Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`2.4
`
`Important Issues With Pharmacologically Related Products
`
`NSAIDs/Naproxen
`
`Recent concerns regarding the cardiovascular safety of NSAIDs as a class have arisen. See
`Section 1.1, Recomme/za’a/io/z 0/7 fiegzz/az‘agzflc/z’o/z, Section 1.3.3, 5494/, and Section 8.6,
`life/”all”? Rel/few.
`
`Triptans/Sumatriptan
`
`No new issues relate to triptans as a class.
`
`2.5 Presubmission Regulatory Activity
`
`Clinical development of Trexima originally was under IND 60,669. A second IND, 68,436 was
`submitted in December 2003 to conduct clinical studies on the fixed dose combination selected
`
`for further development (Table 3).
`
`Appears This Way
`On Original
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N2l—926
`MT400/Trexima
`
`
`Table 3: Presubmission Regulatory Activity
`
`August 2000
`
`October 2000
`
`60,669 (000), original lND
`Protocol MT 400—203
`
`
`EVa/Z/a/z'o/z of/mp/vxe/z and[/7212er 47/0/76 mm’
`
`
`1'17 coméz'lza/[o/z, 1'17 acme ngraz'lze
`
`
`
`60,669(001), Addendum (002)
`
`Protocol MT 400-204
`
`M2201" rewirz'wzy lopro/aco/Mfé’flfl-Zflf [0
`
`
`address 30—5/4 54 6 review [ISM/es
`
`
`December 2000
`
`
`
`
`
`60,669 (001)
`Statistical review, Dr. Yeh-Fong Chen
`
`1124/ 4715’film:forJ/zzq’y/l/f4flfl—Zfl4
`60669 (007)
`
`Pre-IND meeting
`
`
`(for new fixed dose, IND 68,436
`
`
`'
`60,669
`
`Bio harmaceutical uidance from OCPB
`
`
`
`
`February 2002
`
`
`
`
`68,436 (000)
`C/I'Izz'ca/J/zmfiés 0/1 lfleflxea’dare 60772512741sz
`
`
`Je/ecled
`
`May 2004
`
`ohase 2 meetin_
`
`
`April 2002
`
`July 2002
`
`August 2003
`
`December 2003
`
`'
`
`October 2004
`
`.
`
`60,669
`Pozen clarification on Pre-IND Meeting
`minutes
`
`60,669 (010)
`[7170/pflamzaco/ogy ylzzaj/ 1‘0 anyway
`VdJ’OC’O/ZS/f‘fé’lfllé late/71ml
`
`Biopharrnaceutical guidance
`Phase 3 efficac studies
`
`
`
`
`
`November 2004
`
`68,436
`FDA Comments and reuest for information
`
`April 2005
`
`
`
`
`
`April 2005, HFD-86O Consult
`
`68,436
`Pre-NDA meetin;
`
`Biopharrnaceutical guidance
`
`Secondary efficacy measures
`Biopharrnaceutical guidance
`Effect of mi_raine on harmacokinetics
`
`May 2005
`
`Below I note important issues raised during the pre—submission period, along with the associated
`submission or meeting. I generally limit my discussion to the clinical issues raised, but have also
`included important preclinical issues with direct bearing on the cardiovascular safety of Trexima.
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Pre-IND meeting 160,669zlf0r IND 68,436, new fixed dose|
`
`February 28, 2002
`
`The lack of effective dose-finding studies was discussed with Pozen at the Pre-TND meeting:
`
`“There were two proposed dose—ranging studies for dose selection, and it was noted that
`this would not evaluate all possible dose-combinations for sumatriptan and naproxen.
`Likewise it was not apparent from the submission how the sponsor would determine
`which fixed dose combination ultimately considered optimal. The sponsor responded that
`they would most likely “eyeball” the studies looking for the combination product with the
`best response.”
`
`Machined/135216;
`
`The Division requested a safety pharmacology study in dog to assess the effect of naproxen on
`the risk of sumatriptan-induced vasoconstriction of the coronary artery.
`
`End-of—Phase 2 Meeting
`
`May 6, 2004
`
`The Division stated data would be needed to support any statement
`
`_
`
`,
`Nan—Ch'nfca/
`The Division did not agree that the results of the dog cardiovascular study demonstrate that there
`is no evidence of an interaction between sumatriptan succinate and naproxen sodium on coronary
`, artery vasoconstriction.
