Clinical Review
`
`.
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`Appendix Table 10.1.1.f
`
`Demographic and Baseline Characteristics — ALK21-003
`Treatment Group
`
`All
`Subjects
`Placebo
`19Gmg
`380mg
`
`
`No. of SubjectS in the
`ITT Population
`
`62d
`
`239
`
`210
`
`2GB
`
`Sex iN/fili
`;
`
`€ema1e
`
`(years)
`
`Age
`N
`Mean
`Std.Dev.
`Median
`Min-Max
`
`Race 1 Ethnicity (fi.%
`Caucasian
`African American
`Hispanic
`Oiber
`fisian
`Nativa American
`
`(kg)
`
`Hale's Weight
`a
`Mean.
`were.
`Median
`Min~Max
`
`(kg)
`
`-
`
`Female’s Weight
`fi
`Mean
`Std.3ev.
`fiediafi
`Min—Max
`
`(cm)
`
`Male's Height
`fi
`Mean
`Sté.2ev.
`Median
`Min—Max
`
`423 ( 67.8)
`201 t 32.2)
`
`143 { 68.4)
`fié
`( 31.6)
`
`142 ( 6?.6)
`68 ( 32.4}
`
`138 ( 63.3)
`$7 ( 32.7)
`
`-
`
`624
`34.?
`10.6
`46.3
`19- 79
`
`( 83.5)
`S21
`50 r
`8.9}
`32 (
`3.1)
`l3 (
`2.él
`3
`t
`8.5)
`3 (
`9.5)
`
`2G§
`44.?
`16.8
`4é.fl
`21— 79
`
`'
`180 ( 86.1)
`17 t
`8.1)
`7
`t
`3.3)
`3
`l
`1.4)
`1
`t
`$.33
`l
`(
`0.3)
`
`219
`44.6
`13.8
`44.9
`lg“ 72
`
`365
`45.8
`EQ.l
`45.6
`22» 72
`
`309 ( 80.5}
`1? i
`8.1)
`15 (
`?.1)
`7
`l
`3.3}
`1
`(
`0.5}
`l
`(
`6.5}
`
`1?? ( 33.9?
`16 (
`?.8)
`13 (
`4.9)
`5 (
`2.4)
`1
`(
`6.5)
`i
`(
`0.5)
`
`423
`88.5
`:81
`85.0
`50—15?
`
`2G6
`?1.3
`1%.2
`6?.0
`€6~13§
`
`422
`178.3
`?.2
`178.0
`155—205
`
`143
`86.4
`23.5
`82.6
`59~l37
`
`66
`72.2
`36.4
`68.fi
`46'113
`
`143
`178.1
`?.3
`178.0
`157-195
`
`142
`83.6
`19.1
`35.0
`1~159
`
`63
`?G.8
`15.3
`$6.§
`50-129
`
`161
`178.1
`?.§
`2?3.6
`253-205
`
`138
`98.?
`3.93.3
`39.8
`50—156
`
`66
`71.6
`1?.3
`66.§
`46~13§
`
`138
`1?8.8
`<.§
`1?? 5
`165—‘89
`
`(Source: Applicant’s Table 6, Module 5, Clinical Study Report, ALK21-003, P. 50)
`
`(table continues on next page)
`
`178
`
`
`
`
`
`Adooalqgssod{sag
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`Appendix Table 10.1.1.g
`
`Demographic and Baseline Characteristics (contd.)
`
`Treatmeat Group
`
` $zd.Dev.
`
`.:
`16..G
`15au135
`
`.3
`.E
`.0
`,
`13) 2&5
`
`150~1aa
`
`259-183
`
`Median
`[113. z) @452):
`
`7.4)
`45 i
`$.42
`4a (
`6.3)
`39 (
`5.1)
`38 <
`5.8)
`35 (
`5.9)
`35 (
`5.3)
`33 r
`32 4 3.))
`3)
`(
`5.0)
`3)
`l
`3.6)
`39 (
`4.8)
`33 i 4.))
`27 z
`4.3)
`2)
`(
`4.3)
`26 (
`4.2)
`25 (
`a.e)
`23 i
`3.2)
`17 (
`2.?)
`1?
`i
`2.?)
`13 <
`2.1)
`12 (
`1.9)
`a
`z
`1.3)
`6 I
`1.Q)
`5
`(
`0.3)
`
`:3 z
`14
`(
`i) (
`2)
`(
`22 (
`1)
`i
`E
`s
`:0 z
`10 (
`)1 (
`a)
`l
`)0 (
`is (
`a
`i
`8 i
`a
`z
`7
`t
`3 C
`a
`z
`a
`t
`a
`t
`3
`c
`2 l
`2 (
`
`7.2)
`6.7)
`§.?)
`6.7)
`5.?)
`5.3)
`5.3)
`4.8)
`4.3)
`5.3)
`5.3)
`4.s)
`4.8)
`3.9)
`3.8)
`3.8
`3.3)
`2.4}
`2.4)
`2.9)
`1.9)
`1.4)
`1.0)
`1.0)
`
`?.1)
`)5 (
`5.7)
`)2 {
`3.?)
