1977 ntis annual report: phase i clinical testing. antimalarial drugs. annual report

ADA04/1243

PHASE I CLINICAL TESTING. ANTIMALARIALDRUGS

BIO-MED INC WASHINGTON DC

MAR 1976

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REPORT NUMBER 1

Phase I C l i n i c a l Te s t i n gA n t i m a l a r i a l D r u g s

Annua l R e p o r t

R i c h a r d C . R e b a , M . D .

Date A u g u s t 1977

Suppo r ted b y

U.S. ARMY- M E D IC A L R ES EA RC H AND D EV EL OP ME NT COMMAND

Wa s h i n g t o n , D . C . 2 0 3 1 4

C o n t r a c t N o . DAMD 1 7 - 7 5 - C - 5 0 3 6

BIO-MED, I n c .110 I r v i n g S t r e e t , N . W.Wa s h i n g t o n , D . C . 2 0 0 1 0

Approved f o r p u b l i c r e l e a s e ;d i s t r i b u t i o n u n l i m i t e d

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17. D I S T R I B U T I O N S T A T E M E N T ( o f t h e a b s t r a c t e n t e r e d in B l o c k 20, i f d i f f e r e n t f rom R e p o r t )

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Phase I C l i n i c a l Te s t i n g , M e f l o q u i n e , A n t i m a l a r i a l D r u g s ,WR 184 ,806-H3PO4, Human S u b j e c t s11,.: 1,' ' , ' c A. c 0 5\ :- . --,,

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,,weekly for 52 weeks. Clinical, ophthalmologic, hematologic and biochemical

' m o n i t o r i n g a r e p e r f o r m e d s e r i a l l y . D u r i n g t h e i n i t i a l weeks o f s t u d y -comp l i ance h a s b e e n e x c e l l e n t a n d-n o a d v e r s e r e a c t i o n s h a v e b e e n o b s e r v ed .

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accomp l i shed . U s i n g d o u b l e - b l i n d r i s i n g d o s e l e v e l s i n g l e o r a l d o s e swere w e l l t o l e r a t e d t o t h e 1000 mg l e v e l ) s i x s u b j e c t s r e c e i v i n g 1200to 1 4 0 0 mg a l l d e v e l o p e d i n t o l e r a n c e m a n i f e s t e d b y c o m b i n a t i o n s o f l i g h t - •headedness w i t h a s s o c i a t e d d i f f i c u l t i e s s u c h a s c o n c e n t r a t i n g a n d f o c u s i n g ,headache, n a u s e a , i n s o m i a , a n d u rn Iquq , ,d reams . I n a l l s u b j e c t s t h esymptoms w e r e n o n - i n c a p a c i t a t i n g d h a i o f > l e s s t h a n 2 4 h o u r saL a u r a t i o n

' M u l t i p l e o r a l d o s e s w e r e t h e n t e s t e d a d m i n i s t e r i n g d r u g o r p l a c e b o e v e r y 'i g h t 2 h o u r s f o r 7 2 h o u r s . ( 9 d o s e s ) . ) I n t o l e r a n c e m a n i f e s t a t i o n s w e r e

s i m i l a r t o t h o s e o b s e r v e d i n t h e s i n g l e d o s e s t u d y a n d o c c u r r e d a t t h e3600 mg t o t a l d o s e l e v e l ( 4 0 0 m g / i n d i v i d u a l d o s e ) .

I t i s c o n c l u d e d t h a t t h e expanded s t u d i e s o f m e f l o q u i n e a r e o f v a l u e a n dshou ld b e c o n t i n u e d . W R 1 8 4 , 8 0 6 - H PO i s w e l l t o l e r a t e d a n d i n t o l e r a n c e3 4i s m a n i f e s t e d o n l y b y n o n - i n c a p a c i t a t i n g symptoms. P h a r m a c o k i n e t i cs t u d i e s a r e i n d i c a t e d a s a p r e l u d e t o Phase I I s t u d i e s .

REPORT NUMBER 1

Phase I C l i n i c a l Te s t i n gA n t i m a l a r i a l D r u g s

Annua l R e p o r t

R i c h a r d C . R e b a , M . D .

Date A u g u s t 1 9 7 7

AD

• S u p p o r t e d b y

U.S. ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMANDWa s h i n g t o n , D . C . 2 0 3 1 4

C o n t r a c t N o . DAMD 1 7 - 7 5 - C - 5 0 3 6

BIO-MED, I n c .110 I r v i n g S t r e e t , N . W.Wa s h i n g t o n , D . C . 2 0 0 1 0

.Approved f o r p u b l i c r e l e a s e ;d i s t r i b u t i o n u n l i m i t e d

The f i n d i n g s i n t h i s r e p o r t a r e n o t t o b e c o n s t r u e d a s a no f f i c i a l D e p a r t m e n t o f t h e A r m y p o s i t i o n u n l e s s s o d e s i g n a t e dby o t h e r a u t h o r i z e d d o c u m e n t s .

BIO-MED, I n c . i n i t i a t e d Phase I c l i n i c a l t e s t i n g o f a n t i m a l a r i a ldrugs f r o m F e b r u a r y 1 9 7 5 t h r o u g h t h e i n i t i a l c o n t r a c t y e a r .These d r u g s w e r e d e v e l o p e d b y t h e a n t i m a l a r i a l d r u g p r o g r a m o fthe U . S . A r m y M e d i c a l R e s e a r c h a n d D e v e l o p m e n t Command. T e s t i n gwas p e r f o L w e d a t t h e Wa s h i n g t o n H o s p i t a l C e n t e r i n Wa s h i n g t o n ,D.C. u n d e r C o n t r a c t DAMD 1 7 - 7 5 - C - 5 0 3 6 . A c h r o n i c s a f e t y a n dt o l e r a n c e s t u d y o f m e f l o q u i n e w a s s t a r t e d i n S e p t e m b e r 1 9 7 5 . T h es t u d y i n c l u d e s w e e k l y a d m i n i s t r a t i o n o f 5 0 0 mg o f d r u g o r p l a c e b ot o 5 0 h e a l t h y s u b j e c t s f o r a 5 2 - w e e k d u r a t i o n . N o a d v e r s er e a c t i o n s h a v e b e e n d e t e c t e d d u r i n g t h e i n i t i a l s t u d y m o n t h s a n dcomp l i ance i s e x c e l l e n t . I f t h e d r u g i s w e l l t o l e r a t e d t h r o u g h -o u t t h e s t u d y i n t e r v a l i t i s a n t i c i p a t e d t h a t , c l i n i c a l t r i a l s f o rm e f l o q u i n e u s e d a s a p r o p h y l a c t i c a g e n t may b e c o n s i d e r e d .