`
`November 12, 2004
`FDA Clinical Guidance Letter, 68,436 $008, 0111
`“A Double—Blind, Multicenter, Randomized, Placebo-Controlled Single Dose Study T0 Evaluate
`The Safety And Efi‘z‘cacy OfTrexima In The Acute Treatment OfMigraine Headaches”
`
`No major issues raised in this letter remain unaddressed in the NDA.
`
`Teleconference, clarifications from End-of—phase 2 meeting
`
`October 25, 2004
`
`The Division further clarified that at 2 hours a statistical advantage to Trexima on migraine
`associated symptoms was not required for approval, but that inferiority would suggest a
`‘pathological’ interaction of the components.
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`PIPE/V34 meeting
`Selected Issues:
`
`April 20, 2005
`
`0 The Division stated that chronic, intermittent use of naproxen may be an issue in light of
`the evolving cardiovascular safety concerns. DNDP is unsure how this will affect the
`Trexima application. The company indicated that the number of times Trexima could be
`used monthly might be limited by the limitations on the use of sumatriptan. DNDP
`suggested that the company present arguments to support the safety of chronic,
`intermittent administration at the level they intend for use and in the migraine population
`and suggested the company should include epidemiologic data in this presentation. The
`company noted that there are over the counter migraine products. DNDP noted that this
`did not speak to the question of long term use.
`
`Changes in the Conduct of the Study 0r Planned Analyses
`The SAP was changed between studies 30] and 302 to account for baseline imbalances in
`symptom severity, as follows:
`
`“If any of the baseline symptoms (i.e. pain,lnausea, photophobia and phonophobia)
`suggest a treatment imbalance, as evidenced by a p-value of <0.15 for overall treatment
`differences, then the primary analysis (Trexima versus placebo at 2 hours) for that
`symptom will be adjusted for baseline. Logistic Regression, with the baseline symptom
`and pooled investigator sites as covariates, will be done instead of the Cochran-Mantel-
`Haenszel tes .”
`
`The Division was not apprised of this change at the time, thus requiring additional evidence
`(below) that the change to the SAP was prospective.
`
`The Statistical Analysis Plan for MT400-3 02 was finalized on March 21, 2005, the database was
`locked on March 29, 2005 and the study unblinded to treatment assignments on March 30, 2005.
`
`Below is the signature approving the SAP, showing a date before database lock:
`
`Technical Approver:
`
`
`
`Susan E, Spruill, MS
`Senior Director of Biostatistics, POZEN, Inc.
`
`3 2.! was“
`Date of Approval
`
`Amendments Submitted to the Protocol V
`Amendments submitted to the phase III protocols are minor and do not represent review issues.
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`There were four amendments submitted for study 301:
`
`Amendment 1 June 22 2004 Prior to any subject enrollment, changed the sample size
`from 1200 (300 subjects per treatment arm) to 1400 (350 subjects per arm) and increased
`the approximate number of centers from 50 to 54. The rationale was to accommodate a
`higher-than-expected variability in the incidence of individual associated symptoms of
`migraine at baseline and to improve confidence in obtaining statistical significance for
`clinically meaningful changes regarding the outcome of one or more migraine endpoints.
`
`Amendment 2, August 19, 2004 allowed those subjects who had not treated with study
`drug for six weeks after screening to continue in the study until they had either treated an
`eligible migraine or until the study was terminated. The amendment also increased the
`number of sites participating in the study from approximately 54 to 60. Approximately .
`1074 subjects were enrolled in the study after this amendment was finalized.
`
`Amendment 3, September 23, 2004, added spermicide plus a mechanical barrier as an
`additional acceptable method of contraception. The amendment also added history of
`gastric bypass or stapling surgery as an additional exclusion criterion. Approximately 739
`subjects were enrolled in the study after this amendment was finalized.
`
`Amendment 4, January 31, 2005 added key secondary endpoints, changed the statistical
`methodology for analysis of key secondary endpoints and changed the size of sites to be
`pooled from < 25 subjects to < 20 subjects. The amendment specified time points and
`treatment comparisons to be used as key secondary and other supporting endpoints.
`Clinical disability categories Were defined, and details of health outcome measures
`analyses were specified. The study was fully enrolled prior to finalization of this
`amendment.
`
`Other key dates associated with the study included February 1, 2005, when the Statistical
`Analysis Plan was finalized and February 2, 2005 when the database was locked and the study
`unblinded to treatment assignments.
