48
`
`significant differences were observed between the treatment groups in both the Intent to
`Treat and Evaluable patient analyses," with the majority of the Dexmedetomidine treated
`patients requiring no Propofol for sedation compared to the majority of the placebo
`patients who required > 50mg of Propofol for sedation.
`
`Table 24
`
`Total Dose Cate -ories of Pro - fol Dunn Intubation
`Placebo
`Dexmedetomidine
`
`
`
`Treatment
`
`y,
`
`
`
`
`
`
`Effect”:
`- -Value"
`__M
`_———
`
`
`
`.Elm—__-
`
`
`
`__—
`
`
`_———
`
`“IE—__—
`
`
`
`a: p-value from chi-square
`Modified Sponsor’s Table 8.2b Vol 8/10-86-74
`
`SECONDARY EFFICACY ENDPOINTS
`
`Total Dose of Propofol During Study Drug Administration
`
`In both the Intent to Treat and the Evaluable patient analyses, Dexmedetomidine treated
`patients required statistically significantly less Propofol for sedation during study drug
`administration compared to placebo treated patients:
`‘
`
`Table 25
`
`Summary of Total Dose of Propofol (mg/hour)
`Durino Stud Dru - Administration
`‘
`
`Placebo
`
`Dexmedetomidine
`
`
`
`
`
`Iii——
`39.11:4.13
`
`
`Intent to Treat Patients (N)
`
`
`a: p-value from ANOVA
`SEM = Standard Error of Mean
`
`Treatment Effect
`. -Valuea
`
`~
`
`. Modified Sponsor’s Table 8.3a Vol 8/10-86-75
`
`Total dose of Morphine During Study Drug Administration
`
`
`
`

`

`49
`
`In both the Intent-to-Treat and the evaluable patient analyses, Dexmedetomidine treated
`patients required statistically significantly less morphine for pain during study drug
`administration compared to placebo treated patients.
`
`Table 26
`
`Summary of Total Dose of Morphine (mg/hour)
`
`
`
`a: p-value from ANOVA
`SEM = Standard Error of Mean
`Modified Sponsor’s Table 8.3b Vol 8/10-86-76
`
`~ ‘
`
`Statistically significant center effects were detected for the total dose of morphine during
`study drug administration in both the Intent-to-Treat and evaluable patient analyses.
`However, inspection of center level data confirm that the centers differ in magnitude of
`effect, not direction.
`
`In both the Intent to Treat and the Evaluable patient analyses, Dexmedetomidine treated
`patients who received no Propofol during intubation required statistically significant less
`morphine during study drug administration compared to placebo treated patients who
`, received no Propofol during intubation:
`
`Table 27
`
`Summary of Total Dose of Morphine
`
`Mean i SEM
`
`
`
`Placebo
`Dexmedetomidine
`Treatment Effect
`. -Value3
`4 —
`0.41:0.07
`0 25+0 04
`00414
`_
`0.0387
`
`Mean i sENf
`a: p-value from ANOVA
`e SEM = Standard Error of Mean
`Modified Sponsor’s Table 8.3c Vol 8/10-86-77 .
`
`0.421007
`
`0.251004
`
`»
`
`-
`
`In both the Intent to Treat and the Evaluable patient analyses, there was no statistically
`significant difference in morphine use during study drug administration between
`Dexmedetomidine treated patients who received up to 50 mg of Propofol during
`intubation and placebo treated patients who received up to 50 mg of Propofol during
`intubation:
`
`~
`
`
`
`

`

`
`
`50
`
`Table 28
`
`Summary of Total Dose of Morphine (mg/hour) During Study Drug
`Administration for Patients Who Received Up to 50 mg of Propofol
`Durin - Intubation
`
`
`
`
`
`
`. a': p-value from ANOVA
`SEM = Standard Error of Mean
`
`Modified Sponsor’s Table 8.3d Vol 8/10-86—77
`
`Total Dose of Morphine by Time Period
`
`In both the Intent-to-Treat and the evaluable patient analyses, Dexmedetomidine treated
`patients (as compared to placebo treated patients) required statistically significantly less
`morphine for pain:
`3. During the first 6.5 hours of study drug administration. A statistically significant
`center effect was detected for the total dose of morphine in both the HT and
`'Evaluable patient analyses. However inspection ofcenter level data confirm that the
`centers differ in magnitude of effect, not direction
`4. From 6.5 hours after the start of study drug administration to the end of study drug
`administration. There was no center effect for this group.
`
`Table 29
`
`Summary of Total Dose of Morphine "(mg) During First 6.5 Hours of
`Stud Dru Administration
`
`
`
`
`
`
`
`Placebo.
`‘
`'
`-
`Intent to Treat Patients (N) _
`4.091047
`Mean '1: SEM
`8.46i0.64
`Evaluable Patients (N)
`V I_ 200
`
`Dexmedetomidine
`
`
`
`
`Treatment Effect
`-Valuea
`
`
`
`<0.0001
`
`a: p-value from ANOVA
`SEM = Standard Error of Mean
`
`Modified Sponsor’s Table 8.3e Vol 8/10-86—78 .
`
`

