N'DA 20-845 Nitric Oxide
`
`604.13.] Comparison of defined safety parameters up to 28 days (cont)
`No individual has NO; levels >5.0 ppm. Subject 03-59003 had levels >3.0 on several occasions during I-NO
`therapy, with a peak of 3.3 after 11.6 hours. The infant was discharged with both reactive airways disease and broncho-
`pulmonary dysplasia.
`
`.
`2. Incidence of intraventricular hemorrhage and seizures
`lnverventn'cular hemorrhage was detected in 12% of the infants (1/8 with available data).
`Seizures occurred in 3/14 (21%) of the infants.
`The relationship of these adverse events to the administration of l-NO is difficult to establish with these small
`numbers. The overall NDA database includes these subjects, and will address this issue in sections 8.1 and 8.2 below.
`
`-
`3. Laboratory evaluations
`These will be included in the analysis of lab values in section 8.1.-
`
`4. Incidence and relationship of all adverse events and specific adverse events to I-NO
`These will be included in the analysis of lab values in section 8.1.
`Of the other adverse events noted by the investigators, the following adverse events which occurred will be noted
`here, and included in section 8.3 as well.
`..
`-
`1. Asthma
`
`-
`
`Asthma was identified in the INC-03 trial. Subject 03-59001 received l-NO 5 ppm for 73 hours, and developed
`asthma 1 week after starting l-NO. The infant did not receive ECMO, HFOV, or HFJV, but required supplemental O; at
`the time ofdischarge as well as bronchodilator therapy. Long-term follow-up is not available.
`
`2. Air leak syndrome/pneumothoraces
`28% (4/14) of the subjects in the INC-03 trial had experienced a pneumothorax at the end of 28 days.
`.~
`Table 6.0.4.13.l.l Listing of uneumothoraces in the IND-03 trial'.
`
`Subject group
`Duration of
`Notes
`l-NO thera .
`
`l-NO 5 ppm
`03-57003
`03-59004
`
`120 hours
`32 hours
`
`No ECMO, HFOWHFJV
`No ECMO, HFOWHFJV
`No ECMO, HFOWHFJV
`
`'
`
`I-NO 20 ppm
`03-58001
`03-59002
`'
`a. Data from NDA volumes 2.30 and 2.31.
`
`16 hours
`168 hours
`
`ECMO
`No ECMO, HFOV/l-IFJV
`Required 02 at 28 days, BPD
`
`-
`3. PPHN Sequelae
`The percentage of each group which had one of the PPHN sequelae is listed below.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`117
`
`
`
`

