Page 1 of 4
`
`Frontier Therapeutics Exhibit 1029
`
`

`
`Vol. 326 No. 15
`
`METHCITREXATE IN RESISTANT _]T_l‘-/ENILE RHEUMATOID ARTHRITIS — GIANNINI ET AL.
`
`1041-5
`
`as 40 percent in the rate of response between the active drug and
`placebo was considered important to detect as statistically signifi-
`cant. We estimated that approximately 30 percent of t|1e patients
`given plaeeho would be classified as improved. According to tl1e
`tables presented hy Gehan and Sclineidermanfil and assuming the
`use of two-tailed tests, a minimum of 30 patients were required in
`each group.
`We tested proportional data for significance using the ciii-sonar:
`test or, where appropriate, Fisher's exact test. Statistical signif-
`eance by the chi-square test was required For tables with more than.
`1 degree of freedom before partitioning. For continuous variables,
`mean values were compared by one-way analysis of variance. When
`rnulriple-range I‘.ests
`loeearne appropriate, Dunnett's method for
`making multiple comparisons with a placebo” was used. Two-way
`analysis of variance was used to test For the effects of drug and
`country on the change in articular indexes. The Bonferrotri correc-
`tion was used to adjust For the testing o‘|' multiple hypotheses
`(n 9- 12) among secondary variables and in the analysis of response
`in subgroups of patients. Both unadjusted and adjusmd values are
`shown, however, if a P value was significant (‘$0.05) htiorc correc-
`tion, and the results are referred to as statistically significant.
`Ernpliasis was placetl_ on the intention-to-treat analysis rather
`than the analysis of those who completed the entire six-month trial.
`The intention-to-treat technique used the values of response vari-
`ables or the Final visit, whether or not the patient completed the
`entite ttial. This approach o'FFcrcr:l several advantages: more pa-
`tients were nunilnl-_i]e for the analysis of efficacy, data on those who
`dropped out before completion could be included, and it more close-
`ly reflected how physicians evaluate a. tl_iers.pe1itic agent in the clini-
`cal setting, outside an experimental protocol.
`
`Rm-r.ULTs
`
`A total of 12? patients (96 girls and 31 boys) were
`enrolled in the trial (66 in the United States and 61 in
`the Soviet Union). Age and duration 01" disease at
`entry averaged 10.1 and 5.1 years, respectively. The
`-disease course was systernic in 32 patients (25 per-
`cent), all of whom also had polyarthritis. Forty-sir;
`children received low—dosc methotrexatc, '4-O received
`very-low-dose methotrcxatc, and <.1.»l were given pla-
`echo. Randomization worked. well; there were no sig-
`nificant clifi"eren,ces among the treatment groups in
`any of the demographic or disease characteristics
`shown in Table 1. Patients from the two countries
`were di.stribut.=.-d about equally among the three treat-
`ment groups. Those from,
`the United States had a
`higher mean ($513) number of joints with active at‘-
`thritis (2732 vs. 20:2, P-110.046), but the mean ar-
`ticular-severity score (112) was the same for the two
`countries.
`Indotncthacin was the most frequently used concur-
`rent nonsteroitlal drug (25 percent}, J."ollowed by Da-
`proxen (18 percent),
`t|2|l1TlC1LlI'1 sodiu.r.n (17 percent),
`di¢1oi;"on-no sodium [16 percent), aspirin (15 percent),
`and other agents (6 percent).
`
`Efficacy
`
`Patients were included in the a.11a.lysis of ciiicaoy if
`they met all eligibility criteria, received the study drug
`in blinded fashion for a minimum of one motitii, Write
`100 percent compliant with the prescribed regimen
`during at least 80 percent of the follow-up period, and
`nnmpligti with the other specifieati.ons‘ of the protocol
`regarding restrictions on other ‘medications and return
`visits to the clinic.
`
`Table 1. Demographic and Clinical Characteristics of tho Patients
`at Entry. According to Study Group.
`Low-DOSE
`vzrtwr-i..ow»1:>oxr:
`Msrsorssmrs
`Msrsmnsrirs
`(N - 45)
`(N - -10)
`
`CI-l.iI.llACTEl'l.l!lTlC"'
`
`PLACEHO
`{N rt 4|)
`
`one (it)
`Average
`Rsngc
`Disease duration (yr)
`Average
`Range
`No.
`(9%) Female
`No. {on taking low-close
`prednisone
`No. {Em taking two
`Nsftlbsi
`No. {deal with systcnric-
`onset disease
`
`Mean (:t:SE] no. ofjcinis
`with active ttrthritist
`
`10.1
`2.5—l'a'.5
`
`4.8
`l.'|.fi-13-.5
`33 ('72)
`15 (33)
`
`5 [1 1}
`
`9 (20)
`
`9.6
`3-.El—|7.4
`
`4.3
`|.'|.5—~l 1.5
`29 ('73)
`15 (31)
`
`3 (7.5)
`
`ll [23]
`
`10.6
`3.2—l7.S
`
`5.8
`U.5—l4.4
`34 (33)
`14 (34)
`
`'
`
`3- (7.3)
`
`12 [29]
`
`27 (2)
`
`2! (2)
`
`24 (2.)
`
`""l'liere were no slgniflcnnt differences among the trentrnent groups in my of the character-
`iltli¢3.
`TNSAID denotes nnnsteroitiitl Itntlinnarrtmnrory tints.
`ism: the Mctltods section for A definition of native nnltrlrls.
`
`Of‘ the 127 enrolled patients, 1 I4 {SID percent) quali-
`fied For the analysis of eilicacy, including 33 (33 per-
`cent) of the 46 in the low—dosc group, 37 (92 percent)
`of the 4|} in the vcry—low—-close group, and 39 (95 per-
`cent) of the 41 who took placebo. Among the IS pa-
`tients e5tcl,udct,l, from the efficacy analysis, 8 violated
`the specified doses for concurrent nonstcroidal agents,
`3 violated the prednisonc regimen,
`1 was noncom-
`plinnt in taking the study medication, and I was dis-
`covered to have had fewer than. three joints that met
`the criteria for active arthritis at the base-line visit.
`
`Clnly ll of the ll.-‘-lr children in the cilicacy subgroup
`tool; two concurrent nonsteroidal agents during the
`trial, These patients were equally divided among the
`treatment groups, and their data were not considered
`separately. A total of 40 patients in the efficaey sub-
`group received low-dose prcdnisone during the trial,
`including I4 who were given lc«w—dosc mcthotrcxate
`and 13 in each of the other two groups. Since the
`numbers were small, and the close low and constant,
`data for those who received prcdnisonc were not sna-
`lyzcd separately.
`Among the 127 randomized patients, .108 completed
`the entire six-month trial, including 97 (85 percent) of‘
`the I14 in the efficacy subgroup.
`Global Assessment
`
`Figure I shows the percentages of patients at each
`tcturn visit. who had clinical
`improvement from
`their base-l,iric condition, according to the physi-
`eian‘s global assessment. Both methotrexatc groups
`had consistently higher proportions of patients with
`improvement than the placebo group. According
`to the physician's final global assessment, a sig-
`nificantly l-tighct proportion of patients improved.
`in tlio 1ow—elose group than in the placebo group
`[X3 with 2 df = 7.53, P i 0.023). These in the very-
`
`
`
`Page 2 of 4
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`

`
`lD-4-El
`
`THE N.E1W ENGLAND _]Cl'URN.AI_. OF MEDICINE
`
`April is, 1992
`
`tion of the oral mucosa accompanied by headache and
`gastrointestinal problems. Five of the "-1-l patients
`who took placebo (12 percent} bad side effects, all
`of which were gastrointestinal. -All side effects were
`graded as either mild or moderate in severity, except
`for two episodes of stomach pain graded as severe
`in a patient receiving placebo. No patient had evi-
`dence of mcthotrexate—induced pulmonary disease
`during the trial.
`
`Laboratory Evidenco of Toxicity
`
`Patients who received mcthotrexate had more ab-
`normal results on laboratory tests that werejudged to
`be clinically important and possibly, probably, or defi-
`nitely related to the study medication than those given
`placebo. Fifteen patients who received l.ow—dose meth-
`otrexate, l5 who were given very-low-dose rnethotrex-
`ate, and 5 who were given placebo had such results.
`Among the patients given methotrexate, the most Fre-
`quent abnormal results were alterations in the differ-
`ential whitc—cc1l count, hematuria, pyuria, and the ele-
`vation of serum aminotransferasc levels. Elevations
`of aminotransferase levels and anemia were the most
`frequent abnormal results among the patients given
`placebo. Other clinical-chemistry data were unre-
`marl-table.
`
`Dropouts
`
`A total of 19 patients (10 in the United States and
`9 in the Soviet Union) discontinued therapy before
`completing the six-month trial. (Table
`Two pa-
`tients in the low-dose group dropped out because of
`adverse effects: persistent elevations of serum aspar-
`tame and alanine arninotransfcrase (levels up to 120 IU
`per .liter) in one and persistent b.ematuria in the other.
`Both problems resolved quickly after the discontinua-
`tion of the study medication. One patient given very-
`low-dose rnethotrexate had a persistent skin rash and
`was dropped from the study one month after entry.
`The total numbers of dropouts were not significantly
`different among the groups.
`DISCUSSICIN
`
`The results of this trial confirm anecdotal reports
`and evidence from uncontrolled trials that low-dose
`methotrexate has antiinflammatory activity and clini-
`
`Tablo 3. Fleasons Patients Left the Study. According to Study
` Group.
`LUW-Doll
`Wtwr-Low-Dose
`Meritorttitsrit
`Msruonsxvrs
`(N " 45)
`[N " 40}
`no. qfpotienrs |"ill£-,I
`
`Ptxceno
`EN = 41)
`
`Reason
`
`5 (12)
`3'. (5]
`0 (0)
`.l11Isf|'Eel.i\re11es5 of drug
`0 ml
`1 (33
`1 (4)
`Adverse effects
`1
`('2)
`2 i5}
`2 I14]
`Intercurrent illness
`l (2)
`G (El)
`2 (4)
`Adminisbative reasons _
`U (0)
`III
`(0.1
`1 (2)
`Noncompllance with protocol
`
`
`
`7' {I5} 5 (1.2)Total 7 ('7)
`
`cal effectiveness in resistant juvenile rheumatoid ar-
`thritis. We also found a trend. 1'.owar_d a dose—response
`relation in the low-dose and very-low—dose methotrex-
`atc groups, similar to that reported by Furst ct a1.-‘°
`in adult rheumatoid arthritis. The favorable :lin.dings
`from the present study should be encouraging news
`for clinicians faced with managing a ehild’s disease
`that has failed to respond. adequately to nor.tsteroida.l
`drugs. Methotre:>ta.te has distinct advantages over
`other second-line agents,
`including its oral
`route
`of administration, once-a-week dosage, lack of known
`oncogenieity, and lack of long—term effects on fertil-
`ity. The choice of which second—linc agent
`to use
`i1'1itia..l.ly has become more difficult in recent years,
`after controlled trials and long—term. prospective stud-
`ies showed a lack of efficacy among the agents in com-
`mon u.sc.‘-M‘-5" Parenteral gold remains a therapeutic
`option, but its considerable toxicity” and inconven-
`ience must be considered. Furthermore,
`injcctable
`gold salts have never been assessed in a controlled trial
`in children with arthritis. Thus, the tendency among
`pediatric rheumatologists to consider the use of meth-
`otrcxate earlier in the disease, and before other see-
`ond-line agents, is likely to cotitiriuc.
`There was a consistent trend in this study toward
`greater improvement in the low-dose group across all
`indexes of articular disease; some of the mean changes
`were not statistically significant, however. The vari-
`ability of the changes within the treatment groups, the
`limited sample size,
`the corrections for
`testing of
`multiple hypotheses, and the high rate of response to
`placebo in all previous PRCSG studies undoubtedly
`affected our ability to detect some changes as statisti-
`cally significant. The recent development of a child-
`hood health-assessment questionnaire and functional-
`ability tool may provide more sensitive measures of
`response in future trials.”'i” Nevertheless, the results
`obtained here represent by far the most encouraging
`data from a trial of a second-line agent undertaken by
`the PRCSG.
`.
`The equality of response across treatment groups in
`the subgroup of patients with severe disease is unex-
`plained. Since all three groups showed dramatic im-
`provement in the articulanseverity score, it is possible
`that there was a greater regression toward the mean in
`th ese children with severe disease that‘ effectively
`blurred any difference in response produced by meth-
`otrexafe,
`
`The concurrent administration of aspirin is known
`to slow systemi.c and renal clearance and increase the
`unbound fraction of rnethotrcxate, perhaps resulting
`in greater toxicity.” We did not observe such an asso-
`ciation among the 2O children (16 percent} who tool»:
`aspirin. Among the 14- children who had clinically im-
`portant physical adverse effects while receiving meth-
`otrexate, 2 (14 percent) were taking aspirin. Among
`the 30 e.hil.dren treated with methotrexate who had
`substant1'a.l abnorr.nal.ities in la.bI:ir.atary inelestes of tox-
`icity, tl: (13 percent) were receiving aspirin.
`Although mild elevations of serum arninotrans-
`
`
`
`Page 3 of 4
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`

`
`Vol. 326 No. I6 METHDTREXAT.E'. IN RESISTANTJUVENILE RI-IEUMATOID ART!-IRITIS — GIANNINI ET AL.
`
`104-9
`
`the study groups,
`ferase levels were common in a.ll
`only four children in the low-dose group, nnu in the
`ve'ry—low-dose group, and one in the placebo group
`hacl markedly elevated (more than two times the up-
`per limit of normal) enzyme levels (range, 85 to
`l3-4 IU perliter). Possible explanations for the lack
`of hepatotoxie effects include the duration of tl'l.e
`trial,
`the administration schedule of a single dose
`per week, and the low euntulative doses to which the
`children had been exposed. Also, previous concern
`about the hepatic toxicity of methotrexate may have
`been exagge.ra.ted.35 A prospective study of the chil-
`dren who received mcthotreotate during this study is
`now under way to evaluate long-terrn outcome and
`safety.
`In conclusion, II1€tl'lDtl“t;'.3t.:a.tC at a dose of 10 mg per:
`square meter per week appears to have greater clinical
`effectiveness than placebo in children with juvenile
`rheumatoid arthritis. The short-term safety profile is
`acceptable. Given the results of previous trials by the
`PRCSG, the use of methotrexate as the initial second-
`line agent in resistant juvenile rheurnatoid arthritis
`appears to lziejustifiecl.
`
`We are indebted to Academician Valentin.1.A. Nassnnova, M..D.,
`ofthe Academy oi.‘ Medical Sciences, Moscnw;_]ohn Klippel, M.lD.,
`and Lawrence E. Shtllman, M.D.. l’h.l3.. of the National Institiltes
`oi" Health, Bethesda, Mel.; Marlene I-l:i,-i'l'ner__ M_D_,Jol1n Hnrter,
`M.D., and Kent Johnson, M.D., of the Food and Drug Adminis-
`traticn. Washington, D.C.; and Dick Ryan, Harriet Kiltie, M.D.,
`and Margaret Gandt, M.D.. of Lcclcrle Laboratories, Pearl River,
`N.Y.,
`for their assistance in organizing and conducting this
`study.
`The participating clinical. investigators in the United States were
`(in alpliahetical order} Bram H. Bernstein, M.D., Harry L.
`Gewantcr, M.l.'.3.. Jerry C. Jaeolaa, M..U.. Deborah W. Kret:l_ieh,
`M.D., Robert N. Lipnielc, M.D., Daniel__], Lovell, M_D_, M'..I-‘J-I.,
`Lauren M. P-‘tchman, M.D., Murray H. Passn, M_D., Donald A.
`Person, M.D.,_]anc G. Schaller, M.D., Charles H. Spencer, M.D.,
`llona Seer. M.D., and Carolyn L. Yancey,‘ M_D. In the Sov-is.-1;
`Ufllflfl l-l'l¢ P-‘l.1'ti|.‘.ipa.t:ll1g clinical investigators wcrt: Dan-i_it¢ Age‘-,1,u5.
`kcne, M.D‘., Ludrnila Isaeva, M.D. (deceased), Nina Letenltova,
`M..D.. E-lltina Puogienetle.
`lV.l..lll.. Inessa Sltakhbazyan, M.D.,
`lV.la.rina Stehcrhakova, M.D., Alexandra Yaltovleva, M.D.. and
`Sernphima Yandashevskaya, M.D. The senior scientist in_t]1u Soviet
`‘ Union was Boris Shokh, l'vl.D,
`
`Re:-anewces
`
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`York.‘ Cllurehill Livingstone. 199011 M.
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`lEi39:ld:3l3-20.
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