`

`
`
`51
`
`Table 30
`
`Summary of Total Dose of Morphine (mg/hr) From 6.5 Hours After the
`Start of Study Drug Administration to the End of Study Drug
`Administration
`
`
`
`
`
`Placebo
`
`Dexmedetomidine
`
`
`
`Treatment Effect
`- -Valuea
`‘ _
`1
`05510.07
`0.1'6fl.03
`<0.0001
`1
`_
`<0.0001
`.
`
`Intent to Treat Patients (N)
`
`'
`
`
`
`
`
`MeaniSEM -
`Evaluable Patients (N)
`Mean i SEM
`
`a; p-value from ANOVA
`'SEM = Standard Error of Mean
`
`0 56+0 o7
`
`0.16i0.03
`
`
`
`
`
`'
`
`
`
`
`.
`
`Modified Sponsor’s Table 8.3f Vol 8/10-86-79
`
`Ramsay Sedation Score
`
`In both the Intent-to-Treat and evaluable patient analyses, the mean Ramsay sedation
`score during study drug administration was statistically significantly higher for
`Dexmedetomidine treated patients compared to placebo treated patients. The Ramsay
`sedation scores for both groups fell within the protocol defined range of 23. The Ramsay
`sedation score for the placebo treated group was mean 3.1 i- 0.04 (SEM) vs 3.4 i 0.05
`(SEM) for the Dexmedetomidine treated patients. Sponsor states these differences are not
`clinically important.
`
`'
`
`A statistically significant center effect was observed for the Ramsay sedation scores
`during study drug administration in both the Intent to Treat and Evaluable patient
`analyses. However inspection of center level data confirm that the centers differ in
`magnitude of effect, not direction.
`
`Anxiety
`
`In both the Intent to Treat and Evaluable patient analyses, there were no statistically
`significant differences between treatments in the number of patients who reached a
`Ramsay score gf._1._during study drug administration.
`
`The percentage of Ramsay assessments equal‘ to l was also computed for each patient and
`- summarized'by treatment group. Both the Intent to Treat and Evaluable patient analyses
`showed statistically significant differences (p5 0.009) between the treatment groups, with
`7% of the assessments among placebo patients reaching a score of 1 compared to only
`4% of the assessments among Dexmedetomidine patients indicating less anxiety among
`Dexmedetomidine treated patients. A statistically significant center effect was observed
`for the ratio analysis. The mean percentage per center ranged fiom 0% to 42% with the
`sites consistently demonstrating that placebo treated patients had more Ramsay sedation
`assessments that reached a score of I compared to Dexmedetomidine treated patients,
`also indicating less anxiety among Dexmedetomidine treated patients.
`
`

`

`52
`
`Time to Extubation and Weaning
`
`Using Kaplan-Meier estimates and the log-rank test, no statistically significant
`,
`differences were observed between the treatment groups (placebo, 385 minutes;
`Dexmedetomidine, 395 minutes) for the median time between ICU arrival and readiness
`for extubation in both the Intent-to-Treat and evaluable .patient analyses. Additionally, no
`statistically significant differences were observed between the treatment groups (placebo,
`360 minutes; Dexmedetornidine 365 minutes) for the median time between the start of
`study drug and readiness for extubation in both the Intent-to-Treat and evaluable patient
`analyses.
`'
`
`The median time from ICU arrival to actual extubation was similar between the tWO
`treatment groups in both the Intent-to-Treat (placebo, 430 minutes; Dexmedetornidine
`432 minutes) and evaluable patient (placebo, 434 minutes; Dexmedetornidine 430
`minutes) analyses. Likewise, the median time from the start of study drug to actual
`extubation was similar between the two treatment groups in both the Intent-to-Treat
`(placebo, 398 minutes; Dexmedetornidine 404 minutes) and the evaluable patient
`(placebo, 400 minutes; Dexmedetornidine 403 minutes) analyses.
`
`Using Kaplan-Meier estimates and the log-rank test, no statistically significant
`differences were observed between the treatment groups for the median duration of
`weaning in both the Intent-to-Treat (placebo, 15 minutes; Dexmedetornidine 15 minutes)
`and evaluable patient (placebo lSminutes; Dexmedetornidine 15 minutes) analyses.
`
`Nurses’ and Patients’ Assessment
`
`Nurses assessed their impressions of the patient’s overall sedation and tolerance of the
`ICU, tolerance of the endotracheal tube/ventilator, ease of communication with the
`patient. and the ease of patient management. Scdres from each of these assessments were
`summed to arrive at a composite score defined as the “Patient Management Index.” In
`both the Intent-to-Treat and evaluable patient analyses, a statistically significant
`difference was observed between the treatment groups for the patient management index.
`Dexmedetornidine treated patients demonstrated a lower patient management index score ,
`compared with-placebo treated patients, with lower scores corresponding to the ease with
`which patients tolerated sedation, the ICU, and the endotracheal tube/ventilator, as well
`as the ease with which the nurse was able to communicate with the patient and care for
`the patient. fl 7
`h
`-
`
`APPEARS THlS WAY
`0" ORIGINAL
`
`
`
`

