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Marietta M. Henry. M.D. Vice President



Medical .Affairs

Covance Central Laboratory Services Inc.

6211 SciCor Dr. lndlanapolis, Indiana 46214-2985

Tel: 3171273- 7934 800/462.·8885

Fax: 3171213-7990

December 19, 1998

Martha Belker, MS, RPh Study Coordinator Hoechst Marion Roussel 10236 Marion Park Drive Kansas City, MO 64137

S\V\ \J :> ~-T' ~ < +p~o.c~ C\~~ h <.

I-t "fV\ (Z. g. b lsf r It-

FAX: 816-966-5678

Dear Ms. Belker:

Covance has received a call from one of the investigator sites for your Protocol HM R364 7 A/3 008 (Covance Project 501069) which was questioning the number of High flags for creatinine clearances in their patients. Dr. Ziter's site, has noted that all of their patients were nagged with high creatinine clearance results from baseline through the second or third visit. The serum creatinine results were within the normal range.

I have looked at the results for creatinine clearance in your protocol and found that, indeed, the number of High flags appears to be high. However, we usually see this when the creatinine clearance is calculated for healthy persons. With any estimation, there are circumstances where the estimate does not hold true. However, the Cockcroft and Gault formula for estimating thecreatinine clearance works well for persons with poor renal function. .

In this protocol, as well as others, an estimated creatinine clearance is performed, probably to spare your patients and you the trouble of collecting all of the ir urine for a fu II 24 hours and bringing it to the investigator's office for mixing, aliquotting and shipping to us for complete analysis. However, most methods of estimating creatinine clearance do not work well in persons with normal renal function and not well at all';'n obese patients. Your patients fit both categories. I noted that many of your patients with high flags had elevated body weights ( 122 kg, 114 kg, 120 kg, Its kg),

In Tietz Textbook of Clinical Chemistry I, it is slated that ... "Obesity is a source of potentially large error in the clearance estimate, even if correction for weight is made ..... The error contributed by obesity can

lead to the belief that clearance is normal, when, in fact, it is low. This error can be reduced by correcting obese body weight to estimated lean body mass by one or another of the algorithms used for this purpose ... The textbook provides an example: Given a patient with 60 kg lean body mass, observed as 100 kg of body weight, the clearance would be about half the estimate obtained if a body weight of 100 kg had been used.

An older paper 2 also notes that studies of creatinine excretion in obesity gave contradictory results. These persons studied creatinine excretion of obese women during fasting. A more recent paper l

looked at agreement between measured creatinine clearance values in obese, critically ill patients versus estimated creatinine clearances using three common empirically derived formulas with published modifications. In these critically ill patients, none ofthe estimated creatinine clearances had clinically acceptable 95% confidence intervals.

THE AMERICAS

EUROPE

ASIA/PACIFIC

AFRICA

C OV A-flCE'.

Martha Belker, MS, RPh Hoechst Marion Roussel December 19, 1998

Page Two

The other factor that skews creatinine clearance estimations is the random error in creatinine determination, Since the precision of creatinine determination increases as the concentration increases, the error in the estimate ofcreatinine decreases. The converse of this is at lower (normal) creatinine levels, the error in estimation of creatinine clearance increases. The reference quote previously I states that .... " As a general guide, an estimated creatinine clearance should not be considered reliable when the .. creatinine is less than 2.5 mg/dL. ... ". Of course, thlsis somewhat of a purist's view since estimated creatinine clearances are used frequently in clinical trials usually with success in excluding patients with poor renal function. The patients who have good renal function are not a source of worry.

In Attachment I, I have tabulated the results for calculated creatinine clearance for all your ketclide protocols. All of the HMR protocols have a high percentage of high flags for calculated creatinine clearance by the Cockcroft and Gault formula. I also extracted data from two other protocols that enrolled mostly healthy persons. You will note that these protocols also had many high flags.

I hope that this has assisted you in the evaluation of your patients. I would appreciate the chance to share this letter with your investigator, Dr. Ziterand his coordinator Fran who called us originally. Perhaps you would like to expl . . vestigator sites that you are only interested in the Low flags in terms of exclusions an i h fla s can be ignore. If you wish Covanee to assist you in explaining this, please contact Jim Knigh t, your ketolide Project Manager. If you have further questions, please call me at (800) 462-8885, Ext. 7934.

Sincerely,

~\~~ \\" ~_\'.J-.~ ~\\J

Marietta M. Henry, MD

Vice President, Medical Affairs and Laboratory Medical Director

CC Stephanie Buske, IBAH Clinical Trial Manager Jim Knight, Covance Project Manager

Kim Kime, Covance Account Manager

REFERENCES

I. Burtis, CA and ER Ashwood. Tietz Textbook of Clinical Chemistry, Second Edition. WB Saunders Co. (Philadelphia), 1994. Page 1537.

2. Peters, WH, Grosser, V and A. Knapp. The creatinine excretion in women during fasting. Clin Chem Acta, 1972; 39: 273-274.

3. Snider, RD, Kruse, JA, Bander, JJ and GH Dunn. Accuracy of estimated creatinine clearance values in obese, critically ill patients with stable renal function in the intensive care unit. Phannacotherapy

(U n ited States), Nov-Dec 1995; 15(6): 747-753.

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ATTACHMENT I

PROTOCOL NUM- LOW HIGH RANGE, WEIGHT, WEIGHT,
BER FLAGS FLAGS mUMin KG (LBS) KG,AVG
(~tEDlAN)

HMR3647A3005 424 17 (4%) 218 (51%) 59·317 46·145 81(78)
(101-319)

HMR364 7 A3006 334 39 (12%) 180 (54%) 34-268 41-153 77 (73)
(90-337)

HMR364 7 A3007 625 132 (21%) 237 (38%) 29-368 41-137 79 (76)
(90-301)

HMR364 7 A3008 146 2 (3%) 108 (74%) 80-317 40-122 81 (76)
(88-268)

HMR364 7 A3009 85 15 (18%) 45 (53%) 36-245 50-125 81(82)
(110-275)

PROTOCOL A 421 0 (0%) 314 (74%) 76-581 45-135 90(90)
(99-297)

PROTOCOLB 59 2 (3%) 29 (49%) 73-239 49-136 92(92)
(108-299) Protocol A is a dental analgesia protocol with predominately young persons. The average age is 28 years.

Protocol B is a G I reflux protocol with an average age of 40 years.

, EXCLUSIONS
Immunotherapy rJlt TURI AliA- I Flu shot allowed? -(1:_s
Current smokers? '-1 t f I Srnokino history? NO ??S Cr rJ;S. P-b1 k- ~
Blood pressure meds allowed?
-
; I'_"~·: ~ -_-_~r- r.-. ,~ .. WASHOUTS FOR CON MED~
Before screening visit /: .. Throughout study
Deconqestants /
Short-acting antihistamines /
Lonq-acting antihistamines /
Hismanal /
Nasal steroids 1
Intal/Nasalcrom /
Tilade (nedocrimal sodium) /
Atrovent /
Inhaled steroid /
Theophylline /
Short-acting bela agonists L
Long-acting beta agonists /
Caffeine
7 I Other fealures:

\-1 e rc k KGa)I,

t. \ 1'1 / lftUP-P,

Darmstadt, Germany

EMD 90 171-002

Amendment IlNovember 11, 1997

STUDY FLOW CHART, EMD 90 171-002

Check inclusion

x

x

x

x

x

x

x

x

x

x

x

x

For patients on horm~on;a::il-;re;:;p~lac;:;:::e:;;m;;e~nt;7t;;:;=;;;;~;r.:;;;;;r-;;:;;j'=;;;;:;;;;;r;:;;;;;;;t.;;i"T,;ir;;;:;;;_;i7.;;;;;;rt--""

must be obtained prior to beginning washout period.

S Vasomotor symptoms Hot flushes, Kupperman-Index, Greene Climacteric Scale.

•• In patients with an endometrial thickness >6 mm (double-layer. transvaginal ultrasound) at Visit 5, a repeat biopsy of the endometrium must be performed.

§ Patients who have not had a mammogram within 6 months prior to randomization must have a mammogram al Visit t.

~ Safety labs, to consist of: Hb, Hct, RBC, WBC, Platelet ct., Chemistries: GGT, AL T, AST, alkaline phospatase, total bilirubin. albumin, total protein. glucose, creatinine, BUN, uric acid. electrolytes (sodium, potassium, chloride, bicarbonate). calcium, inorg. phosphorus.

1#1 AI this visit, FSH and E2 are to be obtained ooly in patients amenorrheic for between 6 • 12 months.

AMENDl..DOC

\997

"J

";t ":

~.; r : ~ .... .c

"_J

• II ~j 1 ....... \ \ •• \J ,\._

1'1"0)10("/)1 111)"02,1

Study Name: (S:\j{ II)

- /J

Coord ina tor :!j a ,t/-;r. ..-,!/l'J.__

Description of study:

TilE EVALUATION OFTHREE NORASTEMIZOLE DOSES (30 mg, 60 mg, ')() mgl ANI) LOHATADINE WilEN ADMINISTERED TO SUBJECTS W"ITII SEASONAl. /\ LLEHCIC rnliNITIS

ENROLLMENT:

Beginning9~LI through Ie/Ie:> ... ". . Number 01 patients J.'f_

Number of visits and tength of study: ..s:?U."Q:<:" U _ C~(!."-<_.e; .. _Q __ j"= (#/9/?J -----7MDO/Li=_ Long Days? ./"J'1-()

STUDY REQUIREMENTS

EXCLUSIONS

_~~11 n~u n?_t~~aR ,-;_fl£, .. t Current smokers? 0 K__

------- ------

""~iood pressure meds a~o_w~~? _

WASHOUTS FOR CON MEDS

Before screenino visit

:\ n I~' i1 i sea m i ries ::~"";'l;l.ok 0;:: H';'.mY"~C ! I'~: ,: :~~L: i t~e ==- (...e.o~l( .. ;.,

~ :':: :::x.:..: :'·3S";1.,..a:.L-

\:.,'; : ....... :<:.:, ;::..:: =:. A.;t",-~d~ - ....... .c:>

T eu.(!c"- ~::_;: .!:: . ~.:' ~ ~ ~~ i : :!=-: ~~ : Ll~ ;:"':':'Z\JU on:: J

--- --- -- -- ---

:- d~::s =:. dcvs

CisaDlidi

0'1 ~:_:~~'~ 7 c,..:-_"

~ d .. JYs _ ~; ~lJy:.'

Oral a~li fUnlzals (e .g. ke lOCQil0:!201 e I Ma'C'rolid~ 2mibiOlic$ (c.g. er ythrornycm I

:"''':o,;;n.:: HCL '" {,<.:/,- <:1 " .: I' .:,:.~, antihistamines

(~i .. : ~i,;c-" sleep and die l 2 i des "!~",; ~ '~.: : 'rC":·. ,: ,::: ons)

(O~ri ico"s(eroids

Beta' bloc ker,

DecOll2eSlams i ncl ud in!! co Id ore C':l r <!; 10 il~ ;,",lb";:r than short-acting pseudoephedrine I lOpic2L~~sill or oral

M o'nteJ li~:'~-sCiii" rl!! l.::?SI"or 7:; I euto n

~U days - Ocular medicalions

:;0 days - (for relief of allergy svrnptom- '"',,~~cn [')I;\P' i"l,

! ~ de :~·s 0Ve r ~ rbe-coun i e r)

:; da vs I n!rJ nasal medic31 io ns

- -- - ----

? -~3 ~ InralroDiun1

_ ;:; '-g ~J Inh~kJ

z: ~ ;": - --1

g_ '" _;~ ~~1_f!lolvn_

".1- In!:'"::~:;~~;!1

r:

'" " . .J U ~..J

J~." i:: :-: ) :~.;~ -,

- (except corticosteroids and crornolyn. prescriplioll 14 days _ Qf over-the -counter)

2:':!lI~e labl.e'ls

\!~reSCllpl!on levels. nOI Qu.nm<;>.r()n!Jln!fl~ bC'\'~i~~es" such JS tome \Vi!1.C: j

Other features:

.- .

Study Name: .s i i C C/ S/~(' c-' ( Coordinator: (_ I_)'

Description of study: A (),:.. ( r

ENROLLMENT:
Beginning Sv.v I)ihrough Number of patients ; .)
Age 18 -r I Compensation ;J' Q Labs (fasting}l IVO_N~
Number of visits and length of study: I
Long Days? t00 STUDY REQUIREMENTS
PFT requirements I I 4
Time of day for study visits: I L f
Skin test required? ff I / j/_ H Chest Xray?
Contraception f \ / I I
Other requirements: I .._" [
I Immunothera

URI

Flu shot allowed?

EXCLUSIONS

Current smokers?

?

Blood ressure moos allowed?

I, WASHOUTS FOR CON MEDS
<, Before screening visit Throughout study
Decong~ts ,
Short-acting a~tamines
Long-acting antihjsi~s
Hismanal <,
Nasal steroids "-...."-
IntalfNasalcrom <,
Tilade (nedocrimal sodium) <,
Atrovent <,
Inhaled steroid <,
Theophylline ~
Short-acting beta agonists r-,
Long-acting beta agonists <,
Caffeine <, Other features:

f1 ()...J-T -e PhCAJ"\1 rI ~ \ \i S:. /-kHlb \ \\ i -ti.s

Study Name: \-\ rfl R3 ()O <6 Coordinator: ~ 1\ (~1 ,i.._/

Descri~tion of study: PI ~-ti ve. c..o(\-t('D\\~J,. S-t-vcl~ ~~or'\ (I ~ t-\~62.. 3G<-tll, ~o. ~\ 0-.'\ -Ih roM(j 0'/\ -fur +"-<2. -trecrl-n\JI.J'\t 0+ 611121510 LOCCW f'hN~{l~"UI

ENROLLMENT: 1- d12.:'; II rH ~

STUDY REQUIREMENTS

EXCLUSIONS

Flu shot allowed? d0{)'+ b)ot.·

WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants (')1<- Ok.
Sbort-actnq antihistamines f))::_ () Ie I
Long-acting antihistamines O~:._ Oi~
Hismanal
Nasal steroids Ok_ _Q)(_
IntallNasalcrom Ot D\L
Tilade (nedocrimal sodium) Dk.. Ok:....
Atrovent O'F- 01(_
Inhaled steroid, Ole:.. {))'-....
Theophylline _Ok- ~ 01'-
Short-acting beta agonists Ok- Ole
LonQ~acting beta agonists
Caffeine OK.. _Ok_
~ :r:.(,(;,!o -S\Jo~Ie,t')\{lY0"'.s a.br.~ ~+.::.c-e.. dD'>111 I Other fealures:

Study Name: N1 (_/ IN ol._S Coordinator:

Description of study: (0oclunNIA I t:'\'S'ih r'Ylt\-

ENROLLMENT:
Beginning V n through _) ,j-- Number of patients 10
Aqe ISl-t;':;:- I Compensation"!SOf ioo Labs (fasting?) Yps
Number of visits and length of study: r ..
fl"}I/'J S ou.e..'1 r-: T e_
Long Days? S 7" '--rr, PIA .;- ""'?ot ... "\-~ STUDY REQUIREMENTS
PFT requirements "0°10 ~<;_J ;f S..;l
Time of day for study visits: rt-VG 1-). AI'?.£ (/}~d l/~s., 'K 3. a Ufol 1-.1..(
Skin test required? fJ'O I Chest Xray? f.j-c
Contraception MPJ,c14i A cc.p.o-h-:. b 1<
Other requirements: gO% AltGLvU-C iff}..fr1- AL6v~ol
cas'JI~ IJ
Immunothera

URI

Flu shot allowed? c->:

EXCLUSIONS

Current smokers? NO

Blood ressure meds allowed?

WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants
Short-acting antihistamInes ~ JA'1..9 ~MR~ .r'CI,IP(.n.....-
Lonq-actinq antihistamines \I
Hismanal g CU1X7kS'
Nasal steroids ' ,
Intal/Nasalcrom
Tilade -(nedocrimal sodium)
Atrovent t.(Qh.nv~
Inhaled steroid
Theophylline I(g hW/1 c
Short-acting beta agonists &J,OJOS
Long-acting beta agonists '4"15 )t \0(\'> \ /
Caffeine 1? h tV fLS \.. V I Other fealures:

Study Name: ~ll~ oS: 't- 0 SJ Coordinator: L-. .;:[. Co ,i-(-lHU J ;YJ. ~,

Description of study: e p.f!/'J lJ\ ~ 1/ Pit t(~ lie /.- ~C!V r R4Ndc.'~ '-r...P j ;:;4c-/l1.a--

C Q I\t ~ f e J s T obt o-t1 -tA.-C" ~d.o c h ~ I\J.D ..e -I'k~.r .c).,a ,t1~I?t:J tJ (cI / t: 10 vev("

AI'-' ~ on,q./ nedl~C..ue.. ;111 -Ptr{'r-Rv1 tur-tJ, IY), IJ. h ,ft«:i.~,.t ..as::~Al".ez

ENROLLMENT:

Number of patients I iQ

EXCLUSIONS
Immunotherapy ~~b J~ I URI ~ J1i\ 4- I Flu shot allowed? Of"
Current smokers? ,,",0 IJ~ t.U;r1i'JV l41l 1 SHtoking history? I kJe 1/I'V1
Blood pressure meds allowed? C>;--\JA l::>k,(.._ hv.". I wulj «. 4-.-.J_(j
PJ'-'<... .!l-"\o~.l.....""--'- Z ~ rn. c .. -r\; "- ..s. J &100 ~ darvwt'(9.l\) .30~
,-, n C h'J ' --t-,a (i-LA ft 0 IV 4J .. -rJ. ("v (, hLr.) •• It.,:7' h. S' t:!11. /!:I? b ~'N.u·
o-Pt tI'''!>.=t- " CoP.!) D t.I I rn lW IVl eA c.e 6L h 1f.t1-1 'b j, ~ t A-
bn~...,.rh; dr-As.' c ~) Osrao lD",() 0 sis: ' 1-/ I ~ p",c(..:tzVJ.f' 5~ ~
/2J 0 c t==11'b-DI 11..1 IJV ~,,/fC' 1'I-,;t/-~;-r7b..~C- I
7 / WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants o«. Ok.
Short-actina antihistamines {q--h:-\!5'~ D K: f) « ,
Long-acting antihistamines 0((.· OK
Hismanal o«: lfc-
(.
Nasal steroids 4 t,VY(~ lv,L~_ I~ A...) 0
IntallNasalcrom 100
Tilade(nedocrimal sodium) A ;0
Atrovent '-f «;1) ,UD
Inhaled steroid to rn ON -r '-t..s eLI o-.J....i.._, NO
Theophylline ~, k. {/(,
Short~acting beta agonists V ~L.'v). ,.;)j5- L~{<'_
Long-acting beta agonists =t: Y' 0) ~)L'
Caffeine Ok- c> 'k._ [Other features:

--

Study Name: ror~..:b t A lIe- (_)3 Coordinator:

Description of study: \Jy__J..~d-'L,--2_ ~\_,,-S,,,- <,,-~I._ eV S\e_A-Lf'(\_,

=(7 k jJ t_"""'*.'-

ENROLLMENT:

STUDY REQUIREMENTS

EXCLUSIONS
Immunotherapy ~+lLUo(;(L~ I URI i..{u-~k , c->: .J,\._ I Flu shot allowed?
Current smokers? vl.-~) I Smoking history? I 'j~
Blood pressure meds allowed?
P}-J.- Sl_./ • .._,__'L t~ ( _4v.)K l-L)(\_/~h .. c~ ( I' f n\or-e... -.\-,\,_(lj,,/v,- I<.jAQ.'-\J\ Q(Jl /p,
~ WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants )L-C-;'-""" z-,..._t-:~t {et VJ!~k_,-~j,f I
Short-acting antihistamines ~,,_ \'v'-'::;' _ "'- "
Long-acting antihistamines ~I.I& k_. ____ :.. 7
Hismanal 3 r\, l L'll l 'f-\.Lb
Nasal steroids \ l-...:k l-~l 30o.cA.~) ~\ 0.;,." l\ri ..:. ctP *"*'~~~-~ -
Intal/Nasalcrom S4·(~.J_)le ?LJ~'c..f.. u
Tilade(nedocrimal sodium) '3 0 c\o. -. S ~o,)';xl-
Atrovent .J i-,J~ :> vJ (,-"~,
Inhaled steroid 5fct.hle c;i,oJR. l,ert 60&c .-\_ \/\
Theophylline ,;;.... u...._)k s i-. l'1_.~fX \...~ ~
Short-acting beta agonists lt~.
Long-acting beta agonists B wk I"_ ~t'.t.-~'-- [r" \_7
Caffeine o IvV':) - ....---,

.I "':1

'.

£ve/y.J

Description of study: _guf{;TY !;.lUl;i ~ / Y£IJf!_ - FLfxlJ2L2 (JO_Sf~ ~e::t_ PC

H f fJ F L !J 11/ /<; o c l f) E:_ V S 12);~ {_ L 0 /11 E_ //1.'1 <;. 0 tJ f_ D / P R.. o PI tJ 1/ h 3: / PA r. o

Study Name:AI/v~ -/tJIJ-02 .ooo

Coordinator: Cu-e_L y rJ

- _
ENROLLMENT:
Beginning _If -1 q through _!-;-_ 11 Number of patients g' L T/JrA L 260 )
Age- I Z - _ b OTCompensation if "/5. - Labs (fasting?)
Number of visits and length of study f II/ S liS 52 WE.LkS
Long Days?
I
STUDY REQUIREMENTS R/WDffVjIZi1T!ON ftV '> 10 'ic J!
PFT requirements r.<::,[; • .» LD Ie / 1'- I;) vi" t) 2- fJL'fF5 /h e () TfJ<o L
Time of day for study visits: {JLNJ To 11 OD
Skin test required? No I Chest Xray? NO
Contraception 'IE!};
Other requirements fT g,2./tT £6 - US'i NOSE cuPS
Pi. AJ~Eb.s. TO ~P...I JJG 2_t,~ HI( LlltiN2. T6·- V IS IT '7_
;: II

Immunotherap URI

Flu shot allowed?

EXCLUSIONS

Current smokers? 1\1 Cl > I 'I R

? «: I o PACK. Y RS

Blood ressure meds allowed?

·pR;.I"oR... TO _SC.fl2:£.N

r

MUS.T B~ ;0

bA'I ~T~~Lt.

.' bOSE p~£:. ~

, sc R.1:l':N 4,

See p, o. c e, 3<Z WASHOUTS FOR CONMEDS
J / Before screening visit Throughout study
Deconqestants --_._ -- ~- 6K. oK
~e.1 D- -Ad r e II e, f"Cj I C S Blocke rS· I wK , - . ·WIf ..;:--
"7 -" .- --,"
Long-acting antihistamines I $1{0 1'\1- OK
Hismanal OK ~
Nasal steroids .. - __ . csK. £3 K_ - I F NO l' IN
Intal/Nasalcrom (')K TILL V-1. ~ p v-/_ 4-
-
. .
Tilade (nedocrimal sodium) oK II LL V-l ~j p V -2. <::-
Atrovent > tf~ HRS ~'; ~
Inhaled steroid OK ~ifl" -(::---
..
Theophylline SQlfl)C'.t~ro\ 11.. ~ RS '2Y- I-\RS LFI I) <- ox- If No l' I_bi.
Short-acting beta agonists ""7 b ~f\S ~;&,
". " -, ~
."' ,
Long-acting beta agonists »- 10 I-l~S ~kJ·~· ~
Caffeine OK Ok
ORAl ST7_RhI tl<;;, :7" " ct () DR'i S No- t)(c.e..H f6 R. < j Y-
Other features: s. Tub '-/ Mf:b~ b TO q a.-m - t, If) IJ Pm
rOlJltrH ~xAL!.. JS AN A 2:_ ~ R.5:.C(J R.b ,tJ cRJ - ITRfYll NATE PT.
PlfDNc.. f'T iwK P VISIT fl To CI-lH~.K F"ofJ.. A£ 's Do:

Oct-05-98 12:41 Roberts~MD/Rich~MD

o

QUINTILF.s

503 223 1947

P.01

September 23. 1998

Via Facsimile: (520) 322-5060

Jay Grossman. M.D. andJor Laura Hulse and John Ferraro, VIVRA Research Partners

698 E. Wetmore Rd., suite 100 Tucson, AZ 85705

Re: Sepracor 110-024, "The EvaluatWn of Three Norastemizole Doses (3Om8, 60 mg. 90 mg) and Laraiadlne Wilen Administered to Suhjects with Seasonal Allergic Rhinitis".

Dear Dr. Grossman, Laura and John:

I am writing in reference to my first monitoring visit to yOUT site on September 16, 1998. I would like to thank you for your time and efforts during my visit and for your continued support with this important trial.

.

The following is a liSt of cases monitored during my visit:

<

R#9437JYJS S 0031 J10

S 004/ EEe S OOS/DRS R# 142/R-V

Visit 1, Visit 2) Concomitant Medications & AE Visit 1, Screen Failure Folder & ICF

V ish 1, Concomitant Medications & leF Visit 1, Concomitant Medications & leF

Visit 1, Visit 2, Concomitant Medications & AE

S 001 to S026

Informed Consent Forms, except SOlI. S012, 5016, 8024 & 8025. which were not located.

The following is a list of'relevanr findings that may need follow up from your part:

Informed Consent Forms

Some subjects have not dated their initials or signatures. ,

The person conducting the r nformed Consent PruCL'SS must instruct the subjects or legal representatives about the appropriate application of their initials, signatures and dates in the Informed Consent Forms. Please review the Informed Consent Forms during the next visits and collect the missing dates from the subjects or legal representatives.

ENROLLMENT:
Beginning I:;' -98 through Number of patients g
Age s-r»: 1 Compensation L bit.· .") V\S\L.I(", (i~IJJ'\ 5v.;t\~i:rl_.-;lr,~
a s ....... " .. ~.
Number of visits and length of study: 6 Vl'll+~ 0'((( .;t~ Ot-p f/V (n~,(
Long Days? .!JdN·(_ STUDY REQUIREMENTS

EXCLUSIONS
Immunotherapy I f ~~~r.\ (~~I URI - I Flu shot allowed? No
Current smokers? ye 5 I Smoking history? Nt}.
Blood pressure meds allowed? AliA
~{iES .,." f. N() 1#Ir<J-I,IIA'/IO/\J!d !Jm. } t , 1 PI ."JiOVJ ]Jr.(,1./T.
7vIJ ().lR. <J f AtJ AN-hv,'(J\ I I~ iJrr.J,ov~ ~7- Or1'{f
C \(5 -/i( rl hr;, r;J /!"fY\."",; 1-'0 Cavon.Q (,.1\"0', ~.;>.t
I WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants
Short-acting antihistamines ,.
Lono-actino antihistamines
c Hismanal
~o<; Nasal steroids
\;. Intal/Nasalcrom
I
Tilade (nedocrimal sodium)
Atrovent
Inhaled steroid
Theophylline
Short-acting beta agonists
Long-acting beta agonists
,Caffeine I Other fealures:

Nasal steroids

Intal/Nasalcrom

Tilade nedocrimal sodium

Atrovenl

Inhaled steroid

Study Name: \<..0 'll_ ol-'l,

Coordinator: Lc-vvL. - tLJ~'t V\

Description ofstudy: r c. 0"-, t Y ( ,)(_ s + c' -c sPo s ... ·'l ~ pr e_ v Q_ v\ J. " 0 v\. T C) F I <.J

\\ PEP II

ENROLLMENT:
Beginning mrouoh Number of patients
Agef3 -~~ I Compensation Labs .. Ihl'C'lc,,t ~ VlC_S)c,,/ ~L14b
-
Number of visits and length of study: '3 v h, +- ~ lA .Pc -c "Z' I l~ c. '( ~
Lone Days? V\C) vtt' STUDY REQUIREMENTS
PFT requirements I\/V\-
Time of day for study visits: AoAy
Skin test required? V\.6 r I Chest Xray? V\6
Contraception i~.J\.\. M .... te. ~ ~.,,.., .. Je MLJ\\-oA,r«.(. -Lei v'S .. l-'.cf.€C"t;"e.. Mt..+t.-..",,,i
Other requirements: '1 r c vol 0.(. ~ 'X' . (r.. l"d vV\':L,~ I"~ )
CC""SQ.v\.~ Cc..oA I" ~ ~ ,',,- oA J> .\ liP"'v (. v'-<..V\~ 2: (-' jI\ i e \J
( EXCLUSIONS
Immunotherapy I URI I Flu shot allowed? \IQ.~
Current smokers? n~(A..'1 I Smoking history? ou..<-y
Blood pressure meds allowed'? f
p Jo-A.- .!L- • .......:l... ~ c
As~",,,,",,,,- ~ \)',~be~~ .... '" ') V\'" (~C·t.P. + lc..l", ~\c.",-"" c,.,z Ll .V'\ ~ IAQ/c,f\/ 17 We ... II <.::
~ "3~"J..~1 LV.." I
C.
V\0 .£L,d ,\J ; (l II U/'i.-~s " ! oJ

WASHOUTS FOR CON MEDS
Before screeninq visit Throughout study
Decongestants
Short-acting antihistamines
Long-acting antihistamines
Hismanal
Nasal steroids
IntaliNasalcrom
Tilade (nedocrimal sodium)
Atrovent
Inhaled steroid
Theophylline
Short-acting beta aqonists
LonQ-actinQ beta aoonists
Caffeine WV11112

Koene Neuraminidase Inhibitor

Roche Neunnnlnldue Inhibitor

WV15812

:xc ...... CrIIerta (cent.)

