Page 1 of 8
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`Frontier Therapeutics Exhibit 1028
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`Weeltly MTX Dose (Mp)
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`Fig. 1. Weekly MTX doses.
`
`Phase
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`Fig. 2. MTK study design.
`
`Each patient received a single dose of IO mgftnz MIX orally (to the
`nearest 2.5 mg) and ill mg-'m2 N MTX (to the nearest 2.5 mg) for kinetic
`stI.'Idies (J Phone Sci 1989; in press). The doses of these drugs were given
`5-7 days apart and their order was randomized. The patients underwent
`intensive physical and occupational therapy as well as disease related teaching
`during the 12-day inpatient period. At the end of the i.I-Ipatierrt period. patients
`were randomised to placebo or lVi"l"lvl regimens. Medication was given once
`weekly orally. Appropriate identically appearing placebos were used so that
`all FB'LlEl'll.5 ll'lge3lC¢'Cl
`liln telttuct.-I 55kt‘-Ir‘-B: - P3-l-'ICl'l'llE WHITE E\”3Il“Hl3Gd ml‘ l.DXl|'-‘IIY
`every 1-2. weeks and for efficacy every 4 weeks (at 52. I5. l0. I4 and 13
`weeks).
`Beyond 18 weeks. patients were blindly re-randomized to either 5 or 10
`mgiml MTX weekly. All patients continued ingesting 14 identically appear-
`ing tablets weeldy: some were placebo and some were MTX. Over the next
`13 months (and still ongoing}, weekly doses could be varieI:l according to
`clinical need or toxicity. When the dosing regimen was changed. the phar-
`macy was asked to "change the dose by 2.5 mg." The pharmacy person-
`nel then changed the dose within the 14 tablets. thus maintaining the blind
`for laoth patient and Investigator. If patients demeneuated an inadequate
`response after at least Ii weeks of the )6-week double blind outpatient pro-
`tocol (‘Phase 11). they could be “advaneed" to the nonplaoebo. blinded study '
`described above. In this case the patients were called dropouts. although
`they were actI.Ially only dropped from Phase II; they continued in Phase
`l]I. Inadequate response was defined as worsening of the patient's sense
`of wellbeing or pain visual analogue scaled l'W\5)- 35 ‘-'-'9“ 35 .l°i'“ l¢“'5"3l"'
`ness count by at least 15% and patient plus physician agreement that the
`patient had significantly worsened clinically. At all times these patients and
`the investigator remained blinded to the therapy.
`The original design randomized patients to placebo. 10 or 2D rngfmi regi-
`mens. However, after the first 20 ptients had entered the study (With 5
`patients in the 20 mgimi group} it was felt that the 2D mglrnl regimen
`caused too much toxicity (33 ‘ll. discontinuation; see below). This was con-
`cluded by a review group at Lederle Laboratories and did not compromise
`the blinding of the study. A new schedule was designed (allowing for patients
`HM‘-id? entered into the study) which randomized the patients to placebo.
`5 and ill I113-'l"ll1 regimens. The new schedule compensated for patients
`already enrolled so that the study when eon-rripleted had a balanced design.
`
`35.150 Slltdlds. CBC and urinalysis were obtained weekly for I}-In fim 4 W ks
`End E‘-‘El? Other week for the remaining 14 weeks of the study. MuIIIph:.
`chernlstries. serum cmtinine. protlimmbin time. and partial f_I111_-ymbnplal
`dffltt were obtained monthly. Laboratory tests. radiographs and lflicpgy “MI;
`were evaluated as routinely done by the University of Iowa Hggpnafs and
`Clinics. Department of Medicine or Department of Pa1hology.
`Elf-E'u£'.v measurements. Efficacy measurements were done at bB3I5];Ig1gI_- on
`the day of leaving the hospital. and monthly thereafter. The at-alum-,1“;
`included ring size using a ring sizer to measure the diameter of the ind
`through 5th proximal inlserphalangeal joints of the hands (in mm); mod]-_
`fiecl Ritchie tender joint index, with a maximum joint tendet-I-rag; mum 01-
`2O‘.7 (tenderness was scaled from U = no pain to 3+ = severe p;]in)lIlI
`swollen joint count using the same scale and the same joints as the'modi.