`

`53
`
`Table 31:
`
`Summar of Nursin_ Assessments and Patient Mana- ement Index
`Placebo
`Dexmedetomidine
`Mean i SEM
`Mean i SEM
`ITI‘
`
`
`
`
`
`
`
`
`
`
`
`
`N=177
`N=180
`N=170
`N=176
`1.5:004
`1.51004
`1.91-0.07 - ~~
`1.910.06
`Tolerance of the ICU?
`N=177
`N=180
`N=l69
`N=l75
`Tolerance of Endo Tube/
`1.3:003
`1.3:0.03
`1510.04
`1.5:004
`Ventilatorb
`N=176
`N=179
`N=170
`N=176
`Ease of Communication
`2.11007
`2.11-0.07
`2.4:008
`2.4:008
`.w'ith Patientc
`'
`‘
`N=1 7S
`N=179
`N=l69
`N=l75
`Ease of Management of the
`15:0.05
`1.6:.05
`Patientd
`1.3i0.03
`l.2i0.03
`
`.———
`
`Patient Management Index
`N=174
`
`p-value‘:
`I'I'I‘: <0.001
`
`
`
`Eva]: <0.001
`
`Modified Sponsor’s Table 8.43 Vol 8/ 10-86-84
`a: 1=very easy, 2=easy, 3=moderate, 4=difficult
`b: 1=good, 2=moderate, 3=poor
`c:_ 1.=very easy, 2=easy, 3=moderate, 4=difficult, 5=not-possible
`d: 1=good. 2=moderate, 3=poor
`
`
`
`e: p-value from Cochran-Mantel-Haennszel row mean score statistic adjusted for center
`differences
`
`Sponsor claims that these results indicate that patients were arousable, cooperative, and
`had less anxiety than placebo treated patients.
`
`Patient Satisfaction Survey
`
`Patients were surveyed with respect to their experience as a participant in the study.
`Among the ParEIIspatients who completed the survey, responses were generally similar
`between Dexmedetomidine and placebo treated patients in rating their present experience
`compared to prior sedation experience, their overall comfort during ICU sedation, their
`remembrance of pain, discomfort from the breathing tube, people and'noise, and whether
`or not they would have the same sedative treatment in the future. A higher percentage of
`Dexmedetomidine treated patients (70%) rated their overall experience as “better than
`expected” compared to placebo treated patients (60%). 187 placebo treated patients vs
`190 of the Dexmedetomidine treated patients completed the survey.
`
`SPONSOR'S SUWARY OF EFFICACY:
`
`The Intent-toil'reatand evaluable patient analyses of the primary efficacy endpoint
`demonstrated that pexmedetomidine treated patients required statistically significantly
`
`