A n o t h e r q u i n o l i n e m e t h a n o l , WR 184,806-H3PO4 h a s b e e n a d m i n i s t e r e dto human s u b j e c t s i n s h o r t t e r m s a f e t y a n d t o l e r a n c e s t u d i e s .S i n g l e a n d m u l t i p l e o r a l d o s e s w e r e t e s t e d u s i n g d o u b l e - b l i n dr i s i n g d o s e l e v e l s . S i n g l e o r a l d o s e s w e r e w e l l t o l e r a t e d u p t othe 1 0 0 0 mg d o s e l e v e l : a l l 6 s u b j e c t s r e c e i v i n g 1200 t o 1 4 0 0 mgo f d r u g a s a s i n g l e o r a l d o s e h a d c o m b i n a t i o n s o f l i g h t - h e a d e d -ness w i t h a s s o c i a t e d d i f f i c u l t i e s s u c h a s c o n c e n t r a t i n g a n df o c u s i n g , h e a d a c h e , n a u s e a , i n s o m n i a , a n d u n u s u a l d r e a m s . T h esymptoms w e r e m i l d a n d o f l e s s t h a n 2 4 h o u r s d u r a t i o n i n a l l s u b -j e c t s . M u l t i p l e d o s e s t u d i e s c o n s i s t e d o f 9 d o s e s o f d r u g o rp l a c e b o a d m i n i s t e r e d e v e r y 8 h o u r s f o r a t o t a l o f 7 2 h o u r s . •I n t o l e r a n c e o c c u r r e d a t t h e 4 0 0 mg i n d i v i d u a l o r 3600 mg t o t a ldose l e v e l w i t h symptoms s i m i l a r t o t h o s e f o l l o w i n g s i n g l e d o s ea d m i n i s t r a t i o n . N o p h y s i c a l o r l a b o r a t o r y a b n o r m a l i t i e s w e r ea s s o c i a t e d w i t h t h e a d m i n i s t r a t i o n o f WR 184 ,806 .H3PO4.

S i n g l e o r a l d o s e s o f m e f l o q u i n e i n Phase I I s t u d i e s h a v e n o t b e e n •u n i v e r s a l l y e f f e c t i v e i n p a r a s i t e e r a d i c a t i o n . T h e s a f e t y a n dt o l e r a n c e o f r e p e a t i n g a " c u r a t i v e " s i n g l e d o s e 7 d a y s a f t e r t h e1 s t d o s e i s b e i n g t e s t e d . A d d i t i o n a l l y , a p r o t o c o l h a s b e e nd e s i g n e d , p r o c e s s e d , a n d a p p r o v e d f o r i m p l e m e n t a t i o n t o d e t e r m i n ethe t o p t o l e r a t e d s i n g l e o r a l d o s e o f m e f l o q u i n e . T h i s p r o t o c o ls h o u l d b e i m p l e m e n t e d e a r l y i n t h e n e x t c o n t r a c t y e a r .

E x t e n s i o n o f Phas,e I c l i n i c a l t e s t i n g o f m e f l o q u i n e i s w a r r a n t e dto p e r m i t f u r t h e r a p p l i c a t i o n i n Phase I I a n d Phase I I I t e s t i n g .WR 184,806•H3PO4 s t u d i e s d e m o n s t r a t e d t o l e r a n c e a t d o s e l e v e l sw h i c h may b e a d e q u a t e f o r c l i n i c a l p u r p o s e s . I n t o l e r a n c e i sm a n i f e s t e d b y t e m p o r a r y n o n - i n c a p a c i t a t i n g s y m p t o m a t o l o g y w i t h o u ta s s o c i a t e d p h y s i c a l o r l a b o r a t o r y a b n o r m a l i t i e s a t t r i b u t e d t o t h ed rug .

SUMMARY

FOREWORD

Under t e r m s o f t h e c o n t r a c t , P h a s e I c l i n i c a l t e s t i n g o f a n t i -m a l a r i a l d r u g s w a s p e r f o r m e d a t t h e Wa s h i n g t o n H o s p i t a l C e n t e r .A l l p r o t o c o l s w e r e p r o c e s s e d b y t h e c o n t r a c t o r ' s O r g a n i z a t i o n a lReview a n d Human S u b j e c t (Human U s e ) c o m m i t t e e s p r i o r t o s u b m i s -s i o n t o t h e Wa s h i n g t o n H o s p i t a l C e n t e r R e s e a r c h C o m m i t t e e .

A l l p r o t o c o l s w e r e p r o c e s s e d a n d a p p r o v e d b y t h e Wa s h i n g t o nH o s p i t a l C e n t e r p r i o r t o i m p l e m e n t a t i o n . T h e Wa s h i n g t o nH o s p i t a l C e n t e r i s a p p r o v e d f o r p e r f o r m a n c e o f c l i n i c a l r e s e a r c hby t h e D e p a r t m e n t o f H e a l t h , E d u c a t i o n , a n d W e l f a r e . ( D H E WAssurance N o . G O 1 8 0 )

6

TABLE OF CONTENTS

TITLE P A G E

T i t l e Page 1

Repor t D o c u m e n t a t i o n ( D D 1473 ) 2

Summary 5

Foreward 6

O b j e c t i v e s 8

Methods a n d R e s u l t s 8

Study Summary 1 0Exper imen t N o . 2 : W R 184,806.H3PO4Shor t Te r m Dosage, S a f e t y a n d To l e r a n c eR i s i n g S i n g l e Dose L e v e l s

15Study SummaryExper imen t No . 2 : W R 184,806-H3PO4Shor t Te r m Dosage, S a f e t y a n d To l e r a n c eM u l t i p l e Dose L e v e l s

Conc lus ions 1 9

D i s t r i b u t i o n L i s t 2 0

OBJECTIVES

Genera l : T o i n i t i a t e P h a s e I C l i n i c a l Te s t i n g o f a n t i m a l a r i a ldrugs a t t h e Wa s h i n g t o n H o s p i t a l C e n t e r u s i n g m e t h o d o l o g yp r o v i d i n g maximum p r o t e c t i o n f o r t h e h e a l t h a n d w e l f a r e o fp a r t i c i p a t i n g s u b j e c t s .

S p e c i f i c :

1. T o e s t a b l i s h a s p r o j e c t a p p r o v i n g a n d m o n i t o r i n g c o m p o n e n t s ,BIO-MED O r g a n i z a t i o n a l R e v i e w a n d Human U s e C o m m i t t e e s . T h eWash ing ton H o s p i t a l C e n t e r p r o c e s s i n g a g e n c i e s f o r c l i n i c a lr e s e a r c h w i l l a l s o b e u s e d .

2. T o i n i t i a t e a c h r o n i c s a f e t y a n d t o l e r a n c e s t u d y o f m e f l o -q u i n e , a q u i n o l i n e m e t h a n o l w i t h d e m o n s t r a t e d e f f i c a c y f b r _p r e v e n t i o n a n d t h e r a p y o f m u l t i - d r u g r e s i s t a n t P.m a l a r i a . T h e s t u d y i n c l u d e s w e e k l y a d m i n i s t r a t i o n o f 5 0 0mg d r u g o r p l a c e b o f o r 5 2 weeks t o 5 0 s u b j e c t s .