`
`There were 3 amendments submitted for study 302:
`Amendment 1, same as amendment 2 above, of August 19, 2004
`Amendment 2, same as amendment 3 above, September 23, 2004
`Amendment 3, dated March 8, 2005, was almost the same as amendment 4 of study 302,
`above. It added key secondary endpoints, changed the statistical methodology for
`'
`analysis of key secondary endpoints and changed the size of sites to be pooled from < 25
`subjects to < 20 subjects. The amendment specified time points and treatment
`comparisons to be used as key secondary and other supporting endpoints. Clinical
`disability categories were defined, and details of health outcome measures analyses were
`specified. The study was fully enrolled prior to finalization of this amendment but was
`still ongoing and the blind had not been broken.
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21 -926
`MT400/Trexima
`
`2.6 Other Relevant Background Information
`
`None
`
`3 SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES
`
`3.1 CMC
`
`See CMC review.
`
`3.2 Animal Pharmacology/Toxicology
`
`The two components of Trexima, sumatriptan and naproxen, are currently FDA approved, with
`extensive post-marketing experience. As a result, the non-clinical studies of Trexima were
`designed primarily to evaluate the pharmacology/toxicology of their co-administration. As
`agreed with the Division, no primary or secondary nonclinical pharmacology studies,
`pharmacodynamic drug interaction studies, or pharmacokinetic studies (excluding kinetic
`support to toxicology studies) were conducted for the combination. Similarly, a standard battery
`of safety pharmacology studies (cardiovascular, CNS and respiratory) were not conducted.
`‘
`
`Sa/Qg/péammco/ogy
`
`o Coronary vasoconstrictive potential of sumatriptan combined administration with
`naproxen (MT400-T15 and T17).
`
`A cardiovascular safety pharmacology study recommended by the Division examined changes in
`coronary and carotid artery diameter, resistance, and blood flow after intravenous administration
`of sumatriptan (80 ug/kg) alone and in combination with intravenous naproxen (20 mg/kg), in
`conscious, chronically instrumented beagle dogs. Vital signs, including blood pressure, were
`also evaluated.
`
`I find these experiments indicate a possible additive interaction of naproxen and sumatriptan on
`arterial vasoconstriction and blood pressure.
`
`EWéflMéfl/fl/Q’éylgfl
`The study consisted of three phases. Phase I examined the effect of sumatriptan alone.
`0 On Day 1, animals received a 1-minute infusion of vehicle followed by a bolus of 80
`ug/kg sumatriptan.
`- On Days 2 and 3, animals received only the bolus of 80 ug/kg sumatriptan.
`
`Five days after Phase 1, Phase II examined the interaction of naproxen and sumatriptan in the
`same animals.
`
`0 On Day 1, animals received 20 mg/kg naproxen followed by of 80 pg/kg sumatriptan.
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`o On Days 2 and 3, animals received only 80 ug/kg sumatriptan. Since naproxen has a
`long half-life in dogs (about 35 hours), the single dose during Day 1 of Phase 11 provided
`a declining daily blood level over the 3 days of the experiment.
`
`Phase III was amended to the study design to evaluate possible interaction of naproxen with a
`higher dose of sumatriptan, 200 ug/kg. However, this portion of the study is uninterpretable due
`to design issues. An initial dose of sumatriptan was used to establish the baseline sumatriptan
`response, and 60 minutes later sumatriptan was readministered in combination with naproxen.
`Possible tachyphylaxis of the sumatriptan response was not, however, accounted for, preventing
`separate estimate of the contribution of naproxen.
`
`Eyperzhey/a/fl‘lmflzgx '
`
`Vasoconstriction
`
`Cora/za/j/Ar/e/y Sumatriptan alone reduced coronary artery diameter by about 4%. Co-
`administration of naproxen and sumatriptan reduced coronary artery diameter about 8%. In 2 out
`of 6 animals (1101 and 1104), the ddafiz'o/m/reduction with the combined drugs, beyond that
`caused by sumatriptan alone, was almost 10% of total baseline vessel diameter (Table 4; all data
`tables express diameter in millimeters, not percent). Five of the 6 animals showed increased
`vasoconstriction from the combined drugs. Lower levels of naproxen (achieved by giving a
`single dose of naproxen day 1 and allowing for natural metabolism over 3 days after the initial
`dose) did not show this additive vasoconstrictive effect with sumatriptan (Table 5, Table 6).
`Corresponding to the decreased coronary vessel caliber was an increase in vessel resistance,
`greatest on day l of naproxen dosing (Table 7), and decreasing as the naproxen was metabolized
`over days 2 and 3 (not shown).