`

`
`
`54
`
`less Propofol for sedation during intubation compared to placebo treated patients.
`Statistically significant differences were observed between the treatment groups in both
`the Intent-to-Treat and evaluable patient analyses, with the majority of the
`Dexmedetomidine treated patients requiring no Propofol for sedation compared to the
`majority of the placebo patients who required >50 mg of Propofol for sedation.
`
`Statistically significant differences were also demonstrated between the treatment groups
`in secondary efficacy variables for both the Intent-to-Treat and evaluable patient
`analyses. Dexmedetomidine treated patients required less Propofol for sedation during
`the entire study drug. administration period, less morphine for pain during study drug
`administration, less morphine during the first 6.5‘ hours of study drug administration, and
`less morphine from 6.5 hours after the start of study to the end of study drug
`administration.
`
`Ramsay sedation scores were significantly higher among Dexmedetomidine treated
`patients compared to placebo treated patients. Dexmedetomidine treated patients
`achieved a higher level of sedation during the first hour of study drug administration
`compared to placebo treated patients. There were no significant differences between
`treatments in the number of patients who reached a Ramsay score of 1 during study drug
`administration, although the percent of assessments reaching a score of 1 was
`significantly greater in the placebo group than in the Dexmedetomidine group during
`study drug administration, indicating less anxiety among Dexmedetomidine treated
`patients
`
`No statistically significant differences were observed between the treatment groups in the
`analyses of time to extubation and weaning. This outcome may have been influenced by
`the design of the study, which required a minimum of.6 hours intubation.
`. .
`
`Dexmedetomidine treated patients demonstrated -a statistically significantly lower patient
`management index score compared with placebo treated patients, with lower scores
`corresponding to the ease with which patients tolerated sedation, the ICU, and the
`endotracheal tube/ventilator, as well as the ease with which the nurse was able to
`communicate with the patient and care for the patient. Results indicate that
`Dexmedetomidinetreated patients were arousable and cooperative, and had less anxiety
`than placebo trEatéd patients.
`
`Patient satisfae—tions'urvey responses indicated that Dexmedetomidine treated patients
`were more comfortable during ICU sedation and had less memory of pain, discomfort
`from the breathing tube, people, and noise than placebo treated patients. A higher
`percentage of Dexmedetomidine treated patients rated their overall experience as better
`than expected and that they would have the same sedative treatment in future compared
`to placebo patients.
`
`

`

`
`
`55
`
`SECTION 7.2.2.6
`
`REVIEWEFI’S EFFICACY DISCUSSION
`
`As noted in the Primary Efficacy Analysis Section, the final perary efficacy analysis
`submitted in this application is different from what the sponsor proposed in the original
`protocol. None of the amendments to this study reflect the analysis that was performed.
`At a meeting with the sponsor at the conclusion of the Phase Two studies. Dr. Thomas
`Permutt (the reviewing statistician) suggested that the capability of Dexmedetomidine to
`provide sedation would be more convincingly demonstrated by an analysis of how many
`patients needed any rescue medication rather than. by measuring the amount of rescue
`medication utilized‘ by both placebo and Dexmedetomidine patient groups. Consequently,
`the sponsor was encouraged to incorporate calculations of the number of patients
`,
`receiving any amount of Propofol in the primary efficacy analysis. The sponsor followed
`the Agency’s recommendations and performed the calculations prior to unwrapping the
`study blind.‘ ‘
`
`This reviewer agrees that Dexmedetomidine provides-significantly greater sedation than
`placebo. This pivotal study demonstrates that Dexmedetomidine is independently capable
`of providing sedation in intubated patients in an intensive care setting.
`
`With‘respect to analgesia, the study measured the total milligrams of morphine required
`by the Dexmedetomidine group versus placebo group. There was no evaluation of the
`number of individuals in either group who required any morphine. Consequently, while
`the study did show the total amount of morphine administered to the Dexmedetomidine
`group was less than the total amount of morphine given to the placebo group for pain, no
`conclusion can be made that Dexmedetomidine is independently capable of providing
`analgesia. This study did convincingly demonstrate that Dexmedetomidine is capable of
`potentiating morphine.
`
`In the secondary efficacyanalysis, sponsor states that Dexmedetomidine treated patients
`had less anxiety as compared to the placebo treated patients. This claim is based on
`Dexmedetomidine patients scoring a statistically significantly lower percentage of
`Ramsay assessments that reached a score of 1 as compared to placebo treated patients.
`This reviewer agrees the Dexmedetomidine treated patients exhibited less outward
`display of aniié'fyf'agitation or restlessness. However, patients can be dysphoric but
`appear cairn. An example of this situation is with the drug dropen'dol. When given
`without additional sedative/hypnotic agents, patients sometimes reply-that they “feel
`terrible" although by outward appearances they appear calm. Since the Ramsay
`observation scale is not a valid objective measure of anxiety, no claim can be made that
`Dexmedetomidine treated patients had less anxiety than placebo treated patients.
`
`Another claim in the secondary efficacy analysis is based on the patient management
`index. Sponsor states the results of this score indicate the Dexmedetomidine treated
`patients were more arousable and more cooperative and had less anxiety than the placebo
`treated patients. The subjective factors that the index measured were 1) Overall sedation
`and tolerance of the__I_CU 2) Tolerance of Endotracheal tube/ventilator 3) Ease of
`
`

