
`-
`
`_
`
`7-,
`
`
`
`

`

`6.6 Laboratory Abnormalities (cont)
`b. Eosino hilia
`IN 0-0 1/ -02
`
`In the lNO-Ol/ -02 study, there was a trend towards a higher mean eosinOphil count in the subjects who
`received l-NO, especially the 80 ppm group
`
`Table 6.6.6 (from 82.3.2.5) Mean changes in eosinophil counts from [NO-01! ~02“.
`
`l-NO
`Placebo
`l-NO
`80 ppm
`20 ppm
`- —————mm
`1.1 11.3
`2.] $2.2
`1.0 11.3
`2.9 $3.2
`1.2 12.3
`2.9:k3.0
`1.2 :l:i.5
`Eosinophils
`
`
`'
`n=4|
`n=36
`n=41
`n=39
`n=36
`=32
`n=35
`(% WBCs)
`a. Source: NDA volume 2.50r pages 341010—3415“) and volume 2.25.
`_
`b. Per protocol, after values to be taken no more than 12 hours afler end of exposure to treatment gas.
`c. Data shown as meantstandard deviation (it of subjects with data).
`
`
`
`
`3.6:5J
`n=36
`
`This same data is presented as a graph below.
`
`Figure 8.2.3.2.6 Eosinophils in
`the INO-Ol/OZ Trial
`
`3.6
`
`0 Baseline Lab
`I Follow-Up Lab
`
`‘
`
`4
`
`
`
`_Placebo
`
`I-NO 5
`
`ppm
`
`l-NO_.
`
`l-NO
`
`20 ppm
`
`80 ppm
`
`Study Gas Administer
`
`There were also subjects who had a markedly abnormal number of eosinophils after exposure to l-NO,
`identified through examination of the individual laboratory records.
`
`Patient #
`
`Lab Test
`
`Baseline
`
`Placebo
`
`.
`
`l-NO 5 ppm
`01-10002
`01-11012 -
`[-NO 20 ppm
`
`Eosinophils
`Eosino-hils
`
`Table 6.6.7 (from 8.2.3.2.?)
`Individuals with markedly abnormal post-study gas eosinophil couns from
`wow -02 and r—oa trials“.
`
`Post-l-NO_---
`
`
`
`
`
`
`
`
`I-NO 80 ppm
`‘ 02-11007
`
`
`
`Discharged after ECMO, with seizures and
`Eosinophils
`chronic lung disease (CLD)
`'
`
`
`
`
`
`
`Discharged without ECMO. no seizures or CLD
`9
`01-05005
`Eosinophils
`Discharged without ECMO, no seizures or CLD
`ll
`02-15006
`Eosinophils
`
`
`a. Data from NDA, volume 225, individual patient listings and table 8.1.6.211“.
`b. Lab tests identified as markedly abnormal were >2): upper limits of normal.
`
`'
`
`.
`No discharge data available
`Died without ECMO of progressive hypoxia
`
`‘
`
`'
`
`14
`7
`
`22
`
`.
`
`
`
`
`
`
`NDA 20-845
`‘ Primary Medical Review
`10.99
`'
`
`'
`
`78
`
`

`

`6.6 Laboratory Abnormalities (cont)
`CINRGl
`
`In CINRGI no such trend was evident-There was a marked increase in the number of patients with
`--
`eosinophils >5% in both treatment groups, however, evident between days 0 and 2.
`
`Table 6.6.8 Number of patients with eosinophils >5%‘.
`
`
`
`
`2 (3%)
`6 (11%)
`Baseline
`
`13 (24%)
`13 (26%)
`
`
`33 (39%)
`20 (40%)
`
`
`
`19 (42%)
`15 (37%)
`
`
`
`23 (55%)
`23 (54%)
`a. Data from table A—IS, CINRGI study report.
`
`_’
`NINOS, INOSG
`These trials did not collects hematology data.
`
`In conclusion, the data do not suggest an effect of I-NO to increase eosinophil counts, although they do
`suggest that a process common to the infants in. both treatment arms that is associated with the development of
`eosinophilia.
`
`c. Abnormal LFTs
`A normal part of a safety review is an examination of the database for evidence of liver toxicity, as judged
`by increases in liver function tests. Labs were only collected in the CINRGI and INO-Ol/ -02 trials, limiting the
`available data.
`
`~ CINRGI
`
`The.CINRGI trial collected data on the incidence of marked elevations of bilirubin and SGPT as Well as the
`mean changes in both labs. In data not shown, the mean changes were similar between the treatment groups. For the
`incidence of marked elevations, the data, summarized below, do not suggest an increased incidence of elevations in
`the l-NO group. The number of patients with available data (shown for each data point), however, is quite limited.
`Note also the high percentage of patients with abnonnally-eleva—ted AST at baseline.
`
`Table 6.6.9 Elevations of Direct Bilirubin to >1 mg/dl'.
`
`
`
`
`
`
`Baseline
`1/12 (8.3%)
`l/l2 (8.3%)
`308 (10.7%)
`2138 (5.3%)
`
`
`
`481 02.9%)
`51'3"! (13.5%)
`
`
`
`9/30 (30%)
`W3! (22.6%)
`
`a. Data from Cl'NRGl study report, table A-ZS.
`
`Table 6.6.10 Elevations of AST to >70 U/l‘.
`
`
`
`
`
`_—
`
`
`18/39 (46.2%)
`27/50 (50.9%)
`Baseline
`
`“1'34 (32.4%)
`11r29 (37.9%)
`
`
`12/31 (as/7')
`mm. (37.0%)
`
`
`
`6/ l9 (31.6%)
`lszl (47.6%)
`
`a Data from CINRGI study report, table A-25.
`
`NDA 20-345
`Primary Medical Review
`I039
`.
`
`79
`
`