`'
`
`Appears This Way
`On Original
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 4: Coronary artery Diameter, Day 1
`
`(NDA application ‘Study QCBW 106, Table 1.1)
`Maximum Refiuctions in
`Coronary Diameter (mm) on Day 1
`
`Phase I
`Phase II
`(Vehicle 4 80 pgikg Sumatrintan}
`(20 mglkg Naproxan + 80 pgikg Sumatriptan)
`
`Change
`Change
`Change
`Phase II -
`Minimum
`From
`From
`minimum
`Dog
`
`
`
`Baseline In}Diameter {b}Baseline [3]Baseline {clID Baseline [3] Diameter {b} Phase I
`
`
`{101
`3.6071
`3.5633
`«0.0438
`3.5385
`3.1785
`‘0.3601
`~0.3163
`$102
`3.9718
`3.8983
`~0.1635
`4.173‘
`3.7839
`‘0.3941
`~0.2307
`1104
`3.2097
`3.1610
`-0.0487
`3.4923'[d§
`3.1430
`*0.3493
`~0.3006
`1105
`3.0507
`2.9817
`-0.0590
`3.4085
`3.1598
`-0.2436
`~0.1796
`1107
`3.9149
`3.6082
`'0.3°67
`3.1783
`3.0694
`-0.1094
`0.1973
`1108
`2.7476
`2.6103
`'0‘1375
`2,8021
`2.6460
`‘0.1551
`'0.0185
`
`'
`
`Mean
`STD
`95% CI
`p-value
`
`-o.1414
`0.1976
`(~O.3487, 0.0659)
`0.1399
`
`{a} The baseline values were obtained by taking the.mean of the data cgllected during the 5 minute interval
`immediately preceeding vehicle (Phase I) or naproxen (Phase II) administration.
`{b} Minimum Coronary Diameter during the first hour after sumatriptan administration.
`{0} Minimum Coronary Diameter ‘ Baseline Coronary niameter.
`{d} An outlier value of 5.4712 mm at the one minute ore-NAP sampling time was determined
`to be an outlier and was excluded from calculation of the baseline value
`
`Appears This Way
`0n Original
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Table 5: Coronary artery diameter, day 2
`
`(NDA application ‘Study QCBW 106, Table 1.2)
`Maximum Reductions in
`Coronary Diameter (mm) on Day 2
`
`Phase II
`Phase I
`(80 ug/kg Sumatriptan)
`(80 uglkg Sumatriptan)
`Change
`Change
`Change
`Dog
`Minimum
`From
`Minimum
`From
`Phase II -
`ID
`Baseline [a] Diameter {b}
`Baseline [0]
`Baseline [a]
`Diameter [b]
`Baseline [0]
`Phase I
`
`1101
`3.3883
`3.3797
`~o.0086
`3.4682
`3.3657
`—0.1024
`-0.0938
`1102
`4.3101
`4.0378
`-0.2723
`4.1128
`3.9349
`‘0.1779
`0.0943
`1104
`3.0521
`2.9014
`~0.1507
`3.2629
`3.1321
`-D.1309
`0.0199
`1105
`2.9889
`2.8985
`~0.0905
`3.3656
`3.2092
`‘0.1564
`—0.0659
`1107
`4.0199
`3.7575
`-0.2624
`3.1805
`3.0639
`~0.1166
`0.1458
`1108
`2.7941
`2.6550
`-O.1391
`2.6486
`2.5279
`~0.1207
`0.0184
`Mean
`0.0198
`STD
`0.0913
`95% CI
`(~0.0761, 0.1156)
`p-varue
`0.6186
`
`
`
`[a] The baseline values were obtained by taking the mean of the data collected during the 5 minute interval
`immediately preceeding sumatriptan administration.
`[b] Minimum Coronary Diameter during the first hour after sumatriptan administration.
`[c1 Minimum coronary Diameter
`- Baseline Coronary Diameter.