`12 i
`5.7)
`12 (
`5.7)
`)2 i
`5.7)
`)2 <
`6.2)
`11 i
`6.2)
`13 i
`é.8)
`10 {
`4.8)
`1Q (
`a.a)
`1a {
`4.8)
`10 (
`4.3)
`9 1
`$.83
`19 {
`4.3)
`a (
`4.3)
`a i
`?
`i. 3.3)
`6 t
`2.9)
`,é ( 2.))
`4 {
`2.9)
`a
`(
`1.9)‘
`3
`(
`1.4)
`2
`i
`1.0)
`2 i
`1.9)
`
`?.3)
`16 t
`6.8)
`14 i
`6.3)
`13 t
`5.9)
`12 <
`5.9)
`12 i
`s.§)
`12 (
`5.4)
`11 (
`4.4)
`a
`4
`11 ( 3.))
`10 4
`4.?)
`9 ( 4.))
`is 4
`4.9)
`8
`z
`3.9)
`% (
`$.43
`§
`(
`$.4)
`8
`§
`3.9)
`6
`<
`2.9)
`6 i
`2.9)
`6 {
`2.3)
`a
`i 2.))
`4
`z
`2.0)
`2 (
`2.o)
`2 (
`2.6)
`1
`(
`0.3)
`
`303 ( é8.c
`is) ( 1?.5)
`212 ( 3a.s)
`
`i 49.8)
`)0)
`36 g 27.2)
`68 ( 33.n9
`
`2a2 ( 48.6)
`36 {
`7.1)
`72 ( 34.3)
`
`97 1 4?.3)
`3? g 18.0)
`)1 a 34.6)
`
`2?6 < 33.3)
`
`90 i 43.1)
`
`90 i 42.9)
`
`9a ( 43.9)
`
`( 1$.3)
`6)
`r 38.6)
`:9)
`9 ( 2.))
`
`73 ( 12.c)
`15 ( 2.)
`
`9.1)
`t
`=0
`68 c 32.5)
`a
`t
`1.))
`
`i 11.3)
`2)
`5 t
`2.4)
`
`24 < 11.4)
`a)
`( 29.0)
`3
`(
`1.4)
`
`29 < 13.8)
`3 g
`1.4)
`
`21 g 10.2)
`62 L 33.2
`2
`g
`1.0)
`
`23 g 11.2)
`? <
`3.4)
`
`Treatment Centers
`Eidd‘i at. S. 0!)
`Bath Addiction/Reaearch
`Reseaxch
`
`(N,%)‘
`
`Subjects" Treatment Goai‘
`Tetai Abstinence
`Total Abstinence, but
`a lapse is possible
`cacasiofiai Gsa
`fiance
`Tamparary Ab
`
`Regular use but
`quantity controlled
`Ma goal
`
`
`
`
`
`Adogamassed)seg
`
`fie. of gubjecte with Lead—in fl
`rinaiag (fi,%)
`5
`.71 ( n1.5)
`
`:90 ( 90.9)
`
`:33 ( 91.))
`
`188 ( 9).?)
`
`3a). Pic E1*s
`$24
`64.§
`23.)
`u3.3
`0-190
`
`‘cse
`209
`65.2
`24.3
`a6.)
`6-360
`
`210
`66.6
`26.4
`63.3
`0-198
`
`/
`
`292
`64.3
`25.9
`a3.3
`lefie
`
`(fiahle ccnsinues on next page)
`
`Heavy arinkinq Gays 30
`
`N M
`
`ean.
`tfi.§av.
`Median
`Mianax
`
`av
`
`(Source: Applicant’s Table 6, Module 5, Clinical Study Report, ALK21-003, P. 51)
`
`179
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`Appendix Table 10.1.1.h
`
`Demographic and Baseline Characteristics (contd.)
`
`All
`Siubjeaet“
`Pia/Vega
`159ng
`
`
`Treatment Group
`
`$3343 of Heavy winking 235% 38, Says Ere First Ease
`N
`$24
`269
`Mean
`3%.5
`19.3
`Std.0ev.
`7,“:
`2.5
`Median
`192.53
`28.13
`Minn-Max
`flu 3%
`43« 33
`
`»
`°. Drinking Says 39 Days Pre First Dose
`N
`6241
`ivtean
`nae.
`Stacey“.
`23.1
`Median
`8.3.3
`Min—Max
`Q—lfic
`
`2339
`76.4
`22.9
`869.8
`8-306
`
`183:). of Drinking Days 3% Says {Ere Firs: {Jase
`N
`624
`Mean
`22.9
`Stdfiav.
`6.9
`Median
`2i.{.‘a
`Minmax
`0« 3f}
`
`.282
`22.9
`6.9
`24 43
`G~ 30
`
`2.1003201 Dependence Scale
`N
`Mean
`Sad.bev.
`Median
`féiza—Max
`
`cere‘
`306
`1?.1
`7.4
`18.5
`i- 42
`
`100
`1.6.6
`7.2
`16.8
`2- 42
`
`_
`
`2.1a
`19.7
`7.9
`19.?
`(3- 3f)
`
`210
`75.?