`fied Ritchie index but not measuring hips or neck for swelling (maximum
`count was I98): duration of morning stifFness (in min]; average of the gm
`2 of 3- grip strengths measured for each hand (using a single. wrapped Sphyg.
`momanometer bag inflated to 20 mm mercury); time in s to walk 75' an
`the level (walking aids were allowed): physician‘s global assessment of pa.
`rient‘s sense of wellbeing. paIient‘s global sense of wellbeing. patient pain
`assessment (all on 100 mm horizontal VAS). and patient's ability to com.
`plate 18 activities of daily living. on a scale of l—.1.l‘l (ma.Iu‘.rnurn neon: e 180].
`Toxicity. Toxic reactions were ascertained by nondireetive questioning at
`each visit as well as routine and appropriate laboratory testing (as above},
`Ii.‘ the white blood cell count fell below 3.500/tnrn3.
`the polymer-
`phonuclear count below 1,ooo;mm3. platelet count below ‘lO0.DO0fmm3.
`or hemoglobin dropped progressively, rest medication was stopped and
`patients were excluded from the study. If AST or ALT rose to greater than
`3 times normal. or creatinine was :s- 1.4 mg%. test drug was discontinued.
`Significant clinical toxicity. of course. mandated discontinuation of the trial
`for the patient.
`Compliance was monitored using pill counts.
`
`Analysis. Repeated measures analysis of variance (ANOVA] was used For
`examination of the effect of hospitalization and intensive therapy upon dis-
`‘ ease activity during the first 12 days of the trial. as well as for the overall
`study period. The data was examined for efficacy in 2 ways: one used the
`‘ms-..;.‘.'_:e 2. '.'-i_ 1"). 1* .M‘l't'l 1R waairrls-Ira: rho. other utilized the 6. 10. I4
`and 18 weelt points. The latter method tried to faetet‘ out the srrI.er'I Iv-I-I|"¢"‘¢'
`ment resulting from the 12-day hospitalization. The repeated measures
`ANCWA included terms for the treatments [degrees of freedom (d.f):2}. sub-
`jects within trcatrnents ((11143), time (df:4). lime treatment iltlieractjorut (I:l:l'":B)
`and subjects time within treatment interactions (dl".1'l2). It was anticipated
`that some patients would worsen during the outpatient period. relative to
`hospitalization (the placebo group}. while other patients might stay the same
`or improve during the outpatient portion of the study, relative to the end-
`hospital point (Figure 3). Clrthogonal comparisons. which examine the slope
`of response. were utilized to look for dose responses; this method utilizes
`all the data in the study. thus examining 184 points (4 visits >4 -=1-I5 paliiefllsl
`or about 55 points.’group (13-17 patients at each of 4 visits) for each meas-
`ure of response. Orthogonal comparisons are utilized to partition the aura
`of squares of variation among the 3 treatment groups into single degree
`of freedom components that were independent from each other and add to
`the original sum of squares. Each contrast was evaluated for statistical ais-
`niftcance by an F test”. In this study. the total sum of squares for treat-
`ment was partitioned into linear and quadratic components.
`In the efficacy analysis. the last evaluable point for each patient W35 I-15-'-"1
`This allowed the use of all patients. even if they dropped from the stud}?