`

`56
`
`communication with the patient and 4) Ease of management of the patient. No validation
`has been provided to substantiate the claim that the Patient Management Index is a
`measure of arousability, co-operation or anxiety. In addition, while the difference
`between placebo and Dexmedetomidine groups in the patient management index was
`statistically significant, the observed values were so small as to be clinically meaningless.
`
`. SECTION 8.0a..SAFETY ANALYSIS
`
`SECTION 8.1
`
`EXPOSURE
`
`‘ '
`
`[REVIEWER NOTE: THE FOLLOWING INFORMATION IS NOTA VAILABLE AT THE
`TIME OF THIS REVIEW. SPONSOR HAS AGREED TO SUPPLY THE NECESSARY
`INFORMATION; SUCH INFORMATION WILL BE REVIEWED AS AN ADDENDUM
`TO THE APPLICATION:
`
`0
`
`Information delineating all the various doses of Dexmedetomidine administered to all
`subjects/patients
`. Time periods the various doses were administered to all subjects/patients
`0_
`0 Tabulations that compare all deaths, all serious adverse experiences, and all
`premature discontinuations after exposure to Dexmedetomidine, active control, and
`placebo.
`0 Case Report Forms for the discontinuations noted in the 120 Day Safety Update]
`
`Sponsor claims Dexmedetomidine has been evaluated in 83 studies in which over 3303
`subjects/patients received Dexmedetomidine. The agent has been given by various modes
`of administration including rapid or continuous intravenous infusion to normal subjects,
`to subjects with impaired renal and hepatic function, and to patients undergoing cardiac,
`abdominal, peripheral vascular, head and neck, and knee surgery. Patients’ ages ranged
`from 17 to 88553;;
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`
`
`

`

`Ex-osed Patients (All Abbott On'on, and Ja-anese data)
`
`
`
`Periouerative and ICU Sedation Clinical Pro- in
`Phase
`II/III
`
`Phase 1 Studies
`
`
`Phase II/IH Studies
`Clinical
`
`Program
`
`ICU
`~
`Sedation
`
`
`Continuous
`Infusion Rapid
`
`
`infusions
`
`
`Number of
`
`
`Studies
`13
`(Includes
`Crossover
`
`
`
`Studies)
`
`
`l
`Numberof
`Studies
`.
`Crossover
`
`
`2:305“
`233
`1686"
`
`Subjects!
`Patients
`Placebo
`Exposed
`Subjects/
`
`314
`
`.
`
`379
`
`
`
`
`
`
`
`
`
`
`Patients
`.
`_---_N_A_m-
`--______---
`
`
`
`TOTAL: Dexmedetomidine Ex-osed Sub ects/Patients: 3325
`
`TOTAL: Placebo Ex-osed Sub'ects/Patients: 1654
`
`TOTAL: Com-arator Ex-osed Sub'ects/Patients: 411
`
`Modified Sponsor 5 Table Amendment Date May 21,1999
`1M: Intramuscular
`Crossover Studies: Subjects may have been counted in more than one treatment group
`
`57
`
`1
`
`'—~
`
`Table 32
`
`
`
`
`
`
`
`-
`
`-
`
`1004
`
`SECTION 8.2
`
`DEMOGRAPHICS:
`
`-. 7
`
`..~.£- APPEARS THIS WAY
`on ORIGINAL
`
`_
`
`
`
`

`

`
`
`58
`
`Table 33
`
`
`
`All Treated Sub'ects in Phase I Studies
`
`All Treated
`Dexmedetomidine
`N=285
`
`Placebo
`N=97
`
`Gender
`
`
`Alfentanil
`N: 1 2
`
`
`
`_182(64%)
`103(36%)
`
`69(71%)
`28(28%)
`
`8(67%)
`4(33%)
`
`Male
`
`Female
`
`
`Age (Years)
`
`
`82(85%)
`18-35 -
`157(55%)
`12(100%)
`
`
`
`
`15(15%)
`>36-55
`‘ :92(32%)
`
`
`0
`56-65
`16(6%)
`
`
`
`
`0
`>65
`20(7%)
`
`
`
`
`28.2
`Mean
`36.7
`
`
`
`
`- Minimum -
`-'
`18
`1-
`18
`
`
`
`
`Maximum
`82
`45
`
`
`
`Ethnic Origin
`
`
`
`
`
`75(77%)
`212(74%)
`4(33%)
`Caucasian
`
`
`
`
`8(8%)
`32(11%)
`Black
`4(33%)
`
`
`
`
`
`Asian
`6(2%)
`4(4%)
`2(l7%)
`
`
`
`
`
`30(11%)
`5(5%)
`Hispanic
`1(8%)
`
`
`
`
`
`5(2%)
`Other
`1(8%)
`5(5%)
`
`
`Sponsor’s Table 13 ISS Vol 8/10-239-47
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`215-.
`
`i;-
`
`