._.JI'II:IwfIt InMn Signllcant ,.".1 diIeIIe defined IS I creatinine cIMf8nce (tneUUf8d or estIrnIted) s 30 mUmin

Patients with known significant liver dysfunction associated with frank jaundice or with transaminase values within or greater than grade '" of the WHO scale

Patients with NYHA class IV

- Patients with COAD .. '"

- TIWfIIPI8nt ..apienIs (except corneal transplantation)

- PIIienta taking Imrnuno-suppresnt therapies (inhaled steroids or

systemic ttIrOIds less than or equivalent to 5 mg/ day prednisolone are accepted)

- Pregnant or breast feeding females

Active cancer at any site ( patients with basal cell carcinoma or a previoul history of cancer in remission and not requiring therapy will be eligible)

Inc .... lon Criteria

- Patients with chronic cardt.c Indlor respiratory disease defined IS:

Adults and children with chronic cardiac (excluding chronic idiopathic hypertension) or pulmonary disorders (Including bronchopulmonary dysplasia, and asthma BUT EXCLUDING CYSTIC FIBROSIS) severe enough to require regular medical follow-up or hospital care

~ 13 years of age

- Symptoms consistent with influenza:

Fever 38°C PLUS

One respiratory symptom (cough, sore throat, nasal symptoms) PLUS One constitutional symptom [chills/sweats (feeling feverish), malaise (feeling unwell), headache, myalgia (aches and pains), prostration (fatigue)

- Presentation such that the firsl dose may be taken no later than 36 hours post onset of feeling unwell

- Legally effective written infonned consent available

- Known HIV infedlon

- NIrergy to any excipient. In capsule (see section 6.2) or

~hen

Patients who experienced a previous episode of acute upPer .8Ipio'ItoI y tnIc:t Infection (URTI), otitis, bronchitis or sinusitis or received antibiotics for URTI, otitis, sinusitis or bronchitis or antiviral therapy for influenza within two weeks prior to study day 1

- , .• icipation In a clinical study with an Investigational drug within 4 weeks prior to study day 1

- MSQ 7

- Independent and free living In the community (i.e. not in need of or awaiting residential care)

- Women of childbearing potential must agree to utilise an effedive method of contraception throughout the study period and for one reproductive cycle following cessation of study therapy and must have a negative urine pregnancy test prior to drug dOSing

- A cIInicdy relevant history of abuse of llcohoI or other drugs

- Presentation > 36 hours post the onset of feeling unwell

Exclusion Criteria

Patients with uncontrolled renal. vascular, neurologic, metabolic: (diabetes, thyroid disorders, adrenal disease) disease. hepatitis or cirrhosis, defined IS disease requiring change of therapy or hospitalisation within 4 weeks preceding the first dose of study drug. Change is defined as increased dose or change of medication (medication change because of AE is allowed). In-patient hospltallsations for less than 24 hours will be accepted

r,

ENROLLMENT:
BeQinning through Number of patients
Age \ '6 -\, I Compensation \'\\) (\0 Labs (fasting?) \~ \)
Number of visits and length of study: 8 lD(::C~ ~ - L\ -5 V\ $\-\-.5
Lone Days? \'\ 0 STUDY REQUIREMENTS

EXCLUSIONS

Immunothera

URI

Flu shot allowed?

?

c~
J
N
.:
' __
'j
\,
~
"
J
"
f.
'I
i
~
"
.,
,__'
.,
J
.....
~
""-
.,J
,.,
L
"
fl cJ
I
_" Study Name: f-f ,L{ fC. t..{- 0 c, ;;_ Coordinator: ~(t_. Lc _._ (-+ L c r 10,-,0

t : ~'-- L L_ 16. ( t!-,~c_

Description of study: cf Z) c-_L t::! .-:L L~~ J rrt- ' . .

.~ CLU-"ll"-t'- (>fL~ /'H 'd- L ... ~ f-'-t.'J. b~..... (0l_.__) ct ,~.'J_'_ (l'>--t, T ( c ~, ,J-C-,,_'~ (\ , <r...___;

~

ENROLLMENT:
Beqinning I C(<-['(' through r ({ DO (cur Number of patients { J
Aqe [.;1.. -- <....co I Compensation (:)SD~ Labs (fasting?) J ~, V-I
Number of visits and length of study: ~ u ~.L..""_t":J L,,(....._, I Co....) _u_1. <../~
Long Days? ""tL.Q , 1

"

.J

, '

"

STUDY REQUIREMENTS
PFT requirements ">- lc:,':;'- °70 .- }~ ","_C.L) _{__,'L_'_~ j{_(~.l Lt a l._"
Time of day for study visits: I-t~l b> tc"1 " ,_ 6
Skin test required? LVJ.- -i: +0 ,\..4---<\L:..JL ... J Chest Xray? ~LO
Con traception /1-<_.1.' . 1/
(tJ. ~ [, t Lt . ..._~ ~~'-0,L/
Other requirements: LA..) c-t_t) .:k .Jl. ' 0 C~_Tl c.~ 4 ::t.L-\.. 0'«- ~, ( Ll...lJ J1 .;,I,
f-,.\ CJ /l.A..t.','),_:r L \.. U 11 -l L-t.\1_ -hJ (/ _ / 11- lL-L"'--L t: a. c_1:::. '--..6. L-t 1 __
It. ' c: .1 t')~~ 1+;< , L.-U I v ," ,I] A 1-·t'\LU k,<. <L ,
l"t-,/w)c<...- ... l.-(._/ JU._j L-(_~ I
o a I f) to
i EXCLUSIONS
'" r
r Immunotherapy 'j-~_;~ I URI 3(" 0(.'--<.. ;rJ I Flu shot allowed? c ""V-:7
'.J
Current smokers? d ).<-","l (I l jA, J I SmOKing history? )L-<. ... p_lc v • '_t
c j L ,e_L.I.L.__.
Blood pressure meds allowed?' )tl!~_:L.. • - I o« I.
IL;, _I t.1 Ll f?'-''--.lLC-,..._)
P f'---k- JL.""""":.L ~ c :2 ,) 0-'--1 L<--' "·"L_.f!___
, .. )0
.V_ ijc..~ • . I) 9--' 11'---'<._ c, -12.-? ,·t· :3 t\ ;.)(~
V-~,-.0 .Q_.,j _"L I ~.A XL-.ll'
I tJ - V
-...J WASHOUTS FOR CON MEDS

Other features: [£--1.L t:i<{' ~ <L__y /L./L,<.,).._j ... ,l b-«: (_i·----L.' l..' -L ,: l_(~_'" ~
( /1...-<·""""I.A~l_ !LL.L~rL -/0 6L.. J. /L.'LL-' I) 0·<'1' ,1_ tL~.L j'!t-cJ.. ___
I J Study Name: :J-1A-e"_'_ IS- s Coordinator: j;ft/Lu__~ AAJj '~0 Description of study: (t e. ~o-e ;!L--1!J.__ U :;, t:;_-~ c!.-~~

<:::>j- q:... •

!5)-, il Cj c.s-c:c, c:o

ENROLLMENT:
Beginning [(t:~ '1 through .J /eri Number of patients ~ 5() C-6d. of ~J ~
Age I J" 1- I Compensation Labs (fasting?) 3 VI (/ "-/ 0/ 1./ 7
Number of ViSt_:d length of study: 7 - . ~ L.<-'n.<. J
U ULA_1/,) - /;;;z. L(_) _.:z__.., j-<-.<J
. .,
Long Days? STUDY REQUIREMENTS
PFT requirements < 75 ~7o ~ /A_p~ wi /.)_~ ~ l_ l--w /u,/t'-j .A...
Time of day for study visits: ~-c~ ~ I~ ft-~ ~/1~ntI Lr
Skin test required? ).L(:, u I Chest Xray? ~ f
Contraception ri.;
Other requirements: fc~ f1 LFtJ· I JeD ~(~~u.~V -I~c
Ifi 30 ~~::;. f>/~u t1 _. y rM~ c s: .
- e. (!. tl.. J d.._tc
LJ Q EXCLUSIONS
Immunotherapy S-h _1_~ I URI '-I- Lu~ I Flu shot allowed? k..-..o .. J.-.u ~
Current smokers? )CO. Lo tu.c» (.LJ tht..-4 Smoking history? 10 o» «.«: c...j·kJ
Blood pressure meds allowed? LJf<_ I ;()--f.~ v v_
- 9'-' L-O).,c.,cL.._.r CP\,-_;
p f..-.'- .!L """"':l.... ~ c ¥' 0~tc. L<._...;~
h-o A1 _..Q__L---L--~ 6.A-:t II.. ~ r : ..)_ ~~ ~ Gj/'\. )
)l-1 ALe. :to- 1'6. ..Go-c:....-VL<. /l_/) ---_ •
WASHOUTS FOR CON MEDS
Before screening visit Throu_g_hout stu<!Y_
Decongestants Lf '6 " Cc» 6-- .c ok..
Short-acting antihistamines Lf~v 0-'~--:1.L' 0(<-
Long-acting antihistamines '-I (f L' Lu o-.---L- D(e
Hismanal a f'U_c, LAJ 4.tUc) N()
Nasal steroids Of;. - :Sjaj,,--€-,<- I n-o . 0(<-
i(1ntayN_asalcrom A..JD T A...)7 4-L I c; ~ (1u.;JA<.-fC-l<.Jl..<.o,. uk ... o{<._.
Tilade (nedocrimal sodium) I LV .<!.....Ltc..- ~ /lJD
Atrovent ( V--' ~<- /l./'O
Inhaled steroid ~f1.,u'J. S~ d-o.~ tJ/<__
Theophylline ( tc:e-«: /L/O
Short-acting beta agonists ~ 0 W a.:« IA_. o«:
Long-acting beta agonists L,I~ 0 ~6-J.. .. L_ ,-Jo
Caffeine I Other features:

Protocol Summary

9188IL/0155

Title: A Randomized, Double-blind, Placebo-controlled, Multi-center Trial to Determine the Effect of Oral zafirlukast (ACCOLATETM) when Dosed with Simplified Patient Instructions in a Patients Receiving ~2-agonist Alone or P2-agonist in Combination with Inhaled Corticosteroids

The objectives of this trial are as follows:

Primary:

• To determine if ACCOLATETM improves lung function, reduces symptoms, and decreases ~2-agonist use when the patient, using ~ragonist alone or using ~2-agonist in combination with inhaled corticosteroids, receives instructions to take the medication in the morning and at bedtime

Secondary:

• AM PEFR before ~2-agonist use

• office visit FEV 1 (expressed in liters and as a percent of predicted normal)

• daytime asthma symptoms score, symptom -free days, and problem-free days

• mornings with asthma

• nighttime awakenings because of asthma

• peak flow variability during the 4-week single-blind run-in portion ______,__

Trial design:

This is a randomized, double-blind, placebo controlled, multicenter trial that consists of the following three periods: screening period, 4 week single-blind placebo run-in to determine eligibility, and 6-week double-blind efficacy period.

2

Type and number of subjects:

Approximately 1000 subjects, 12 years of age or older with symptomatic asthma (15% reversibility to inhaled bronchodilator plus ONE of the following criteria over the last week of the 4-week run-in period:

• Symptom score of 2 or more on at least 4 days in the last week of the 4-week placebo run-in period

OR

• Total of four puffs or more of bronchodilator use on at least 4 days in the last week of the 4- week placebo run-in period

OR

• Four nights with awakening due to asthma in the last week of the 4-week placebo run-in period).

The groups will be balanced for the proportion of patients receiving background medication of ~ragonist alone or ~ragonist in combination with inhaled corticosteriod to achieve approximately 500 randomized subjects.

Trial treatment:

Zafirlukast and matching placebo will be supplied as tablets for oral use. The dose of zafirlukast will be 20 mg twice daily (bid).

Duration of treatment:

After a 7-day screening period and a 4-week single-blind placebo run-in period, eligible subjects will be randomized to 1 of 2 treatment groups (20 mg zafirlukast or placebo given twice daily [bid] for 6 weeks).

3

Inclusion criteria

Inclusion in screening period

Subjects are eligible to enter screening if they provide written informed consent and meet the following additional criteria (subjects 12 to 17 years of age will also have a parent or legal guardian sign the consent form):

( 1) Male or female 12 years of age or older

(2) If sexually active or of child-bearing potential, a woman must practice a reliable method of contraception during the trial unless she is not capable of becoming pregnant (either she is post-menopausal [2 years since last menstrual cycle], surgically sterilized, or monogamous with surgically sterilized male partner). Reliable methods of contraception include doublebarrier methods and hormonal contraceptives.

(3) Non-smoker for 6 months before screening and less than or equal to a 10 pack-year history of smoking.

(4) Documented clinical history of asthma and the following:

• demonstrated reversible airway disease by at least a 15% increase in FEV! after inhaled bronchodilator

(5) Able to demonstrate a FEV! no greater than 75% of predicted during the screening visit.

(6) Able to perform 3 acceptable forced expiratory maneuvers with 1 reproducible FEV! within 10% of the largest FEV 1. Or, if the subject is unable to achieve a reproducible FEV! within 10% of largest FEV!, up to 2 more expiratory maneuvers may be done to obtain at least 2 acceptable expiratory maneuvers with FEV!'s within 10% of each other.

4

(7) Able to communicate with the investigator, to understand, and to comply with the requirements of the trial.

Subjects on background steroid therapy

Each site will be asked to recruit at least 8 subjects, with at most 50% of whom may be on background steroid therapy as described below:

Subjects who have been on a s~dy dose of 1 of the following inhaled steroids for at least 60 days before screening are eligible for screening provided the total daily dose of inhaled steroidSls

----

at least dosed at the levels indicated below.