`
`Table 6: Coronary artery diameter, day 3
`
`Minimum
`Dog
`10 Baseline [3} Diameter {b}
`
`(NDA application ‘Study QCBW 106, Table 1.3)
`Maximum Reductions in
`Coronary Diameter (mm) on Day 8
`
`Phase I
`Phase II
`{80 ug/kg Sumatriptan}
`{80 pglkg Sumatriptan)
`Change
`Change
`Change
`From
`Minimum
`From
`Phase II -
`Baseline 10}
`Baseline [a]
`Diameter [b]
`Baseline [6]
`Phase I
`
`~o.1869
`3.4491
`3.4023
`-0.0468
`0.1402
`‘0.1218
`4.1699
`3.8438
`-0.3261
`~D.2044
`‘0.2461
`3.5305
`3.2353
`~0.2952
`~0.0491
`~0.0990
`3.8221
`3.1880
`~0.1340
`«0.0350
`~O.1546
`3.1711
`3.0566
`~0.1145
`0.0401
`~0.1585
`2.7131
`2.5319
`~0.1812
`~0.0227
`
`1101
`1102
`1104
`1105
`1107
`1108
`
`3.4381
`3.9887
`3.1713
`3.0257
`3.3684
`2.8176
`
`3.2512
`3.3669
`2.9252
`2.9267
`3.2138
`2.6591
`
`
`{a} The baseline values were obtained by taking the mean of the data collected during the 5 minute interval
`immediately preceeding sumatriptan administration.
`Eb) flinimum Coronary Diameter during the first hour after sumatriptan administration.
`{0] Minimum Coronary Diameter - Baseline Coronary Diameter.
`
`Mean
`STD
`95% 01
`p-value
`
`»0.0218
`0.1134
`{-0.1408, 0.0972)
`0.6572
`
`10
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 7: Coronary artery Resistance
`
`(NDA application ‘Study QCBW 106, Table 2.1)
`Maximum Reductions in
`
`Phase I
`(Vehicle + 80 pglkg Sumatniptan)
`
`Coronary Resistance imLImmHg.min) on Day }
`Phase 11
`(20 mg/kg naproxen + 80 pgikg Sumatriptan)
`
`
`Change
`Change
`Change
`Phase II -
`From
`Minimum
`From
`Minimum
`Dog
`
`
`Resistance Eb} Baseline to]Baseline [3]ID Baseline [a] Resistance to] Baseline [c] Phase I
`
`1101
`0.2782
`0.2626
`~0.0157
`0.2244
`0.?809
`«0.6436
`~0.0279
`1102
`0.3623
`0.3989
`0.0367
`0.4144
`0.3088
`~0.1057
`-0.1423
`1f04
`0.1496
`0.1557
`0.0062
`0.1365
`0.2057
`-0.0307
`-0.0369
`1105
`0.1837
`0.1022
`A0.0315
`0.1420
`0.1098
`-D.0322
`~0.0007
`1107[d]
`.
`.
`.
`.
`.
`.
`.
`1108
`0.1430
`0.1294
`«0.0136
`0.1459
`0.1218
`-0.0241
`—0.0105
`
`-0.0437
`Mean
`0.0570
`STD
`(~0.1144, 0.0271}
`95% CI
`0.1617
`p-value
`
`
`(a) The baseline values were obtained by taking the mean of the data collected during the 5 minute interval
`immediately preceeding vehicle (Phase 3) or naproxen (Phase II) administration.
`[b] Minimum Coronary Resistance during the first hour after sumatriptan administration.
`to] Minimum coronary Resistance - Baseline Coronary Resistance.
`(o) Period t.) denotes a missing value.
`
`Caro/1%aria/y. Similarly, coadministration of sumatriptan and naproxen appeared to have an
`additive vasoconstrictive effect on the dog carotid artery. Sumatriptan alone caused about a 10%
`constriction, while naproxen + sumatriptan caused about 20% constriction (Table 8). The
`additive vasconstrictive effect was present in 5 of 6 animals, and approached statistical
`significance (p = 0.08) despite the small sample size. The additive effect was about the same one
`day after naproxen was given (12% sumatriptan alone; 22% sumatriptan + naproxen) (Table 9),
`while by the third day after naproxen the additive effect was not present (12% sumatriptan alone;
`16% sumatriptan + naproxen)(Table 10). The resistance of the carotid artery did not to increase
`as a result of the vasoconstriction (Table 11).
`
`Appears This Way
`On Original.
