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-.I/ -asQ A933 VW3 JO Noislhla v sl:lMP l 2.r uo quaurtuo:, PUP MGI~A~J03 K~~un$Joddo UP sey pue saLdo:, aye 40 auo S~AL~D~J ICy:,!dkl puour/c~~ l da JPIJ$ avlnsw aswld nolC ptnoM l /CpnJs asuodsa asop aJnSSC3Jd poolq t? 40 lo~o$oJd $~PJP P 40 saldo:, aa~y~ 3JP paSOt3U~ l aJtISSaJd poolq uo auy.ue~ou~doJd~hmqd 40 3x344~3 ayr~ aultu~qap 03 Lpnqs asuodsw asop au~we~owdoJd~haqd P a04 [03O$OJd e ~$LM nOif ap!AOJd 03 paq.~~wo:, aM bz l@dy 40 6u~~xm.u Jno 6u~Jng lN3CllWd illA1 ‘M NHOf 0009-szt-102 ‘131 Lb880 A3WF M3N ‘NOW33 uu -. ‘ . i 5,; ; ‘$’ ,I PPA Dose-Blood Brief 1. and Statement in 3 phases: will be conducted Phase I: This will titration with in 20 (according to Screenin& below) normobaric and upper weight lim its, the 1983 subjects 25, will non-drug will Life will 50, day). randomized 2 treatment about in receive the first 10 alternate regimen. in 2, 5, 6, 7 and 8 hours 0, 1, 2, drawn of at blood determinations). PPA The titration c by at subjects either at must will which be placebo or washout, rate 0, and blood for 1 will a l-day post-dosing endpoint least each of positions (venipuncture 20 and Each titration after post-dosing in PPA doses BP and.pulse and standing 3 and 4 hours levels oral hours, day, lower Tables) ages of days, to BP * defined Company (separated manner the height single these inpatient be measured 3, 4, for between-the of Baseline to +15$ of using second treatment supine -5 days a double-blind PPA, and on the under 150 and 200 mg. 100, On the normotensive Insurance proceed 75, involve require will (within (IO male and 10 female) 12.5, step described oral administered clearly respectively, Metropolitan rising (PPA), healthy, criteria The titration 45. of the of Objectives: be a placebo-controlled, phenylpropanolmine conducted orally, Response Study of Study The study dose w Description Pressure will l/2, 1, will be estimation follow be.either BP that -- PPA dose baseline The which studies in out-patient Phase I, response Patients weekly at 0, 3, 4, phase visits estimation studies in repeated II maximal will consist the of dose of generate to a the are and whether In will undergo dose after t.i.d. PPA which, during rate this dose the phase a single post-dosing and blood 4 hours 0, will l/2, 1, of drug will post-dosing . Again, BP determinations. 2 will be points. determine whether PPA changes who have dose be drawn and with accumulates patients 3,*4, 2, phase ,be monitored at these to rechallenge of PPA used in Phase I. at this w baseline release PPA dose and blood designed vasoactive III: a PPA 3 weeks of during BP and pulse phase be measured follow to of PPA concentrations this dosing Phase 3, desigrred be seen weekly and 5 hours BP response 2, SDBP from curve. of will for Phase are administration these The in or 200 mg. phase This increase caused a peak increase in SDBP of 10% over The drug will be given as an immediate (PPA+")* capsule. drawn this pressure Phase II: at a peak of 25% (PPA+25), dose-blood * produces In this 5, for 6, completed with the phase BP will 7, and 8 hours PPA levels blood-lettings at 0, 1, must ,The study chronic this treatment development drug in which of phase with tolerance produced is designed a vasoactive to the significant to dose of effects BP elevations 3 determine of whether PPA results a dose of in Phase I. in the 2. Selection A. of Study Inclusion ‘Population: Criteria: 1. Age 20-45. 2. Weight within upper limits, -5% and +15$ of respectively, defined in Company Tables. Ability to for 1983 Metropolitan the the Life lower and height as Insurance . 3. sign read, the informed 4. Availability for 5. Ability 6. to comprehend consent the understand the Willingness to abstain or other the tobacco, from Cola and supplements to the protocol. Coca alcohol to study. adhere coffee, methylxanthine-containing food--e.g., vitamin of and of willingness form. duration requirements all and all for and beverages and drugs the tea, chocolate), and dietary or duration of the study. B. Exclusion 1. Fixed 2. Current Criteria: need for any drug therapy. cardiovascular, gastrointestinal, hematological, endocrine “. pulmonary, genito-urinary, musculoskeletal, disease. 