• Doses ofbeclomethasone (BECLOVENfT"', Glaxo Wellcome) should be at least

336 meg/day ~

~

• Doses of flunisolide (AEROBIDT"', Forest) should be at least 3 puffs/day, or a total of

750 meg/day ------------..

• Doses of fluticosone propionate (FLOVEN'fT"', Glaxo Wellcome) should be at least

~ 176 meg/day

~

• Doses of triamcinolone acetonide (AZMACOR'fT"', Rhone-Poulnec Rorer) should be at

least 8 puffs/day, or 800 meg/day ---

~

• Doses of budesonide turbuhaler (PULMICORTTM, Astra) should be at least 200 meg/day. ~

The dose of background therapy must remain constant throughout the trial.

Inclusion in trial (qualification for randomization)

To be eligible for randomization, each subject must meet the following criteria:

5

(1) Subjects must demonstrate a FEV 1 no greater than 75% of predicted on the day of randomization, Visit 4. Subjects who meet this parameter on the 1 st day of screening, but do not meet this parameter on the day of potential randomization are not eligible to continue in this trial.

(2) Able to perform 3 acceptable forced expiratory maneuvers with 1 reproducible FEV 1 within 10% of the largest FEV I. Or, if the subject is unable to achieve a reproducible FEV 1 within 10% of largest FEV I, up to 2 more expiratory maneuvers may be done to obtain at least 2 acceptable expiratory maneuvers with FEV J ' s within 10% of each other

(3) Able to demonstrate clinically mild-to-moderate asthma defined by meeting ONE of the following criteria:

• Symptom score of 2 or more on at least 4 days in the last week of the 4-week placebo run-in period

OR

• Total of four puffs or more of bronchodilator use on at least 4 days in the last week of the 4- week placebo run-in period

OR

• Four nights with awakening due to asthma in the last week of the 4-week placebo run-in period

(4) Subjects must have a morning-to-evening PEFR variability greater than or equal to 10%, calculated as the mean (arithmetic average) of the daily PEFR variability values from the last 7 consecutive days of the 4-week single-blind placebo run-in period. For each day of the placebo run-in period, PEFR variability will be calculated from Minidoc™ electronic diary card data using the following formula:

Daily PEFR variability =

IPM PEFR - AM PEFRI PM PEFR + AM PEFR 2

X 100%

(5) able to demonstrate compliance with oral trial medication of at least 85% during placebo runin period

6

(6) Subjects must be able to comply with the dosing regimen, which includes the proper use of inhalers and the ability to take tablets, the proper use of a peak-flow meter, and daily electronic diary entries

These criteria must be met before any randomized trial medication is dispensed.

Exclusion criteria

Prospective subjects will be excluded from this trial if they meet 1 of the following criteria:

(1) clinically significant deviation from the reference range in laboratory results except for abnormalities related to asthma or allergy

(2) evidence of hepatic disease other than isolated hyperbilirubinemia associated with a diagnosis of Gilbert's syndrome

(3) evidence of chronic lung disease other than asthma, including cystic fibrosis or bronchopulmonary dysplasia

(4) evidence from physical examination or medical history of any disease that affects gastrointestinal absorption

(5) immunization with a live viral vaccine (eg, measles-mumps-rubella, varicella) within 3 weeks of screening

(6) use of salmeterol (SEREVEN'fTM, Glaxo) within 48 hours of screening (NB: Salmeterol usage is not permitted during the trial.)

(7) use of cromolyn sodium (CS)E~ Fisons), nedocromil sodium (TILADETM, Fisons), or theophylline within 1 week of screening

(8) use of astemizole (HISMANALTM, Janssen) within 3 months of screening

(9) new use or changing regimen (dose and frequency) of CS nasal solution (NASALCROMTM, Fisons) or nasal corticosteroids within 4 weeks of screening (Subjects whose regimen did not change during the 4 weeks before screening are

7

eligible, and their regimen cannot change during the screening and double-blind periods.)

(10) use of cisipride (PROPULSIDTM, Janssen) within t week of screening

(1 1) current use of beta blockers

(12) upper or lower respiratory tract infection with a significant asthma flare requiring additional or increased amounts of asthma medication within 4 weeks of screening

(13) acute illness within 1 week of screening

(14) history of convulsive disorders or any significant central nervous system disorder; mild stable depression is acceptable

(15) seasonal asthma as defined by symptoms or therapy confined to less than 2 months per year

(16) entry into the single-blind lead-in period of this trial (ie, Trial 9188IL10155) on a

. .

previous occasion

(17) participation in another trial with an investigational medication within 4 weeks of screemng

(18) participation in a previous trial involving zafirlukast or previous exposure to zafirlukast, montelukast, or zileuton

(19) use of warfarin within 2 months of screening

8

Table 1 Trial plan
Assessment Screenin Single-blind Double-blind
g
Week 0 3 5 6 8 11
Visit 2 3 4 5 6 7
Medical history X
Physical examination X X
(complete)
Physical examination X X X X
(routine)
Vital signs X X X X X X
Hematology, clinical X X
chemistry
Urine pregnancy X X
screen
Genetic marker assay X
Pulmonary function X X X X X X X
test
Reversibility test FEV I X
Subjective symptoms X X X X X X X
reviewed
Electronic diary X X X X X X X
reviewed and
dispensed
Single-blind drug X X
dispensed
Randomization X
Double-blind drug X X X
dispensed
Albuterol dispensed X X X X X X 1-1 n Le13J aJl L--