`

`6.0.4.13.1 Comparison of defined safety parameters up 10.23 days (cont)
`
`Details of these adverse events will be included in section 8.1 and 8.2.
`
`N'DA 20-845 Nitric Oxide
`
`Table 6.0.4.13.1.2 Comparison of the rates of specific safety parameters from IND-03.' Note that not all subjects
`have data for a -iven .arameter.
`
`
`
`
`_
`
`'
`
`Chan_es in safe
`
`end-oints m [-140 20 - m MW 80 um
`
`Incidence of methemoglobinemia >5%
`Incidence of elevated NO: level (>5 ppm)‘
`
`0/4 (0%)
`0/4 (0%)
`
`Combined l-NO
`
`
`
`
`0/8 (0%)
`1/14 (7%)
`1/2 (50%)
`
`
`
`
`
`
`0/8 (0%)
`0/2 (0%)
`0/14 (0%)
`
`
`
`
`
`
`3/14 (21%)
`0/2 (0%0
`3/7 (43%)
`0/4 (0%)
`
`
`
`
`
`
`4/14 (28%)
`0/2 (0%)
`2/8 (25%)
`2/4 (50%)
`
`
`
`
`
`
`2/14 (14%)
`1/2 (50%)
`1/7 (14%)
`0/4 (0%)
`
`
`
`
`
`
`0/4 (0%)
`1/7 (14%)
`1/2 (50%)
`2/14_(14%)
`
`
`
`
`
`
`2/14 (14%)
`0/4 (0%)
`1/7 (14%)
`1/2 (50%)
`
`
`
`
`
`
`
`
`
`1/2 (50%2/8 (25%) ' 3/14 (21%)
`
`
`
`
`lntracranial abnormalities detected by
`
`
`ultrasound. CT or MRI scan
`
`
`
`
`
`
`Abnormality on cranial ultrasound”
`0/3 (0%)
`1/4 (25%)
`0/1 (0%)
`l/8(12%)
`
`
`
`0/3 (0%)
`1/4 (25%)
`0/1 (0%)
`1/8(l2%)
`lnterventricular hemorrhage
`
`
`
`
`
`
`0/3 (0%)
`1/4 (25%)
`0/1 (0%)
`1/8(12%)
`lntracranial infarct detected
`
`
`
`
`
`by CAT scan or MRI
`
`
`
`a. Occupational health guidelines have set an eight hour maximum exposure limit at 5 ppm for nitrogen dioxide (NO;)(76).
`b. Only those infants who had a normal cranial ultrasound at the start of the trial and an ultrasound at the end of the trial are included.
`c. Air
`leak syndrome
`includes
`the occurrence of any one of
`the
`following:
`interstitial
`emphysema;
`pneumomediastinum;
`pneumopericardium; and pneumothorax. in this trial, the only abnormality noted was pneumothorax.
`d. Bronchopulmonary dysplasia defined as: use of supplemental 0; at28 days of life in the presence of an abnormal CXR; or the use of
`bronchodilators suggesting severe reactive airway disease on discharge.
`e. Senson'neural hearing loss was detected using brain stem auditory evoked responses (BAER).
`
`Incidence of seizures
`incidence of air leak syndrome‘
`Incidence of bronchopulmonary dysplasia‘1
`Subjects requiring O; at 28 days
`Subjects with reactive airways disease
`at 28 days
`Incidence of sensorineural hearing 1055'
`
`0/5 (0%)
`
`-
`
`-
`
`‘
`
`
`
`4. Subject deaths: no subject deaths occurred in the IND-03 trial
`
`6.0.4.14 IND-03 Efficacy summary
`The primary intent of the IND-03 study was to collect further safety data. This, coupled with the absence of a
`control group, and the smallnumber of subjects entered into the trial, limit the information regarding efficacy in this trial.
`Fifiy-seven%of the subjects in the {NO-03 trial met one of the four primary PPHN endpoints. This compares
`with 56% of the control subjects, and 50% of the l-NO group in the INO-Ol/ -02 trial.
`None of the infants in the IND-03 trial died, compared with 2% of the control group in the INO-Ol/ -02 trial, and
`8% of the I—NO group in the INO-Ol/ -02 trial.
`Twenty-one % of the subjects in the IND-03 trial received ECMO, compared with 39% of the control subjects in
`the INO-Ol/ -02 trial, and 29% of the 1-140 group in the INO-Ol/ -02 trial.
`
`Overall, the infants in the IND-03 trial had similar incidence rates for the primary endpoints to those seen in the
`[NO-Oil ~02 trial.
`
`6.0.4.15 IND-03 Safety summary
`No deaths, and no unanticipated adverse events Were identified in this small study.
`The safety data from this study (summarized in Table 6.0.4-1312) will be incorporated into the overall safety
`database in sections 8.1 and 8.2 below.
`'
`
`-
`6.0.4.16 [NO-03 Reviewer’s Summary
`1. While eflicacy was not specifically part of the proposal for this trial, the subjects were transferred to ECMO at
`rates similar to those of the subjects in the larger trials.
`'
`2. No adverse events were seen which did not also occur in the other,
`larger, trials. The small numbers d'
`subjects preclude the use of statistics to analyze the safety data, but the safety information agreed in large part with the
`other trials. The rates of occurrence for specific adverse events were tabulated, and will be incorporated into the larger,
`overall Safety Review in sections 8.1 and 8.2.
`
`118
`
`

`

`.
`7.0 Integrated Review of Efficacy
`There are three aspects of the determination of eflioecy for l-NO: meeting pre-specified primary endpoints;
`demonstrating physiological effect; and demonstrating clinical benefit. The latter two aspects of efimcy were included in
`the-secondary and exploratory endpoints of the three trials. A summary of the primary and SEN-:9” endpoints of the
`NINOS, INOSG and INO-Ol/ “-02 trials is below.
`'
`
`7.0.] Primary and secondary efficacy endpoints from the NINOS, INOSG, and INO-OI/ -02 trials
`
`NDA 20-8J5 Nitric Oxide
`
`Primary efficacy endpoints
`WW
`1. Death before discharge or 120 days (whichever comes first), and/or the initiation of ECMO.
`
`!.
`.
`IIZEE
`-
`1. Number of acute oxygenation 'successes' following 20 minutes of treatment gas.
`
`'
`
`‘
`in." [big-oil -0; pn'mam endpoint
`l. The occurrence of one or more of the PPHN major sequelae prior to discharge:
`a.. Death.
`b. Initiation of ECMO.
`
`c. Evidence of abnormal neurological sequelae.
`d. Bronchopulmonary dysplasia.
`
`Secondary efficacy endpoints
`Wanton
`1. Change in PaO; levels measured 30 minutes after initial administration of the study gas.
`2. Change in mean 01 levels measured 30 minutes after initial administration of the study gas.
`3. Change in Aa-DO; levels before and 30 minutes after initial administration of the study gas.
`4. Neurodevelopmental outcomes assessed at 18-24 months corrected age (data not yet submitted).
`5. The average length of hospitalization among surviving infants.
`, 6. The number of days of assisted ventilation.
`7. The incidence of air leak.
`
`8. The incidence of chronic lung disease.
`9. The proportion of infants transferred for potential ECMO.
`
`WW
`1. The number of subject deaths within 120 days and/or receipt of ECMO
`2. Percentage of subjects receiving oxygen therapy at 28 days.
`3. Percentage of subjects surviving.
`
`l
`
`-
`
`-
`
`I —
`
`a
`
`l. Physiologic response to I-NO, measured by change in OI and time-Weighted OI.
`2. Number of days requiring supplemental oxygen.
`.
`3. Number of days requiring mechanical ventilation.
`4. Number of days in hospital (defined as to end of medically indicated hOSpitalization, not related to social
`
`issues).
`
`.W_I'
`I[‘-']|] I
`.I-OI-
`-
`lll
`
`1.1ncidence of hearing abnormalities.
`2. Incidence of developmental delay.
`
`Ilc.
`
`-
`
`-
`
`l -
`
`e
`
`i. Postductal P301.
`2. Preductal 02 saturation.
`. Postductal O; saturation.
`. Mean ‘Arterial Pressure.
`
`oeucnm-txw
`
`. Positive Inspiratory Pressure.
`. Positive End-Expiratory Pressure (PEEP).
`. Arterial-alveolar 0; ratio.
`. Arterial-alveolar 02 gradient.
`
`'ll9
`
`
`
`