3. T o p e r f o r m s h o r t t e r m s a f e t y a n d t o l e r a n c e t e s t i n g o fWR 184 ,806•H3PO4, a q u i n o l i n e m e t h a n o l w i t h some p h y s i c a land b i o l o g i c c h a r a c t e r i s t i c s o b s e r v e d i n p r e - c l i n i c a l t r i a l sw h i c h s u g g e s t p o t e n t i a l a d v a n t a g e s a s c o m p a r e d w i t h p r e v i -o u s l y t e s t e d q u i n o l i n e m e t h a n o l s .

4. T o d e t e r m i n e t h e t o p t o l e r a t e d s i n g l e o r a l d o s e o f m e f l o q u i n e .

5. T o d e t e r m i n e t h e s a f e t y a n d t o l e r a n c e o f r e p e a t i n g a d m i n i -s t r a t i o n o f a " c u r a t i v e " s i n g l e o r a l d o s e o f m e f l o q u i n e 7days a f t e r t h e f i r s t a d m i n i s t r a t i o n .

METHODS AND RESULTS

1 O r g a n i z a t i o n a l R e v i e w a n d Human U s e C o m m i t t e e s :BIO-MED e s t a b l i s h e d a n O r g a n i z a t i o n a l R e v i e w C o m m i t t e ei n c l u d i n g p h y s i c i a n s q u a l i f i e d i n r e s e a r c h a n d c l i n i c a lm e d i c i n e who a r e n o t o f f i c e r s o r e m p l o y e e s o f BIO-MED.Th i s e l i m i n a t e s a p o t e n t i a l e l e m e n t o f b i a s i n r e v i e w i n gp r o t o c o l s . T h e c o m m i t t e e e v a l u a t e s p r o t o c o l s f o r s c i e n t i f i cm e r i t a n d r i s k t o t h e s u b j e c t a s w e l l a s r e f i n i n g m e t h o d o l -ogy a s a p p r o p r i a t e .

F o l l o w i n g a p p r o v a l b y t h e O r g a n i z a t i o n a l R e v i e w C o m m i t t e ethe p r o t o c o l i s p r e s e n t e d t o t h e Human Use C o m m i t t e e w h i c hi s c o m p r i s e d o f l a y i n d i v i d u a l s w i t h a n i n t e r e s t i n c l i n i c a lr e s e a r c h a n d p r o t e c t i o n o f t h e human s u b j e c t s . M o s t membershave p a r t i c i p a t e d a s s t u d y s u b j e c t s a n d many a r e g r a d u a t es t u d e n t s i n l o c a l u n i v e r s i t i e s . T h i s c o m m i t t e e i s f r e es t a n d i n g , e l e c t s i t s o w n o f f i c e r s , a n d s e r v e s t h e v i t a lf u n c t i o n o f a n o n - m e d i c a l c o m m i t t e e i n a s s u r i n g t h e c i v i l

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r i g h t s o f t h e s u b j e c t s a r e p r o t e c t e d . I n a d d i t i o n t oa s s u r i n g m in imum d i s c o m f o r t a n d r i s k t o s u b j e c t s , t h ecommi t tee h a s o n o c c a s i o n recommended p r o t o c o l m o d i f i c a -t i o n s o f a s c i e n t i f i c n a t u r e w h i c h h a v e b e e n a d o p t e d .

A f t e r a p p r o v a l b y t h e Human U s e C o m m i t t e e , e a c h p r o t o c o li s s u b m i t t e d t o t h e R e s e a r c h C o m m i t t e e o f t h e Wa s h i n g t o nH o s p i t a l C e n t e r a n d i s p r o c e s s e d t h r o u g h t h e g o v e r n i n gb o d i e s . T h e Wa s h i n g t o n H o s p i t a l C e n t e r i s a p p r o v e d b yDHEW f o r p e r f o r m a n c e o f C l i n i c a l R e s e a r c h .

The p r o c e s s h a s r e s u l t e d i n e x t r a o r d i n a r y a t t e n t i o n t othe c o m f o r t a n d p r o t e c t i o n o f s u b j e c t s a s a Human U s eCommit tee member m o n i t o r s e a c h s t u d y " o n - s i t e " p r o v i d i n gs u g g e s t i o n s t o i m p r o v e c o m p l i a n c e a s w e l l a s s u b j e c tc o m f o r t .

O v e r a l l , t h e p r o j e c t p r o c e s s i n g p r o c e d u r e w i t h i t s m u l t i p l er e v i e w a n d a p p r o v a l c o m p o n e n t s h a s p r o v i d e d t h o r o u g hc o n s i d e r a t i o n a n d b e n e f i t v e r s u s r i s k f a c t o r s a n d h a s n o tbeen u n d u l y cumbersome.

2. M e f l o q u i n e - - 5 2 Week S t u d y :Th is d o u b l e - b l i n d s t u d y was d e s i g n e d t o p r o v i d e f i v e g r o u p so f 1 0 s u b j e c t s e a c h i n c l u d i n g d r u g a d m i n i s t e r e d a n d c o n t r o ls u b j e c t s . E a c h s u b j e c t w i l l r e c e i v e a s i n g l e 5 0 0 mg o r a ldose o f d r u g o r p l a c e b o w e e k l y f o r 5 2 w e e k s . T h e f i r s tgroup e n t e r e d s t u d y i n S e p t e m b e r 1 9 7 5 a n d a t t h i s t i m et h r e e g r o u p s ( 3 0 s u b j e c t s ) a r e i n s t u d y . T h e d u r a t i o n o fthe s t u d y r e q u i r e s c a r e f u l s e l e c t i o n o f s u b j e c t s s i n c em o t i v a t i o n m u s t p e r s i s t t o m a i n t a i n a n a c c e p t a b l y l o wd r o p o u t r a t e . C o m p r e h e n s i v e m e d i c a l e v a l u a t i o n i s p e r f o r m e ds e r i a l l y . N o c h a n g e s a t t r i b u t a b l e t o d r u g a d m i n i s t r a t i o nhave b e e n n o t e d i n a n y s u b j e c t .

3. S h o r t Te r m S a f e t y a n d To l e r a n c e , WR 1 8 4 , 8 0 6 . 11 ' 1130 4 :

The s t u d i e s w e r e i n i t i a t e d A p r i l 1 9 7 5 u s i n g a s i n g l e o r a ldose, d o u b l e - b l i n d , r i s i n g d o s e l e v e l m e t h o d . T h e d r u g wasw e l l t o l e r a t e d u p t o t h e 1 0 0 0 mg d o s e l e v e l : a l l s i x s u b -j e c t s r e c e i v i n g 1 2 0 0 t o 1 4 0 0 m g d r u g m a n i f e s t e d c o m b i n a t i o n so f l i g h t - h e a d e d n e s s w i t h a s s o c i a t e d d i f f i c u l t i e s c o n c e n t r a -t i n g a n d f o c u s i n g , h e a d a c h e , n a u s e a , i n s o m n i a , a n d u n u s u a ldreams. T h e symptoms w e r e m i l d a n d o f l e s s t h a n 2 4 h o u r sd u r a t i o n . N o o t h e r c h a n g e s a t t r i b u t e d t o d r u g w e r e o b s e r v e d .The c o m p l e t e r e p o r t f o r s u b m i s s i o n t o t h e t e c h n i c a l m o n i t o ri s i n p r e p a r a t i o n . T h e S t u d y Summary i s p r e s e n t e d i n t h ef o l l o w i n g p a g e s :