Study Name: ZeA £t!Jt. 0 I~) (J Coordinator: j' ;i? (t e 11 ,1~6&«) t~1£

Description of study: 1Yl;/ d ~ Moc/e/!..{),je_ 4-s~

., _'II'\~Ov\ . t---=.:~:_:_:_::_:~...!.2---'=:-~~~=~~-....--..-r..;.-""::":-~....--.-',---=,,"~~7"-'-=-":~~~~~7f=t" S~lhd.

~~~~~~~~~~~~~~~~~~~b

Current smokers? ff

Blood ressure meds allowed?

Hismanal

Nasal steroids

IntallNasalcrom

Tilade nedocrimal sodium

Atrovent

Inhaled steroid

\f)
~
~
:l- N')
'1-1
...
'3
-g
.I_
~
~ fl) QyIJ.. ~ ~OL€K\, ® fu~ P""+- ~'dd. 0,,- ~~ i\ .: -\e k "XI~. 1"V\. s~dy~ ® r4))t+ - 0 K.

G) ,J 0 JCMt\cJod l~ bJw \j \ <\- \J 3. ~FT -? P~,( t\M¥\r-k~. t~)'~5ti, OV1ty ClVl(~ .

Study Name: /-:_'(lj/ £Vi- 0/50 Coordinator: LlfUA'....ft If{ U/l115 Description of study: 1Yl;/ d Iv lYIo~k A-$~

LIIJ

ENROLLMENT:

STUDY REQUIREMENTS

Immunothera

Current smokers? _g-

Blood ressure meds allowed?

WASHOUTS FOR CON MEDS

Inhaled steroid

Before screenin visit

Nasal steroids

Intal/Nasalcrom

Tilade nedocrimal sodium

Atrovent

I

I

f ~

\50

? -Q.cJ.i o.:r\'\ '- 5 - , \ 'it ~ ~ \ \-\::::) - '('r'IO ~ E:.- Q f\ TE:

el - t\ 'i()~u-t·

...

III

Trial Plan

Assessment

Week

Visit

Screening

Single-blind

Double-blind

4

4

o

2

6

9

6

12

7

Medical history

Physical examination (complete) Physical exam ination (routine)

Vital signs

Hematology, clinical chemistry, and urinalysis

Electrocardiographic examination X

Pulmonary function testing" Reversibility testing FEVl Subjective symptoms reviewed

Asthma diaries dispensed/reviewed X

Single-blind drug dispensed

Randomization'

Double-blind drug dispensed Plasma samples for assay of zafirlukast

Samples for genetic marker Albuterol dispensed"

Health outcomes questionnaire Asthma QOL questionnaire' Caregiver questionnaire' Assessment of overall condition

Assessment of response to treatment

2

3

X X

x

X X

X

X X

x X

5

X X

X

x X

X

x X

x X

X X

X

X X

X

X X X X X X

X'

X X

X

X X

X

X

X X X X X

X

x

X

x X

a Performed at trial completion or upon withdrawal from trial.

b Polgar standards will be used to calculate percent of predicted FEY,.

c Subjects will be randomized to I of2 treatment groups: 10 mg zafirlukast bid or placebo. d New a1buterol inhalers will be dispensed as needed.

'Asthma QOL will be administered before any other trial procedures at Visit 2,6, and Visit 7. Patient QOL is performed in Subjects ~ 7 years old. f Caregiver questionnaire will be administered to all caregivers, regardless of age of child before any other trial procedures at Visits 2,6, and 7.

X

X X X

X

X X

X

X

X X

X

X X

X X X X

X

X

X

91881UOiSO

. , .

.. ~--_.

Study Name: r (!Q 13 q Description of study:

Coordinator:

STUDY REQUIREMENTS ~'
PFT requirements fy D - 'OS ( ,;; '") f:J. I- (,..- , " ~.,_l'
" l,. ("
Time of day for study visits: ,:~'fJ..-)'"'r\__c... --h . .-~ (' Df i . ( i.. i:»: c, 1. (I-I--
.. af! I'_~ 't"'l>\... )
Skin test required? ~.' c. I Chest Xray? cl "-JC)
j ,
,v
Contraception
Other requirements: --r M Y\ '(\ e "R. <'4-c. q p V -I
-, '. (_;._ c. , .. -l J ~ .,j_ t c. ~ l_<. .. e.. )
.' L,~ Ii. .\. ;_,L.' ~t.''l.---. L J ( I'" ~ (_~. ___
~/'k{LL c C-c CL. ic-€.:_- 71) /lA. :_.' (_t._ '- (' li)...__ ~ . ( 2:.. .. to-. C c. -r j
~ f=XCLUSIONS
Immunotherapy @-I!- I URI «: - I Flu shot allowed? (. .(( /;__,y
Current smokers? IJO-l\C I Smoki~g. history? N/r I~_ <2. ..
Blood pressure meds allowed?
pJ--_J;- s: .... ......_::l_ ~ ( 4 Lu v i: .. .J_.J
WASHOUTS FOR CON MEDS
Before screeninq visit Throughout study
Decongestants Cf- .
Short-acting antihistamines 4-f.;;" .A {v' Yl tri- W IPf IS
Long-acting antihistamines -J/ ,
Hismanal '.:OS M~t.J~ . .J
Nasal steroids OK.
IntallNasalqom ~ U.L(f,i0·
Tilade (nedocrimal sodium) ~ • I L(CJ(__,
Atrovent lJ- U L"-U... t)/
Inhaled steroid '-f IJ,' a: rt0;,/
Theophylline L./ .I I <r h ,>
Short-acting beta agonists ( i ». • r ) • /',.1:
" ..
Long-acting beta agonists 'J~ _k~'/ J.jb,,;_
t. \.-
Caffeine I Olherfealures:

~chQnn(6 Y\av'a \'""-

Study Name: c.. q <g - ~ b :)_ Coordinator: L \ f\

-c

Description of study: T\)jD '1QC,V- s.t-JJ~ 01\ ~ L-ffQO-~ of ffio(Y'l(2_iCtS:otlQ

Sf-' \J (0(,0- Q, 'w (" 'tJ P Ov..'l d,~- :r r'\ " CA. \ QJ 0 y'"\ ~ 0 II .e. ~s \Jv, \ '\ \..( oJ (\ ~

f\ d~ rr

(Y\ DST

N h \ \I t.:

ENROLLMENT:
Beginning i ";J_/, hI, through (5! I CY._, v; ',t-; Number of patients
Age 3. ~ ~.~ ';t?.,1 Compensation $/200 Labs (fasting?) Y 5 Vi~I'TS
Number of visits and length of study: 'ot_ '01' s;. <., 3. v.,) ,,-, ~ ,.,;-~~ V o; l ~ F~-\ S-u '<-Q A~ 1'\ ~ •
Long Days? N t-ofu \ - I 'd.. v ~ .~~ +- _) 4, iJ I'~; t.J .- b':>1"I-Q.. ~(_ U\.I'lS
.:3 Dr:::>'n-, cd fr.1.5. ~ ,'X. 0.. rl1._)
STUDY REQUIREMENTS
PFT requirements '> fo5ci D I d.'7b r: C!..N srt: oj ( ~';;TD~ \ \.Q'_) ;- D 12.. ()'\." Jth·
Time of day for study visits:
Skin test required? I Chest Xray?
Contraception - '-( -e ~ - d. 0 I.)}.." \.Q. bw r It,:! r (Y\MI. ,.- 0 (0,. \ - 3 M D 1\ <,;,. T()"b l-.Q.
Other requirements: .L- \ ')_ D~ J cl P roJ~'I'''', \ , (l(J n', cl~l Shl,Pt
\i : .. ~ EXCLUSIONS

Flu shot allowed?

WASHOUTS FOR CON MEDS
Before screening visit Throtmhout study
Decongestants OK
Short-acting antihistamines _D\{'_ (\0 j'Q_l' -fut\~ i
Long-acting antihistamines _at£- Q,O <::.IS~r)·1 ~b
Hismanal
Nasal steroids Q weg \c.~ :) SQUs..>n'b I..,,. I!:: &U)~s"
Intal/Nasalcrom Ok.. .
Tilade (nedocrimal sodium)
Atrovent J d. hr-J @:>~
Inhaled steroid .3 N\o A-th.s. Y1()
Theophylline () k... ri..l\ hr 5 (\__D_
Short-acting beta agonists &;_ hYs On l4 vJ hOvJ C.OMpQ\1\ ~
Long-acting beta agonists d..wk~ U f\_D_
Caffeine :i QJ S) .. -'VQ,..;;::J\ d.. vJ\:.~ Y\_Q_ ~2.lh rnClt) cs ~d )

I~

\ ~~ rnl.>l1 w(\!>h,

VIVRA RESEARCH PARTNERS STUDY CHEAT SHEET

STUDY NAME: Schering Plough C98-302 COORDINATOR: Lin LeBlanc

TITLE: "Two year study on the effects of mom etas one furoate dry powder inhaler (MF DPI) on bone density in Young Adult Asthmatics."

ENROLLMENT:

Beginning: 12/03/98 through ?Feb 99

Number or patients: 6 minimum (have drug for eight total)

Age: males: 18-50, females: 18-40 Compensation: $1200

Labs: 5 (all AM, but not fasting)

Number of visits and length of study: 12 visits (13 week intervals) 2 year study

Additional Testing (off site): 1 chest x-ray (if not w/in 12 month), 5 DEXA bone scans, 3 eye exams

STUDY REQUIREMENTS

PFT requirements: 65% FEVI with 12% reversal, mandatory at screen and visit 2

Time of day requirements: all lab visits (5) within 1 hr of 8AM. PFT's can be done any time Contraception: double-barrier minimum. subcutaneous rods - excluded

EXCLUSIONS

o No inhaled steroid use for 60 days, Q Diseases of bone metabolism,

o Premenarcheal or post-menopausal women,

o Investigational drug - 30 days,

o Need to use hormone replacement drugs(birth control pill -OK) or methotrexate, cyc1osporin, gold

o Eye cataracts or glaucoma

o COPD, CF

o Nebulized beta - agonist use on regular basis or> 12 puff albuterollday

o URI within 2 weeks of screen and visit 2

o NO night shift

o current smokers or of less than 6 months quit

o Body weight - > 265 lbs.

o no oral steroid within last 3 months

WASHOUTS FOR CON MEDS

Albuterol

Serevent Theophylline Oral steroid Inhaled steroid Nasal steroid Intal

study drug Accolate Fenfluramine Hormone implants Astemizole

6hr 12hr 48hr

3 month 2 month 2 weeks 12hr

1 month 2weeks

1 month 3 months 3 months

Methotrexate,etc.

3 months

Decongestants- oral, nasal- OK

Nasal Steroid use - seasonal (6weeks only)-OK

Oral Antihistamines - OK

Elcon creme - not allowed, other topical steroids OK

-, r"-

ENROLLMENT:

STUDY REQUIREMENTS

.----------~~------~

EXCLUSIONS
Immunotherapy tJft I URI AJ/4 I Flu shot allowed? ~'ts'
Current smokers? '-1 t f [ Smoking history? NO '> 1S Cr (/;,t ke1.& ~
Blood pressure meds allowed?
; ~ 7
.. ~ ~~ -_-_- _- -: - .- WASHOUTS FOR CON MED$
Before screening visit 1-" Throughout study
Decongestants I
Short-actina antihistamines /
Long-acting antihistamines / ,
Hismanal /
Nasal steroids 7
Intal/Nasalcrom /
Tilade (nedocrimal sodium) I
Atrovent /
Inhaled steroid /
Theophylline /
Short-acting beta agonists /
Lonq-actmc beta aqonists /
Caffeine /
/ I Other features:

Coordinator: ~\ '\ R v~

ENROLLMENT:
Beginning through Number of patients (9 -\ L
Age $~ c ~~'''\J-..' I Compensation 8~SQS Labs (fastinQ?) ?
.J
Number of visits and length of study: \3 11\"' .... \\-<;. _~ lr' \_\ '--I...) (, c \<:. .s
Long Days? ~\,) STUDY REQUIREMENTS
PFT requirements /' l SOlo 'K..ev C\-<;' (' \ L 0 1'0 -{ \-\\ s~\-....\_ v,,\ \1_ \Y\ 0" \
Time of day for study visits: Py'tV\
Skin test required? \----\. \.) I Chest Xray? ~V-I) v: \
Contraception ~) \-\ f\~'V l\ j u) v \ S ~_ 'k-V"" e"'-l r..L
Other requirements: a_ S-\--~c:\ \ Of'l\ ~c:w_ \-.\\- s; - lo <I;, ~ fYl 0;:, \'? r\ c c 'Th, S lJl lSLQ
\310---\ S -\)\) '{\'\o'l;-l' '~'f'\A C\ -....\ \1<. S ~ \"'0 So. '(~'\- 'v--J ~s. <C: \ \ -(\___t_
G--\\-\S -L (\ '-\ -a. s CI~\ \--:J (j_A_<,.) \ \ V\.___Q_ ( '" -;:, v c Y\ 1.")\ J\.C· '\_\, l \-J l~ <"\ \.:_~~ '0 \) I
S--\-~ c\ \ O'\Y\ A- (' R \--\\-. W ~\\'" S'-\\"C\ V G\ '-:J+~ C'l c, o v-, S G.-c-:_ -\J-_) \'\ l \
\"' C' s \' (' c \- --\;--0 C\<;.0( '" ~I~
'-J EXCLUSIONS
Immunotherapy U.Jb ';;'\V;~~c I URI ',) \~I.,__\-<. S. T Flu shot allowed? \.1 ~ J
Current smokers?' I Smoking history? \
Blood pressure meds allowed?
T.'---\J1. <?_'i- ~ '\'('\ <;. -i: ~,;,___. , S, ~ G--' "\ V'\iV,VC:Y?_ r 'i. 'AM ~L\
L ~\.) <; 't-- ~ ( \. Y\ '- \ '--'-. t\ \ ""t ( O'Y---:\- \ ":;. C) \ \
\ 1_ \;\\e.. "
~ I.,__J'\)....""-...-- ~
\~D S. ? Q)~ L'\,_[) WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Deconqestants 0\<.., 0\<:'
Short-acting antihistamines (__)\<~ o \C:~
Long-actinQ antihistamines c_.....,\<:..... C)\<
Hismanal --\; <r: c\ IJ_j,,,, .... 1;L --\ ("1>'1 () \'\_ <.:_')
Nasal steroids ',), \.._'-_ 'K \"\ u
IntaliNasalcrom OK D\C
Tilade (nedocrimal sodium) b\e. e:,\<._
Atrovent 12 \-\ '-I2_, \"\. I;:)
Inhaled steroid lo '\\ID ~(__")
Theophylline D'\:: D\c
Short-acting beta agonists r" \-\ vz, l')\c
Long-acting beta agonists \~ \-\ \.K, O\c
Caffeine y \--\ 'vZ DY Other features:

ENROLLMENT:

20

- V--6

S i//sr - /2 L-V1cfiFrS

STUDY REQUIREMENTS /2.e(/C-ILSc:: I Z 'i ..
PFT requirements 40 - so {ie" t} B L t. I~ iu,rF'<TiIND t hf'~ i<.-'/c Bl.. :1GC III i
Time of day for study visits:_ (-) [v - /0 w
Skin test required? No I Chest Xray? No
Contraception - 1 4/', fiOS7 tn£Nof.4 uS.t.lL.
Other requirements: <;5 «s r s m» EXI1l. <:-- g LA) « , PP..IOP. V-I
Fo cm. /n ~ DS' m o s r: (',c f:,'T/)I3L £ "/ b {.UK PIVoR V-I
fJ /I,IJ f(./VI o CO k £ N ~ Ti C S ( g BL ClO/) DI<...4 .os ) (i) V-3
.2 Wk /3.1}SELIAJF fJ FIE t2.. sc A..2.£1J VISIT /
£.V~L o s r c. P...E S P r fl1 .4 T - P P-.. I !VJ y__ x /0
EXCLUSIONS
IURI<=: I Flu shot allowed? --
Immunotherapy >:l.y r: Io (,V K
Current smokers? N'O I Smokinq history? <:: J o pk..7y/(..
Blood pressure meds allowed?
<,ZJ Ol2qL- COILTI Ceo SF c 12-01 b < g {'uk... (JlrlOf<_, "7"0 VI SiT I
d Bt.TIJ l3L.ock.'i:.(~
¢ IF Noc f.JSTH. >~ X wI-(
95' IF B/z'o/lCHlfiL INF£_CT!ON /" X3 JOe/' VR.. I ST

WASHOUTS FOR CON MEDS

"I _._,~ ..

The Following Medications Must Not be Taken for the Specified Times Before the Study and are Not Permitted for the Duration of the Study:

Astemizole Oral Steroid Accolate® Zyflo® Singulair Salmeterol/formoterol Nasal Steroids Azelastine Long -acting methylxanthines ~2 Agonists (oral) Short-acting methylxanthines Inhaled anticholinergics

r
3 months
8 weeks
4 weeks
4 weeks
4 weeks
2 weeks