`before 18 weeks. This approach was conservative. as it included patienld
`who might have dropped out for lack of etiicacy. Although data are pl‘:-
`sented. for comparisons. from baseline and end-oi‘-hospitalization (Table
`l). the statistical ens displayed in Tables I through 3 are ‘Fr-E|I'l'l the end of
`the 12-day hospitalization unless otherwise specified. Although the same
`results were found when the baseline was the initial evaluation. the enrl-of-
`hospitalization results are more conservative. as the MT}: would have W
`have effects greater than the results of the 12-day hospitalization pt'FJl1' ID
`
`
`
`
`
`ActivitiesOfuailvLivingscore
`
`
`
`-I-____1_..I..=.-.-IPnunnl
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`
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`
` ——
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`3!-1
`
`The Journal of Rhetrmuroiogy 1989.‘ Id-'5
`
`
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`Page 2 of 8
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`

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`;._._-
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`II
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`_
`,
`
`=_
`
`
`
`
`mm C) Piaoebo
`[W 5 mgirn”
`
`X 10 mglmz
`
`5
`12 Days
`ii
`weeice
`* Statietieaily Different From Initial Evaluation
`1‘ Linear Doee Fieeponee By Orthogonal Comparisons
`’r1'Mean 3 Standard Deviation
`1- It Mean
`
`
`1a
`.14
`13
`D
`
`V"
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`TenderJointCount 3
`
` Placebo
`
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`0
`12Daye
`'
`E__
`10
`14
`M
`13
`Weeks
`
`%
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`Placebo
`5 mefm’
`
`X 10 mgimi
`
`'
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`5'":
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`5;;
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`=='
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`* Statietioaliy Different From initial Evaluation
`t Linear Dose Fieaponae By Orthogonal Domparieona
`if Mean : Standard Deviation
`we sviuiean
`D
`
`Fig. 31'). Efioct of hospitalization. piaccho 5 mglmi or 10 rng-‘mi MTX on tender joint count (Max = 207).
`
`
`Furxr. M .:2.!'.' M73! in rpfixfggaf
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`3
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`Page 3 of 8
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`

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`
` PatientGlobalVA5(mn1)3it2ES333
`
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`rI'IIIIIIlllllllIllllllIIIIIllllrlllllllIIIIIIIIrlllllIlllllllIIIIllfilrlIIOMIIIIIIIIlllllIit'll‘lllllllmlIl"W""""“""“"""""""“""'mu
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`Placebo
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`0
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`12 Days
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`,+—-j-—-j--—
`14
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`to
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`Weeks
`* Statlatleally Different From initial Evaluation
`1“ Linear Dose Response By Drthogonal Comparisons
`H" Mean a Standard Deviation
`at ahlean
`
`Fig. 3.:-. Effect of hospitalization, placebo 5 mgi'm3 or 10 mg/n12 MTX on patient global VAS in RA.
`
`be shown effective. Thus. one asstnncs all patients improve during the 12-day
`hospitalirations (as actually occurred, Table 1) and then uses that improved
`baseline as it starting point. In this analysis. patients ntight even get worse
`relative to baseline during the outpatient study (Figure 3).
`The time to dropout from the stlvly was test-.d ttsinr ANCIVA followed
`by Duncan's multiple range test (if statistical significance was found}, For
`this analysis. dropout referred to discontinuation secondary no toxicity fe.g..
`WBC.‘ -: 3.500. platelets -e 100,000, elevated liver function tests 5- 3 x
`upper limit of normal or clinical side effects), discontinuation for inef‘l'1ea-
`ey or advance to next phase for inadequate response (see previous defini-
`tion). xi analysis or Fisher's exact test were used to measure differences
`among categorical adverse drug reactions (Milk) and to examine efficacy
`in tenns of those patients with greater than 50% response. ANOVA was
`used for eztamination of differences in ADP. for continuous variables. if
`differences were found. Duncan’s multiple range test was employed to ascer-
`tain pairwise t:liFferences a.m-ong treatrnents. Usual descriptive statistics were
`calculated and means ;l: standard deviations are displayed in the tables unless
`otherwise stated. No efficacy analysis was done on the 6 patients given the
`20 mgfmz dose because dtey represent too few patients for legitimate statis-
`tics. On the other hand, the ADR analysis includes those 6 patients.
`
`Table 1 shows, in part, the effect of 12 days of rest, inten-
`sive therapy plus 2 MTX doses on the activity of RA. As
`can be seen, patients improved significantly in 9 of 11 meas-
`ures. This result deserves emphasis, as it shows the major
`.'n:lt.e...... :..... rest and intensive physiotherapy can ::_;-_E__ 1.:
`patient symptoms and signs.