4 neurological or 3. Prior history of significant cardiovascular, gastrointestinal, pulmonary, hematological, genito-urinary, musculoskeletal or neurological disease. 4. Family history of cardiovascular significant disease, accident, subarachnoid aneurysm, arterio- hypertension, cerebrovascular hemorrhage, venous intracranial- malformation or brain tumor. 5. Significant abnormality on physical examination. 6. Significant abnormality (as described 7. Known similar allergy drug in Appendix or (or pill). 5 adverse any on laboratory A), or chest reaction decongestant screen x-ray. to PPA or or diet -- Baseline 3. BP Screening: The'screening Subjects basis who qualify of will, the inclusion IO measurements in supine Monday, will readings the min. time and means of the 3 measurements In order to qualify of the times must for the each of be between for the entry 3 days BP's day both Timing observations diagrammatically for the on defined above pulse rate and made 3 times 8 AM and 4 PM on, Korotkoff Phase and pulse are into the (as defined on which standing 1 week. 5 rates at as the defined SBP and DBP. 95 and 12'7 mmHg for DBP in of 1 week. each for at over study positions of DBP. mean BP's 81 mmHg for summarized of the BP by 5 min) Friday out criteria have (8AM and 4PM) for study, into and standing be used as the measure each entry rest, separated Wednesday be carried and exclusion a the will for after (with * procedure dose-titration in Fig. above) for measurements 60 and positions. BP screening 1. both are made SBP and between and supine the phase period is \ I \ . 1 0 L c ” .’ . . 4. Phase I: Study A. Procedure: Subjects the basis above of will results a each “treatmentrf day. For Step 5 = 100 mg PPA, PPA) subjects After will regimen in-hospital treatment 3 blood times with day. to 7 and 8 hours post-dosing. will be rates at timepoint dosing at each 7 = 200 mg PPA, or least a ml samples of be measured 2, of defined timepoint. 3, 5, 4, venous 6, blood concentrations post-dosing. Blood be PPA supine between 1, l/2, the second days, will to placebo. 24 hours on rate at mg PPA, manner treatment pulse and Seven will at 2 mg PPA, W 4 = 75 intervening measurements. made Step either of periods 4 hours BP 3 measurements and and follow of of 1 = 12.5 a double-blind On both estimates 3, described intervening administered for must each be pressures obtained in period prior one (Step mg PPA, washout measurements, 2, steps day min. 1, consists treatment 5 baseline, titration least on outlined 6 = 150 mg PPA and Step will study As be randomized an out-patient the examinations at the into procedure. the 3 = 50 Step in-hospital standing screening by of Step alternate and of each = 25 mg PPA, entrance titration separated Step a first the step days llwashouttv for of begin previously, - qualifying at Blood-lettings pressures as the and means pulse of the *e Subjects will receiving a higher unless through proceed dose a 25% increase encountered at 10% increase preceding interval PPA at each in supine DBP from supine or subsequent separating sequence of any post-dosing in the point, DBP from hourly steps steps, succeeding in step, baseline association baseline in BP measurement titration of must be is with a either the (PPA+25). The at least 24 hours. After for the the B. Adverse subject’s laboratory last screen Withdrawal Reactions . 1. during iii. and any position any position rate >130/min Irregular pulse. iv. Sustained chest V. Headache vi. vii. viii. Visual in Appendix Procedures will be drawn A. for Handling Criteria DBP at Pulse blood Phase I: SBP in ii, step, detailed Criteria Withdrawal 1. titration 110 mm Hg or exceeding higher 170 mm Hg. or <50/min. discomfort. disturbance. Seizure. Paraesthesia or or weakness, localized. 