`

`7.0.1 Success of trials in meeting pro-specified primary Endpoints
`Two of the three trials submitted in support of efficacy met their pre—specified primary endpoint: the NINOS and
`-1NOSG trials. Of these, only the NINOS trial endpoint was previously held to be of sufficient clinical benefit to support
`approval of I-NO. The INOSG endpoint, acute improvement in oxygenation, was felt by the C... Jiovascular and Renal
`Drugs Advisory Committee to be an inadequate endpoint to demonstrate clinical efficacy (see section 2.3).
`
`d The table below summarizes the rates ofthe pre-Specified, primary endpoins from the three efficacy trials in NDA
`20845 .
`
`NDA 20445 Nitric Oxide
`
`
`
`Table 7.0.1.] Prima
`Study Endpoint
`
`NINOS: death before 120 days
`andior initiation of ECMO
`
`
`
`
`end-oints from the NINOS, INOSG, and TNO-Ol/ -02 trials.
`
`Control
`I-NO
`I-NO
`p value
`
`80 . m
`Pooled
`
`57/119 (47.9%)
`
`
`
`2/28 (7%)
`INOSG: acute oxygenation success
`
`
`16/30 (53%)
`
`
`23/41 (56%)
`INo-or/ -02.- PPHN major sequelae‘
`13/33 (39%)
`52/104 (50%)
`
`
`
`
`
`a. p value calculated from the subjects who actually received study gas, grouped according to the study gas actually received, using
`unadjusted chi-square.
`b. p value calculated using unadjusted chi-square.
`.
`c. PPHN major sequelae: death; initiation of ECMO; bronchopulmonary dysplasia; neurologic abnormalities. p value calculated using
`unadjusted chi-square.
`d. Data from individual study reports, sections 6.0.], 6.0.2, and 6.0.3.
`
`
`
`'
`70/111 (63%)
`
`.
`
`.
`
`-
`
`.
`
`18/36 (50%)
`
`"
`21/35 (60%)
`
`7.0.2 Analysis of the NINOS primary endpoint in the INOSG and [NO-Oil -02 trials
`Another way of analyzing the data is to ask whether the significant effect of I-NO as regards the NINOS primary
`endpoint wasfseen in any of the other trials. The table below summarizes that information.
`
`Table 7.0.2.1 Post-hoe analysis of the NINOS primary endpoint (death before 120 days and/or initiation of ECMO)
`from the times. INOSG and INO-Ol/ -02 databases”.
`
`Study
`Control
`l-NO
`p value
`51m
`
`l-NO
`80mm
`
`I-NO
`20mm
`
`I-NO
`Pooled
`
`52/114 (45.6%)
`0.006'
`77/121 (63.6%
`NINOS‘
`
`56/118 (47.4%)
`0.022c
`71/112 (63%)
`NINOS“
`
`
`
`
`
`0.0182'
`13/30 (43%)
`21/28 (75%)
`INOSG
`
`
`
`
`
`
`33/113 (29%)
`0.25‘
`11/40 (28%) 14/36 (39%) 3/37 (22%)
`16/41 (39%)
`use-on -02
`
`
`
`
`
`
`a, p value calculated using unadjusted chi-square.
`b. Data from individual study reports, sections 6.0.1, 6.0.2 an 6.0.3.
`1:. Analysis based on intent to treat (l'l'l') population.
`d. Analysis based on 'gas received' population. p value calculated using Cochran-Mantel-Haenszel adjusted chi-square test.
`a. p value calculated using one-way ANOVA.
`
`.
`
`
`
`'
`
`As can be seen from the table above, while there was a significant diflerence in the NINOS and INOSG trials in
`this endpoint, no significant difference in the IND-01! -02 trial was seen. There was a reduction in the % of subjects who
`met the primary endpoint in two of the three I-NO groups in the INO-O 1/ -02 trial, however. The table below expresses the
`reductions in the rate of the primary endpoint in the three trials, using the ITT population in the NINOS.
`
`Table 7.0.2.2 Percent of subjects who met the NINOS primary endpoint (death before 120 days andlor initiation of
`ECMO) in the NINOS, INOSG. and IND-0U -02 trials'.
`I-NO
`Study
`.
`Control
`I—NO
`20mm
`.
`Sum
`
`NINOS
`
`
`
`
`43% (-43%)
`INOSG
`
`
`
`
`
`22% (-44%)
`IND-01! —oz
`39% (0%) 29% (-26%)
`
` 28% (-28%)
`
`
`a. Percent reduction calculated as control minus l-NO/control X100.
`
`
`
`l-NO
`80mm
`
`l-NO
`Pooled
`45.6% (48%)
`
`
`
`
`
`
`The initiation of ECMO can also be compared across the three trials, in a search for demonstration of efiicacy. The
`first table below shows the absolute rates, while the following table shows the % reductions floor the control late for each
`of the trials. Note the lower rate of use of ECMO in the INO-Ol/ -02 trial in the control group (34%), when compared with
`either NINOS (55%) or INOSG (71%).
`
`120
`
`