`23.2
`83.3
`ease
`
`21%
`23.G
`7.9
`25.12}
`Bu 3%
`
`11433
`1.2.8
`7.2
`17.6
`(£— 40
`
`380221;:
`
`235
`29.2
`7.8
`3.9.9
`0.. 30
`
`265
`26.1
`23.3
`83.3
`0—200
`
`2055
`22.8
`7.0
`25.0
`0m 38
`
`3.03
`16.9
`7.9
`16.0
`' 1' 39
`
`m
`(D
`%
`
`23°
`0.,
`$1
`{5'
`
`(D
`0
`o
`.0
`<
`
`Gnemplcyad at Baseline2
`1.826
`'
`Yes
`
`8‘33 43
`S33 {
`89 { 14 ’5}
`
`12‘;
`31
`
`( 84.7)
`( 14 8)
`
`128 i 84.3)
`31
`( 3.4.8,)
`
`178 ( 86.8)
`2‘?
`( 13.2)
`
`Attan-fieax‘ An; Salf Help Groups; at Baseline“
`so
`533 i 88.6)
`Yes
`65% ( 3.1.1)
`
`18.3 t 88.5)
`23 (1.1.8)
`
`( 89.0)
`18‘?
`22 ( 3.0.3)
`
`181 t 82.3)
`2!;
`( 11.7)
`
`stroking Status at Easvalima?2
`N3
`Yes
`{Inknown
`
`328 (533.6%)
`2353
`(47.0%)
`3
`( 6.5%)
`
`(511.4%)
`12:?
`88 (42.2%)
`1
`I 0.5%)
`
`(49.2%)
`3.233
`2% (52.5%)
`1
`l 0.5%)
`
`.
`165 (53.2%)
`99 (48.3%)
`l
`( 9.5%)
`
`
`'
`'
`'
`4
`actor:
`‘Perc Yr.
`*The 23:13 was added 1:0 the prance-01 in April 2&2, after earcllment had: pagan. Subjects
`crammed prior to that cats did no: complete the questioanaire.
`
`(Source: Applicant’s Table 6, Module 5, Clinical Study Report, ALK21-003, P. 52)
`
`Applicant’s Efficacy Analysis
`Overview:
`
`The Applicant found that, with respect to the primary endpoint, treatment with Medisorb
`Naltrexone 380-mg was associated with a 25% decrease in the event rate of heavy drinking
`compared to treatment with placebo, and the difference was statistically significant. The event
`rate of heavy drinking in the 190-mg group was also less than placebo (17% less). However, this
`
`180
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`difference did not reach statistical significance. Similar results were obtained with the definition
`of heavy drinking was made slightly more stringent (2 3/4 drinks per day instead of 24/5 drinks
`per day).
`
`Among patients abstinent at baseline, the event rate of heavy drinking was even more reduced in
`the Medisorb Naltrexone l90- and 380-mg groups. Again, however, the difference was
`statistically significant only for the 380—mg group.
`
`The effects of treatment on an individual patient basis were explored using a responder analysis.
`Treatment response was defined using various cut—offs of the average number of heavy drinking
`days per month. Alkermes found that there were more responders in the 380-mg group than in
`the l90—mg or placebo groups, especially at the broader (i.e. less stringent) cut-offs for treatment
`response.
`>
`
`Due to the DSI-findings of protocol violations that could potentially have led to reporting or
`assessment biases, the Applicant was asked to reanalyze the efficacy data after excluding
`subjects from these two sites. Alkermes found that the reduction in the event rate of heavy
`drinking in the Medisorb Naltrexone groups was lower than that observed upon analysis of the
`entire database (reduction in heavy drinking compared to placebo was 6% for the 190-mg group
`and 12% for the 380-mg group). Alkermes considered these results to still show a positive
`overall treatment effect.
`
`In summary, based on its analyses, Alkermes concluded that treatment with Medisorb Naltrexone
`380-mg (but not l90-mg) is efficacious in the treatment of alcohol dependence.
`
`Primary Efficacy Analysis: Event rate of heavy drinking
`
`a) Medisorb Naltrexone vs. pooledplacebo group
`
`The primary efficacy analysis was performed on all heavy drinking events from the first day of
`treatment up to 30 days following the last dose of study drug. A heavy drinking event was
`defined as a day on which alcohol consumption was 2 5 drinks (men) and Z 4 drinks (women).
`The analysis used 8 strata corresponding to predefined factors used in the dynamic
`randomization: gender (male/female), lead-in-drinking (yes/no), treatment goal of abstinence
`(yes/no).
`
`Appendix Table 10.l.l.i (next page) displays hazard ratios for the event rate of event drinking
`for the Medisorb Naltrexone l90-mg and 380-mg groups, compared to the pooled placebo group.
`The table shows that, compared to placebo, treatment with Medisorb Naltrexone 380-mg was
`associated with a 25% decrease in the event rate of heavy drinking and this difference was
`statistically significant (p = 0.0245). Treatment with Medisorb Naltrexone 190-mg resulted in a
`17% decrease in the event rate of heavy drinking, but this difference was not statistically
`significant (p = 0.744).
`
`' 181
`
`

`

`Clinical Review
`
`-
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`
`Medisorb Naltrexone ,
`
`'k
`
`
`
`Appendix Table 10.1.1.i: Applicant’s Analysis: Event rate of heavy drinking (2 4 drinks/day
`women or 2 5 drinks/da men vs. ooled lacebo routs — Stud ALK21-003
`
`
`
`
`Medisorb N23322:? 190—mg vs.