8 either generalized or ix. other Any neurological considered be by the of Nausea X. xi. 2. Phase Any e- an adverse cardiac physical in patient’s and the has subsided for an adverse 24 hours be seen At the and adverse a medical reaction 12-lead out React;ions during pressure have V returned Subjects resolution 1 week investigator, staff and drug 9 the screen monitoring and until the to the normal within the of after temporally h. continue in-hospital may be considered. q.1/2 for from the study from the study at least in-hospital of for a complete withdrawn remain monitored, the blood withdrawal the study immediately, Cardiac will within the instituted, and prompting will from ECG obtained, A obtained. re-examined of study. hospitalized carried complete of withdrawn pressure reaction dose is be completely. a carefully the the Adverse blood signs discretion consent, Handling who reaction after CIBA-GEIGY with blood vital range from prompt depersonalization. begun, supine of to vomiting. will Appendix monitoring of subject examination detailed sufficient to I: monitoring of investigator subject and/or for reaction monitoring of Feelings Procedures monitoring severity withdrawal disturbance for reaction hospital with and discharge. permission obtaining will from informed PPA rechallenge associated with the -- _ . Phase II: 5. Phase II dosing in with invalve the dose increase in supine whichever is greater. phase must by at least During pill release found Phase I Commencement of from outpatient formulation baseline be separated t.i.d. capsule in DBP over open, the to of produce PPA a 10% (PPA'I' > or 50 mg, dosing with PPA in in Phase I last step 2 days. Phase II counts subjects will and supine 3 weeks of an immediate either this k will will be made, standing previously described) preceding dose withdrawn at of new medication BP's and 0, 2, PPA, these be seen weekly. 1, pulse 3 and 7 ml timepoints concentrations. and bottles rate supplied, measured 4 hours samples for At each visit of after the venous blood estimations Venipunctures (as must of follow PPA BP determinations. Data from than 1201, subjects of found prescribed to have used PPA for less than any weekly 80% or more period will not for this ,.r be included phase, in but Phase III in such if the primary subjects compliance effectiveness will analysis be eligible has been in IO for the participation 60-80% range. Criteria study, will for and withdrawal procedures be those outlined of for in subjects from attention to Section this withdrawn 4 (Phase I) i’ .’/.li’Timing titration af observations step are and summarized -phase interventions diagrammatically j of the patients above. __ 8, i 7 : .f,_^ for’. a typical b ,Li in -Fig. 2. ,’‘, ‘,_; ; I‘ ‘<‘; i,, .,.I,,.,i, : ,$ 4x :~,$‘ .> . ,’>, .,a:, 1- ‘-.,, * ‘i ,, ,&. i:+v : ‘,f )b .8 ,.‘! ,.‘~ 11 - j 6. This phase subjects with Because that Staridirig phase last for prior for of the assess the be carried of PPA+2S dose. possibility effects to 2, rate and l/2, administration 3 and withdrawal for to and pulse must follow procedures described must BP's oral 1, a rechallenge hypertensive Seven ml samples 0, of of out on PPA may the day day of Phase II. described Venipunctures Criteria designed the and supine after consists administration rechallenge the solution. the study is to the previously hours the a single this following at of tolerance develop, 8 . Phase III: attention of 4 be measured 1, 2, of venous hour will the 3, 4, PPA"25 blood will post-dosing 5, as 6 and dose in be obtained timepoints. BP measurements. of the to Phase I in Section 12 subject during withdrawn 4B above. this subjects phase and are, as “4 7. Follow-up subjects All from the the At this by in be seen regardless adverse visit a reaction will Appendix be collected 1 week whether or the merely of carried for the A. 13 will In laboratory departure departure and systems out. of followed interventions review examination within of protocol-prescribed physical urine must study, prompted of Visit: be was completion observations. obtained addition, screen blood and avjd described Appendix Laboratory A Screen: CBC, electrolytes, CPK, Ca++, phosphatase, BUN, creatinine, AST, ALT, total GGT, T3, TY, 12-lead FBS, Alb, Glob, bilirubin, PO4, alkaline ECG, urinalysis. 14 I. / . -g .* . 1’ 9 3 .* .0 ;“ .’ .’ /