`
`11
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 8: Carotid Diameter, Day 1
`
`(NDA application ‘Study QCBW 106, Table 4.1)
`Maximum Reductions in
`Carotid Diameter (mm) on Day 1
`
`Phase I
`Phase II
`(20 mg/kg Naproxen + 80 yg/kg Sumatriptan)
`(Vehicle ¢ 80 pgikg Sumatriptan)
`
`Change
`Change
`009
`Minimum
`From
`Minimum
`From
`ID
`Baseline (a1 Diameter 1b;
`Baseline 193
`Baseline 13}
`Diameter [b]
`Baseline [c]
`
`1101
`5.1569
`4.1227
`v1.0342
`4.9081
`4.0581
`1102
`5.9945
`5.7021
`~0.2924
`4.2856
`3.7571
`3104
`2.9883
`2.7129
`~0.2754
`3.6837
`2.9264
`1105
`7.0062
`6.8267
`<0.1795
`6.2442
`4.1210
`1107
`6.5184
`6.4419
`~0.0765
`6.6695
`'6.2246
`1108
`7.2671
`5.5006
`-1.7665
`10.8691
`7.3404
`
`v0.8500
`‘0.5285
`—0.7573
`«2.1232
`~0.4449
`~a.5287
`
`Change
`Phase II -
`Phase I
`
`0.1842
`—0.2361
`-0.4818
`-1.9437
`~0.3684
`-1.7621
`
`Mean
`STD
`95% CI
`p‘value
`
`~0.7680 '
`0.8720
`{-1.6831, 0.1471)
`0.0835
`
`
`[a] The baseline values were obtained by taking the mean of the data collected during the 5 minute interval
`immediateiy proceeding vehicle (Phase I) or naprnxen (Phase II) administration.
`in} minimum carotid Diameter during the first hour after sumatriptan administration.
`[0} minimum Carotid Diameter - Baseline Carotid Diameter.
`
`Table 9: Carotid Diameter, Day 2
`
`(NDA submission ‘Study QCBW 106, Table 4.2)
`Maximum Reductions in
`Carotid Diameter (mm) on Day 2
`Phase I
`Phase II
`(80 yglkg Sumatriptan)
`(ao pgkkg Sumatriptan)
`
`Change
`From
`Minimum
`Dog
`ID
`Baseline {a}
`Baseline [c]
`Diameter {b}
`Baseline {3!
`
`4.8989
`1101
`4.0453
`n0.8536
`5.0104
`1102
`5.8973
`5.2248
`‘0.6725
`4.6516
`~0.2948
`1104
`3.0779
`2.7831
`4.2516
`1105
`5.4824
`4.4615
`‘1.0209
`5.7116
`1107
`6.5983
`6.0631
`-0.5352
`6.7288
`6.8887
`6.2406
`1108
`—0.6481
`7.7285
`
`Change
`Change
`Phase II -
`From
`Minimum
`Diameter [b]
`Baseline [c]
`Phase I
`
`3.4912
`-1.5192
`~0.8656
`4.1798
`-0.4718
`0.2007
`3.0123
`~t.2393
`‘0.9445
`4.1349
`~f.5767
`-0.5559
`6.3346
`-0.3942
`0.1410
`5.5450
`-2.1835
`~1.5354
`
`
`
`[a] The baseline values were obtained by taking the mean.of the data collected during the 5 minute interval
`immediately preceeding sumatriptan administration.
`[b] Minimum Carotid Diameter during the first hour after sumatriptan administration.
`In] Minimum Carotid Diameter - Baseline Carotid Diameter.
`
`Mean
`8T0
`95% CI
`p-value
`
`~0.5599
`0.6604
`(«1.2530, 0.1331)
`0.0924
`
`12
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`
`Table 10: Carotid Diameter, Day 3
`
`(NDA application ‘Study QCBW 106, Table 4.3)
`aaximum Reductions in
`carotid Diameter (mm) on Day 3
`
`Phase 1
`?hase TI
`(80 nglkg Sumatriptan)
`(80 pg/kg Sumatriptan}
`...__.a.._,a__._m_____._._~_,,.__,,‘___.Mm _-__~.a..._wa______._._._._____.__.___“_,
`Change
`Change
`Change
`Phase II -
`Minimum
`From
`From
`Minimum
`Dog
`Phasel
`Diameter- [bl
`Baseline [33
`Baseline 10]
`Baseline {c}
`Baseline [a] Diameter {b}
`10
`
`1101
`4.8403
`4.2777
`-0.5627
`5.0929
`4.1!81
`v0.9749
`~0.4122
`1102
`4.0582
`3.6919
`‘0.3663
`4.6492
`4.0117
`-0.6374
`-0.2711
`1104
`3.0864
`2.8132
`-0.2732
`4.0423
`3.1709
`~0.5714
`~0.5982
`1105
`6.1634
`4.2834
`—1.8800
`5.4037
`4.7223
`v0.6814
`1.1986
`1107
`6.5951
`6.2973
`~0.2978
`6.7821
`6.1394
`~0.8¢27
`«0.3449
`1108
`7.8122
`7.0105
`—0.8017
`8.8397
`6.7994
`-1.5403
`-0.7386
`mean
`~0.1944
`STD
`0.7037
`95% 01
`(«0.9328, 0.5441)
`p-value
`- 0.5286
`
`
`[a] The baseline values were obtained by taking the mean of the data collected during the 5 minute interval
`immediately preceeding sumatriptan aominisrration.
`[b1 Hinimum Carotid Diameter during the first hour after sumatriptan administration.
`[c] Minimum Carotid Diameter ~ Baseline Carotid Diameter.
`
`Table 11: Carotid Resistance
`
`(NDA application ‘Study QCBW 106, Table 5.1)
`Maximum Increases in
`Carotid Resistance (mLimmHg.min) on Day 1
`
`Phase I
`Phase II
`(Vehicle + 80 pgikg Sumatriptan}
`(20 mglkg Naproxen + 80 ugikg Sumatriptan)
`._____.____________.____.___________..___.
`____..____________._________..____________.
`change
`Change
`Change
`Phase II ~
`From
`From
`Maximum
`Maximum
`009
`Phase I
`Baseline 13]
`Baseline [a] Resistance [bi Baseline 1c]
`Resistance to} Baseline 163
`10
`
`1101
`0.5360
`0.4056
`~0.1304
`0.9393
`0.3694
`0.0300
`0.1604
`1102
`0.2970
`0.4214
`0.1244
`0.3588
`0.3437
`“0.0145
`~0.1890
`1104
`0.3399
`0.8009
`~0.0390
`0.3280
`0.2813
`“0.0468
`«0.0078
`1105
`0.3593
`0.3541
`—0.0052
`0.3170
`0.3602
`0.0432
`0.0484
`1107
`0.2175
`0.2876
`0.0502
`O;2255
`0.1972
`v0.0283
`(0.0785
`
`0.0430
`1108
`0.3075
`0.2722
`’0.0554
`0.3604
`0.3680
`0.0076
`0.0044
`Mean
`STD
`0.1052
`95% CI
`(~0.1050, 0.1148)
`p~value
`0.9218
`
`'
`
`________._.___._._._._____._..__._.___._.____.______..___._________~__.___..____.____,__.._.___._.____.____
`la} The baseline values were obtained by taking the mean of the data collected during the 5 minute interval
`immediately preceeding vehicle (Phase I} or naproxen (Phase II) administration.
`[bl Maximum Carotid Resistance during the first hour after sumatriptan administration.
`[cl Maximum carotid Resistance ~ Baseline Carotid Resistance.
`
`13
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Blood Pressure
`
`The variation was very large in the response of dog mean arterial pressure to sumatriptan and
`naproxen.
`I sampled the raw blood pressure data, and find that a striking degree of baseline
`instability, or ‘noise,’ was present. Given such limitations of the data, however, strikingly 3 of 6
`dogs had a large increase of blood pressure attributable to the combination gshown as ‘change,
`phase 11- phase 1’), of from 18 mm Hg to more than 30 mm Hg mean arterial pressure (Table 12),
`and 4 of 6 had some increase.
`
`Table 12: Mean Arterial Pressure
`
`Study 0081‘! 106
`7able 8.1
`
`Maximum Increases in
`MAP (mmHg) on Day 1
`Phase II
`Phase I
`{Vehicle + 80 yg/kg Sumatriptan)
`(20 mg/kg Naproxen + 80 yg/kg Sumatriptan)
`
`Change
`Change
`From
`From
`Baseline [c]
`Baseline [c3
`
`Maximum
`Baseline {a} WP [b]
`
`Change
`Phase II -
`Phase I
`
`Baseline [a]
`
`flaximum
`13A?
`[13}
`
`009
`10
`
`1101
`1102
`1104
`1195
`1107
`1108
`
`105.66
`115.55
`117.23
`108.86
`135.14
`134.51
`
`118.68
`129.29
`135.54
`140.36
`154.77
`154.09
`
`13.02
`13.74
`18.31
`81.50
`18.63
`19.58
`
`103.83
`113.19
`108.25
`135.53
`112.12
`101.19
`
`135.01
`125.18
`129.18
`135.46
`155.88
`151.38
`
`31.18
`11.99
`20.93
`4.07
`43.25
`50.19
`
`Mean
`STD
`95% CI
`p-value
`
`18316
`~1.75
`2.62
`452.56,
`24.63
`30.61
`
`6.95
`23.04
`(47.23, 31.13}
`0.4931
`
`4 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY
`
`4.1 Sources of Clinical Data
`
`Most data, including all efficacy data, was derived from trials of Trexima conducted by Pozen.