`

`59
`
`Table 34
`
`All Treated Patients in Phase II/III Continuous Infusion Studies
`Abbott S onsored Trials; Excludes Orion and la anese Data
`All Treated
`Placebo
`Dexmedetomidine
`N=_817
`N: 1 337
`
`
`
`
`
`
`
`
`
`Male
`555(68%)
`934(70%)
`
`
`Female
`262(32%)
`403(30%)
`
`
`
`
`‘Age (Years)
`‘
`-
`
`
`
`18-35
`55(4%)
`34(4%)
`
`
`
`
`36-55
`345(26%)
`l96(24%)
`
`
`
`
`‘212(26%)
`56-65
`409(3 1 %)
`
`
`
`
`’ 375(46%)
`>65
`528(39%)
`
`
`
`
`Mean
`60.6
`61.9
`
`
`
`
`17
`17a
`Minimum
`
`
`
`
`Maximum
`88
`87
`
`
`
`
`
`Ethnic Origin
`
`
`
`751(92%)
`Caucasian
`1 194(89%)
`
`
`
`
`Black
`91(7%)
`38(5%)
`
`
`
`
`Asian
`11(<1%)
`7(<l%)
`
`
`
`
`Hispanic
`3 l (2%)
`17(2%)
`
`
`
`
`Other
`3(<1%)
`10(<l %)
`
`
`
`
`Missin
`0
`
`l(<1%)
`
`
`Modified Sponsor’s Table 14 I88 Vol 8/10 ~239-48
`
`_
`
`- -
`
`a: Study W97-246 had 2 patients who were 17 year ofage; these patients are
`Summarized in the 18-35 age group.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`
`
`_
`
`60
`
`Table 35
`
`Demographic Characteristics: All Treated Patients in Phase II/III
`Continuous Infusion ICU Sedation Studies (Pivotal Studies)
`'
`
`All Treated
`Placebo
`Dexmedetomidine
`
`
`
`
`
`425(74%)
`271(72%)
`15 1 (26%)
`
`108(28%)
`
`Age (Years)
`
`
`18-35
`.29(5%)
`l6(4%)
`
`
`
`
`36-55
`139(24%)
`79(21%)
`
`
`
`
`
`
`56-65
`172(30%)
`90(24%)
`
`
`
`
`"f-"1_94(51%)
`>65
`236(41%)
`
`
`
`60.8
`' Mean
`(53
`
`
`
`
`
`
`17
`17
`Minimum
`
`
`
`87
`Maximum
`88
`
`
`
`
`
`Ethnic Origin
`
`
`
`561 (97%)
`Caucasian
`
`
`4(<1%)
`Black
`
`
`
`
`70%)
`Asian
`
`
`4(<l %)
`Other
`
`
`Missin -
`0
`
`
`
`
`Surgery Type
`
`
`
`Cardiac
`206(54%)
`214(54%)
`
`
`
`
`
`
`
`Head and Neck
`34(9%)
`27(7%)
`
`
`
`
`95(24%)
`~
`Laparotomy
`87(23%)
`
`
`
`
`63(16%)
`52(14%)
`Others
`
`
`
`
`Country
`
`
`Austria
`22(4%)
`20(5%)
`
`
`
`35(6%)
`Belgium
`14(4%)
`
`
`
`
`Canada
`29(5%)
`13(3%)
`
`
`
`
`France
`98(17%)
`62(16%)
`
`
`
`
`Germany
`94(16%)
`69(18%)
`
`
`
`Greece
`33(6%)
`22(6%)
`
`
`
`
`" 7
`Italy
`22(4%)
`15(4%)
`
`
`
`
`Netherlands
`77(13%)
`54( 14%)
`
`
`
`
`Spain
`70( 12
`37( 10%)
`
`
`
`
`Sweden
`6(l%)
`3(<1%)
`
`
`
`
`UK
`90(l6%)
`70(18%)
`
`
`
`
`Modified Sponsor’s Table 15 188 Vol 8/10-239-49
`
`. ; ,
`
`'4"
`
`-
`
`SECTION 8.3
`
`DEATHS
`
`