9

•

BlO- MED, Inc°

INTRODUCTION:

EXPERIMENT NO. 2 : W R 184,806-H3PO4SHORT TERM DOSAGE SAFETY AND TOLERANCE

RISING SINGLE DOSE LEVELS

STUDY SUMMARY

Tel: (202) 882-0977

The s t u d y was p e r f o r m e d t o d e t e r m i n e t h e s h o r t t e L m dosages a f e t y a n d t o l e r a n c e o f WR 184,806-H3PO4 a d m i n i s t e r e d o r a l l yto human s u b j e c t s . A t o t a l o f 1 2 s t u d y i n t e r v a l s w e r e u s e dto a d m i n i s t e r d r u g o r p l a c e b o t o 4 5 s u b j e c t s .

SUBJECTS:

R e c r u i t m e n t :

S u b j e c t s w e r e h e a l t h y m a l e s a g e d 2 1 t o 4 5 y e a r s w e i g h i n g b e -tween 5 0 - 1 0 0 k g . T h e y w e r e r e c r u i t e d f r o m t h e Wa s h i n g t o n ,D.C. m e t r o p o l i t a n a r e a a n d w e r e h i r e d a s t e m p o r a r y emp loyees .

Sc reen ing :

Cand idates f o r emp loymen t u n d e r w e n t q u a l i f y i n g e x a m i n a t i o n sto o b t a i n t h e s u b j e c t s f o r s t u d y . T h e i n i t i a l e v a l u a t i o ni n c l u d e d a c o m p l e t e h i s t o r y a n d p h y s i c a l e x a m i n a t i o n , c h e s tx - r a y , e l e c t r o c a r d i o g r a m a n d t h e f o l l o w i n g t e s t s : u r i n a l y s i s ,w h i t e b l o o d c e l l a n d d i f f e r e n t i a l c o u n t , r e d b l o o d c e l l c o u n t ,hemog lob in , h e m a t o c r i t , MCV, NCR, MCHC, p l a t e l e t c o u n t , g l u c o s e ,BUN, c r e a t i n i n e , N a-F, C l-, C O 2 , u r ic a c id , t o ta l p r ot e in ,

a lbumin , g l o b u l i n , c a l c i u m , p h o s p h a t e , c h o l e s t e r o l , t r i g l y c e r -i d e s , a l k a l i n e p h o s p h a t a s e , SGOT, SGPT, L D H , t o t a l b i l i r u b i n .L a b o r a t o r y t e s t s w e r e p e r f o r m e d i n d u p l i c a t e b y N a t i o n a l H e a l t hL a b o r a t o r i e s , I n c . u s i n g s t a n d a r d methods . C h e s t x - r a y s w e r epe r f o rmed i n t h e D e p a r t m e n t o f R a d i o l o g y a t t h e Wa s h i n g t o nH o s p i t a l C e n t e r . E l e c t r o c a r d i o g r a m s w e r e p e r f o r m e d b y t r a i n e dp e r s o n n e l u s i n g a Cambr idge V S - 4 p o r t a b l e e l e c t r o c a r d i o g r a p hmachine. U r i n a l y s e s w e r e p e r f o r m e d b y p h y s i c i a n i n v e s t i g a t o r si n t h e r e s e a r c h u n i t l a b o r a t o r y u s i n g s t a n d a r d me thods .

I n f o rmed C o n s e n t :

Q u a l i f i e d c a n d i d a t e s w e r e p r e s e n t e d w i t h a c o m p l e t e e x p l a n a t i o no f t h e b a c k g r o u n d a n d r a t i o n a l f o r t h e s t u d y a s w e l l a s p r o c e -dures t o b e u s e d . C a n d i d a t e s w e r e i n t e r v i e w e d a s a g r o u p a n di n d i v i d u a l l y . A t i n d i v i d u a l i n t e r v i e w s i t was a s c e r t a i n e d t h ec a n d i d a t e u n d e r s t o o d t h e s t u d y a n d p e r s o n a l r i s k f a c t o r s .Q u a l i f i e d c a n d i d a t e s w e r e a s k e d t o r e a d a n d p e r m i t t e d t o s i g nthe c o n s e n t s t a t e m e n t .

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Washington, D.C. 20010

Exp. 2 : S t u d y Summary ( C o n t . )R i s i n g S i n g l e Dose L e v e l s

Human Use C o m m i t t e e :

Th is f r e e s t a n d i n g c o m m i t t e e composed o f c o m m u n i t y members a n do f s i m i l a r a g e a n d o c c u p a t i o n t o t h e human s u b j e c t g r o u p m u s tg i ve a p p r o v a l f o r e a c h s t u d y p r i o r t o i m p l e m e n t a t i o n . A mem-be r o f t h e human u s e c o m m i t t e e p a r t i c i p a t e d i n t h e c o n s e n ti n t e r v i e w s a n d made f r e q u e n t v i s i t s t o t h e r e s e a r c h u n i t t om o n i t o r t h e s t u d y a n d a s s u r e t h e s u b j e c t s ' h e a l t h a n d w e l f a r ewere g i v e n p r i m a r y c o n s i d e r a t i o n . E a c h s u b j e c t c l e a r l y u n d e r -s tood t h a t h e c o u l d t e r m i n a t e h i s p a r t i c i p a t i o n i n t h e s t u d ya t a n y t i m e .

HOUSING:

Sub jec t s w e r e h o u s e d o n t h e c l i n i c a l r e s e a r c h u n i t o f t h eWash ing ton H o s p i t a l C e n t e r , u t i l i z i n g s e m i - p r i v a t e rooms w i t hmodern f a c i l i t i e s . A l o u n g e a r e a was a v a i l a b l e w h i c h c o n t a i n e dt e l e v i s i o n , r e a d i n g m a t e r i a l s , games , c h a i r s , a n d d e s k s . S u b -j e c t s , s u p e r v i s e d b y t h e i n v e s t i g a t i n g t e a m , w e r e a l l o w e d t ouse t h e t e n n i s c o u r t s , s w i m m i n g p o o l a n d r e c r e a t i o n a l f a c i l i t i e so f t h e Wa s h i n g t o n H o s p i t a l C e n t e r . A c h o i c e o f m e a l s was madea v a i l a b l e t o e a c h o f t h e s u b j e c t s b y t h e F o o d S e r v i c e D e p a r t m e n ta t t h e Wa s h i n g t o n H o s p i t a l C e n t e r . E a c h s u b j e c t u n d e r w e n ts e r i a l p h y s i c a l e x a m i n a t i o n s i n t h e u n i t e x a m i n i n g r o o m a n ds p e c i a l t e s t s w e r e p e r f o r m e d i n s p e c i a l t y a r e a s w i t h i n t h eh o s p i t a l .