`

`7.0.2 Analysis or the NINOS primary endpoint in the INOSG and 'IN'o-011-02 trials (cont)
`
`
`
`Table 7.0.2.3 Rate of the initiation of ECMO in the NINOS. INOSG. and INO-OI/ -02 trials".
`
`NBA 20-545 Nitric Oxide
`
`
`
`NINOS'
`NINOSc
`INOSG
`[NO-011’ -02
`
`66/121 (54.5)
`62/112 (55%)
`20/28 (71%)
`14/41 (34%)
`
`.
`
`44/114 (38.5%)
`48/118 (41%)
`
`10/41 (24%)
`
`9/36 (25%)
`
`25/114 (22%)
`6/37 (16%)
`
`a. Based on 1T1" pepulation, p value calculated using unadjusted chi-square.
`b. Data from individual study reports, sections 6.0.1, 6.0.2 and 6.0.3.
`e. Based on 'gas rcccived' population. p value calculated using Cochran-Mantel-Haenszel adjusted chi-square test.
`
`Table 7.0.2.4 Percent reduction in the rate of the initiation of ECMO in the NINOS. INOSG. and TNO-‘Ol/ -02 trials'.
`Study
`Control
`l-NO
`room:
`41% (-25°/a)
`
`-'
`
`40% (44% )
`16% (-53%)
`
`22% (-35%)
`
`I-NOm- to...“
`
`
`
`
`
`NINOS
`INOSG
`IND-.0]! -02
`
`
`
` 24% (-29%) 25% (26%)
`
`a. Percent reduction calculated as control minus l-NO/control X100.
`
`The other component of the NINOS primary endpoint, the mortality rate, is discussed in section 8.1.1. There
`was, however, no detected difference between the control and I-NO groups overall with regards to the mortality rate. The
`two overall rates calculated below yield a relative risk of 1.098 with 95% confidence interval fiom 0.78 to 1.54 using the
`method of Kai: and Fisher‘s Exact Chi-square test.
`
`from table 8.1.1.1 Incidence of death in the NINOS. INOSG. INO-Ol/ -02 and INC-03 studies”.
`Table 7.0.2.5
`me-
`
`
`NINOS (0-120 days)
`201121 (16.5%)
`161114 (14%)
`NINOS (0120 days)”
`171112 (15.1%)
`17/118 (14.4%)
`mosc (0-445 days)
`3128 (10.7%)
`2130 (6.7%)
`1NO-011-02 (0-28 day)
`1141 (2.4%)
`91113 (8%)
`1N0-011-02 (0-1 yr)
`2141 (4.9%)
`101113 (8.8%)
`1N0-03 [0-28 days)
`No control groa'p
`0114 (0%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Total”
`
`Total"
`
`
`
`
`
`
`
`
`
`241190 (12.6%)
`221181 (12.1%)
`
`271271 (9.9%)
`291275 (10.5%)
`
`
`
`
`
`
`
`
`
`
`
`a. The comparability of the incidence rates between the trials is limited by the varying length of follow-up for each trial.
`13. Data from individual study reports and electronic datasets.
`c. Grouped from the NlNOS subjects who actually received study gas, according to the gas actually received, using unadjusted chi—square.
`(1. Based on NINOS ITI' population, 13 value calculated using unadjusted chi-square.
`c. This overall incidence figure includes the 1T1“ NINOS population, the [N050 trial, the INC-01! -02 0-28 day population, and the [NO-
`03 trial population.
`1'. This overall incidence figure includes all known deaths out to one year, using the 'gas received' population in the NINOS trial.
`
`It is reasonable to conclude from this data that I‘-NO administration was associated with a signifith reduction in
`the number of infants who were started on ECMO in the NINOS trial. The other two trials supported this effect of I-NO. In
`these trials, the percent reduction in the rate of both the primary endpoint and in the initiation of ECMO were reduced by
`amounts which were similar to those seen in the NTNOS trial. The INOSG data suffers from problems with blinding and
`incomplete data. The INO-Ol/ ~02 trial data did not show a significant effect of I-NO on the use of ECMO, due in part to
`the small numbers of subjects in each group. The subjects in the IND-01! -02 trial were also less critically ill at time (1'
`entry, and the control infants received ECMO at a lower rate than in the INOSG or NTNOS trials (see Table 6.0.3.1213).
`This lower 'event rate' meant that a larger number of subjects would be needed to detect a significant difference between the
`two groups.
`-
`There was no effect of l-NO on the mortality rate detected, and this component contributed little to the overall
`significance for the NINOS primary endpoint.
`
`‘
`
`