`
`Table 1 also demonstrates the change in disease activity
`over 16 weeks in the 3 groups. It displays the results of ortho-
`gonal comparison testing for the existence of a linear dose
`response. using end-of-hospitalization data as baseline. A
`linear dose response relationship was shown statistically for
`5 of 11 clinical variables. Orthogonal testing using the pre-
`hospitalization data as baseline showed greater changes. will!
`6 of 11 variables demonstrating a linear dose response rela-
`tionship (p values not shown). Figure 3-a—c illustrates some
`of the results.
`
`Another measure of efficacy is the time to dropout from
`- RESULTS
`the double blind study. In this case dropout means either
`M Although 52 patients entered the study (if one includes the
`"study discontinuation or blinded advance of the patient out
`M6 patients given 20 mgimz MTX), only 46 were evaluated
`of the double blind phase into the next phase. This
`M for efficacy. There were 29 females and 17 males with an
`measure does not separate dropout secondary to lack of
`aw-'=rage age of 55 .6 years (range 31-74 years). Eighty-seven
`efficacy from that secondary to toxicity. It is a very gflfld
`percent (40 patients) were RP positive and 54% (25 patients)
`M measure of drug therapeutic index. Among the 16 placcbfl
`were taking prednisone (all in doses of 10 mg/day or less).
`patients, mean time to dropout was 14.9 :I: 3 weeks with
`Mean prednisone dose was 8.5 i 1.8 mgfday. All patients
`10 patients either discontinuing therapy or advancing prernar
`had failed gold therapy and 45 of the 46 had also failed either
`turcly in a blinded manner to the next study phase (533
`D-pcnicillamine or azathioprine. Thirty-four patients had
`Methods). For the 13 patients in the 5 mglmi group, Tm‘-'-3“
`failed 3 or more disease modifying antirheurnati-c elrugs.
`time to dropout was 1'i".2 i 1.5 weeks with 3 patio“?-9'
`Table 1 outlines the baseline disease activity measures among
`advancing. also still blinded. Finally, for the 10 rnghllz
`the 45 patients at the time of entry into the hospital.
`group it was 17.8 :1: 0.8 weeks among the 17 patients. N0
`:rtmp
`3M
`
`ihe Joanie! of Rheumutology 1939-‘ 15-'3
`
`Fm:
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`
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`Page 4 of 8
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`RF (nephelornetrie units)
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`190 :l: 135
`203 s 2452
`73 g 84
`Time to onset of fatigue 0;}
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`75' walking time Isl
`31.2 s: 35.7
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`69 e 16
`69 :l: 19
`54 e 19
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`P3t"="T Pall‘!
`Physician global
`ADL (max = 180)
`Joint tenderness oaunt
`{max = 207}
`Joint swelling count
`{mm I: 193)
`Average grip strength
`NS
`107 :l: 57
`107 :l: 7'?
`B2 i 47
`(mm Hg)
`N5
`57 5: 7
`54. 5|: 4
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`Average ring size (mm)
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`1132 :1: 2403
`1099 :l: 3-68
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`RF [nephelorneu-in units)
` %____%__
`ESE (mmfh)
`51 :t 33
`55 :|: 29
`4'.’ _.-I; 36
`NS
`NS: not significant: ND: not done
`‘
`’ Using intent-to-treat analysis
`** Using orthogonal comparisons
`* I3-=:O.DOl comparing baseline vs 12 clays
`
`=2
`5?"
`.:
`11.
`
`patients in this group advanced early. The placebo group
`dropped out earlier than the active treatment groups (p =
`0.001) but there was no difference between the 5 and 10
`
`mgfmz patient groups.
`A clinically important measure of therapeutic response is
`an examination of the number of patients who improved by
`greater than 50% in any given response variable. Table 2
`
`shows that 5 of 11 measures improved by the criterion using
`data from end-of—hospita1ization (p 5 0.05). The p value
`refers to the presence of dose response relationships.