`

`6.6 Laboratory Abnormalities (cont)
`INO-Ol/ -02
`
`-
`
`' ~ The interpretation of l-NO effects on LFTs in the INO-Oll -02 study is complicated four things.
`I) the high incidence of abnormal LFTs at baseline. The table below shows the number of subjects with
`abnormal labs at baseline in the iNO-Ol/ -02 trial, including high percentages of both alkaline phosphatase and LDH
`abnormalities at baseline.
`-
`
`
`
`Table 6.6.1 1 (from 82.2.1.2) Number of subjects with normal baseline LFTs fi'om INO-Oll -02“.
`Laboratory
`Control
`l-NO 5 ppm
`l-NO 20 ppm
`l-NO 80 ppm
`
`
`n=37
`‘
`n=38
`n=45
`n=41
`
`
`
`
`Alkaline Phosphatase
`16/34 (47%)
`12/32 (38%)
`19129 (66%)
`19/29 (66%)
`
`
`2/28 (7%)
`2/29 (7%)
`5/31 (16%)
`LDH
`1/25 (4%)
`
`
`
`
`
`AST"
`8/33 (24%)
`6/28 (21%)
`7/32 (22%)
`5/29 (17%)
`
`
`
`
`
`
`
`
`Total Bilirubin
`19/34 (56%)
`22/39 (56%)
`
`19/32 (59%)
`
`16/32 (52%)
`a. Data from original NDA volume 2.18, Table T-Zl.
`b. 8001’ (serum glutamate pyruvate transfininase) = AST (aspanate nansaminase); SGPT (serum glutamie-oxaloaoetic
`transaminase) or ALT ( alanine transaminase); GGT (gamma-glutamyl transferase).
`-
`c. No data was collected during the [NO-0|! -02 and [-03 trials on GGT or SGPT levels.
`
`
`
`2) the absence of data on changes in ALT (serum glutamic-oxaloacetic transaminase) and GGT(gammaL
`glutamyl transferase).
`No data was collected during the CINRGI or INO-Ol/ -02 and MB trials on ALT or GGT levels. This limits
`the ability of this database to detect hepatocellular injury largely to detected changes in AST (in the context of altered
`alkaline phosphatase, LDH, and total bilirubin, which were collected).
`
`3) the lack of available follow-up for abnormal labs.
`As discussed above, two sets of labs were collected, and no follow-up labs are available for abnormalities
`identified on the second set.
`-
`d) the changing normal ranges for individual labs shortly after birth.
`The normal values for some labs (total bilirubin in particular) change from day to day in the early neonatal
`period. Labs were deemed normal or abnormal depending on the limits associated with each individual lab sample
`and subject.
`
`Overall, the mean LFTs tended to fall from baseline to post-1N0”. In all groups except I-NO 20 ppm,
`alkaline phosphatase fell significantly. Mean values for LDH and AST also fell, but the differences were not
`significant.
`
`Table 6.6.12 (from 8.2.2.2.3) Mean LFT values from [NO-Oil -02_"b".
`
`
`Placebo
`l-NO 5 ppm
`I-NO 20 ppm
`
`Baseline
`Baseline
`Baseline
`_
`Post-l-NO
`Alkaline
`
`302.8i313
`1641206
`465581
`353552
`Phosphatase
`n=~40
`n=34 ,
`n=36
`
`
`1617 '
`1069
`3060
`£1519
`$1275
`16615
`
`
`-
`
`Post-I-NO
`1 75:1:285
`n=34
`1134 i937
`n=33
`
`1479
`$1096
`
`n=36 - n=32
`
`121 $89
`
`64:1:53
`
`312 i760
`
`
`
`l-NO 80 ppm
`
`Baseline
`Post-I-NO
`Post~l-NO
`155i217
`366514
`141192
`
`n=30
`' n-34
`1218
`1976
`$1783
`:l:2l60
`
`
`-
`
`n=29
`
`81:1:86
`
`n=34
`
`258 $584
`
`1338
`$1271
`
`n=31
`
`' 78 £61
`
`6.8 $6.3
`
`'
`
`4.6 13.2
`
`n=38
`
`109:10]
`
`‘
`
`n=32
`
`69 $72
`
`.‘
`
`
`
`4.8 13.1
`
`5.0 14.8
`
`4.2 $2.7
`
`5.3 $4.9
`
`5.0 $3.6
`
`Total
`
`5.1 $3.4
`Bilirubin
`
`
`
`
`
`a. Source: NDA volume 2.50. pages 3410104141510 and volume 225.
`1). Per protocol. follow-up labs were to be taken no more than 12 hours after end of exposure to treatment gas.
`c. Data Show as memmndud deviation (ii of subjects with data). Shaded boxes indicate that baseline and post-study gas labs differ,
`significantly using 2-sided unpaired t test.
`'
`
`1n the database from INO-Ol/ {NO-02 and -03, newly-abnormal AS’I‘ occurred in 1 control subject (2%) and
`in 3 I-NO subjects (2%). AST values which became more abnormal, includingthose who started with abnormal
`baselines, occurred in 5% of control subjects and 11% of l-NO subjects. The table below shows the number of
`subjects in each l-NO group. The numbers are too small to infer a relationship between l-NO dose and AST
`abnormalities.
`
`
`
`NDA ill-845'
`Primary Medical Review
`10.99
`
`80
`
`

`

`6.6 Laboratory Abnormalities (cont)
`
`Table 6.6.13 (from 8.2.22.4) Abnormal LFTS from lNO-Ol/ -02 and [NO-03‘.
`Control
`l-NO 5 ppm
`l-NO 20 ppm
`I-NO 80 ppm ‘
`
`n=45
`
`n=41
`
`n=37
`
`' '
`
`
`— n=38
`
`Elevated Total Bilirubin
`
`1~N0 combined
`
`n=123
`
`
`
`1 (3%)
`3 (8%)
`
`4 (9%)
`4 (9%)
`
`'
`
`1 (2%)
`5 (12%)
`
`'
`
`
`
`
`
`5 (5%)
`l (3%)
`New abnormalities'
`
`12 (10%)
`3 (8%)
`Values >12
`Elevated AST
`
`
`
`
`
`l (3%)
`
`
`0 (0%)
`2 (5%)
`1 (2%)
`New abnormalities'
`
`3 (2%)
`2 (5%)
`
`6 16%)
`6 (13%)
`New or worsening
`2 (5%)
`
`
`
`”(11%)
`
`
`abnormalities "
`
`Elevated Alkaline
`
`PhoSphatase
`
`
`
`New abnormalities'
`l (2%)
`
`o (0%)
`
`0 (0%)
`
`
`
`
`I (<1%)
`New or worsening
`2 (4%),
`o (0%)
`2 (2%)
`o (0%)
`
`
`
`
`
`
`
`
`abnormalities b
`
`
`a. These subjects had a normal value at baseline and an abnormal value within 12 hours of discontinuation of l-NO.
`b. These subjects include all of those in the 'new abnorrnalities' category. as well as any subject who had an abnormal value at baseline
`which was more abnormal on the follow-up lab.
`.c. Data was obtained from NDA volume 2.31, Data Listing 13.1; volume 225, Appendix 16.22.12; and volume 2.18, Table T-30, and
`electronic datasets.
`-
`‘
`
`0 (0%)
`0 (0%)
`
`Another source of data on the effects of I-NO on LFTs is the individual subject lab data. The subjects who
`experienced a markedly abnormal AST from the individual labs was identified (from Table 8.1.6.2.2.la.1). While no
`control subject was identified, 4 I-NO subjects (3%) were identified. No follow-up labs are available for the subjects
`listed.
`'
`
`' 03*".
`
`.. Table 6.6.14 (from 82.2.2.5) Individuals with markedly abnormal AST post—l-NO from lNO-Ol/ -02 and /-
`
`
`
`“EE—
`—
`
`
`
`
`
`Post-I-Nmarue
`
`
`
`_——_
`l-NO 5 ppm
`----_
`
`02-11008
`
`
`
`SGOT
`
`‘
`
`78
`
`145-“
`
`Discharged without ECMO
`
`I—NO 20 ppm
`01—03025
`01£3008
`
`
`
`
`
`I-NO 80 ppm
`01-02003
`
`SGOT
`SGOT
`
`_
`SGOT
`
`109
`181
`
`358
`264
`
`120
`
`Died
`Discharged without ECMO
`with seizures
`
`Discharged without ECMO
`data missing
`
`
`
`a. Data from NDA, volume 225, individual patient listings, and from electronic datasets.
`b. Lab tests were identified as markedly abnormal Were >2X upper limits of normal on post-l-NO value. Normal values were taken
`from individual lab ranges associated with each specimen.
`c. CLD: chronic lung disease.
`
`A-“
`
`_
`
`NDA 20-845
`Primary Medical Review
`10.99
`
`
`0
`
`‘
`
`. 81
`
`