1 week
48 hours
48 hours
24 hours
12 hours
12 hours "

~Ill

ENROLLMENT:
Beginning "1(98' through '-I n:» ·._..L.i_~L Number of patients 10
Age (J --1' I Compensation Labs _(fasting?l t/-7 - _!!P ri. .:f,-<-...___j)_;
Number of visits and length of study: '9 (_? t:-:L-..___:t:;/) LJl-~ r;,. /'1-c..6)<-J I ~
Long Days? \z.__u STUDY REQUIREMENTS
PFT requirements SO-d'"OCf6 w/(~ % /Lcu .L.-L-J .,.___L
Time of day for study visits: {po -r 0 ~ cc
Skin test required? t00 I Chest Xray?
Contraception Ih.cy -: A 6') T I,__) EA.J C E OK. S TE/c.Jc/Z AT? ()A_! or- A..{/!-L€ ,1-1
Other requirements~H~b~L.i¥ii0 c/, . j)/'f___u_ en ( J..sF rs.« 30 /J4~S '
A,s Tl-{ .u /+ (0 j-v,._c, /lFTl-l ;') I}SE tit::: S/{:j. At:7A /U') -r t, ~~C(<::!s·
A 0 n-f./L-I- A ,
;<Jo _s;- E A ,.)o......J,q L
EXCLUSIONS

Current smokers? ;0 0 history? ~// I Sf --\.. .

Blood pressure meds allowed? DK. - ,5/A,0L~ ..s.K _- ;L)(_)

_, WASHOUTS FOR CON MEDS
~ Before screening visit Throughout study
l Decongestants O{(_ <:;Jjf. ~ l-<..J~~ e LJtA. fctJ Of<_
.~ Short-acting antihistamines CK- t c I I " I. O(_,
.,) Long-acting antihistamines c«: It t c .' " Qf<_
-. Hismanal 3 I LLO><J: /....___ 0
to
Nasal steroids e o "'" C{-<_ .Jy. 'Lu~ e, ;r,-, OK..
U'4..
IntallN asalcrom .u}\~:AL-"" o~ tf- L0~Z__ L-c}~ 100
Tilade (nedocrimal sodium) Lf. Lv.~z__ C.D i>--LJ...__ ,,00
Atrovent ~ u.....>RJ_j-c Cu~ AJo
Inhaled steroid :Q-h:;~i)·,w~ 'I AJO
Theophylline i.f- 0_) .u.....-tG 1..-0{~ 1\-10
Short-acting beta agonists f_c u». WJ~ ()~ A..e./L~ _II. -'
Long-acting beta agonists d. w'"~ L.u(.~ IJ/\JO
Caffeine &" tLJL. (-U O-F.-[<-- ~',.e .--L'-1 r » _,z_;_J:._
(] Other features: A ~

I

"" 001

FAX

Pharmaceutical Research Associates, Inc.

Caw: December 17. 1998 Number of Pages: 1
(inclUding COV9"
To: Jay Grossmen, MD Fax#:
1-520-292-6623
Company: VIVRA Research Partners
From: Pete Miles Sent by: Cozetta R Dcrritt
(d cfjJ'f.,-.nt thttll Ftom:) Program Assistant n
ee: File cc Fax#:
Jennie Wolf (eRA.)
Subject: Glaxo Wellcome Inc. FL TA4039: FP vs Singulair Comparison Study Message:

Singulair' when taken in combination with Loratadine (C/aritine) may effect the potency of Singulair". Section 3.5.4. of the protocol excludes concurrent u.$e of any pre$crlptIon or over the counter medication that may Interact with leukotriene antagonists. Therefore. Loratadine should notbe used while the patients are in the study. An amendment is scheduled to be arriving In early January.

Please contact me if you have any questions at (913) 577-2780.

The lnfOTmflllon in thu tranmrittalls prlYiJeged aJrd c(mjidenlial and is Intended Dnb' for the Nlcipiost(s) lLued aboFe. If you are neither the intended Tl!clplentM "(11' II penon raponsibl4 for d,~ tklhwy Of this traMmittaI to the intended recipielll(S), you lire hereby notified #hilt lin)' unaut/totiud dlslrlbution or copying of this tmnsmittal i.s prol.lblkd. If YOII luzve teCJ!ived this trllllSmiital in IlTror, pktlse notify us /mmdlu.tel, anti rdurn the tranlltllttlll to us at tit#! /lddnBS IIdow_ Tlulnk you.

If IOU wWt to respond 10 thb flU or have not received all pages, plellSt!. caN (913) 438-76,6 or/ax (913) 599-2755

lUfJO CoUete Boulevard .. Lenexa. Jr$ 66119

Tel: (913) 418-7696 • FIIX: (913) 599-2753

Coordinator: ~, ~~""'

1T)VI(_ •
ENROLLMENT:
Beginning through ,qqCj Number of patients /2.;
Age /2 T I Comp_ensation it ( 00 . «o Labs (fasting?) V, f lij t l/:1. ·f 1/4-
Number of visits and length of study: G vt'slts
Long Days? =n. STUDY REQUIREMENTS

EXCLUSIONS
Immunotherapy 1/(5 I URI '/Jl5 I Flu shot allowed? 71/tv
Current smokers? (j v I Smoking history?
Blood pressure meds allowed?
pJ-.L S!--"'~L-.~ i:. );0 m(A';d~/
v' <J WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants (TJ<._ lJI<0
Short-acting antihistamines ell<--- 616
Long-acting antihistamines --no "(1..0 "
Hismanal =n» -ru
Nasal steroids 5{ a h-u clnt- SfG_~ ck
IntallNasalcrom _II - -'11 -
Tilade (nedocrimal sodium) ./ '"
Atrovent OK_.... d1(_/
Inhaled steroid 5tQb-0.. c~~ £-1: 4- b.Ct. ,J AlL _p
Theophylline 0lL.. staJ·Ct_ d iQ1L. fJ1L
Short-acting beta agonists ()'"10 (J1L
Long-actin_g beta aqonists ILr. IiLn
Caffeine .U<A 'l!J<A .
(j o I other fealures:

Study Name:!Ji/(i. - /!1 b - 02 - Don Coordinator: c. ve /_ YAlE vel 'I ij Description of study: _qij f (;1Y !_~ i ot. y - / Y i: lir<. - F Lfx II?Lt fJ O~~ e - :!.t::.t.. r ri f n F LiJ Iv I .s D LI /) E::.. v' S f!)::::. c: L '-' rn :i.:... rt! /~ .:". o tJ f_ DIP R.. o P IfJ -1 1f .3: I P..A r. c

OP{;_N L (-)A~L

ENROLLMENT:
Beginning 5- 9<1 through _I)"" 1 (j Number of patients ,<{ LTO(AL 260 )
Age../2. ". b 0 I Compensation Labs (fasting?l
Number of visits and length of study: r rJl S, IS 51 Wf:..L.kS
Long Days? --
SrUDY REQUIREMENTS {(,4/1l!»fJJI24 DON rtv /' 1() ~% l.-
PFTrequirements r<CI/,,::> t.o 'lei l' J:J.IJ{(t f 2- fJ/Jff~ IlL 8vT'i:ROL
Time of day for study visits: 6(. DC; I"t.) II Of)
Skin test required? No I Chest XraJ_? NO
Contraception 'iE!i
Other requirements: r t: g,£AT E6 - US'i. N 0$ E C.LI fJS
PI. Al f:..E.bS TO 8R..1 JJG V~ H R. tl. (U NE- it) V IS II '2.
EXCLUSIONS

Blood ressure meds allowed? ruo Bc.Tf\ A ~I)_~N£:RGIC. h.Lf)C_K.~ ~

r-

MlJ~T B~ ;0

bA'I ~Tft.~LE bOSE pp'~-

S,C-IU:l:N ~

See J:) a. Q e... .3'l WASHOUTS FOR CON MEDS
I I Before screening visit Throughout study
Decongestants 6K OK
f)e10. -Ad r e n e.f"H c. 5 "BlocKer'S I wk ~ W:
"7 -"f---
Long-acting antihistaminesL 6KO"" OK OK.
Hismanal DK.. ~fe t--
Nasal steroids "- 6K. C k:. - I F NO l' IN
IntallNasalcrom oK TILL V-1. 'N~ p V-2. 4-
Tilade (nedocrimal sodium) oK 'ILL V-l ·tJ'O' p V-L~
Atrovent >- 4'6 HRS ~N E;
~ '.0. -
Inhaled steroid OK 'tN-O· t--
Theophylline ~QlAje.-t ew-o\ 11. \-\RS{l.4- HRStJI II OK- If No1' IN
Short-acting beta agonists 7' b ftl\~ ~kN<Q ~
Long-acting beta aqonists I?- JoH~ ·"""0 ~
Caffeine DK. Ok
{)~AIC;r;-Rf>1 hS "7 " 'I i'J J)_f\_'LS\ No- ~)(c..eJIT fo ~ < i <f-
Other features: STub 'I m« b5";. b 10 9 tVYn - t. ,0 I J fJ frI
fOURTH ~'llA{!. J~ AN A2:. - R5:c,ofdl oJ cRJ - iER.1YI1 NAIf:.. PT.
rifONc. PT I wI< P VI~IT ~ To C.H~C.K F'oft tieS t:

{)I

,.

Study Name: NovAR.TI S o4-..cJ Description of study: j:l Mo N T Ii (:'oll'1pD.re ~

1').1..1.,( AND

. j/'- \ I ~ i. f;' r\ Coordinator: G. V e.l ~ tt._)i tL .... t ,,; 4 "i

DOL>lkc_ P,I..IND V I 50% i__;S d

" f' v k r S I NC L 'C. J C';(::

~ ~ -. ~ ~ __ ~IN~Al

I

I '+ V I S/T"~ - i y<:(J,..I~ ,; 'v (-,i

Nt'> t.:. ~ F-F~ II ~e ,pPO \' 1---5 -/ Lj-

\ , ;iJ

EXCLUSIONS
Immunotherapy 'f. e.s. I URI ¢ c:::.:..._ I (VI (I 1'\ t h l Flu shot allowed? No
CYH8Rt smokers9 ¢ l..sm""";n .... ~. .o,

.... ":::t "'""'_I_UI I... ,
"Blood pressure meds allowed?
P f'-..>- L\!..- ,~.l_. ~ (.
~R !-\o~h TA l RTT ~ ( V\o1~"'NTH
\ , .c:... Ii: d (~ ~ "~n~R..G J b .v Vl~b

WASHOUTS FOR CON MEDS
Before screening_ visit Throughout study_
Decongestants
Short-acting antihistamines t/'y. d~~s PRIOR. v- 2-- 5 -I+-
Long-acting antihistamines >I..j d_Q~l.ts ,
Hismanal
Nasal steroids
Intal/Nasalcrom
Tilade lnedocrimal sodium}
Atrovent
-
Inhaled steroid OK IF NOT 1'- r e~W"l M c!! 1\(
Theophylline I> :p4· Ii ('S 1) r H~ I~ V- 1.- !)- -I +
Short-acting beta agonists
Long-acting beta ag_onists
Caffeine [/11- hrs prior- V-"z.. 5 -r+ ~d(

"",

I Other features:

Study Name: ~ "'\I '" ,<.\\ s t_·2 5 Coordinator: i"\ '\ '" 'f\ h'l't.u\Q/v\ ( L ~ Description of study:

EN ROLLMENT:

STUDY REQUIREMENTS

WASHOUTS FOR CON MEDS

Before screenin visit

I Other features:

.. __ -,.- - ' ..

"

i
:. i
i
; , \
!
i
1
J
:1 ,
./ ~
! !
;.~ ~
;
.~
I
:ijd --f
- .,.~
·i ;i!i~~1 3
. ~
>i
·1
:~ e:
·;.1 '-
. j .~ .
,:j
,.1
. ,~
.,i
. ! ,)
~
I/)
~
. j <;
l J
J
,
!
·1
! .

Study Name: AJOVA~cr I.)

Description of study: R 1--+ u,ct l.:=j /:!J

,ENROLLMENT:
Beginning -r /1 through ;/4 ( '),_! q? Number of patients ~/r:
Age {J_-1S" I Compensation Labs (fasting?) (~tYL"""k).IJ._.
Number of visits and length of study: ~o u~ ~ . .;t ~.
Long Days? k_u . I g /u.n..;t i: t~ -~ £-0 ~L~ WASHOUTS FOR CON MEDS
. Before screening visit Throughout study
Decongestants .. -; • .~ -_" -' .', 'L • ·0«- C1<.
Short-actin.g antihistamines 3D-.,. 0J~~V( OK f/._-~ ...t I'~'
Y
Long-acting anUhistamines ,biJ~_I.-<---~ - V-I o« -f1vt-c..._ i A,....
Hismanal .3 j1..<_.;:,(J, L._.,~ t\_,.1i)
Nasal steroids /~L~+-L,.._+, It.::.}.;._ :t:.r :s{-~ b..o~ .0'1(.- /l~ J.......__.
Intal/Nasalcrom /,Ll,<. , .,. ,~ '7",J T-4L. / I1A-<:> / OK '/-,.JT4 c: NO / 0<..
Tirade (nedocrimal sodium) / n-:: . (._,~ ...._)D
Atrovenl .,,!y" ~ L'_; 'L.~i_) "-,,,)0
Inhaled steroid Sr<4-e...- ,3fk.<>. 5Do _tAO!) /k'-}. "),...0 -h b.iJjJ
Theophylline ct· 6 ~ 7"'J.-· Ih II) ~VJ' ~ $ t.....c-"L.""t _r ~ v: u» ..,_.j.... u 7L.Jo
Short-acting beta agonists - ./ Y·~ v I i2..E..Jc.u~
~~ L<..; A ::'/-1.
Long-acting beta agonists I?, 0 (.<J'~ ___ /\..10
Caffeine Dr<:_ Qf<-
tUu /TCe. 0 L.41"7E 1;( 0 (...u6--.J.- ~, •. ) () I Other features:

Study Name: N C)"\} \=i1R_\-' S t_ -,? 5 Coordinator: ,V\ '-V~'\ 1(\ h-< ~ Description of study:

"~

, . ~: ,

i. .,'

WASHOUTS FOR CON MEDS
Before screening visit Throl!9_hout stud_y_
Decongestants. 0\<
Short-acflnq antihistamines '3 ~ ~ \.)._)\{'T~ V \_ O\<
keftg:-acting antihistamines S' j~ \.u\h-~\' V\ D'C:
Hismanal .:.. ,"0\\11.- ~c...~ ~ '0 ~t9 IJ_)'VY"'vt \'-\. \;:)
Nasal steroids \ ~" ~ \...As. \ Y\.~ I.Q'J .... \.0 y-.."\o cV\-\-_C_'f' \ N. s\ '4..
IntalfNasalcrom ~ V\ \- c.,.\ \ \ '(V\ 0 - ,'t '0 I ~~~\ c \\)""vvi -o\..c
Tilade (nedocrimal sodium) \ '('f'\ t::::> \...J...)Y'l-s~ Nb
Atrovent ,:::) L\ _l--\ vt \_t,~_h \"l 0
Inhaled steroid .5~e. 3 \'Y\. 0 5DO-\LL>IJ VV\. c C .. Bb IF' -
Theophylline ('V" ~ r:L": -p, \ c\ - L\ g- \) _ S ~ u-...-._i_ ;J._ \l C) - N 0
Short-acting beta aqonists (0 'rl. Y< \....lJ\fr~ I( g- \-\ y<: \(J'r-\.1)\:_ V \ )
Lonq-actno beta agonists I.;)_ D \ Am. ili _i"'-.\_ C "
Caffeine b\c . ,

;: ·1

h" v, ,"",~ Other features:

Study Name: ().C[ .). '""-- :_J (,.... r....(

. J ,I

Coordinator:

rc\..·.\. ( .

(' ) - .:... 'J- .

")~.

((_ l t- l (, l • l. ..

Description of study: {i.._ l \_ 'L ( t:

ENROLLMENT:
Beginning through Number of patients ( ;).
Age I.)' - I.e .r I Compensation 'la/l ~ Labs (fasting?) ~- C ... (; . l'l \ ,-Jot • ~ •• J
.~ -
Number of visits and length of study: >( L't..j__ I.. .: ;:_) lC",- 8 c, _ _, • _ -, _"_-L__
Long Days? h.0 STUDY REQUIREMENTS

- .

(' L ~ (.L. (_···e"..·, ~..._) ~~~~~tmi~'PjiJ.~~~~~~~~~t2::~~:!2=S:~~~~~~:ni:~

t-H.~".J. ~.'" _<-y.(! .. (_ ,.~.' L~ .• L ..

,'j(,<'76 Lui A:.I·iL C /'/-.1'>:.7 rr/·~.

visits: ~, . (i: ~I. (t

J L~.( '- -a , i: t, l .L.'_ d ... _.L 6-.. •. L,.,...I:_

j Ll.~ LJ..._-t-

I~ :.J t .•.• ( .•.. ~-

: ,.,,-_" __ ... ---

[_.I •. ~-i.::.' i. (.

).:.. ... c __ .t: (' ..

,

,/]__ ~_t_'. Il_ .... L

I

:-.,,-' ")

-'. »<

. l -

\_

-',--

EXCLUSIONS
Immunotherapy ,j; k ... '. ')/"I.-~~,~ URI '-I- c , .. ~;. .,:,-- .. I Flu shot allowed?
Current smokers? '\ ~ c- I Smoking history? )..-~0 X t • II - <, (.)pli lJ
-
Blood pressure meds allowed? t/ .. 'j ,J ,J I~' - .. ,-" __ J ~
P J....L ,j.i__"~L e"-"- ( 'I- , '_.' ~,' _ t-: : L __ .' .•. _ 1---'
(l..L.._..__¢_t J~ (-e: /)0'10 o---lJ'O~ (c~ (_ ~~L, r....L_j"t • ~
)LC l L._ . ..._· "- j._"'C \. -, C'_ C t. c . ...,..._ ~ ... \.__; , .--.~ \ L" -, u_l, .~ ~.' .j '--<--I ";' • C~n..".-_-t (._ "y}.~<- .......
T~ ol_...\..~·<--?n ~ ,d........... , J. '.'. Ir ... ~ -. o'J r1" ~ ....... /, .j"./ i ' .• ~.. 'f i{ ... .: ' C'~ j"L,,-T l-: .,,,,,,,,,,__,
- - ~
- --.' . - . ' .. ;_ . "_:...~,
~ WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants l/ r.....L.j ..J..._p ~'J. J ,,/ __ ,
Short-acting antihistamines -' / '
-1 i._,,_ ( ': ,. -, .1 _
Long-acting antihistamines •
Hismanal =rc .: I ~2_ ~ ~_- c« .) ) lo -:»
Nasal steroids '~t' r-'-" j i. .: J c : - ( <'1 ( (--...I<"._ ( ::. 7 .. ~ ,~ I J" - .. ) (\("
Intal/Nasalcrom .~ ... _', L" .~ . II. to,' • , J •• )l ~-,
Tilade (nedocrimal sodium) ~..,) ll.) (. i.. -t:» L.(,_ oC_- ;J.-i_ .... J ( c, "
Atrovent
Inhaled steroid L/- l '-'. ,- ..__Jc_ L~ ""'_-'I._ /1.. C'
Theophylline I CL' , ';._'-":_ L '-' ,~-I_ _'F(_ t,
Short-acting beta agonists ;g /i.s». \.. ) ,A': . .J r- -, <--.__. (y-- It ~ct.
Long-acting beta agonists / Lc·.t < t «: <'<',u-.t_/-.; ':)t_ 0
Caffeine flLt. ( '\ .'(' J ~. - ... ",. " « « ' ( DK (I (t1_,---- I t, ,. _ ~

J f.) L'

'. , ( .

.. -, ,."~. ~--~,

Other features: /2_· I~-,~ (,' ... \-._ - .:) Ilo l.J ,J_ \. '- ~ e....J
.. 1 L-L .J i_..~( "
-h: .i.: .• .r , t,. .... ! !t_t. I/_ ._ r.:. ..! .. -:C,
L, _.'\_ L- ·r .... t' . , ~ - .-
f ,) i .J Pfizer 264-101

CTMS recommendations for conducting study per phone conversations with Randy Perkins 1217/1998 1218/1998

1) Medical History

a. --name of PCP must be written on the source-request for records must be done

b. --record all attempts to retrieve records --phone record, letters, etc.

c. --if Dr. G. is PCP must make note on source

2) PIT's

a. --must record the total number of attempts patient made-up to the six maximum.

b. --must use Crapo FEYl predicteds in metric chart-Pfizer will provide (don't have one as of 12/8/1998)

c. --Patient must be standing

3) Con Meds

a. --alLcon meds except 1 aspirin a day and occasional Tylenol use must be called for approvalincluding all vitamins, supplements, Claritin, ibuprofen.

b. --Patients must record all occasional events if <gd on diary.

c. --Any medication not used in previous two months-do not record.

4) All concomitant disease must be approved --rule of thumb >3 diseases NQ

5) Any lab value 10% outside lab reference ranges must be documented by PI and/or sub investigator as to it's clinical significance with REASONS.

--All of the above labs must be approved by CTMS before allowing Patient to continue in study

--All redraws for abnormal lab values must be approved by CTMS

6) ECG's

--any ECG deemed abnormal by the cardiologist at GDXI must be faxed right away to CTMS for continued approval

«if a comparison ECG is available fax that as well

--fax a comparison to GDXI too for comment by cardiologist.

-vmust follow the GDXI exclusion criteria (pg 11) carefully

7) Informed consents-must assign a screening number the day consent is signed ll.Q1 at screen.

8) Patient Diaries

--must write return appointment on diary plus center's phone #

--Patient must record all occasional drug use-each event

--Patient must note whether there is cough post study drug dosing-note all changes in

intensity, duration, nature, etc.

9) Physician progress notes

--physician must capture asthma history, duration, at first visit

10) At screen-physician only needs to document the physical exam page. The other notation in the source does not need to be noted

VIVRA ASTHMA AND ALLERGY CARE CTMSI PFIZER 264-10 1 STUDY

NOTES PER PHONE CONVERSTATION WITH RANDY PERKINS, CRA JAN. 12TH, 1999

1. PK sample logs - require only one sample per sheet,visits requiring more than one sample will need additional sheets.

2. Make sure chest x-ray is done before visit -2

3. Staci Dickhut at CRL laboratories is the contact person for PK samples. May only ship on Monday through Wednesday. Must call ahead of time to schedule shipment at 1 800-455- 6917 ext. 253

4. Fax the data queries from BFM to me, forgot at last monitoring visit - DONE

5. Screening lab abnonnals must be designated CS or NCS and a comment must be written by PI or sub-investigator. Comment must also be recorded on CRF.

6. Make photocopies of all PFT's and Chest x-ray (must have screen number, pt. Initials and 264-101-5009 on all pages) to expedite monitoring visit

7. Must request PCP records. Document all follow-up phone calls.

8. All outstanding AE's at the end of study must be followed up and noted on an unplanned CRF page noting resolution of AE.

9. On 9900 CRF pages - the date of visit is the last visit date. Use the term "unk" instead of dash for an unknown onset time.

10. Need the calibration sheets for the following dates for both PFT machines: 11/25/98,12/01198,12/02/98, 12/08/98, 12/09/98, 12/15/98, 12/16/98, 12/17/98, 12/22/98, 12/23/98, 12/29/98, 12/30/98 - DONE

11. Randy wanted us to use another freezer for the PK samples because there were temperatures less than -20 C. I explained that only an analytical grade freezer would keep a more consistent temperature. Kitchen grade refrigerators routinely ramp down after the door has been opened and then come to equilibration afterwards. He agreed to keep the samples were they were kept originally.

12. Enter one more vento lin to ventolin log for RSL on visit 1 - DONE

Pfizer 264-101

CTMS recommendations for conducting study per phone conversations with Randy Perkins 1217/1998 1218/1998

I) Medical History

a. --name of PCP must be written on the source-request for records must be done

b. --record all attempts to retrieve records --phone record, letters, etc.

c. --if Dr. G. is PCP must make note on source

2) PIT's

a. --must record the total number of attempts patient made-up to the six maximum.

b. --must use Crapo FEYI predicteds in metric chart-Pfizer will provide (don't have one as of 12/8/1998)

c. --Patient must be standing

3) Con Meds

a. --allcon meds except 1 aspirin a day and occasional Tylenol use must be called for approvalincluding all vitamins, supplements, Claritin, ibuprofen.

b. --Patients must record all occasional events if <gd on diary.

c. --Any medication not used in previous two months-do not record.

4) All concomitant disease must be approved --rule of thumb >3 diseases NQ

Any lab value 10% outside lab reference ranges must be documented by PI and/or sub investigator as to it's clinical significance with REASONS. --All of the above labs must be approved by CTMS before allowing Patient to continue in study -All redraws for abnonnal lab values must be approved by CTMS

6) ECG's

--any ECG deemed abnormal by the cardiologist at GDXI must be faxed right away to CTMS for continued approval

--if a comparison ECG is available fax that as well

--fax a comparison to GDXI too for comment by cardiologist.

--must follow the GDXI exclusion criteria (pg 11) carefully

7) Informed consents-must assign a screening number the day consent is signed llQ.t at screen.

8) Patient Diaries

--must write return appointment on diary plus center's phone #

--Patient must record all occasional drug use-each event

--Patient must note whether there is cough post study drug dosing-note all changes in

in tensity. duration, nature, etc.

9) Physician progress notes

--physician must capture asthma history, duration, at first visit

10) At screen-physician only needs to document the physical exam page. The other notation in the source does not need to be noted

Protocol Specific Services

_ ..

Pfizer

CP 325,366 264-101

Patient Information Form (PIF)

. J

The PIF has been designed to assist in the gathering of data which will be linked with each ECG . Please complete the demographics section, including the ID number from the Data Control Card. GDXI operators will also ask for the visit designation and dose date and time. Space has been provided on the fonn for this information. A sample fonn is provided in the appendix.

_-

ECG Assessment Schedule

,J

Protocol Visit # Screen Baseline End of Study Unplanned
GDXI Visit Code -3 0 4 55 -

.'"

Please be sure to provide our operator with the correct visit designation.

Report Delivery - Clinical Interpretation

Routine: ECGs will be reviewed by a GDXI cardiologist and mailed to your site within 24 hours of transmission.

Emergencv: GDXI operators are trained to recognize life threatening waveform patterns. If such an emergency occurs, the ECG will be immediately reviewed by our cardiologist and faxed to your site. A Data Center supervisor will phone your site to ensure the report was received.

Special Requests: You may request a fax report of any ECG. Simply let the operator know at the time of transmission. Unscheduled ECGs may also be transmitted at the investigator's discretion.

Investigator Exclusion Guidelines

Pfizer has determined that the following criteria may exclude the patient from this protocol. If any of these findings are present on the cardiologist reviewed ECG waveform report received from GDXI, further assessment may be required. Direct questions concerning these ECG findings to the Medical Monitor.

1. Arrhytlunia (exception: 1 VPC or 2 APCs in a 2-minute rhytlun strip)

2. Tachycardia> 120 bpm

3. Bradycardia < 45 bpm

4. Intraventricular Conduction Disorder (exception: incomplete RBBB)

5. Ventricular Hypertrophy (exception: LVH by voltage only)

6. Myocardial Infarction (exception: old MI, age undetermined)

QTc > 460 msec

PR> 220 msec

10. 2nd or 3rd degree A-V block

11. Any ECG which is significantly abnormal (GDXI Overall Assessment Code 9220)

GDXI©

11

<603$

APPENDIX VII TABLE 2 METROPOLITAN LIFE INSURANCE HEIGHT AND WEIGHT STANDARDS

(D F,"{_Q)

3octo >- +h~Y\ + 0p H rf\ ) +- u f'\ ~T -t~b\Q_ u'lf:_--

o...t\~ty,)f\ ~ obtx/-.Q..._ fuO\-l- - N ~ )

,

PROTOCOL #264-101

to

Following are 1983 Metropolitan Life Insurance Company weight tables by height and size of frame, for
people aged 25 to 59, in shoes and wearing five pounds of indoor clothing for men, three pounds for
women
Height Weight Pounds x 0.45 Kilograms
(in shoes, in Indoor Clothing
1-ineh heels)
Ft In x 2.54 em Small Frame Medium Frame Large Frame
Men
52 157.5 128-134 57.6-60.3 131-141 59.0-63.5 138-150 62.1-67.5
53 160 130-136 58.5-61.2 133-143 59.9-64.4 140-153 63.0-68.9
54 163 132-138 59.4-62.1 135-145 60.8-65.3 142-156 63.9-70.2
55 165 134-140 60.3-63.0 137-148 61.7-66.6 144-160 64.8-72.0
56 168 136-142 61.2-63.9 139-151 62.6-68.0 146-164 65.7-73.8
57 170 138-145 62.1-65.3 142-154 63.9-69.3 149-168 67.1-75.6
58 173 140-148 63.0-66.6 145-157 65.3-70.7 152-172 68.4-nA
59 175 142-151 63.9-68.0 148-160 66.6-72.0 155-176 69.8-79.2
510 178 144-154 64.8-69.3 151-163 68.0-73.4 158-180 71.1-81.0
511 180 146-157 65.7-70.7 154-166 69.3-74.7 161-184 72.5·82.8
60 183 149-160 67.1-72.0 157-170 70.7·76.5 164-188 73.8-84.6
61 185 152-164 68.4-73.8 160-174 72.0-78.3 168-192 75.6-86.4
62 188 155-168 69.8-75.6 164-178 73.8-80.1 172-197 n.4-88.7
63 190.5 158-172 71.1-n.4 167-182 75.2-81.9 176-202 79.2-90.9
64 193 162-176 72.9-79.2 17H87 n.0-84.2 181-207 81.5-93.2
I ~inshoes,
inch heels) Women
410 148 102-111 45.9-50.5 109-121 49.1-54.5 118-131 53.1--59.0
411 150 102-113 46.4-50.9 111-123 50.0-55.4 120-134 54.0-60.3
50 152 104-115 46.8-51.8 113-126 50.9-56.7 122·137 54.9-61.7
51 155 106-118 47.7-53.1 115-129 51.8-58.1 125-140 56.3-63.0
52 157.5 108-121 48.6-54.5 118-132 53.1-59A 128-143 57.6-64.4
53 160 111-124 50.0-55.8 121-135 54.5-60.8 131-147 59.0-66.2
54 163 114-127 51.3-57.2 124-138 55.8-62.1 134-151 60.3-68.0
55 165 117-130 52.7-58.5 127-141 57.2-63.5 137-155 61.7-69.8
56 168 120-133 54.0-59.9 130-144 58.5-64.8 140-159 63.D--71.6
57 170 123-136 55.4-61.2 133-147 59.9-66.2 143-163 64.4-73.4
58 173 126-139 56.7-62.6 136-150 61.2-67.5 146-167 65.7-75.2