`Six patients discontinued the study for toxicity or inefficacy
`at 18 weeks orearlier. One patient (taking 20 mglmi. 35
`mg weekly) developed severe stornatitis at Week 4 and
`wished to stop MTX. Another patient (also taking 20
`
`Fursr. er an MD: in resistant as
`
`3:7
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`Page 5 of 8
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`

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`_
`5
`
`Table’ 2. The percent ofpcm'cnr.r wrfli
`
`::-50% iinprovemenr
`
`p value
`pa
`10 mg/m2
`5 rngln-:3
`Placebo
`
`Morning stiffness
`is?
`45
`53
`N5“:
`Time to onset oi‘ fatigue
`69
`459
`55
`N3
`75* walking time
`19
`23
`24
`N5
`Patient global vas
`0
`23
`29
`0.007
`Patient pain VAS
`s
`23
`as
`0.01
`Physician global VAS
`13
`23
`41
`[L02
`ADL
`0
`_ s
`29
`0.009
`Joint tenderness count
`13
`39
`53
`()_[)5
`Joint swelling count
`l9
`l5
`4'.’
`0.0]
`Average summed grip sI.reng1.lt
`19
`45
`41
`NS
`Average ring size
`0
`0
`0
`N5
`* Fisher's or xi‘ test for a dose response relationship.
`** No statistically significant dose response.
`
`I
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`(77)
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`(33)
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`infections
`Central nervous system
`{night-mares. depression)
`GI
`Stornatitis
`Nausea. vomiting
`Pain. dyspepsia
`Skin (psoriasis)
`Lung (upper respiratory
`infection. cough)
`(43)
`6
`Patients with at least one
`adverse experience
`(5)
`1
`Patients with an adverse
`experience requiring dose
`we
`I
`reduction. drug discontinuation,
`
`
`'or “advance“ ma I , ‘I
`" p level for number of episodes.
`‘
`'.‘
`we
`'”' All MTX vs placebo.
`,
`‘
`3Q
`“"** 10 rn3:"I'n= vs placebo and 5 rngfrn” vs: placebo.
`I
`,,
`I
`SCII
`"advance :seelc:tt.
`;
`
`Finally, one patient developed dose related tlutomboeytopenis"
`rngfttf-’, 27.5 mg weekly) developed stornatitis at Week 6,
`and required lowering of the dose in a blinded manner.
`but continued taking the drug (without consulting us); she
`Table 3 displays the adverse experiences in the MT}; vs I
`then developed diarrhea, dehydration, leukopenia, sepsis and
`placebo groups over l8_weeks. There were more episodes
`acute tubular necrosis. She eventually recovered but her
`of gastrointestinal (GI) toxicity among the active treatment
`creatinine remains elevated at 2.0 mgfdl. One patient dis—
`groups. In general all MTX groups had to be combined in
`continued MTX after 14 weeks (5 mg/mi, 7.5 mg weekly)
`order to differentiate drug from placebo (e.g., GI toxicity,
`because it was ineffective (according to both patient and phy-
`combined MTX groups vs placebo p = 0.002). Howe».-er_
`sician). One woman developed dyspepsia and vomiting; her
`5 mgfmz MTX caused more dyspepsia (p = 0.03) and
`symptoms led to advancement to Phase III, after 14 weeks
`stomatitis (p = 0.09) than placebo.
`in the initial placebo controlled study. She was taking
`No significant changes in mean values of A51‘, ALT, alka.
`placebo. Another woman. with underlying chronic obstrue-
`line phosphatase. bilirubirl, or serum crcattninc occurred.
`tive lung disease, developed a pulmonary tntectton and t.‘1iS-
`On the other hand, one patient (taking 5 mg/mi) had a
`continued: she had been taking 10 mg/m2 (15 mg weekly).
`Table 3. Adverse clinical experiences in patients taking MIX - number ofparicnts 1%)
` I
`5 mg-‘tn?