`

`7.0.3 Success of trials in meeting secondary efficacy endpoints: demonSti‘ating a physiological effect of l-NO
`1. Acute changes in oxygenation
`The acute effect of l-NO on oxygenation, measured in all three efficacy trials, are summarized in the table below.
`Shown are the average changes (istandard deviation) from baseline to the first measurement 1.5.4.. -starting study gas
`(placebo or l-NO).
`
`_
`
`-
`
`d
`trials .
`
`Table 7.0.3.] Results: comparison of acute changes in oxygenation fi‘om the NINOS, INOSG and l‘NO-Ol/ —02
`
`NDA 20445 Nitric Oxide
`
`
`
`
`
`
`Changes in clinical
`markers of oxygenation
`
`NINOS Trial'
`
`Change in P2102(t'1'1rnl~lg)‘l
`97151.7
`58.21852
`
`
`
`
`Change in 01‘1
`0.81211
`-14:1121.0
`
`
`
`
`—6.7i57.5
`Change in A-a DO; (mmHg1‘
`160.0181]
`
`
`
`INOSG Trial”
`
`1919.6 ‘
`47.4168
`Change in PaO; (mmI-lg)
`
`Change in OI
`'
`--16111.5
`-2.0115
`
`
`lNO-Dll -02 trial‘
`
`
`Change in mean PaO;
`18.0i53
`32.3:t56
`38.6169
`”'1 64.4:t'84 ‘
`-
`44.61:“ _'
`
`
`
`
`Change in mean 01
`-'7.419.o,_ :..;. 6.518.“),
`1317.7
`-4.714.6
`14.319.6."-";,.'
`
`
`
`
`
`
`Preductal 02 saturation
`02613.4
`,
`0.35141
`0.771328
`0.14130
`_
`0,413.2 .
`
`
`
`
`
`
`Postductal 02 saturation
`--. 14313.88
`0.27145
`18513.86
`14914.72
`"1.60141
`
`
`
`
`
`00310.08 00510.09
`0.0610.11
`Arterial-alveolar 0; ratio -
`0.101013
`0.171011
`
`
`
`
`
`
`»,-44.3170
`Arterial-alveolar 0, gradient (A-aDoz) 49.5156
`61.6156 _
`_
`-39.6168
`#632181
`
`
`
`
`:1. Shown is the mean: 3.1!. of the change from baseline for each parameter, measured after 30 minutes.
`b. Acute effects measured at baseline and alter 20 minutes.
`1:. Acute effects measured at baseline and after 30 minutes.
`d. Variable in which the I-NO and control group means differ significantly (<O.DS) using Student t-test are shaded.
`
`-
`
`The fNO-Ol/ -02 trial also suggests that this effect of I-NO to improve oxygenation is dose—dependent in the range
`from 5 to 80 ppm. The figure below, based on table 6.0.3.12.3b.1, shows the change in P30: following study gas
`administration in the [NO-0U -02 study. The change from baseline was statistically significant using one-way ANOVA (p
`value = 0.029).
`"
`
`'
`‘
`
`Figure 7.0.3.2 Effect of study gas on P302
`7' 0
`
`E as 60
`
`E E 30
`Eng 20
`00
`
`§ -|
`
`\‘i
`
`\
`
`NO20
`
`ppm
`
`I-NO80
`Study Gas Administered
`
`DPT"
`
`I-NO
`
`Combrned
`
`122
`
`
`
`

`

`7.0.3 Success of trials in meeting secondary efficacy endpoints: demonstrating physiological effect of I-NO (cont)
`The long-term effects of leO on oxygenation were examined in the INO-Ol/ -02 trial, using the time-weighted Ol
`(TWOI), a measure of the average OI/bour of study gas administration.
`-
`
`NDA 20-845 Nitric Oxide
`
`Table 7.0.3.3 Effects of NO on ox
`Contra!
`I-NO 5
`
`enation and hemodvnarnics bevond 30 minutes‘ in the TNO-Oll -02 trial.
`m
`l-NO 20
`I-NO 80 ' m
`
`Combined I-NO
`
`Change in TWOI
`
`4.60:8.0
`(-22 to 15)
`
`51:4.67t757-2'33,‘ -4.7aa10.1
`.
`I
`
`f #25 told)
`-'
`(-36 to 14)
`
`22159114"?
`.
`.
`(-24 to 8)I’
`
`
`
`.-'.‘:5.018.4 '
`-36 to 14
`
`
`
`
`
`a. Data taken from baseline to beyond 30 minutes to the time of withdrawal from I-NO, from NDA volume 2.l7, Table 23.
`b. Repeated ttest comparisons with control group were significant ((0.05) for the 5 and 80 ppm group. as well as the pooled I-NO
`group(shaded boxes above).
`
`
`
`see note”
`
`‘
`
`The majority of this effect was manifest in the first few hours of study gas administration, where there was a clear
`separation of control and l-NO groups with regards to their average 01.
`
`Figure 7.0.3.4 Time vs. OI in
`the IN 0—01/02 Trial
`
`I
`- -O- - - Placebo
`—-I-— l-NO Combined!
`
`30 7
`J
`
`,_.\
`
`‘9MeanOI(cmH20/torr)
`
`o H m N \O
`.
`1—!
`
`C: V
`
`Time (hours)
`
`2. Effect of I-NO on pCO;
`The {NOSG trial reported a significant, acute efiea of I-NO on pH when comparing the initial baseline value to
`the value at the end of 20 minutes. No significant difference between the second baseline and the 20 minute value was
`detected. The second baseline value was taken after reducing the HO; to 90%, just prior to starting the study gas. Thus,
`the comparison between the second baseline and the 20 minute value is the best comparison to use to determine the acute
`effect of I-NO, independent of any efi‘ect of reduced Fi02. No effect of INC on pCO; was seen in the larger INO—Ol/ -02
`trial, although there was an numerical decrease in pCOz in that trial in all dose-groups of l-NO. As shown in Figure
`6.0.3.149, the average pCOz remained stable in both LNG and control groups during chronic administration of study gas.
`
`Tabie 7.0.3.4 Results: comparison of acute changes in pCO; from the TNOSG, and IND-01! -02 trials (no data
`submitted from the NINOS trial at
`
`
`m—mm l-NO 80 um Combined I~NO
`
`
`
`moss Trial
`_
`Change in pCOz from first baselineb
`
`
`Change in pCOz from second baseline"-
`
`lNO-Ull -02 trial'
`4.24:5.0
`-l.31i3.6
`.
`Mean change in FCC:
`-1 2414.9
`
`
`a. Shaun is the mean: set. of the change from baseline for each parameter.
`b. Acute effects measured at first bueline and after 20 minutes of study gas.
`c. Acute effects measured at second'baseline and after 20 minutes of study gas.
`d. Variable in which the l-NO and control group means differ significantly (<0.05) using Student's t-test are shaded.
`e. Acute effects measured at second baseline and afier 30 minutes of study gas.
`
`
`
`-
`
`
`
`
`
`
`
`123
`
`

`

`7.0.3 Success of trials in meeting secondary efficacy endpoints: demonstrating physiological effect of LNG (cont)
`3. Effect of I-NO on pH
`.
`No significant efi'ect of I-NO on pH was detected in either the INOSG or the INO-Ol/ -02 trials. As shown in
`Fi'giJre 6113.14.10, the average pH remained stable in both l-NO and control groups during Cluullic administration cf
`study gas.
`
`NDA 20-845 Nitric Oxide
`
`Table 7.0.3.5 Acute effect of l-NO on -H in the INOSG and INO-Ol/ -02 trials'.
`“‘40 20 um MIC 80 - m Combined I-NO
`
`iNosc Trial”
`Change in pH
`
`
`
`
`0.02:0.07
`0.05i0.09
`
`
`
`
`
`[NO-Dbr -02 trialc
`
`
`
`
`0.01:0.05
`0.02i0.05
` 00210.06Mean pH 0.02i0.06 0.02:0.04
`
`
`a. Shown is the mean: s.d. of the change from baseline for each parameter.
`b. Acute effects measured at baseline and after 20 minutes.
`c. Acute effects measured at baseline and after 30 minutes.
`
`
`
`
`
`d. Variable in which the l-NO and control group nieans differ significantly ((0.05) using Student Most are shaded.
`
`4. The effect of LNG on hemodynamics and pulmonary pressures
`The effects of I-NO on hemodynamics and pulmonary pressures was measured in the INOSG and INO-Ol/ -02
`trials, which are summarized below. The INOSG trial reported .an acute, significant decrease in mean systemic blood
`pressure only between‘thefirst baseline value and the 20 minute value. There was no significant difference between the
`second baseline value and the 20 minute value in the INOSG trial. The larger lNO-Ol/ -0; trial found a small, non—
`significant decrease in mean arterial pressure in the I—NO group, and no long«term efl‘ect of l-NO on blood pressure (see
`figure 6.0.3.F4.12).
`There was no acute effect of l-NO on mean airwaypressures detected in the INO-Ol/ -02 trial, as seen. in the table
`below. There was also not a long-term trend towards a more rapid decrease in mean airway pressures in the I-NO group
`(see figure 6.0.3.14.1 1). Additionally, no acute or chronic efiect of LNG on the amount of PEEP required by the infants, or
`the average positive inspiratory pressure (PIP) was detected.
`
`trials.
`
`Table 7.0.3.6 Acute effect of I-NO on pulmonary and systemic hemodynamics in the INOSG and [NO—01! -02
`
`mosc Trial”
`Change in mean systemic
`blood pressure (mmHg) from first baseline‘
`Change in mean systemic
`blood pressure (mmHg) from second baseline'
`Change in heart rate (beats per minute)
`IND-01f -02 trialc
`
`
`
`
`
`
`Changes in pH
`
`7
`
`Control
`
`u
`
`u
`
`I-NO
`20 I m
`
`I-NO
`80 I I!!!
`
`
`
`
` +4.]i9.0
`
`#31131. f}.-
`
`
`
`“dioxin"?
` +l.5ilO
`
`
`
`
`
`+1.0110.2
`+2.0i15
`
`
`
`
`Mean Arterial Pressure (mmHg)
`«0.73i10.9
`-2.39i9.69
`-3.22:l:9.4
`+0.69i10.0
`-l.7:l:9.8
`
`
`
`
`
`
`Mean Systolic Pressure
`4.64il4
`+1.862t12
`—2.0i13
`-l.321!3
`55.29112
`
`
`
`
`
`
`Mean Diastolic Pressure
`068:9
`4.39:8
`«14717.3
`-0.08:l:8
`-l.3li8
`
`
`
`
`
`
`
`Mean Peak Inspiratory Pressure (PIP)
`+0.3l:l:l.06
`+0.27:l:1.l" +0.07i0.4l
`+0.03:l:0.16
`+0.13:l:0.66
`
`
`
`
`
`
`
`Positive End-Expiratory Pressure (PEEP)
`+0.02i0.16 +0.00t0.24
`-0.03:l:0.l6
`+0.01'0.19
`+0.%0.0
`
`
`
`
`
`
`
`-0.1i1.2
`-0.l:l:l.4
`+0.0il.3
`+0.0:t1.2
`Mean Airway Pressure (Paw)
`+0.1i0.7
`
`
`
`
`
`
`a. Shown is the meanzt s.d. of the change from baseline for each parameter, measured after 30 minutes.
`b. Acute effects measured at baseline and afier 20 minutes.
`,
`e. Acute effects measured at baseline and alter 30 minutes.
`
`d. Variable in which the I-NO and control group means differ significantly (<0.05) using Student t-test are shaded.
`e. Statistics calculated using Wilcoxon Rank Test comparing {in} baseline value to 20 minute value.
`f. Statistics calculated using Wilcoxon Rank Test comparingm baseline value to 20 minute value.
`
`The effect of LNG on cardiac output, pulmonary vascular resistance, systemic vascular resistance, or reduction in
`the right-to-left shunting of blood from pulmonary hypertension were not examined in any of the trials.
`
`7.0.3 Success of trials in meeting secondary efficacy endpoints: demonstrating physiological effect of LNG (cont)
`
`124
`
`
`
`

`

`
`
`N'DA 20-8435 Nitric Oxide
`
`5. Summary of physiological effects of l-NO
`The most striking, and consistent effect of LNG is to improve oxygenation in a fraction of the subjects exposed.
`In all three trials, there was an acute improvement in oxygenation which was highly significant. In the INC-01! -02 trial,
`this improvement persisted beyond the initial measurement, compared with controls.
`" .,
`-
`There was a nonsignficant decrease in both pCO: and mean systemic blood pressure acutely following I-NO
`administration. No long-term effect of i-NO on blood pressure, pH, or pCO; was seen in the INO-Ol/ -01 trial. No acute or
`chronic effect of I-NO on the pulmonary airway pressures was detected. No information about the pulmonary and systemic
`vascular resistance, or the reversal of the right-to-left shunting fi'om pulmonary hypertension was obtained in these trials.
`
`7.0.4 Success of trials in meeting secondary efficacy endpoints: demonstrating a clinical benefit for l-NO
`Each of the three efficacy trials measured several other endpoints, either as part of secondary endpoints or as part Cf
`the safety measurements, which could be used to argue a clinical benefit. A summary of these potential benefits is below,
`along with the efficacy data that was collected for each benefit. Overall, no significant beneficial efl‘ect of I-NO was detected
`for any of the listed endpoints.
`‘
`'
`'
`
`urat'nofu
`
`e
`
`e
`
`. nd
`
`—
`
`e eta
`
`a
`
`Table 7.0.4.1 Incidence of use of supplemental O; at time of discharge in the-NINOS, INC-01! -02 and /-03 and
`{N086 trials‘.
`
`-
`
`
`
`5 - um
`-
`9/45 (20%)
`
`20 - um
`14/98 (14%)
`4/43 (9%)
`
`
`
`20/127 (16%)
`
`at time of dischare
`0.89
`l_5/100 (15%)
`NINOS
`0.51
`7/39 (13%)
`6/41 (15%)
`[NO-011-02 and [-03
`0.19
`1/27 (4%)
`-4/21 (19%)
`[NOSGb
`a. Data from NDA, volume 2.26 appendix 16.2.2.2], and 2.31 data listing 16.5. Data shown as "/n of all subjects with data. lNOSG data
`from NDA volume 2.16, Appendix 16.2.7.
`b. p values calculated using unadjusted chi-square.
`
`80 I urn
`
`Pooled
`
`Table 7.0.4.2 Duration of supplemental O; therapy in the INOSG trial and INO-Ol/ -02 trials (no data available
`from the NINOS trial).
`
`Duration of supplemental o1
`(davs
`NINOS
`
`
`
`
`lNOSGb
`INO-Ol/ -02
`a. NA = not available
`
`_
`
`NA‘
`
`19:21
`6:7 .
`
`l-NO
`5 - -m
`
`u
`
`.
`
`l-NO
`80 i -m
`
`l-NO
`Pooled
`
`pvalue’
`
`'
`
`5:5
`
`.-
`
`5:3
`
`11:6
`6:8
`
`5:6
`
`0.066
`0.47
`
`
`
`1). Excludes one infant in the control group reportedly required 0; for 445 days.
`
`The use of 02 after discharge is discussed in section 6.0.1.133. No control infant required 02 after discharge,
`while 12 of the infants who received I-NO (13% of the children with available data) required 0; afier discharge.
`
`e
`
`'clv
`
`Table 7.0.4.3 Duration of mechanical ventilation in the NTNOS, INOSG and IND-01! -02 trials.
`Duration of mechanical ventilation
`l-NO
`l-NO
`80 I III]
`Poofed
`12.3:14
`
`t
`
`I
`
`,
`
`1
`
`a
`
`
`
`11.1:13
`NINOS
`27:84
`INOSG
`
`
`8:5
`iNO-Ol/ -02
`
`
`a. NA = not available
`b. p value calculated by unadjusted unpaired t test.
`
`9:7
`
`8:5
`
`'
`
`8:4
`10:10
`
`9:7
`
`p value _
`
`
`
`
`7.0.4 Success of trials in meeting secondary efficacy endpoints: demonstrating a clinical benefit for I—'NO (cont)
`0
`
`125
`
`
`
`