`Medisorb Naltrexone 380-mg vs. Placebo
`'
`Hazard ratio
`P value
`Estimate
`Hazard ratio
`P value
`AnalySIS
`950/0 CI)
`950/0 CI
`
`0.83 (0.68,l.0)
`0.75 (0.60, 0.94)
`-0.186
`StratifiedbySStrata
`* Not adjusted for baseline percent heavy drinking
`(Source: Applicant’s ALK21-003 Study Report, Appendix Tables, Table 14.2.1, P. 39)
`
`0.0744
`
`
`
`0.0123
`
`b) Medisorb Naltrexone 190—mg vs. 2-mL placebo, and 380-mg vs. 4—mL placebo
`
`Treatment comparisons were repeated using the respective placebo to the Medisorb Naltrexone
`dose and the 8 randomization strata (Appendix Table 10.1.1.j). Comparisons using 7 strata and
`an unstratified analysis were also conducted. A 7-strata analysis was used because one of the
`strata (gender: female, lead-in—drinking: no, treatment goal of abstinence: yes) consisted of only
`5 subjects, none of whom was assigned to the placebo group. Since there were no placebo
`patients in this stratum, the preplanned analysis would exclude data from this stratum.
`Therefore, the 2 smallest strata were collapsed to permit a stratified analysis that included all
`subjects.
`
`Using the 8 strata analysis, the treatment effects for both the 190-mg vs. 2-mL_ and the 380—mg
`vs. 4-mL comparison were statistically significant. Compared to treatment with the respective
`placebo groups, treatment Medisorb Naltrexone reduced the event rate of heavy drinking by 76%
`and 35%, respectively (p = < 0.001 each) However, the treatment effect was not significant
`based on the 7 strata or on the unstratified analysis:
`
`Appendix Table 10.1.1.j:
`
`Applicant’s Analysis: Event rate of heavy drinking, individual
`placebo groups — ALK21-003
`
`
`- Vivitrex l90—m vs. 2-mL lacebo
`
`.
`
`Hazard ratio
`
`Analysis"
`
`'
`
`'
`
`Vivitrex380—m vs. 4-mL tlacebo
`
`Hazard ratio (95%
`
`Stratified by8strata
`Stratified by7strata
`
`
`
`0.245 (0192,0214)
`-1.406
`0.861 (0.671,1.104)
`-0.150
`0.971 (0.725,1.282)
`-0.029
`* Not adjusted for baseline percent heavy drinking
`(Source: Applicant’s Tables 14.2.6.2, 14.6.2.4, and 14.2.6.8, Demographic Data Summary Figures and Tables,
`Clinical Study Report ALK21-003, P. 62, 64, and 68)
`
`<0.0001 —0.420
`0.2276
`—0.456
`0.8259
`-0.254
`
`
`
`0.650 (0.502,0.842)
`0.624 (0489,0822)
`0.702(0.526, 0.919)
`
`0.0011
`0.0006
`0.0100
`
`The effect of placebo volume on the event rate of heavy drinking was also evaluated. The
`difference between the 2-mL and the 4-mL placebo group was not statistically significant
`regardless of which stratification method was utilized.
`
`182
`
`
`
`
`
`
`
`
`
`'
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`Appendix Table 10.1.l.k
`
`
`
`'
`
`Applicant’s Analysis: Event rate of heavy drinking - Effect of
`VI lacebo volume — ALK21—003
`Hazard ratio (p- value)
`4—mL lacebo vs. 2-mL ulacebo
`
`
`
`
`
`
`REVIEWER COMMENT:
`
`
`
`
`The stratified and unstratified analyses comparing each Medisorb Naltrexone dose with its
`respective placebo group show different outcomes than that of the 8-stratum analysis of the
`Medisorb Naltrexone doses and the pooled placebo group. This suggests that the placebo
`groups are distinct. However, per the Applicant’s evaluation, there does not appear to be an
`effect of placebo volume on the efficacy outcome. Therefore, pooling of the placebo groups
`for comparison of efficacy is acceptable
`'
`
`c) Imputing Heavy Drinking Days for Missing Data
`Alkermes constructed a sensitivity analysis for the event rate of heavy drinking, in which
`missing data during the middle of the study (i.e., between randomization and discontinuation)
`were imputed as heavy drinking days. A total of 136 applicable drinking days were imputed to a
`heavy drinking day; 21 in the placebo group, 64 in the Medisorb Naltrexone 190 mg group, and
`51 in the Medisorb Naltrexone 380 mg group. The results of this analysis showed statistically
`significant reductions with Medisorb Naltrexone 380 mg versus placebo for the 8-strata, 7-strata,
`and unstratified analysis. These results were similar to those of the primary efficacy analysis in
`which no imputation strategy was implemented for missing data.
`
`Appendix Table 10.1.1.1:
`
`Applicant’s Analysis: Event rate of heavy drinking, Imputing
`heavy drinking days for missing data — ALK21-003
`
`
`Vivitrex 190—m_ vs. 2-mL lacebo
`.