METHODS:

Drug a d m i n i s t r a t i o n :Drug l o t s u s e d , d o s i n g s c h e d u l e s , n u m b e r o f s u b j e c t s i n e a c hs tudy p e r i o d a n d i n c r e m e n t a l i n c r e a s e s i n d o s e s a r e o n f i l e .16 s u b j e c t s r e c e i v e d d r u g a n d 1 3 p l a c e b o .C l i n i c a l a n d l a b o r a t o r y e v a l u a t i o n s :S e r i a l c o m p r e h e n s i v e m e d i c a l e v a l u a t i o n i n c l u d i n g p h y s i c a l , b i o -chemica l , h e m a t o l o g i c a n d p h o t o t o x i c i t y t e s t i n g was p e r f o r m e d o na l l s u b j e c t s . S p e c i a l t e s t s w e r e p e r f o r m e d i n s e l e c t e d g r o u p sa t 1000 t o 1 4 0 0 mgm d o s e l e v e l s a s f o l l o w s : o r t h o s t a t i c t o l e r -ance, a u d i o m e t r y a n d e l e c t r o n y s t a g m o g r a p h y. A t t h e 1400 mgm dosed e t a i l e d o p h t h a l m o l o g i c e x a m i n a t i o n s w e r e p e r f o r m e d b e f o r e a n da f t e r d o s i n g .

RESULTS:

Symptoms a n d p h y s i c a l f i n d i n g s :The o n s e t , d u r a t i o n a n d d e s c r i p t i o n o f symptoms a n d p h y s i c a lf i n d i n g s o n a l l s u b j e c t s a r e o n f i l e . N o symptoms o r f i n d i n g ss u g g e s t i v e o f i n t o l e r a n c e t o WR 184,806-H3PO4 w e r e o b s e r v e d b e -low t h e 1000 mgm d o s e . T w o o f t h e 4 s u b j e c t s r e c e i v i n g 1000 mgmhad t r a n s i e n t symptoms s u b s e q u e n t l y a t t r i b u t e d t o d o s i n g : o n ewas l i g h t h e a d e d f o r o n e m i n u t e a n d t h e o t h e r c o m p l a i n e d o ftempora ry m i l d l i g h t h e a d e d n e s s a n d nausea . T h e f o u r s u b j e c t sr e c e i v i n g 1 2 0 0 mgm a n d t h e t w o r e c e i v i n g 1400 mgm a l l h a d symptom

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p a t t e r n s s u g g e s t i v e o f i n t o l e r a n c e i n c l u d i n g c o m b i n a t i o n s o fl i g h t h e a d e d n e s s w i t h a s s o c i a t e d d i f f i c u l t i e s c o n c e n t r a t i n gand f o c u s i n g , h e a d a c h e , n a u s e a , i n s o m n i a a n d u n u s u a l d r e a m s .I n a l l s u b j e c t s t h e symptoms w e r e m i l d a n d o f l e s s t h a n t w e n t y -f o u r h o u r s d u r a t i o n .

P h y s i c a l e x a m i n a t i o n s :Two a b n o r m a l i t i e s w e r e n o t e d i n i t i a l l y a f t e r d o s i n g . O n es u b j e c t h a d a p o i s o n o a k r a s h w h i c h was n o t c o n s i d e r e d d r u gr e l a t e d . T h e o t h e r s u b j e c t h a d a t e m p o r a r y d e c r e a s e i na m p l i t u d e o f accommodat ion w h i c h was p o s s i b l y b u t n o t p r o b a b l ydrug r e l a t e d .

L a b o r a t o r y t e s t s :There w e r e n o s i g n i f i c a n t a l t e r a t i o n s i n t h e s e t e s t s a t t r i b u t e dto d r u g i n g e s t i o n .U r i n a l y s e s - T h e r e w e r e n o s i g n i f i c a n t a l t e r a t i o n s i n u r i n ep r o t e i n o r changes i n u r i n a r y s e d i m e n t a t t r i b u t e d t o d r u gi n g e s t i o n .E l e c t r o c a r d i o g r a p h y a n d p h o t o t o x i c i t y t e s t i n g - N o e l e c t r o -c a r d i o g r a p h i c changes a t t r i b u t a b l e t o d r u g i n g e s t i o n w e r eobserved . P h o t o t o x i c i t y was n o t p r o d u c e d u n d e r c o n d i t i o n so f t h e s t u d y .

S p e c i a l t e s t s :O r t h o s t a t i c To l e r a n c e :

Tes ts f o r o r t h o s t a t i c t o l e r a n c e w e r e p e r f o r m e d o n 1 0 s u b j e c t s .Only o n e s u b j e c t d e m o n s t r a t e d o r t h o s t a t i c i n t o l e r a n c e f o l l o w -i n g o r a l a d m i n i s t r a t i o n o f 1000 mgm o f t h e d r u g . T h i s s u b j e c td i d n o t h a v e symptoms. I t was c o n c l u d e d t h a t n o n - r o t a t i o n a lv e r t i g o f o l l o w i n g a d m i n i s t r a t i o n o f WR 184,806.H3PO4 i n t h i ss t u d y was n o t a s s o c i a t e d w i t h o r t h o s t a t i c i n t o l e r a n c e .

Aud iomet ry a n d E l e c t r o n y s t a g m o g r a p h y ( E N G ) :One s u b j e c t who i n g e s t e d 1000 mgm o f t h e d r u g h a d a m i l d u n i -l a t e r a l s e n s o r i n e u r a l h e a r i n g l o s s . A l l o t h e r s u b j e c t s h a dnormal a u d i o g r a m s .ENG a n a l y s i s r e v e a l e d a n o r m a l l y f u n c t i o n i n g v e s t i b u l a r mecha-n ism f o r e a c h s u b j e c t w i t h t h e f o l l o w i n g t h r e e e x c e p t i o n s : S u b -j e c t No . 3 9 r e v e a l e d a p o s i t i o n a l nys tagmus p r o b a b l y r e l a t e d t ov e s t i b u l o g e n i c d r u g e x p o s u r e i m m e d i a t e l y p r i o r t o s t u d y ; r e p e a tENG 4 weeks l a t e r was n o r m a l . S u b j e c t N o . 3 3 h a d a 2 2 p e r c e n tdecrease i n l e f t v e s t i b u l a r r e s p o n s e s u g g e s t i v e o f p e r i p h e r a lp a t h o l o g y. E N G was n o r m a l when r e p e a t e d . T h e d e c r e a s e d v e s -t i b u l a r r e s p o n s e was n o t c o n s i d e r e d d r u g r e l a t e d s i n c e i t wasu n i l a t e r a l . F i n a l l y , s u b j e c t number 101id v o m i t e d f o l l o w i n gc o l d w a t e r i r r i g a t i o n ; h i s ENG was n o r m a l . T h e r e was n o e v i -dence u n d e r c o n d i t i o n s o f t h e s t u d y t h a t WR 184,806-H3PO4a f f e c t e d t h e v e s t i b u l a r mechanism.