`

`EEra‘
`
`[I
`
`'1"
`
`NDA 20-845 Nitric Oxide
`
`Table 7.0.4.4 Duration of hos-italization in the NINOS. INOSG and INO-01/-02 trials.
`Duration of hospitalization
`Control
`l-NO
`l-NO
`20"!“
`80"!"
`0.17
`36.4:45
`0.24
`20:8
`
`0.45
`24:1:11
`24:12
`
`
`
`
`NINOS'
`29.5123
`INOSG
`42i9l
`IND-01! -02
`26i20
`
`
`a. NA = not available
`
`ll
`
`22111
`
`21i10
`
`I-NU
`Pooled
`
`p value
`
`
`
`4. Qegths
`As shown in table 7.0.2.5 above, no difl'erence in the rate of death between the control and I-NO groups was
`detected in any of the submitted trials, or in the combined population,
`.
`
`There were also several adverse events, which, if they occurred with less fi‘equency in the I-NO group, could be
`taken as supportive of a beneficial clinical effect of I-NO. A list of these events, followed prospectively in one .or more
`clinical trials, includes:
`1) Air Leak Syndrome (ALS);
`2) Bronchopulmonary dysplasia;
`3) Chronic lung disease, including lung disease during the 1 year after the initial discharge from the hospital;
`4) Reactive airways disease;
`.
`5) Abnormal neurological development, including neurologic development 1 year after the initial discharge from
`the hospital;
`.
`6) Seizures;
`7) Clinically significant bleeding, including interventricular and intracranial hemorrhage.
`
`and
`
`The incidence of these adverse events is discussed in detail in section 8.1 and 8.2 below (Integrated Review cf
`Safety and Review of Systems). In short, no beneficial effect of I-NO on any of these outcomes was detected in either of the
`large trials (NINOS and INO-Ol/ -02). Instead, there is a possible association between i-NO administration and increased
`incidence of pulmonary adverse events. In the INOSG trial, the subjects who received l-NO demonstrated a trend towards
`fewer days of supplemental oxygen (see 6.0.2.15 for my discussion).
`
`7.0.5 Clinical effect of I-NO from the secondary data sources
`Almost all of the published data on I-NO, with the exception of the papers reporting the NINOS and INOSG trial
`results, come from single centers administering I-NO in unblinded, uncontrolled fashion. For efficacy results, then,
`the
`studies are under-powered to detect a significant impact of I-NO on clinically relevant endpoints.
`Improvements in
`oxygenation have been reported in almost all trials. The percentage of infants who had such an improvement with I-NO
`has varied from 44% (30) to nearly 100% depending on the study. In a review of the available trials on I-NO, one group
`estimated that 59% of neonates have an initial improvment in oxygenation, and that 60% of these infants have a sustained
`response (22).
`in regard to the use of ECMO, one randomized, controlled, open-label trial failed to demonstrate a reduction in
`the use of ECMO in subjects recieveing I-NO (2]). This trial enrolled similar numbers of subjects as in the INOSG trial
`(23 control, 26 l-NO). In atrial using historical controls (16 total subjects), a small decrease in ECMO following I-NO
`was suggested (36), while another using a cross-over design (17 total subjects) found no effect of LNG on ECMO use (30).
`Another investigator, in an unblinded study, estimated that 'NO apparently cut out a 15% segment from the patient group'
`(30 total subjecLs) who would otherwise have received ECMO (24).
`'
`The death rates in each of the trials was low, so no statement of an l-NO effect can be inferred from these papers.
`~ No other clinical benefits of I-NO have been demonstrated from any of the published trials.
`
`
`
`126
`
`

`

`NDA 20445 Nitric Oxide
`
`7.5 Summary of Efficacy Review
`1. I-NO administration is associated with an acute and durable increase in Pa02. This effect of l-NO is dose-
`related between 5 and 80 ppm.
`- -
`2. I-NO administration in the NINOS trials wa