`Hazard ratio
`Analysis"
`
`
`
`
`0.0815
`0.0826
`
`
`
`0.825 (O.681,1.022)
`-0.180
`Stratified by 8 strata
`0.826 (0.682,1.022
`-0.179
`Stratified by7strata
`
`0.900 (0.726,1.116)
`-0.106
`Unstratified
`* Not adjusted for baseline percent heavy drinking
`(Source: Applicant’s Tables 14.2.7.1; 14.2.7.3, and 14.2.7.5, Demographic Data Summary Figures and Tables,
`Clinical Study Report ALK21-003, P. 70, 72, and 74)
`1
`
`Vivitrex 380-m_ vs. 4-mL tlacebo
`Hazard ratio (95%
`
`.
`
`-0.256
`-0.275
`-0.279
`
`0.700 (0.562,0.872)
`0.687 (0550,0858)
`0.756 (0596,0959) '
`
`0.0016
`0.0009
`0.0210
`
`
`
`
`
`
`REVIEWER COMMENT:
`
`Data missing due to premature withdrawal from the study (i.e. prior to Day 169) were not
`imputed as heavy drinking days. As already shown, 222 patients discontinued treatment
`prematurely, and these patients’ missing days of data were not accounted for in the
`Applicant’s sensitivity analysis. Therefore, this was neither an adequate nor an appropriate
`strategy to evaluate the effect of missing data on the efficacy results.
`
`183
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`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`
`
`Su lemental anal ses of the rimar efficac end oint event rate of heav drinkin
`
`a) Sensitivity analysis ofthe definition ofheavy drinking
`The rate of heavy drinking was reanalyzed using a modified definition of heavy drinking (24
`drinks/day for males and Z3 drinks/day for females). The event rate of heavy drinking was
`calculated using the pooled placebo group for comparison. Results for this analysis were similar
`to those of the primary analysis.
`
`Appendix Table 10.1.1.m: Applicant’s Analysis: Event rate of heavy drinking — Alternate
`definition of heavy drinking (2 4/3 drinks per day)
`
`
`
`Vivitrex 380—m_ vs. 4-mL ulacebo
`Vivitrex 190-m_ vs. 2-mL lacebo
`-
`Hazard ratio (95%
`.
`Hazard ratio
`CI
`P ““6
`95% CI
`0.801 (0656,0978)
`-0.222
`0.4222
`0.928 (0.768,1.120)
`-0.075
`(Source: Applicant’s Table 14.2.8.1, Demographic Data Summary Figures and Tables, Clinical Study Report
`ALK21-003, P. 75)
`
`Analysis"?
`
`.
`
`P va'“
`0.0292
`
`b). Controllingfor baseline percent heavy drinking -
`Baseline percent heavy drinking was a'highly influential predictor variable for heavy drinking
`overall in the study. For each increase of 10% in baseline percent heavy drinking (i.e. 2 5/4
`drinks per day), there was an increase of 26% in the event rate of heavy drinking during the
`study period (P<0.0001).
`
`Controlling for baseline heavy drinking, where baseline was defined as 30 days prior to the first
`drug dose, the analysis showed that patients in the Medisorb Naltrexone 380 mg group
`experienced a 25% reduction (hazard ratio 0.748) in the event rate of heavy drinking compared
`with subjects in the placebo group (p = 0.0047). Patients in the Medisorb Naltrexone 190 mg
`group showed a 14% (hazard ratio 0.861) reduction in the event rate of heavy drinking compared
`with subjects in the placebo group that was not statistically significant (p = 0.1060).
`
`Appendix Table 10.1.1.n
`
`Applicant’s Analysis: Event rate of heavy drinking adjusted
`for baseline percent heavy drinking — ALK21-003
`
`
`
`380-m vs. .lacebo
`0.748 (0 0047)
`0.737 (0.0029)
`0.759 (0.0104)
`
`Analysis
`
`Hazard ratio (-value)
`190-m_ vs. lacebo
`0.861 0 1060)
`Stratified b 8 strata
`0.861 (0 1055)
`Stratified by 7 strata
`0.89 (0 2396)
`Unstratified
`(Source: Applicant’s Table 12,- Clinical Study Report ALK21-003, P. 60)
`
`FDA Requested Analyses
`
`.
`a) Responder Analysis
`Alkermes conducted a responder analysis using different definitions (or categories) of a
`treatment responder. Response (or treatment success) was based on the extent to which patients
`could abstain from heavy drinking, where heavy drinking was defined as Z 5 drinks/day (men)
`
`184
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`

`

`
`
`
`
`Adooelqgssodiseg
`
`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`and 2 4 drinks/day (women). The monthly proportion of responders in each treatment group was
`calculated, and the proportions in the Medisorb Naltrexone groups compared to those in the
`pooled placebo group. The results are shown below:
`
`Appendix Table 10.1.1.0
`
`Applicant’s Analysis: Responder Rates — ALK2'1-003
`9-Vaiuat
`
`
`E (s)
`wrangmw’fiéifiiég
`Poet—Baseline} Reavy
`mu7???a___aEEE33£3MumMmAHm§§§E§-wfl_——§§Efifimmufll?2acefib
`Placgi“
`Drinking Days per Hench?