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O p h t h a l m o l o g i c e v a l u a t i o n :

Tes t s w e r e p e r f o r m e d o n s u b j e c t s r e c e i v i n g 1 4 0 0 mgm o f WR184,806.H3PO4. S u b j e c t Number 10Ba c o m p l a i n e d o f b l u r r e dv i s i o n when r e a d i n g . T h e o n l y a b n o r m a l i t y was a d e c r e a s ei n t h e a m p l i t u d e o f accommodat ion . T h i s p e r s i s t e d f o r t w odays a n d r e t u r n e d t o n o r m a l w i t h i n a week . T h e p r e s e n c e o fa s m a l l r e f r a c t i v e a s t i g m a t i s m t e n d e d t o e x a g g e r a t e h i ssymptomato logy. T h e t e m p o r a r y change i n accommodat i ve r e -serve was p o s s i b l y d r u g r e l a t e d .

CONCLUSION:

I t was c o n c l u d e d t h a t i n t o l e r a n c e t o s i n g l e d o s e a d m i n i s t r a t i o no f WR 184,806.H3PO4 was m a n i f e s t e d b y l i g h t h e a d e d n e s s a n da s s o c i a t e d symptoms w i t h o u t d e t e c t e d o b j e c t i v e c h a n g e . I n -t o l e r a n c e was m a r g i n a l a t t h e 1000 mgm a n d d e f i n i t e a t t h e1200 mgm d o s e l e v e l . S y m p t o m a t o l o g y was m i l d t o m o d e r a t e ,most n o t i c e a b l e a t 1400 mgm, a n d o f l e s s t h a n t w e n t y - f o u rhours d u r a t i o n i n a l l s u b j e c t s .

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3. S h o r t Te r m S a f e t y a n d To l e r a n c e , WR 184,806-H3PO4: ( C o n t . )

F o l l o w i n g c o m p l e t i o n o f t h e s i n g l e o r a l d o s e s t u d y , am u l t i p l e o r a l d o s e s t u d y was i n i t i a t e d . A d o u b l e - b l i n d ,r i s i n g d o s e l e v e l was u s e d w i t h d r u g o r p l a c e b o a d m i n i s -t e r e d e v e r y e i g h t h o u r s f o r n i n e d o s e s . S y m p t o m s o fl i g h t - h e a d e d n e s s a n d t r e m u l o u s n e s s , m i l d a n d t e m p o r a r yo c c u r r e d a f t e r t h e s i x t h a d m i n i s t r a t i o n o f t h e 4 0 0 mgdose o f d r u g i n b o t h s u b j e c t s r e c e i v i n g a t o t a l d o s e o f3600 mg. T h e s t u d y was c o m p l e t e d O c t o b e r 1 9 7 5 . T h eStudy Summary i s p r e s e n t e d i n t h e f o l l o w i n g p a g e s :

14

— m S U B J E C T S :

— M E D9 —r i c o

INTRODUCTION:

EXPERIMENT NO. 2 : W R 184,806.H3PO4SHORT TERM DOSAGE SAFETY AND TOLERANCE

MULTIPLE DOSE LEVELS

STUDY SUMMARY

Tel: (202) 8 8 2-0 9 7 7

I n s i n g l e d o s e s t u d i e s p r e v i o u s l y r e p o r t e d , n o i n t o l e r a n c e•to WR 184,806.H3PO4 was o b s e r v e d b e l o w t h e 1 0 0 0 mg d o s el e v e l . A t h i g h e r d o s e l e v e l s , l i g h t h e a d e d n e s s w i t h a s s o c i -a ted d i f f i c u l t i e s c o n c e n t r a t i n g a n d f o c u s i n g , h e a d a c h e ,nausea a n d s l e e p d i s t u r b a n c e s o c c u r r e d . T h e r e w e r e n oa s s o c i a t e d o b j e c t i v e f i n d i n g s a n d t h e symptoms w e r e o f l e s sthan t w e n t y - f o u r h o u r s d u r a t i o n . T h i s s t u d y was p e r f o r m e d

2 t o d e t e r m i n e t h e s h o r t t e r m s a f e t y a n d t o l e r a n c e o f WRm m 1 8 4 , 8 0 6 . H 3 P O 4 a d m i n i s t e r e d o r a l l y i n m u l t i p l e d o s e s . Ac— — t o t a l o f e i g h t s t u d y l e v e l s w e r e u s e d t o a d m i n i s t e r d r u g o rN

p lacebo t o 2 9 s u b j e c t s .0 2?..-

• ' .- T h e s u b j e c t s w e r e r e c r u i t e d f r o m t h e Wa s h i n g t o n , D . C .m e t r o p o l i t a n a r e a a n d w e r e h i r e d a s t e m p o r a r y emp loyees .=

ig A d v e r t i s e m e n t s i n u n i v e r s i t y newspapers p r o v i d e d i n i t i a l' f Em c o n t a c t s w i t h p o t e n t i a l s u b j e c t s . T h i s m e t h o d p l u s p o s i t i v e

:-I5 0 recommendations by participating subjects to their class-

5m m a t e s e n l a r g e d t h e c a n d i d a t e p o o l . A p p r o x i m a t e l y 807 o f t h e_c0 • s u b j e c t s w e r e u n i v e r s i t y s t u d e n t s w i t h s u p e r i o r m o t i v a t i o n ,m u n d e r s t a n d i n g a n d c o m p l i a n c e .oom S c r e e n i n g :c •;:--m 0E —›.. - C a n d i d a t e s f o r emp loymen t u n d e r w e n t q u a l i f y i n g e x a m i n a t i o n sm >m t o o b t a i n t h e s u b j e c t s f o r s t u d y . T h e i n i t i a l e v a l u a t i o no _1m i n c l u d e d a c o m p l e t e h i s t o r y a n d p h y s i c a l e x a m i n a t i o n , c h e s t, m0 m x - r a y , e l e c t r o c a r d i o g r a m a n d t h e f o l l o w i n g t e s t s : u r i n a l y s i s ,o c. ,J0 — w h i t e b l o o d c e l l a n d d i f f e r e n t i a l c o u n t , r e d b l o o d c e l l c o u n t ,

hemog lob in , h e m a t o c r i t , MCV, MCH, MCHC, p l a t e l e t c o u n t , g l u -.5- ..

cose, BUN, c r e a t i n i n e , N a + , K + , C l-, C O 2 , u r i c a c i d , t o t a l

= .-Es E protein, albumin, globulin, calcium, phosphate, cholesterol,

t r i g l y c e r i d e s , a l k a l i n e p h o s p h a t a s e , SGOT, SGPT, L D H , t o t a lm - 0

.c < b i l i r u b i n a n d G6PD. L a b o r a t o r y t e s t s w e r e p e r f o r m e d i n d u p -l i c a t e b y N a t i o n a l H e a l t h L a b o r a t o r i e s , I n c . u s i n g s t a n d a r d

"o =o m. — m e t h o d s . C h e s t x - r a y s w e r e p e r f o r m e d i n t h e D e p a r t m e n t o fm R a d i o l o g y a t t h e Wa s h i n g t o n H o s p i t a l C e n t e r . E l e c t r o c a r d i o -

grams w e r e p e r f o r m e d b y t r a i n e d p e r s o n n e l u s i n g a Cambr idge

15

Washington, D.C. 20010

Exp. 2 : S t u d y Summary ( C o n t . )M u l t i p l e Dose L e v e l s

VS-4 p o r t a b l e e l e c t r o c a r d i o g r a p h i c m a c h i n e . U r i n a l y s e swere p e r f o / m e d b y p h y s i c i a n i n v e s t i g a t o r s i n t h e r e s e a r c hu n i t l a b o r a t o r y u s i n g s t a n d a r d me thods .