`l0 mginti
`20 mg/m’
`(15-10 mgiwk)
`(1542 mgfwlt)
`(27.5-35 mg/wk)
`13
`17
`I5
`(3)
`(12)
`(17)
`I
`4 (31)
`__
`__
`I
`(62)
`3
`I2 (71)
`(83)
`5
`4 on
`T
`(41)
`(50)
`3
`l
`(B)
`4 (24)
`2 (33)
`5
`(39)
`I5
`(35)
`2 (33)
`_
`I
`(5)
`—
`(I5)
`I
`(6)
`—
`
`I
`
`Placebo
`is
`{til
`__
`(36)
`(13)
`(13)
`(13)
`—
`(ii)
`
`5
`2
`2
`2
`
`i
`
`3 I3
`
`7714: Jotrmcrl cf Rheumarolagy 1939':
`
`[I553
`
`I
`
`,
`
`Fm"
`
`
`
`Page 6 of 8
`
`

`
`
`
`“git; episode of elevated AST (139 IU) at Week 10: she
`antinued without dosage change and her AST returned to
`D,-mat within a week. Another patient had an elevated ALT
`(I25 ILT) while taking 10 rngfml MTX, occurring at Week
`114; it did not recur although the drug dose was not changed.
`one patient had a single WBC of 2,800 at Week 6 (taking
`placebo): on: patient,
`taking 5 mg/m3 Mrx, had wee
`3_30t3 at Week 8. The closing regimem was not changed for
`eitl'J€I' patient and the values were normal when repeated
`within 1 week. One patient had thrornbocytopenia (platelet
`
`ing temporarily discontinuing MTX; she restarted at ‘xi her
`previous dose (still blinded) and continued the protocol. Upon
`.‘ unblinding, this patient‘s dose was found to have been 10
`"H1-nglml. This patient's platelet count responded to lowering
`[the MTX dose, and she continues on protocol (now over 2
`I years. at doses of 5-7.5 mgfweelt MTX). One patient had
`' a serum creatinine of 1.5 mg% on 2 occasions (Weeks 10
`and 18). Thereafter. on blinded extension, her creatinine
`returned to normal 'Wifl‘lO1.lt a clear explanation for these find-
`ings. From the above. the incidence of significantly abnor-
`mal laboratory values (defined as the number of patients with
`the abnormal value divided. by the number of patients in the
`treatment group) was as follows: (1) for 5 mg/tn”, AST:
`7.6%; creatinine: 7.6%; (2) for 10 mgiml, ALT: 5.9%;
`WBC: 5.9%; thrombocytopettia: 5.9%; (3) for 20 mg/mi,
`creatinine: 16.6%: (4) for placebo. WEE‘: 6.3%. No other
`significantly abnormal laboratory values were noted during
`the 13 weeks of the study.
`
`~'
`
`DISCUSSION
`
`"""l" ’'‘’i5P5‘3l ‘*3 d05l"E Tfiglmcnfil to examine the data and tell
`"5 if “"3 ‘M51313 Tfiglmfin WES more toxic than the others.
`The 20 mgfnii dosing regimen caused more toxicity lead-
`ing to dose reduction or drug discontinuation (33%) (Tania
`3), so it was decided to drop that close and replace it with
`a 5 mg/m‘-’ regimen. The 20 nigfmt patients were dropped
`from the efficacy analysis. although they were retained in
`the toxicity analysis. Uninvolved statisticians issued a new
`randomization schedule. This schedule compensated for pa-
`tients already enrolled into the study so that. when complet-
`cd, each group contained similar numbers of patients. This
`change in closing regimens, done for ethical reasons, did not
`unblind the evaluators and did not invalidate t.l1e study.
`For 5 of 11 outcome measures, we show a dose response
`relationship in patients with recalcitrant RA (98% had failed
`2 disease modifying drugs). with increasing doses of MTX
`leading to increasing response. Three additional. measures
`(time to onset of fatigue, 75' walking time. and joint swell-
`ing count) demonstrated numerically (though not statistically)
`more response in the higher dose group. These results taken
`together are suggestive of the presence of such a dose
`response relationship. The same conclusion is reached
`whether one examines the absolute change in disease activity
`measures (Table 1), or the percent of pat_ients with ::- 50%
`improvement (Table 2). Time to discontinuing the study
`differentiated MTX from placebo, but no differences between
`doses were found using this measure.