`Some safety data was derived from other studies of sumatriptan and naproxen used individually.
`
`4.2 Tables of Clinical Studies
`
`See Table 1: Overall Clinical Development Program for Trexima, and Table 62: Phase I studies:
`objectives, design, patient enumeration, Table 63: Phase 2 studies: objectives, design, patient
`enumeration, and Table 64: Phase 3 studies: objectives, design, patient enumeration.
`
`14
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21 -926
`MT400/Trexima
`
`4.3 Review Strategy
`
`The main efficacy trials reviewed were MT400-301 and MT400-302. Trial MT400-204 was
`conducted with a different formulation and dose of sumatriptan, but was used to assess safety
`and dose/response.
`
`4.4 Data Quality and Integrity
`
`4.4.1 Randomization
`
`Treatment randomization is shown in Table 13 (study 301), and Table 14 (study 302), and was
`balanced within sites.
`
`15
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Table 13: Enrollment by site, study 301
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`16
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 14: Enrollment by site, study 302
`
`(NDA submission Table 14.1.1? study MT400-302)
`
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`Enrollment
`All Sub§ecps znxthg Saiety Population
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`Total, Subfiegts '
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`Naproxan ‘
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`
`17
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`4.4.2 Subject Disposition
`
`The disposition of all subjects is shown in Table 15 (study 301) and Table 16 (study 302). The
`attrition between ‘randomized’ and ‘treated’ populations was about equal between groups in both
`studies (about 15%). Almost all treated patients submitted treatment diaries and were included
`in the ITT population.
`
`Table 15: Subject Disposition, Study 301
`
`
`
`Table 16: Subject Disposition, Study 302
`
`DA submission Table 14.1.2, Stud 302
`
`Trexima
`
`Sumatriptan Naproxen
`Sodium
`
`Placebo
`
`Total
`
`Treated_(Safety
`Population)
`
`Efficacy Intent-to-Treat
`Population 1
`
`370
`
`3 64
`
`365
`
`3 61
`
`361
`
`3 56
`
`365
`
`3 60
`
`1461
`
`1441
`
`
`
`
`
`
`
`
`
`
`
`ilncludes all subjects who took study drug, recorded moderate or severe pain at baseline and recorded at
`least one post-dose pain assessment 2Excludes all subjects with a major protocol violation and all subjects
`at site 355.
`
`18
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`4.4.3 Examination of Major Outcome Variables by Study Site
`
`Both study 301 and 302 were conducted at more than 50 sites each. No site in either study
`contributed more than 56% of total study enrollment.
`
`Large site outcomes
`Immediately below I examine the major outcome variables of “2 hour pain” and “Sustained Pain
`Free, 2-24 hrs” for the largest sites in study 301 (sites 146 and 338) and study 302 (sites 100,
`304, 351, and 358). Treatment outcomes were approximately as expected from overall study
`averages.
`
`Slzmj/ M74000?!
`0
`Site 146: 4-5% of total enrolment
`~ ,
`
`Pain Score 2 hours”
`
`
`
`
`
`
`
`
`
`
`1Na’mxehli}
`
`
`
`
`
`'31P1acebo
`
`VTreXIma
`
`Site 3378
`
`
`
`19
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`527/51} MTé’flfl-JflZ
`
`0
`
`Site 100: 4-5% of total enrollment
`——
`
`Pain Score ‘2 hours _
`
`
`Site 100
`Na-roxen .
`
`
`'rPla'cebo
`
`
`fSumatri-tan
`.
`
`jvTrexiina
`"
`
`
`
`
`
`
`Site 100
`. 5
`
`taN'ap'roxen
`. '
`'
`Placebo
`
`Sumatritan
`
`:IreXima '
`
`0
`
`Site 304: 4-5%
`'—
`
`Pain Score 2 hours
`
` 0
`
`Site 351: 5%
`
`' —~
`
`20
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Pain Score 2 hours
`
`Site 3 5 l
`
`'1\.la_roxen
`
`
`Sustained ain free, 2-24 hours
`
`Site 351-—--
`
`
`
`
`Placebo -
`»
`18
`2
`
`
`Slimatriptan V
`13
`TreXima
`
`15
`
`3
`
`0
`
`--
`_._ .
`Site 358: 5-6%
`
`Pain Score 2 hours
`
`Site 358
`
`I
`
`" ”
`
`-1
`
`,NarOXen'l
`Placebo ‘
`
`
`
`Outcomes at all sites
`
`I examined for all sites the major outcome variable for satisfying the combina