I n f o rmed C o n s e n t :

Q u a l i f i e d c a n d i d a t e s w e r e p r e s e n t e d w i t h a c o m p l e t e e x p l a n a -t i o n o f t h e b a c k g r o u n d a n d r a t i o n a l e f o r t h e s t u d y a s w e l las p r o c e d u r e s t o b e u s e d . C a n d i d a t e s w e r e i n t e r v i e w e d i n agroup a n d i n d i v i d u a l l y . A t i n d i v i d u a l i n t e r v i e w s i t was a s -c e r t a i n e d t h a t t h e c a n d i d a t e u n d e r s t o o d t h e s t u d y a n d p e r s o n a lr i s k f a c t o r s . Q u a l i f i e d c a n d i d a t e s w e r e a s k e d t o r e a d a n dp e r m i t t e d t o s i g n t h e c o n s e n t s t a t e m e n t .

Human Use C o m m i t t e e :

Th is f r e e s t a n d i n g c o m m i t t e e composed o f commun i t y membersand o f s i m i l a r a g e a n d o c c u p a t i o n t o t h e human s u b j e c t g r o u pmust g i v e a p p r o v a l f o r e a c h s t u d y p r i o r t o i m p l e m e n t a t i o n .A member o f t h e Human Use C o m m i t t e e p a r t i c i p a t e d i n t h e c o n -sen t i n t e r v i e w s a n d made f r e q u e n t v i s i t s t o t h e r e s e a r c h u n i tt o m o n i t o r t h e s t u d y a n d a s s u r e t h e s u b j e c t s ' h e a l t h a n dw e l f a r e w e r e g i v e n p r i m a r y c o n s i d e r a t i o n . E a c h s u b j e c tc l e a r l y u n d e r s t o o d t h a t h e c o u l d t e r m i n a t e h i s p a r t i c i p a t i o ni n t h e s t u d y a t a n y t i m e .

HOUSING:

S u b j e c t s w e r e h o u s e d o n t h e C l i n i c a l R e s e a r c h U n i t o f t h eWash ing ton H o s p i t a l C e n t e r , u t i l i z i n g s e m i - p r i v a t e roomsw i t h modern f a c i l i t i e s . A l o u n g e a r e a was a v a i l a b l e w h i c hc o n t a i n e d t e l e v i s i o n , r e a d i n g m a t e r i a l s , g a m e s , c h a i r s a n ddesks. S u b j e c t s , s u p e r v i s e d b y t h e i n v e s t i g a t i n g t e a m , w e r ea l l o w e d t o u s e t h e t e n n i s c o u r t s , s w i m m i n g p o o l a n d r e c r e a -t i o n a l f a c i l t i t e s a t t h e Wa s h i g n t o n H o s p i t a l C e n t e r . A c h o i c eo f mea l s was made a v a i l a b l e t o e a c h o f t h e s u b j e c t s b y t h eFood S e r v i c e D e p a r t m e n t a t t h e Wa s h i n g t o n H o s p i t a l C e n t e r .Each s u b j e c t u n d e r w e n t s e r i a l p h y s i c a l e x a m i n a t i o n s i n t h eu n i t e x a m i n g r o o m a n d s p e c i a l t y a r e a s w i t h i n t h e h o s p i t a l .

METHODS:

The d o s i n g s c h e d u l e a n d number o f s u b j e c t s i n e a c h s t u d y p e r i o dare o n f i l e . S i x t e e n s u b j e c t s r e c e i v e d d r u g a n d 1 3 p l a c e b o .

C l i n i c a l a n d l a b o r a t o r y e v a l u a t i o n s :

S e r i a l c o m p r e h e n s i v e m e d i c a l e v a l u a t i o n i n c l u d i n g p h y s i c a l , b i o -chem ica l , h e m a t o l o g i c a n d p h o t o t o x i c i t y t e s t i n g was p e r f o r m e don a l l s u b j e c t s .

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RESULTS:

Symptoms a n d p h y s i c a l f i n d i n g s :

The o n s e t , d u r a t i o n a n d d e s c r i p t i o n o f symptoms a n d p h y s i c a lf i n d i n g s o n a l l s u b j e c t s a r e o n f i l e . M i l d symptoms o f t r a n -s i e n t d i a r r h e a , c o n s t i p a t i o n , l e t h a r g y , f l u s h i n g a n d d i s t u r b -i n g d reams o c c u r r e d i n b o t h c o n t r o l a n d s u b j e c t s r e c e i v i n gdrug. T w o s u b j e c t s , r e c e i v i n g 3600 mg d r u g ( 1 2 0 0 mg d a i l yf o r 3 d a y s ) c o m p l a i n e d o f v a g u e t r e m u l o u s n e s s a n d l i g h t h e a d e d -ness s i m i l a r t o t h a t o b s e r v e d when 1 2 0 0 - 1 4 0 0 mgs o f WR184,806.H3PO4 w e r e a d m i n i s t e r e d a s a s i n g l e d o s e i n a p r e v i o u ss t u d y. T w o o t h e r s u b j e c t s r e c e i v i n g 6 0 0 a n d 7 5 0 mg o f d r u gd a i l y e x p e r i e n c e d s l e e p d i s t u r b a n c e s . I n a l l s u b j e c t s t h eabove n o t e d symptoms w e r e m i l d , t e m p o r a r y a n d w i t h o u t a s s o c i -a ted p h y s i c a l o r l a b o r a t o r y a b n o r m a l i t i e s .

P h y s i c a l E x a m i n a t i o n :

One s u b j e c t r e c e i v i n g 3000 mg d r u g d e v e l o p e d a m a c u l o p a p u l a rrash 1 0 d a y s a f t e r c o m p l e t i o n o f d r u g a d m i n i s t r a t i o n w h i c hwas a l s o a s s o c i a t e d w i t h t h e s u b j e c t ' s u s e o f a c o m m e r c i a lsoap f o r t h e f i r s t t i m e . T h e r a s h d i s a p p e a r e d upon d i s c o n t i n -u a t i o n o f u s e o f t h e s o a p a n d was c o n s i d e r e d a s o a p p r e c i p i t a t e dc o n t a c t d e r m a t i t i s b y t h e c o n s u l t i n g d e r m a t o l o g i s t .M i l d s u n b u r n i n 2 s u b j e c t s a n d swimming p o o l c h e m i c a l c o n -j u n c t i v i t i s i n o n e s u b j e c t w e r e n o t c o n s i d e r e d d r u g r e l a t e d .