`

`
`
`61
`
`The following is a review of all deaths (N=12) that occurred in Abbott sponsored trials.
`There were no deaths in the Japanese trials. The Orion studies involved one death (N=l)
`but information on this subject is not provided by sponsor.
`
`STUDY 95-002
`
`Patient 1115
`
`82 year old with cancer of the colon underwent a low anterior colon resection. Patient
`experienced intermittent low blood pressure. Two hours after being initiated,
`Dexmedetomidine was stopped. Two days later, patient experienced a cardiac arrest and
`died. Autopsy findings indicated severe ASHD.
`'
`'
`Reviewer Comment: There is no apparent relation to study drug.
`
`STUDY 95-004
`
`Patient 000202
`
`77 year old with history of diabetes, hypertension, hyperlipidemia, Class III CHF
`underwent 3 vessel coronary artery by-pass grafting. 2 days after extubation and
`discontinuation of Dexmedetomidine, patient developed pulmonary aspiration and
`expired. Patient appeared stable after discontinuation of Dexmedetomidine.
`Reviewer Comment: There is no apparent relation to study drug.
`
`Patient 0622
`
`59 year old with coronary artery disease, hypertension, hypercholesterolemia, paroxysmal
`atrial fibrillation, gout, depression, and chronic renal insufficiency underwent coronary
`artery bypass. Post operatively patient developed acute renal failure. While on
`Dexmedetomidine infusion. patient was reasonably stable for post operative coronary
`artery bypass procedure. Date and exact cause of death-are not clear but occurred a few
`days after study infusion was discontinued.
`Reviewer Comment: From the supplied documentation, the death has no apparent relation
`to study drug? r; ~.s-.
`
`, .
`
`STUDY 9650f5 I"
`
`Patient 1004
`
`72 year old with a history of abdominal aneurysm, hyperlipidernia, COPD, epilepsy,
`malaria, and cutaneous ulcer underwent an aorta-femoral by-pass procedure. 11 days
`after Dexmedetomidine was discontinued, patient developed retroperitoneal bleeding,
`"septic shock and died.
`Reviewer Comment: There is no apparent relation to study drug.
`
`

`

`
`
`62
`
`STUDY 96-021
`
`Patient 0406
`
`64 year old with history of myocardial infarction, angina, CHF, and two coronary artery
`by-pass procedures underwent total knee replacement} days after discontinuation of
`Dexmedetomidine, patient experienced cardiac arrest and died. Patient appeared stable
`after discontinuation of Dexmedetomidine.
`Reviewer Commenr:._There is no apparent relation to study drug.
`
`STUDY W97-246
`
`Patient X0202
`
`78 year old with history of ischemic heart disease and renal failure underwent a repair of
`abdominal aortic aneurysm. 48 hours after discontinuation of Dexmedetomidine, patient
`experienced cardiac failure, renal failure and cardiac arrest. Patient appeared stable after
`discontinuation of Dexmedetomidine.
`Reviewer Commenr. There is no apparent relation to study drug.
`
`Patient x0403
`
`53 year old with severe kyphosis, hiatal hernia, and dyspnea with mild exertion,
`underwent instrumentation and repair of kyphosis. 5 days after discontinuation of
`Dexmedetomidine, patient developed bronchopneumonia; 11 days later the patient
`expired.
`.
`.
`.
`Reviewer Comment: There is no apparent relation to study drug.
`
`Patient X4602
`
`70 year old with insulin dependent diabetes, COPD, cachexia, and lung cancer underwent
`a pneumectomy. l2 days after Dexmedetomidine was discontinued, patient developed
`pneumonia, pulmonary edema and died.
`Reviewer Comment: There. is no apparent relation to study drug.
`_-_
`.
`
`Patient 202
`
`72 year old with esophageal cancer underwent a thoracic esophagectomy. 2 days after
`study drug was stopped, patient developed adult respiratory distress syndrome and
`possible pulmonary embolism. His liver enzymes were minimally elevated. Autopsy
`disclosed cirrhosis.
`Reviewer Comment: There is no apparent relation to study drug.
`
`

`

`
`
`Patient 7405
`
`75 year old with abdominal aortic aneurysm, cirrhosis, effort dyspnea with respiratory
`failure, history of pneumonectomy underwent an abdominal aortic aneurysm repair and
`splenectomy. 3 days after patient completed the infusion protocol for Dexmedetomidine
`without incident, patient vomited, aspirated and sustained a cardiac arrest.
`Reviewer Comment: There is no apparent relation to study drug.
`
`Patient 10202
`
`~74 year old with ischemic cardiac disease; hypertension, diabetes secondary to steroid
`treatment, hypercholesterolemia, hyperuricemia, pulmonary fibrosis, underwent .coronary
`artery bypass. Patient developed hypotension soon after institution of study drug.
`Hypotensioncontinued intermittently during Dexmedetomidine infusion. Study drug was
`’ discontinued prematurely 9 hours after initiation. Following infusion, renal insufficiency
`occurred. Over the next 3 days, patient appeared stable. However 3 days after termination
`of Dexmedetomidine, patient developed an acute myocardial infarction and died.
`Reviewer Comment: Relation of Dexmedetomidine to acute MI and death is not clear.
`While Dexmedetomidine is likely causal for the hypotension while it was being infused,
`patient appeared hemodynamically stable for 3 days until the occurrence of the MI. It
`appears doubtful the Dexmedetomidine was causal for the MI and death.
`
`STUDY 97-249
`
`Patient 109
`
`Sponsor coded this patient as a Discontinuation. However, patient died 16 days after start
`of study drug. This is a 47 year old with a history of coronary artery disease, prior
`coronary artery surgery, hyperlipidemia, dyspnea on exertion, and obesity who
`underwent coronary artery by-pass surgery. Approximately 14 hours following initiation
`of Dexmedetomidine, patient developed circulatory collapse, hypotension, and acute
`myocardial infarction. At this time, Dexmedetomidine was discontinued and patient was
`returned to the Operating Room for apparent repair of incomplete coronary re-
`vascularization. Patient died as a result of multi-organ failure.
`Reviewer Comment: The record is not clear as to the proximate cause of death: was the
`initial surgical repair insufficient as to cause a myocardial infarction and subsequent
`circulatory collapse or did Dexmedetomidine causehypotension that resulted in an acute
`MI? This reviewer is of the opinion that the cause of death was the direct result of the
`surgical repair.
`
`SECTION 8.4
`
`DISCONTINUATIONS
`
`The following is a review of all discontinuations (N=41) that occurred in Abbott
`sponsored trials. Sponsor reports no discontinuations in the Japanese trials. Fourteen
`
`