`

`fi_‘_ - __...__ _.._..-
`
`-
`
`-—---—-----—--——~-----—-—----—-———..—.-.______
`
`6.6 Laboratory Abnormalities (cont)
`Individuals in all treatment groups also had marked elevations in their LDH and/or bilirubin. No markedly
`abnormal alkaline phosphatase values were identified."
`-
`
`Placebo
`
`'
`
`
`
`
`
`
`
`
`
`
`
`
`n-
`LDH
`
`LDH
`
`LDH
`
`LDH
`
`
`Bilirubin
`
`
`l-NO 20 ppm
`01-17006
`LDH
`
`
`01-07003
`Bilirubin
`
`01-07005
`Bilirubin
`
`
`
`01-09003
`Bilirubin
`
`
`
`01-14001
`Bilirubin
`
`
`
`03-52001
`Bilimbin
`
`
`
`
`l-NO 80 ppm
`
`
`01-03003
`LDH
`
`
`LDH
`01-06003
`
`
`
`01-11004
`LDH
`
`
`
`02-04004
`LDH
`
`
`
`01-02003
`LDH
`
`
`
`02-11007
`LDH
`
`
`
`03-59003
`LDH
`
`
`
`01-05003
`Bilirubin
`
`
`
`01-03005
`Bilirubin
`
`
`
`02-1300]
`‘Bilirubin
`.
`
`
`a. Data from NDA, volume 2.25. individual patient listings. and electronic datasets.
`b. Lab tests were identified as markedly abnormal were >2X upper limits of normal on post-l-NO value.
`
`Individuals with markedly abnormal LDH and total bilirubin post-l-NO
`Table 6.6.15 (from 8.2.22.6)
`chemistry labs from [NO-011’ -02 and 1-03 trials“.
`
`
`
`
`
`01-03013
`01-04001
`02-14004
`01-14002
`01-07007
`
`LDH '
`LDH
`Bilirubin
`Bilirubin
`Bilirubin
`
`
`
`
`
`
`
`
`l-NO 5 ppm
`
`01-03002
`01—06002
`02-14001
`'02-15001
`01-01004
`
`
`
`
`
`
`
`.
`
`Conclusion
`~
`Given the iarge fraction of infants with abnormal elevations-in one or more of these at baseline, and the
`small number of infant with available data, we are limited in our power to detect such an effect of i-NO. Overall,
`however, no clear association betwoen l-NO administration and abnormalities in AST, All: Phos, and Total Bilirubin
`were detected. No chronic damage, and no deaths due to hepatic failure were identified in the database.
`
`6.7 Other Laboratory Measurements
`The other laboratory measuremean performed in the [NO-011' -02 trial are reviewed in the previous
`document dated 11.19.97. A review of the laboratories measured in the CINRG] trial reveal that, with the exception
`of the labs discussed above, no relevant differences between the two treatment groups is suggested by the data.
`
`NDA 20-845
`Primary Medical Review
`10.99
`"
`
`
`32
`
`'
`
`

`

`6.8.Miscellaneous Adverse Events
`In this section adverse events that are normally evaluated as part of an NDA review are summarized.
`
`.
`_
`GI Bleeding
`The incidence of GI bleeds through the time of discharge was collected in the NINOS trials.
`
`Table 6.8.1 (from 6.0.1.1312) Comparison of specific safety parameters during the NfNOS trial'.
`Characteristic
`Placebo Group
`I-NO Group
`p value'
`
`
`(n=121)
`(n=114)
`
`
`
` ———urs-
`
`_
`V
`.
`-
`-
`.
`'
`lntracranial Bleeding
`The incidence of intracranial bleeding was examined in the NINOS, [NO-0U -02 and CINRGI trials, and the
`results are summarized in the Acute Neurologic lnjury Section above (section 6.4). Overall, no difference in the rate
`of these bleeds, both detected clinically and those detected through radiological procedures (U/S, CT scans) was
`detected between the control and l-NO groups in any of the trials.
`Allergic Reactions
`Part