`As our study lasted 18 weeks, we cannot comment upon
`the possibility that lower doses (e.g., 5-7.5 mg weekly) might
`,,.rduce tin: same results as ll)-1.5 mg tve_;_' ,
`_',-E-.;:: -.'.'__ I-_‘_._.-__
`is followed for longer periods.
`
`Although RP and ESR decreased in our study, these meas-
`ures did not differeniate MTX from placebo (Table I). It
`is not surprising that the placebo patients also improved, as
`patients tend to enter studies when they are flaring and tend
`to improve over time due to the waxing and waning nature
`of RA. In a study such as ours, one might expect to see some
`improvement in these measures secondary to the natural his-
`tory of the disease.
`-
`
`Our study incorporated an initial 12-day hospitalization dur-
`ing which rest plus intensive nomnedical
`therapy such as
`occupational and physical therapy, as well as 2 doses of
`weekly MTX. were given. During this period all patients‘
`disease improved significantly. corroborating previous
`studies showing that a period of inpatient treatment improves
`active resistant RA. (Table 1)”. This finding is important,
`as it is sometimes of equal magnitude to the effect of MTX.
`Although all patients received 2 doses of MTX (10 mglm?
`to the nearest 2.5 mg) during the inhospital period, it is
`Adverse experiences occurred. relatively commonly in all
`unlikely that the MTX per se had a marked effect on disease
`groups,
`including the placebo patients. Thus, 43% of the
`measures during this period. On the other band, we wished
`placebo group had at least one adverse experience (Table
`to avoid any possible carry—over effect of these 2 drug doses,
`3). The expected incidence of GI toxicity, stomatitis, and
`so we did not analyze efficaey results until at least 5 weeks
`dyspepsia occurred and differentiated MTX from placebo.
`after the last of the 2 inpatient MTX doses. Thus we showed
`From Table 3, severe adverse experiences also appeared
`the dose response relationships discussed below utilizing end-
`more commonly,
`in a dose related manner,
`in the MTX
`of—hospitalization (2 weeks), 10, 14 and 18 week data.
`treated groups. No statistically significant dose-to~toxicity
`We initially wished to compare placebo. low, and high
`relationship was found, despite the apparent trend. This may
`weekly MTX doses. Thus. our
`initial design included
`have been due to the small number of patients in each group.
`placebo. 10 mg/ml and 20 mg/m1 weekly MTX. However,
`precluding statistical significance despite the apparent rela-
`we noted an unexpected high incidence of toxicity in the first
`tionship.
`20 patients entered into the study. Therefore. we asked per-
`Although liver function tests and serum creatinine have
`sonnel at Ledcrle Laboratories (who were not involved in
`been a very common reason for study discontinuation in at
` .
`
`
`
`
`
` FtJt‘.'tt. er of: M?'Xi'n resistant RA
`
`
`
`Page 7 of 8
`
`

`
`
`
`6. Ki-enter JM. Lee 1K: The safety and eflicacy of the use of
`' methotrexate in longterm therapy for rheumatoid aI'thritis_
`Arrlu-i.tt'.t Ritetrm f9ti'd'.'29:E22—.”:‘-l.
`‘ 1'. Thompson RN, Watts C‘. Edelrnan J. Esdaile .T. Russell AS: A
`controlled two-center trial of‘ parenteral methotrexate therapy -
`for refractory rheumatoid arthritis. J Rhettmaroi
`l.9t‘i‘4.'l 1:51.760-3.
`'
`. Weinbltltt ME. Coblyn IS, Fox DA, I-loldsworth DE. Glass
`DN. Trenthatn DE: Ellieaey of low-dose melltotrexate in
`rheumatoid arthritis. N Eng! J Med I9-5‘5.‘3l2:Bl8-22.