`

`64
`
`(N=14) discontinuations occurred ii “sponsored trials; sponsor states 3 of the
`case report forms involving these discontinuations are not available. In addition, sponsor
`says no patient data listings are available for any of the Orion discontinuations.
`
`STUDY 95-002
`
`Patient 0202
`
`65 year old with cholangiocarcinoma, mild COPD, and angina underwent a biopsy of
`' peritoneal implants and alcohol splanchnicectomy. Patient was discontinued because
`surgeon decided to extend surgical prep to the neck which necessitated removal-of’study
`required EKG leads. Patient received a minimal amount of agent.
`Reviewer Comment: Discontinuation not related to study drug;
`
`STUDY 95-004
`
`Patient 0109
`
`59 year old with coronary artery disease, insulin dependent diabetes, hyperlipidemia.
`hypertension and morbid obesity underwent 4 vessel coronary artery by-pass. Surgeon
`canceled study drug infusion 44 min prior to scheduled termination; at time of
`cancellation of infusion, patient was hypotensive with low 02 saturation and receiving
`inotropic support. Postoperatively, patient developed cerebrovascular accident.
`
`Reviewer Comment: While there are many confounders associated with this subject,
`Dexmedetomidine maybe involved in the development of the hypotension.
`
`Patient 212
`
`68 year old with coronary artery disease, hypertension, cardiac arrhythmias, unstable
`angina underwent coronary artery by-pass grafting. Study drug was discontinued about 3
`hours after initiation secondary to an aortic dissection. A long coronary artery by-pass
`time occurredrliyer function enzymes were mildly elevated the day after surgery.
`Reviewer Comment: Discontinuation is not likely related to effects of the drug.
`_,
`Postoperative elevation of liver function enzymes is likely due to long by-pass time.
`
`Patient 503
`
`'
`
`-
`
`51 year old with a history of non insulin diabetes, symptomatic peripheral vascular
`disease. hypertension, history of hepatitis, history of myocardial infarction, and
`congestive heart failure underwent coronary artery bypass. Left ventricular ejection
`fraction was poor (31%) preoperatively. The patient should have been excluded from the
`study but was inadvertently included. Patient deve10ped hypotension soon after start of
`study drug. Hypotension was persistent. Infusion" began prior to the repair of coronary
`vessels.
`-*-
`'
`
`

`

`
`
`65
`
`Reviewer Comment: Dexmedetomidine appears responsible for the hypotension. It is
`possible however that the hypotension was primarily the result of the patient’s very poor
`myocardial function.
`
`Patient 612
`
`45 year old with prior myocardial infarction, angina, multivalvular heart disease (but
`good left ventricular function), and hypercholesterolemia underwent coronary artery
`bypass. Study drug was infused for approximately 1.5 hours. Operation was uneventful
`until opening of pericardium when cardiac arrest occurred. Following revascularization,
`- patient experienced a routine postoperative course. Dexmedetomidine was discontinued
`at time of cardiac arrest.
`.
`.
`Reviewer Comment: There is no clear relationship of study drug to the cardiac arrest.
`
`Patient 930- l
`
`52 year old with coronary artery disease, insulin dependent diabetes, hypothyroidism, and
`hypercholeSterolemia underwent coronary artery bypass. Study drug was stopped after 10
`minutes because of need to awaken patient. Subject had a malformed airway making
`intubation impossible.
`Reviewer Comment: Study drug was not responsible for premature discontinuation.
`
`STUDY 96015
`
`Patient 113
`
`56 year old with Type II diabetes, hepatitis seco