`
`
`Ali Subjects
`a
`
`Neal:
`86 i 24%)
`
`nw2ea
`23 t 13%}
`
`Nwzfifi
`29 ( 14%)
`
`Nwfifll
`34 (
`i?%§
`
`$.3938
`
`G.§626
`
`an:
`
`0-2
`
`0~3
`
`3-4
`
`165 ( 2%)
`
`2m r 22%)
`
`53 ( 23%)
`
`623
`
`r 34%;
`
`(3.3217
`
`0.0059
`
`295 l 34%)
`
`56 l 27%)
`
`68 ( 33%)
`
`$1 ( d0%)
`
`6.2285
`
`6.0663
`
`248 r 41%)
`
`6a ( 33%}
`
`83 ( 40%)
`
`9?
`
`( 4$%)
`
`Q 2&42
`
`0.Q022
`
`289 ( 41%)
`
`0.3133
`110 ( 55%)
`85 ( age)
`84 ( 32%)
`
`
`O.fi063
`
`‘ Brinking dean up Ln 3% days after the last dose.
`3 Heavy firinking Gaye per Month 2 {Percent Eeavy Brinking Daya‘Bfi.d)iiQO.
`* Chi—Sum re. new; .
`
`(Source: Applicant’s Table 25, Clinical Study Report ALK21-003, P. 92)
`
`REVIEWER COMMENT:
`
`.
`
`The table above presents response rates on an “average number of heavy drinking days per
`month” basis, and shows the proportion of patients in each treatment arm that met Varying
`cut-offs of monthly average number of heavy drinking days. This analysis did not require
`that patients never exceed the specified number of heavy drinking days in a given month;
`instead, all of the patients’ heavy drinking days during the observation period were divided
`by 30 to calculate an “average monthly number of heavy drinking days.”
`
`The difference in the proportions of responders between the Medisorb Naltrexone 190—mg
`and placebo groups was numerically small and not statistically different at any definition of
`treatment success (i.e. cut-off for average number of heavy drinking days per month).
`
`While there were more Medisorb Naltrexone 380-mg patients (17%) than placebo patients
`(11%) who showed a sustained absence of heavy drinking over the treatment period (i.e. 0
`average monthly heavy drinking days), this difference was not statistically significant.
`Among persons who averaged up to 1 heavy drinking day per month (i.e. up to 6 heavy
`drinking days, on average, during the treatment period), the difference between the Medisorb
`Naltrexone 380—mg and placebo groups was numerically large and reached statistical
`significance. Similar results were observed at the higher cut—offs of monthly average number
`of heavy drinking days.
`
`Although these findings may suggest a beneficial treatment effect, it is important to keep in
`mind that the results of the Project MATCH and NAS re—analyses showed a greater
`
`185
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`likelihood of adverse drinking-related consequences when patients display drinking patterns.
`other than a sustained absence of heavy drinking over the course of therapy. Therefore the
`most relevant results of this analysis are the results of the first row in the table (“0 post-
`baseline heavy drinking days per month”): a numerically small and statistically non-
`significant difference between Medisorb Naltrexone 380-mg and placebo with respect to the
`proportion of patients who averaged no heavy drinking days each month.
`
`Another critical limitation of the Applicant’s analysis is that it is based on observed data
`only. No imputations were made for missing data, including data missing following
`premature discontinuation from the trial.
`
`Responder analysis — Cumulative plots ofper-subject heavy drinking rates
`Alkermes plotted cumulative distributions of percentage of heavy drinking days for the treatment
`groups pre-study and on during the study. The graphs show that prior to treatment, both the
`placebo and the Medisorb Naltrexone patients had similar frequencies of heavy drinking days.
`Following treatment, all groups had a considerable decrease in the proportions of reported heavy
`drinking days. However, there was not much difference between the plaCebo and 190-mg
`groups.
`
`Appendix Figure 10.1.1.i: Cumulative distribution per-subject heavy drinking rate
`'
`(Medisorb Naltrexone 190 mg vs. placebo)
`
`mammog-
`
`allfi‘lllll
`
`Figure '7’: CumnEafire Distribution: Per-Subject Hem-"y Drinking Rate fliedisorb Naltrexone 190 mg vs Placebo)
`
`(Source: Applicant’s Figure 7, Clinical Study Report ALK21-003, P. 71)
`
`On the other hand, at the end of the treatment period, the proportion of Medisorb Naltrexone
`380-mg patients who reported heavy drinking days was substantially lower than the placebo
`
`186
`
`
`
`
`
`Adogems-sodrsag
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`
`group. For example, approximately 11% of patients in the placebo group reported zero heavy
`drinking days, compared to almost 17% of patients in the 380-mg group.
`
`Appendix Figure 10.1.1.ii: Cumulative distribution per-subject heavy drinking rate
`(Medisorb Naltrexone 380 mg vs. placebo)
`
`mammal
`
`b) Event rate ofdrinking above the NIAAA derived “safe ” level (2 I drink/day (women) and Z 2
`drinks/day (men)) over the 24-week period
`'
`The Division requested that the Alkermes conduct this analysis as an evaluation of the relevance
`of a statistically significant finding with respect to any observed differences in the event rate of
`heavy drinking.
`
`Alkermes found that, without stratification for gender, lead-in drinking, and treatment goal, there
`was no statistically significant difference between either of the Medisorb Naltrexone groups and
`the pooled placebo group, with respect to the event rate of drinking above the NIAAA “safe”
`level.