L a b o r a t o r y t e s t s :

E i g h t y - t h r e e p e r c e n t o f t h e s u b j e c t s h a d a t l e a s t o n e hema-t o l o g i c o r b i o c h e m i c a l a b n o r m a l i t y . A b n o r m a l i t i e s w e r e d i s -t r i b u t e d w i t h e q u a l f r e q u e n c y amongs t s u b j e c t s a d m i n i s t e r e ddrug a n d p l a c e b o . N o d e v i a t i o n s w e r e a s c r i b e d t o d r u gi n g e s t i o n .Ten s u b j e c t s h a d a b n o r m a l u r i n a l y s e s , 6 o f t h e s e r e c e i v e d d r u g .G l y c o s u r i a ( 1 + ) w i t h a n o r m a l b l o o d s u g a r was d e t e c t e d o ndays 2 a n d 4 i n o n e s u b j e c t r e c e i v i n g 9 0 0 mg o f d r u g . I n t e r -m i t t e n t t r a c e p r o t e i n u r i a was d e t e c t e d i n o n e s u b j e c t r e c e i v i n gdrug a s w e l l a s o n e who r e c e i v e d p l a c e b o . I n c r e a s e d numberso f r e d a n d w h i t e c e l l s i n t h e u r i n a r y s e d i m e n t i n c o n t r o l a n ddrug a d m i n i s t e r e d s u b j e c t s d e m o n s t r a t e d n o p a t t e r n a n d a r e n o tc o n s i d e r e d s t u d y r e l a t e d . N o s u b j e c t h a d c y l i n d r u r i a . N oe l e c t r o c a r d i o g r a p h i c changes a t t r i b u t a b l e t o d r u g i n g e s t i o nwere o b s e r v e d . P h o t o t o x i c i t y was n o t p r o d u c e d u n d e r c o n d i t i o n so f t h i s s t u d y .

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CONCLUSION:

P o s s i b l e i n t o l e r a n c e t o m u l t i p l e doses o f WR 184,806.H3PO4was d e t e c t e d . S o m e s u b j e c t s r e c e i v i n g d r u g , a s w e l l a sc o n t r o l s , e x p e r i e n c e d f l u s h i n g , v i v i d dreams a n d o t h e r symp-toms c o n s i d e r e d p o t e n t i a l l y d r u g r e l a t e d i n t h e p r e v i o u ss i n g l e d o s e s t u d y . T r e m u l o u s n e s s a n d l i g h t h e a d e d n e s so c c u r r e d o n t h e l a s t d a y o f d o s i n g i n t w o s u b j e c t s r e c e i v -i n g 3 6 0 0 mg t o t a l d o s e . T h e l a t e o n s e t o f t h e s e symptomsand s i m i l a r i t y t o symptoms o f i n t o l e r a n c e a t 1200 a n d 1400mg s i n g l e d o s e l e v e l s s u g g e s t s t h e y may b e d r u g r e l a t e d .G a s t r o i n t e s t i n a l symptoms o c c u r r e d i n t h e c o n t r o l s u b j e c t sas w e l l a s t h o s e r e c e i v i n g d r u g . I n t h e l a t t e r , t h e symptomsd i d n o t p e r s i s t o r i n c r e a s e i n s e v e r i t y w i t h c o n t i n u e d d r u ga d m i n i s t r a t i o n . N o p h y s i c a l o r l a b o r a t o r y a b n o r m a l i t i e swere a s c r i b e d t o d r u g i n g e s t i o n .

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4. T o p To l e r a t e d S i n g l e O r a l D o s e M e f l o q u i n e :Th is p r o t o c o l h a s b e e n p r o c e s s e d a n d a p p r o v e d f o r i m p l e -m e n t a t i o n . S c h e d u l e d t o i n i t i a t e s t u d y F e b r u a r y 1 9 7 6 .

5. M e f l o q u i n e :S a f e t y a n d t o l e r a n c e s i n g l e o r a l d o s e r e p e a t e d 7 d a y s a f t e rf i r s t a d m i n i s t r a t i o n . T h i s d o u b l e - b l i n d e d , r i s i n g d o s el e v e l s t u d y was i n i t i a t e d December 9 , 1 9 7 5 . A n y r e p o r t a tt h i s t i m e w o u l d b e p r e m a t u r e .

CONCLUSIONS:

The a c c o m p l i s h m e n t s o f t h e f i r s t c o n t r a c t y e a r may b e e n u m e r a t e das f o l l o w s :

1. T h e O r g a n i z a t i o n a l R e v i e w C o m m i t t e e a n d t h e Human U s e Commi t -tee a r e p e r f o r m i n g i n a s u p e r i o r m a n n e r. T h e Human UseCommittee members , b y p r o v i d i n g c o n t i n u o u s m o n i t o r i n g d u r i n gs t u d i e s , h a s p e r f o r m e d a s i g n i f i c a n t s e r v i c e i n t h e a r e a s o fs u b j e c t p r o t e c t i o n , u n d e r s t a n d i n g , a n d c o m p l i a n c e . T h eWash ing ton H o s p i t a l C e n t e r p a r t i c i p a t i o n h a s b e e n p r o d u c t i v eand n o t o b s t r u c t i v e . T h e c l o s e l i a i s o n w i t h t h e W a l t e r Reeds c i e n t i s t s i n c r e a s e s e f f i c i e n c y a n d p r o d u c t i v i t y .

2. T h e 5 2 - w e e k m e f l o q u i n e s t u d y i s w e l l u n d e r w a y. T h e c a r e f u ls e l e c t i o n o f s u b j e c t s a n d s u b j e c t management d u r i n g t h es t u d y s h o u l d a s s u r e a l o w d r o p o u t r a t e .

3. W R 1 8 4 , 8 0 6 . H 3PO4 i s a p r o m i s i n g compound b o t h b e c a u s e o f a na c c e p t a b l e t o p t o l e r a t e d d o s e a n d i n t o l e r a n c e m a n i f e s t e d b yt e m p o r a r y, n o n - i n c a p a c i t a t i n g symptoms w i t h o u t a s s o c i a t e dc l i n i c a l a b n o L m a l i t i e s .

4. T h e a p p l i c a t i o n o f m e f l o q u i n e i n Phase I I c l i n i c a l t r i a l st h r e a t e n e d t o o u t s t r i p n e e d e d Phase I t e s t i n g . T h i s t h r e a ti s b e i n g e l i m i n a t e d b y t h e P h a s e I t e s t i n g b e i n g p e r f o r m e dt h r o u g h t h i s c o n t r a c t .

19

4 c o p i e s

12 c o p i e s

1 c o p y

1 c o p y

DISTRIBUTION L I S T

HODA (SORD-RP)WASH DC 2 0 3 1 4

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