`Williaans HJ. Willltens RI-'_. Samuelson CD. or cl: Comparison
`of low-dose oral pulse rnethotrexate and placebo in the
`treatment of rheumatoid arthritis. A controlled clinical trial.
`Arthritis Rheum .1985.-2B:72t—30.
`Ridge SC. Rath N. Galivan J. Zahrislte J. Clrtrnsky AL. Kerwar
`ss: Studies on the effect of D-penicillamine. gold Lhioglucose
`‘ and mcthotrexate on streptococcal cell well arthritis. J
`ititettmcrci I9-i6,'895—8.
`._ Rodnan GP. Schurnacher I-IR. Zvaifler NJ‘. eds. Primer on the
`Rheumatic. 8th Ed. Philadelphia: Arthritis Foundation.
`1983220"/HS.
`
`‘
`
`I
`
`j to.
`
`ll
`
`l2.
`
`l3.
`
`"
`
`Sncdeccr GW. Cochran WCi: Statistical Metitcds. ‘itlt Ed.
`Ames: Iowa State University Press. I977.
`Lee P. Kennedy AC. Anderson .1’. Buchanan WN: Benefits of
`hospitalization in rheumatoid arthritis. QJ Med
`.F§‘?4'.'-4Zl:2D5—lt1.
`‘
`
`‘-
`.: ‘
`
`i
`
`[1'L'I!'!'fl.'I'-'-|'-|‘1-
`
`.._-
`
`
`
`-..L_r..H.r-.rn=.-.-1.:-u-nA.>-h-ui-u“tu!L-:L-Jtdafi-IFrrI|'_'t-..ffi'§-‘I
`
`3.
`
`I-loffmeister RT: Mcthotrexate therapy in rheumatoid arthritis -
`15 years experience. Am J’ Med 1933.-12:69-73.
`'
`4. Willkens RF. Watson M.-ll: Methctrexatc: perspective of its
`in the t.reatment oi‘ rheumatic diseases. J Lab Clin Med
`I982,-l0D:314—21.
`5. Groff GD. Shcttbergcr KN. Willte W5, Taylor TH; Lg“: dos:
`oral rnethetrexate in rheumatoid arthritis: An uncontrolled [rial
`and review of the literature. Semin Arrlzriris Rheum
`.i933.'I2:_'-l33—47.
`
`use
`
`_~
`
`5
`
`‘I
`
`least one other study”. we did not discontinue patients for
`a change in liver fiinction tests unless the abnormality was
`greater than 3 times normal. Although mean changes in liver
`function tests were quite minimal in most cases. the inci-
`dence of significant laboratory abnormalities (as a percent
`of _patients in a treatment group) was similar to published
`studies”.
`
`A major caveat with respect to the toxicity in our study
`is this study’s relatively short term nature, In our longer-
`term followup. more toxicity occurred. Some adverse experi-
`ence occurred in all patients during 76 weeks of therapy.
`Llalthough only 12%. stopped drug permanently for adverse
`. "effects (manuscript submitted for publication). Thus. the rela-
`M tively benign appearance of MTX in our study must be
`viewed with caution.
`
`i
`
`In summary, this 18-week study of weekly MTX in resis-
`M
`tant RA (1) establishes a dose response relationship for cit":-
`caey;
`(2)
`indicates a trend towards a dose to toxicity
`relationship.
`
`ACKNDHTLEDGNEENT
`
`We wish to gratefully acknowledge the secretarial assistance of Karen Adams
`‘ and Doris Walters. and the administrative support of Richard Ryan.
`
`REFERENCES
`
`1. Gulaner R5, August VR: Therapeutic suppression of tissue
`reactivity to effective an-iinopterin in rheumatoid arthritis and
`psoriasis. Am J Med Sci J9.50:2."lD.' l'7'6--83.
`‘ 2. Weinstein GD: Methotrexate. Arm Intern Med
`1977;35:199-204.
`
`320
`
`The Journal of Rhditntdralagy 1989.‘ 75-'3
`
`7
`
`Page 8 of 8