`'
`
`The Applicant attempted to determine whether patients’ pre-randomization drinking patterns
`influenced this result. Patients were sub-categorized according to whether they were abstinent
`from any drinking in the 4- and 7- days prior to randomization/initiation of study treatment. For
`both the 190-mg and the 380-mg groups, prior abstinence (for either 4 or 7 days) was associated
`with a considerable decrease in the event rate of drinking above the NMAA “safe” level.
`
`187
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`REVIEWER COMMENT: These results should be interpreted with caution due to the small
`numbers of patients in these groups.
`
`Subgroup
`
`
`Abstinent 4 days_pre randomization
`
`18
`17
`
`
`Abstinent 7 days re randomization
`
`Placebo, N
`
`190 m, N
`
`380 mg, N
`
`
`
`
`
`
`Appendix Table 10.1.1.p
`
`Applicant’s Analysis: Event rate of drinking above the
`NIAAA-derived ‘safe’ drinkin level — ALK21-003
`Vivitrex 190-m vs. 2 mL '- lacebo
`Vivitrex 380-m vs. 4-mL nlacebo
`
`»
`
`
`
`Analysis*
`
`.
`
`Hazard ratio
`
`.
`
`Hazard ratio (95%
`
`AbStlnentT‘dfySpmr
`to randomlzation
`
`Amman” dawn“
`to randomizatlon
`
`0.954(0.809,1.126)
`0.251(0.152,0.808)
`
`0.0128
`
`-0105
`-1.202
`
`0901 (0759,1068)
`0.200 (0 142,0626
`.
`
`)
`
`0.2295
`0.0017
`
`0.160 (0049,0522)
`
`0.0024
`
`-1.428
`
`0.240 (0 085,0 680)
`
`0.0072
`
`* Not adjusted for baseline percent heavy drinking
`(Source: Applicant’s Tables 142.21.], 142.212, and 142.213, Demographic Data Summary Figures and Tables,
`Clinical Study Report ALK21-003, P. 238-240)
`
`0) Event rate ofany drinking over the 24-week period
`The Division also requested that the Applicant calculate the event rate of any drinking,
`regardless of quantity. Alkermes found that, in the overall population, there was no significant
`difference in the event rate of any drinking between either Medisorb Naltrexone dose and the _
`pooled placebo group. After reanalyzing the data based on pre-randomization drinking behavior,
`the Applicant showed that for both the 190-mg and the 380-mg groups, prior abstinence was
`associated with a considerable decrease in the event rate of any drinking.
`
`Appendix Table 10.1.1.q
`
`Applicant’s Analysis: Event rate of any drinking — ALK21—003
`
`Sub rou
`' g
`
`p
`
`
`
`Hazard ratio -value
`190-m_ vs. lacebo
`380-m_ vs. lacebo
`0 982 (0 08041)
`0.959 (0.5811)
`0 362 (0 0056)
`0.323 (0.0008)
`0205 (O 0018)
`0.295 (0.0079)
`
`Abstinent during the 4 days prior to randomization
`No lead-1n drmkmg (abstlnent during the 7 days pr10r
`to randomization)
`(Source: Applicant’s Table 30, Clinical Study Report ALK21—003, P. 98)
`
`Secondary Efficacy Analyses
`a) Percent days abstinent
`Using a last observation carried forward (LOCF) imputation strategy for missing data, the
`Applicant calculated the each group’s percent days abstinence per month. Alkermes found that
`at baseline, the median percent days abstinent at baseline were 19.2%, 16.7%, and 16.7% for the
`placebo, 190 mg, and 380 mg groups, respectively. There were no statistically significant
`
`188
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`differences among groups at baseline. There were no statistically significant differences between
`placebo and the 380 mg group or placebo and the 190 mg group at any time in the study. At 30
`days post-6th dose, the median percent days abstinent increased to 52.4%, 57.0%, and 52.5% for
`the placebo, 190 mg, and 380 mg groups, respectively.
`'
`
`b) Time to relapse to drinking
`Alkermes also compared the time (days) to relapse to any drinking, heavy drinking, and drinking
`above the NLAAA “safe” level across the treatment groups. However, as had previously been
`communicated, the Division does not consider endpoints that rely on time to an initial event to be
`clinically relevant. This is because the intention of alcohol treatment is not to delay drinking, but
`to lead to discontinuation or a clinically meaningful reduction of drinking.
`
`APPEARS ““8 WAY
`0N camera
`
`189
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`10.1.2 Protocol ALK 21-003-EXT
`
`This study is complete.
`
`Title: A multi—center, double blind, extension of Alkermes Study ALK21-003 to evaluate the
`long-term safety of Medisorb
`
`Objective:
`Primary: To evaluate the long-term safety of repeat IM injections of Medisorb Naltrexone
`administered every 4 weeks.
`
`Secondary: To monitor outcome measures related to drinking activity, social functioning, and
`healthcare utilization over the treatment period.
`
`Study Description:
`This was a multi-center, double blind extension of the efficacy trial ALK21-.003 Study ALK21-
`003 was a 6-month, randomized, double-blind, three--arm, parallel group, placebo--controlled
`study of Medisorb Naltrexone (190 mg or 380mg q 4 weeks) vs. placebo1n 624 alcohol-
`dependent patients.
`
`In ALK21-003—EXT, 332 alcohol-dependent patients were treated with Medisorb Naltrexone
`(190mg or 380mg IM) every 4 weeks for 52 weeks beyond their participation in ALK21-003.
`Therefore, subjects who successfully completed both ALK21-003 and ALK21—003-EXT were
`administered a total of 19 injections over 1 year, and subjects who received placebo in ALK21-
`003 were given 13 doses of active drug in the extension study. Subjects administered active drug
`in ALK21-003 continued on the same dose of Medisorb Naltrexone. Thus, total drug exposure
`ranged between 28— 76 weeks. Receipt ofpsychosocial support therapy (BRENDA) was
`voluntary.
`
`The primary outcome was the incidence of adverse events. Secondary outcomes included
`alcohol consumption, social functioning, physical exam findings, injection site assessment, and
`changesin laboratory values.
`\
`
`Number of subjects: A total of 332 subjects (88% of those eligible) entered this extension
`study. At least 6 injections were administered to 212 of these subjects (64%), and 148 subjects
`(45%) completed the study
`
`Study results: Data from this trial Were included in the Integrated Summary of Safety.
`
`190
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`10.1.3 Protocol ALK 21—010
`
`This study is ongoing.
`
`Study Title: A Multi-Center Extension of Alkermes Study ALK21-003-EXT to Evaluate the
`Long-Term Safety of Medisorb Naltrexone
`
`.
`Objectives:
`Primary Safely Objective: To further evaluate the long—term safety of repeat intramuscular'(IM)
`injections of Medisorb Naltrexone (190 and 380 mg) administered every 4 weeks to alcohol
`dependent adults.
`
`Secondary Objectives: To monitor measures related to social fimctioning and healthcare
`utilization
`
`Study Design: This is a multi-center extension of Alkermes studies ALK21-003 (the efficacy
`study) and ALK21-003-EXT (the first extension of the efficacy study). Subjects who
`successfully completed study ALK21-003-EXT are eligible to enroll.
`
`Subjects are given monthly IM injections of Medisorb Naltrexone. Subjects continue to receive
`the same dose administered in ALK21-003-EXT (i.e., Medisorb Naltrexone 190 mg or 380 mg).
`The planned duration of ALK21-010 is 3.5 years or until the study is discontinued.
`
`Safety evaluations include assessment of adverse events (AE5), injection sites, vital signs,
`laboratory test results (hematology, biochemistry, and urinalysis), electrocardiogram (ECG)
`findings, and physical examination results. Additional endpoints include self—reported social
`functioning and healthcare utilization as determined by subject-completed questionnaires.
`
`Number of subjects: As of the original NDA data cut-off date, 99 subjects were enrolled, all of
`whom received study drug. One subject has completed the study, 8 subjects have discontinued,
`and 90 are continuing.
`
`Study results: Interim data were available at the time of NDA submission, and these were
`included in the Integrated Summary of Safety.
`
`191
`
`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`10.1.4 Protocol ALK 21-006-EXT
`
`This trial had not been initiated at the time ofNBA submission.
`
`Title: “An open-label, multi-center study to evaluate the long-term safety of Medisorb
`Naltrexone”
`
`Objective:
`1. To further evaluate the long-term safety of repeat intramuscular ([M) injections of Medisorb
`Naltrexone in patients with alcohol and/or opiate dependence
`2. To monitor measures related to social functioning, healthcare utilization, and drinking
`behavior
`
`Study Design:
`0 Open-label, repeat dose, safety study
`0
`18 sites
`
`0 Treatment duration: 3 years
`_
`0
`Population: N = 200 subjects with alcohol and/or opiate dependence
`. Medisorb Naltrexone dose (IM, dorso-gluteal region): 380 mg IM Q 4 weeks
`
`Key Inclusion Criteria:
`1. Completion of study ALK21-006, or other qualifying trial of Medisorb Naltrexone. Patients
`must have received all previously scheduled doses.
`~ 2. Females of childbearing potential: approved contraception during the study and for 1 month
`following the last dose
`
`Key Exclusion Criteria:
`1. Premature discontinuation of study drug in a previous Medisorb Naltrexone trial
`2. Pregnancy
`-
`3. Any finding that, in the view of the PI, would compromise the patient’s ability to complete the
`study
`
`Prohibited medications:
`
`Acamprosate, disulfiram, oral naltrexone, methadone, levomethadyl acetate/LAAM, and buprenorphine.
`Prescription opiates are permitted only when clinically necessary.
`
`Conduct of Study:
`Visit I/Enrollment
`
`Study enrollment coincides with the final visit of ALK21-006 or any other qualifying Medisorb
`Naltrexone trial. The end—of-study and the enrollment/Visit 1 procedures are combined. Patients
`who provide informed consent undergo physical examination including vital signs and
`assessment of the injection site, as well as laboratory testing, and an ECG. Laboratory tests are
`hematology, blood chemistry with LFTs, urinalysis, and serum pregnancy. The previous 30-
`days’ drinking history is determined using the TLFB method, and subjects complete
`questionnaires regarding health status, social functioning, and healthcare utilization. Any AEs
`
`192
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`

`

`Clinical Review
`
`Mwango A. Kashoki, MD, MPH
`N 21-897
`Medisorb Naltrexone
`
`and concomitant medications are reviewed. Prior to dosing with Medisorb Na