59 175 129-142 58.1-63.9 139-153 62.6-68.9 149-170 67.1-76.5
510 178 132-145 59.4-65.3 142-156 63.9-70.2 152-173 68.4-n.9
511 180 135-148 60.8-66.6 145-159 65.3-71.6 155-176 69.8-79.2
60 183 138-151 62.1-68.0 148-162 66.6-72.9 158-179 71.1-80.6 Study Name: FLI~ 3 t:'2 L

Coordinator: f'('l '\ v<. \l~

A

~.~i7

ENROLLMENT:
Beginning through Number of patients
Age 1d.-1' I Compensation I 000 0 ~ Labs (fasting?) X-z. c t,-..-.\'nJ ~ N -'r ('~)- '(.-1-
Number of visits and length of study: 1 'is V\s.,\-,; ,\.0 \J..J o:::c'\:::" .s
Long Days? \"\",, STUDY REQUIREMENTS

EXCLUSIONS
Immunotherapy r~1 :\~ s" ~ I URI -::t_ ,--",'<.5 1 Flu shot aliowed?\..J.,'-1.~~~:'_\
Current smokers? 1---\ I,) - \ -'I ..e., I Smoking history? S to V'f\C\C ~~~ - \ f) thqQ. l-=o
Blood _pressure meds allowed? _i ~ \.<- \L. \,l (U-- t'-""u.. C\'i \j':).,RS
3 O\-- '1;"<'-,0\- C- \)os.. R\.~\Y\\' ..",.",-\ \."'"--" r __ 0 ,\-\-..,..--.. \ lV::>~ '-\ eo ~
I b-~'«. \J \ <, ... \- 0"1- \) 0':: R \-\ ,p., \ \L \{>,~, ,-",- ~.'(' r-., s -y(>\..J'("\A. C, \...t.)\~,,< '='1 v.-J \<: S'
'l\{\j;~ ... '"' .... \)\?'vC\-\L J
\')C\)("Y"\ l\.Q ....... \
G,. \ IA-' .. A (_ o"Vv\. e.. <>. nl.\i Q\- _"P os, \-c.'n 0';- S. ,.A ~ C. \f1~ s \.J....\ 'A 'r C v:.::. --\ 'f'r \- ~ ...... L \- S
I
WASHOUTS FOR CON MEDS
Before screenifl9 visit Throy_ghout stu~
Decongestants O\<::
Short-actini] antihistamines ~v"f\'_n"'l:>--\ ~ It. \_...,..__". _() 'K.
Iu~\ c t: ~ e -;: .. \-... J'''_ ~
Long-acting antihistamines ? l1. ~-'-'> - Z .... \. v...'W W\o,)U D'C
f_i"' ,I,.... ...I'" <. ,.l..:
Hismanal
Nasal steroids
~IINasalcrom 'l t=\OY"lo..f.l..Q.. M'RW O,.c::
Tilade (nedocrimal sodium) L\ '-v: " ',C. " ).. , \I':t S \'\ 0 \..J....- \-
Atrovent j j Y'1-\1[.; \ \._~ ,---u;_r\( \.'-.;\At\· A_-\;
Inhaled steroid ~8Q" (n"- - L\:\;\\<; \_"_''A5.\-\,:: ._l..;.-V\"',-'< \
I- ,v\c._ L ,'">, S: c u._.._-ls_ - \d. ,'r- --:t..__
Theophylline ~ 1\-\1-.. 01 l\ P, (Cl-1""<-c\' ... ("\ ~ S.R - 11.. IJ'''-.....o ... L \ "'-;\.-0
ir- '(I \ V"\"\ ,. V\ '6 - I"l._ \A.A./;, - .,.
Short-acting beta aqonists l..\ r-\~\ v\ \ c~ c\.., ,,\ ~ ,+ "Z.. 'i ~ - z: '3 I..l> ""--"--0
Long-acting beta aqonists \ 1. \-\ \?. "vi. l\ c\\ V\<,\\..I b\( cU .r L"""-"> 't ~ v.... ~ c\ ose
Caffeine .f J\.I1 t\ v.. p '\ .~

" ... J

Other features: ¥::: eA- b. L ()"Y\ 't\"""L 0 \ e. _ 1-1. 0-'>-. ~ \ \ 0 \.J...) e v\

ENROLLMENT:
Beginning 919ft through cj ru» '-4~L Number of patients Iv.,
Age f,') --1' I Compensation Labs (fasting?) r/-7 - up ti. i.1').._-U
Number of visits and length of study: 9 [,7 (,..Q_...__:t:;":) (5l..~ c- /1..<_6).,_j" ,~
Long Days? ~ STUDY REQUIREMENTS
PFT requirements SO-?6 ~6 Lu/f'::' '70 /Lf_.t_.) X'_...L-.J c L
Time of day for study visits: &_, -r o : u7:J
Skin test required? AlO I Chest Xray?
Contraception fIu__y -z: A6') T 1k..J E:.A.JCE OK. 5 TEIC..-/L./ZAT7 c,') ... __! OF A....{-4LE /.,
Other requirements~w;@fg{f.~Yvv>'- l)/Lu 0:>_ USc f7,~ 30 ;J4VS,
A s TZ-r .A-U''+ to t-u:o /LI TN ~ /)Se- &r- -s),~ 6t::7A A~ 1'" &. c:» c7 (..::! S -
A c5 n-f./Lt- A r
,AJD .s E A 'J 0 _.,_j ,.q c.
EXCLUSIONS

!mmunothera

"

3}11

~

j

J o

,1,

\

~ WASHOUTS FOR CON MEDS
~ Before screening visit Throughout study_
I
l Decongestants O{(_ <:>L 'f-" f..AJ tJ.....t--(""" e. U'/A. ~) O{C_
't Short-actinq antihistamines CfC_ t c { I ,. . , 0(<-
J Long-acting antihistamines c«. I' i, ,. " Of<._
-, Hismanal 3 I (..L.£ ... <.....:t: t,-, ..00
Nasa! steroids If.'.oAA Cf<... ".J tf • (_u~ e__ - ;(.'2. OK
U<d,.
IntaliNasalcrom 0A~:Al,...L... D'fC-- tf. W.L.U-L Lu~ A-JO
Tirade (nedocrima[ sodium) t.f. L.0,~ L0~ ~..J 0
Atrovent c:J L.-<--) ,~ L.u~ 100
Inhaled steroid ~&2~~~~~':i:~: - .. -:~::.~~ " iLJO
Theophylline tf G_) cs-tc: (.<..J~ ,,-10
Short-acting beta agonists f.c tL.\ , vu fJ.4--{;.__. D"1rt_ll_ A...e_.-L~ .s, -'
Long-acting beta agonists d w . .u-i-L.- Lu~ o AJO
Caffeine &£1.JL.. [.v~,-, .L '--f. A-'-1 ,J 'A.A.'X
a
Other features: A/.) h 0. c. i-'Ul...- O/<._ jJ ___})__u ~ e__ Ok... '
A....t 'x 6::L<-_':"_' 01:.-0, kun. ' J o<._&' c........p ill / "
.s: <.~ _c~'<'">- .J t,) ~£±__ I
t~ l.-t..-o-t ' 0
~0L..-..J ~_ ",--- •



E1 C_UTe, Sl<)vs.·d--\~ Study Name: Hrn~ 300':>

Coordinator: L_ ~ r-. / J~r- .:>

Description of study: t\<....\IJ':I.. (,:>. ... -h,::>\\Q'__l.. .'D0'"\pc'J(d-':'v~ s"'-..l~,-\ bit. \--\f1\Q.. 3bLJi (.\.(H\ E\fr.,>~.<...,,\,~\ /CIC/,.j~\cu~.it... c'-.A~ --~-T::';\ -\".;.1.... D+ (J.c...v-tQ YY\O'v::i 1\(l..<-"1

01 C'\0'.;trt 1';::. \(\ U I ~
ENROLLMENT:
Beginning'D / (J 9J through '3/'lt; Number of patients .£-.)
AQe I'i> .- I Compensation ~ \ S f_J Labs (fasting?) Q.ll I.J;.'>~ i"J
Number of visits and length of study: 5 v t s . T .s, - TDT(,_I -3 \ d OJi:;"
Long Days? l'l D STUDY REQUIREMENTS
PFT requirements '(\on.a_
Time of day for study visits: ·("Iv·!'\....9..._.. 61'(1, V_J
Skin test required? Y'Dne> I ~Xra1.? f'f\'0 ... nd ( .... ...,.(.:)(\.4 -F ;;::,.- ; nc.\v"::,, b
Contraception - TYl·_;·.>1- u...:,....;>_ ,.. \ 0.) b'.Q.. 'b0 ...... ( ,.Q..- Q,.;JQ. (",\ ',~' 0."....,. o'(..:d<::..
Other requirements: -. o..C()"t-e, s\ " ~ .. )!I~ .<""::;0 '"" fY\D1b'-"r1 '> ~ -f"o..c.:~CI';\ Po.\11
. () :j r:» \ -u~;r--~ ck i,!.., h ("(' ('r o . J
DO'.:.. ..... \ 1-- \-R_. ·~'\J)(/,d IACv.-., . .o',Q'::'~\}{-'2.
• \o~l\n VI \ "2 s 5. ~ \. .... '-\ -j,5b, c11::_ "-IS ,
I EXCLUSIONS

Flu shot allowed? don' + k m ...

(lD

!\~0ihe~r~~~~~~~~~~~~~~~~~~~~~~~~ __ ~

or. f\ o..bCL\

WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants OIL 01<-
. Short-acting antihistamines DK D'K- r
Long-acting antihistamines
Hismanal
Nasal steroids nO 1\"0
IntallN asalcrom
Tilade (nedocrimal sodium)
Atrovent
Inhaled steroid l\o 1)0
Theophylline ~
Short-acting beta agonists
Long-acting beta agonists
Caffeine I Omer features:

Study Name:5B ~\{o5fo'~(OO{,

Coordinator: ;:(0 h (\

ENROLLMENT:
Beginning 1-'19 through Number of patients (, -I ~
Age l'i- 5; I Compensation Labs (fasting?)AII"-O,f elr'( 'I "'J'd·.
Number of visits and length of study: /;2. Visits 7o~ .. so.:«. (s:....~J
Long Days? N<Jrr'- EXCLUSIONS
Immunothera_py SfAUtcl.. .... G,3""tlJ URI ,(. WI+1- v' _?'_/\( ... I Flu shot allowed? ~~
Current smokers? NQ Smoking history? d5M j( ,'''''' i... /II~ j I;;.. ....... , A1.~
Blood pressure meds allowed? .t:J&.-M iJ )~/r lYIurl fv,. -e e: 5",A../. .,.. A .• br.
p~~"''''''_:l.....~ 1. \1 \.Ji(_ ..... 1l~L,,+ , J
WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants
Short-acting antihistamines
Long-acting antihistamines
Hismanal
Nasal steroids M At.
IntallNasalcrom MAl/oil ( r: A7"0/Y'./:[..,._. -h ) M
Tilade (nedocrimal sodiumJ J.h I "w
Atrovent Ilk /VV'
Inhaled steroid WWI!d:::-=r/J.';~i. )0"..1. -r1r1 .f..J_ oJJu (m;1x Jrf' ... M 1()J{b..·~ u: 11
Theophylline M '/ IW -JI
Short-acting beta agonists lJ~ •. Irs A V. r . 1·( l/ k:H If f/, ! 1-11
Long-acting beta agonists IV () I.vA .. )"', + -fn-f <;,.. P. n".J
Caffeine .J1Iu .N"v I Other features:

(GFXAtWoV Study Name: GLAXO ~r.XJ'I

. ~,.-.:--

Coordinator: 5~J1r1

qjv LlJc'rA .

Description. of stu~y: A rAN~Ot<1;1.(cl/.LA,I<--I,1 rr' ,1~lnyltro.,.-/4-WV>-ffl(·[}tJt,J e . .f ~ ~~.tt~;~rJ;Lj,

",?11~+Y ~ (:rr" ('Il ~IL) xfl~~ .,:J (f.r:>'M j"'(tJtr-5 "(" ~(}{j,..~, 0lJ,":" .)v.,Iy II...J ?rl~j J..k n,r'~,: ,,. (lJ.1I..: Ir-l) J 'I

lo.J~ Ix of ~-h~+5 (;.tJ/~ Ac,wk £A':.'ki"/jl/ &~(.t."~f.-hiNl ofq~r-""llJrJ,·h·,

ENROLLMENT:

STUDY REQUIREMENTS
PFT requirements tJ/fl
Time of day for study visits:
Skin test required? I Chest Xray?Tl!vSTk JJl!.r &''11&1 w .. I{t/lJ l(g A r! aa« tJ /, ~
Contraception 8('1' A/,J~(ji/1lJ+ 1lJO. f}uM-I/fAJrr. t ,4/';eI11."(;",.r;IIy,,k$;'0<" ",L,,,.d (tlr
Other requirements: ./
[eG- -c.fo~ tJ frnrr~eN V"+,"
o ....... 0\ IS J .1-
S"u+1I1'" S"M,C1tN, ._ fhoJsf6t f'.olkd""i ir A'.f4!If[bI~ ON frocr'r::ft0 Vlrt!-:I:l-..J #] A,<.(#C;
J ...... :lJ..,roJ •

EXCLUSIONS
ImmunotherapYNw.t",.IllJl,'", l"r,t;·.:. I URI I Flu shot allowed?
Current smokers? I I Smoking history?
Blood pressure meds allowed?
P}-.L &_""_'__:L e"""_'_ c > lOrn, pir dAY
AN+th/rrk.r;/l) /l1;cf'(1J4J~:' ~Y5~.'t A~~'Jjl< d~""vllI..", p~~,"/, 7d~ ..... or ~)nJ( cwr('("tiy"'-Ix
~//.,~t n+ A8G C £ If 7 ~ f
WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants
Short-acting antihistamines J ~o JrllIr..1{_
. Long-acting antihistamines J ~
Hismanal \l
Nasal steroids
IntalfNasalcrom
Tilade (nedocrimal sodium)
Atrovent
Inhaled steroid
Theophylline ..;
Short-acting beta agonists
Long-acting beta agonists
Caffeine - [1111; + IN"fJ4. f. (_ ,

... ..,

ENROLLMENT:
Beginning Ilift through Number of palients /J..
Age ~ yc7 I Compensation (" .. c (_ . - Labs (fasting?) Yes V, ;1' ... (5 rT .. ~;;((J k. i;
Number of visits and length of study: 13 Ih ,.f.; (I'~ :2k!V.;/l.j·
Long Days? yf J ~({. '
0-<.. (.;Lim St". (,,11 i er: A,; r'\
./ STUDY REQUIREMENTS
PFT requirements <'657, F';vj r\( -n:L' ,(_1t=}1l0
Time of day for study visits: (',4d~~""_ c - '1
Skin test required? NO I Chest Xray? Yes
Contraception AtoAI t J1. ~#.. c.._.6-, i
Other requirements:
J)/~<lt--OJtJ crF Co r o
fix i (~J"''' (., r AIle A ~_.f-_ 5 ,.,....,.,I;""T o("'lr .J',,-rs
v EXCLUSIONS
Immunothera_Qy JURI lu) lL'£C'~'" h'- fl/?;l J Flu shot allowed? yes
Current smokerslD(, t;rrr"E' ( )f'I10~O )G {'ftQ(CfhI I Smoking history? >:J.(}pk\yr-
Blood pressure meds allowed? 6{<_
.p J....'- S:_~~LC'-J- e _ILl- ~, ........ y> _ L- ..... -c-a:> i-.--
I)
C()rf.l·rAJ5fer().J. .",A ~l.,,'f {, v_~ (Jr;6r' ( s i<.9. (J..a..... + A II", .t.: ) (~(' )I..l<)
I , WASHOUTS FOR CON MEDS
l~ ft( dAr fVN-:N P':;'("(j" Throughout study
Decongestan ts ci;
Short-acting antihistamines , <«.
Long-acting antihistamines C' K_
Hismanal _~\s CJc.
Nasal steroids 1\ 0:_'!V . .(
J L ..
Intal/Nasalcrom J \ ,··.n::::\' .N.''' \~ .,,'d
Tilade (nedocrimal sodium) I \'./ I f:>l- "~ .... ,/
Atrovenl V / \ <-J.-~;V'
Inhaled steroid J'/
Theophylline Wlu sf kN, . .} A r; ~ hi- ./.:>rc
Short-acting beta agonisls ((_ I L·'\..'~. Lu !'-'_' I--
Long-acting bela agonists V ( )_ 1\...·1. J. u_· ,.-._I-,....o " .-"
Caffeine 8lvr pr;:I'" ~Art) rlb·if \ I Other fealures:/u,Jl

VI
V> ....... Yi
1.4- '-+
'4- " ~ .
- " -
J <s vo
1:1>
\ I
_ >-- J>-
<I
Q ")_.g
'- <; ..__
or ~ .,..
u V ..
t .; {
t> Ij U
" () v
~ ~ 0
- - r-(
\JI \J\ vi CIA)( a c, e.lt Co 1"-1 ~ Study Name: S Wl '5 <-to 00 S

Coordinator: I

l <'u /e_.._____

Description of study: C Cv<-\ Ie.. s, s 0 '" 3~ +- w q_oa 0'\ S e 0'2., v' « jI\ \- A ...... J. 'S.' ....... i uk: IZ.

0 ...... ?-l- W\"'o L~t- .r .... t-l.e..I(lo{ Coll--l-~c_c.':,+clo: ... t s

ENROLLMENT:
Beginning t).. "'t'i through Number of patents I~
Age I S" 'I .../1'" I Com_pensation fi' 500 oQ. Labs (fasting?) V\r. l A ~ S.
Number of visits and length of study: ~ u ,,:>,+"::, 'StlJc>-. ... ( (<..~.t- rt.l W(_OI.lt S
Long Days? AoVl.6' Immunothera

WASHOUTS FOR CON MEDS
Before screening visit Throughout study
Decongestants ¥\ \\c. ..... ~J rA lIow~.J
Short-acting antihistamines tlllcve.J: AHcv~J
Long-acting anlihistamines au. ~ (\ tHtc ....... .lI._d
Hismanal - -
Nasal steroids ~\ ~l (7 trJooi. C/1 t4 II" we c.l
Inlal/Nasalcrom (I..( \)<:..,' Wc,SL., V\ t,.-\ 1I1llo ...... ~ ,J
Tilade (nedocrimal sodium) I L( () <, '/ l.0 A-<" IA /,\C.(.. ~(t.'-'~ cJ
Atrovenl ;( L( f-\.l WG.":Hr'\. V\.eA- ~~ tl G' .... -( eX
Inhaled steroid '3 G .1"., r~ -k..g r e, Ue'\ '"'-
Theophylline t( ~ ..... 1 w.:... ":, ",\ v'lv--\- L.::J II C" ..... ~ ci
Short-acting beta agonists G ,.{,t Wc....<::,I..-->.. f\
Long-acting beta id_ crr<>..l ~k q~H.<. \'
Wc..~lA II'c_,!· \I\. t l<A..- -e (_)
Caffeine ~ ~ I Other features: