ADA04/1243

One Source. O n e Search. One Solution.

PHASE I CLINICAL TESTING. ANTIMALARIAL

DRUGS

BIO-MED INC WASHINGTON DC

MAR 1976

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U.S. Department of Commerce

National Technical Information Service

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REPORT NUMBER 1
Phase I C l i n i c a l T e s t i n g
A n t i m a l a r i a l Drugs
Annual R e p o r t

Richard C. Reba, M.D.

Date

A u g u s t 1977

Supported b y
U.S. ARMY
Wa s h i n g t o n , D . C . 2 0 3 1 4
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AD

REPORT NUMBER 1

Phase I C l i n i c a l T e s t i n g
A n t i m a l a r i a l Drugs
Annual R e p o r t

Richard C. Reba, M.D.

Date

A u g u s t 1977

by

U . S . ARMY MEDICAL RESEARCH AND DEVELOPMENT 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 ;
distribution unlimited

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 n
o f f i c i a l Department o f t h e Army p o s i t i o n unless s o designated
by o t h e r a u t h o r i z e d documents.

SUMMARY

BIO-MED, I n c . i n i t i a t e d 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
drugs 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 f
t h e 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 g
was p e r f o L w e d a t t h e W a s h i n g t o n H o s p i t a l C e n t e r i n W a 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 d
tolerance s t u d y o f mefloquine was s t a r t e d i n September 1975. T h e
study 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 o
to 5 0 h e a l t h y s u b j e c t s f o r a 52-week d u r a t i o n . N o a d v e r s e
reactions h a v e been 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 months a n d
compliance 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 out 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 r
mefloquine u s e d as 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 1 8 4 , 8 0 6 - H 3 P O 4 h a s b e e n a d m i n i s t e r e d
to 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 .
Single and m u l t i p l e o r a l doses were t e s t e d u s i n g d o u b l e - b l i n d
r i s i n g dose l e v e l s . S i n g l e o r a l doses were w e l l t o l e r a t e d up t o
the 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 mg
of drug as a s i n g l e o r a l dose had combinations o f light-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
focusing, headache, nausea, i n s o m n i a , a n d unusual dreams. 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 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 dose s t u d i e s c o n s i s t e d o f 9 doses o f drug o r
placebo a d m i n i s t e r e d e v e r y 8 hours f o r a t o t a l o f 72 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 400 mg i n d i v i d u a l o r 3600 mg t o t a l
dose l e v e l w i t h s y m p t o m s 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 e
administration. N o physical o r laboratory abnormalities were
a 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 1 8 4 , 8 0 6 . H 3 P O 4 .
S i n g l e o r a l doses 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 been
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 and
tolerance 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 dose 7 days a f t e r t h e
1st dose 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 has been
designed, p r o c e s s e d , a n d approved 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 e
the 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 l
should be implemented 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 d
to 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 1 8 4 , 8 0 6 H 3 P O 4 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 s
which 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 s
manifested b y temporary n o n - i n c a p a c i t a t i n g symptomatology w i t h o u t
associated physical o r l a b o r a t o r y abnormalities a t t r i b u t e d t o t h e
drug.

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 was p e r f o r m e d a t t h e Washington H o s p i t a l C e n t e r.

A l l protocols were processed by t h e c o n t r a c t o r ' s Organizational
Review a n d Human S u b j e c t ( H u m a n 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 Washington H o s p i t a l C e n t e r Research Committee.
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 approved b y t h e Washington
H 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 Washington
Hospital Center i s approved f o r performance o f c l i n i c a l research
by 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 W
Assurance No. GO 1 8 0 )

TABLE OF CONTENTS
TITLE

T i t l e Page

Report Documentation (DD 1473)

Summary

Foreward

Objectives

Methods a n d R e s u l t s

S t u d y Summary
1
0
Experiment N o . 2 : W R 184,806.H3PO4
S h o r t Te r m D o s a g e , S a f e t y a n d To l e r a n c e
R i s i n g S i n g l e Dose L e v e l s
Study Summary
Experiment No. 2 : W R 184,806-H3PO4
S h o r t Te r m D o s a g e , S a f e t y a n d To l e r a n c e
M u l t i p l e Dose L e v e l s
Conclusions
Distribution List

9
2

15

OBJECTIVES

General: T o i n i t i a t e Phase 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 l
drugs a t t h e W a 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 y
p 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 f
participating subjects.
Specific:
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 e
Wa s h i n g t o n 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 l
research w i l l a l s o b e used.
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 quine, a q u i n o l i n e methanol w i t h demonstrated 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.
malaria. T h e s t u d y includes weekly a d m i n i s t r a t i o n o f 500
mg d r u g o r p l a c e b o f o r 5 2 w e e k s 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 f
WR 1 8 4 , 8 0 6 H 3 P O 4 , 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 l
and 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 s
which suggest p o t e n t i a l advantages a s compared w i t h p r e v i ously t e s t e d q u i n o l i n e methanols.
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 dose o f mefloquine 7
days 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 A N D 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 e
including physicians q u a l i f i e d i n research and c l i n i c a l
m e d i c i n e w h o 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.
This 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 g
protocols. T h e committee evaluates p r o t o c o l s f o r s c i e n t i f i c
merit and r i s k t o t h e subject as w e l l as r e f i n i n g methodology a s a p p r o p r i a t e .
Following 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 Review Committee
t h e 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 U s e C o m m i t t e e w h i c h
is comprised o f l a y i n d i v i d u a l s w i t h an i n t e r e s t i n c l i n i c a l
r 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 h u m a n s u b j e c t s . M o s t members
have 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 m a n y a r e g r a d u a t e
students i n l o c a l u n i v e r s i t i e s . T h i s committee i s f r e e
standing, e l e c t s i t s own o f f i c e r s , a n d serves t h e v i t a l
function o f a non-medical committee i n assuring t h e c i v i l

rights o f the subjects are protected. I n addition t o

assuring minimum 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 e
committee 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 tions o f a s c i e n t i f i c n a t u r e which have been adopted.
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 l
i s s u b m i t t e d t o t h e R e s e a r c h Committee o f t h e Washington
Hospital Center and i s processed through the governing
bodies. T h e Washington 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 y
DHEW 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 o
t h e 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 e
Committee 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 g
suggestions t o improve compliance as w e l l a s s u b j e c t
comfort.
Overall, t h e p r o j e c t processing procedure w i t h i t s m u l t i p l e
review a n d a p p r o v a l components h a s p r o v i d e d t h o r o u g h
consideration and b e n e f i t versus r i s k f a c t o r s a n d has n o t
been u n d u l y c u m b e r s o m e .
2. M e f l o q u i n e - - 5 2 We e k S t u d y :
This 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 s
o f 10 s u b j e c t s each 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 and c o n t r o l
subjects. 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 500 mg o r a l
dose 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 t
group 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 e
three groups ( 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 f
the 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 e
motivation must p e r s i s t t o maintain an acceptably low
dropout 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 d
s e r i a l l y. N o changes 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 n
have 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 , W R 1 8 4 , 8 0 6 . 11 ' 11
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 l
3
0 4 : dose, 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 w a s
w e l l t o l e r a t e d u p t o t h e 1000 mg dose 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 1200 t o 1400 mg d r u g manifested combinations
of light-headedness w i t h associated d i f f i c u l t i e s concentrating and focusing, headache, nausea, insomnia, and unusual
dreams. T h e s y m p t o m s 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
duration. N o o t h e r changes a t t r i b u t e d t o d r u g were observed.
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 r
i 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 e
following pages:

BlO- MED, Inc

Tel: (202) 882-0977

EXPERIMENT NO. 2 : W R 1 8 4 , 8 0 6 - H 3 P O 4
SHORT TERM DOSAGE SAFETY AND TOLERANCE
RISING SINGLE DOSE LEVELS
STUDY SUMMARY
INTRODUCTION:
Washn
igo
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The s t u d y w a s 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 d o s a g e
s a f e t y a n d t o l e r a n c e o f WR 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
t o 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 d
to 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:
Recruitment:

Subjects were h e a l t h y males aged 21 t o 45 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 W a 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 e m p l o y e e s .
Screening:
Candidates f o r employment underwent q u a l i f y i n g e x a m i n a t i o n s
to 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 n
included a complete h i s t o r y and physical examination, c h e s t
x - r a y, e l e c t r o c a r d i o g r a m and 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 ,
white blood c e l l and d i f f e r e n t i a l count, r e d blood c e l l count,
h e m o g l o b i n , h e m a t o c r i t , M C V, N C R , 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
-a l b u m i n , 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 , S G O T, S G P T, L D H , t o t a l b i l i r u b i n .
F, C l
Laboratory t e s t s were performed i n d u p l i c a t e b y N a t i o n a l Health
- 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 e
L
, erformed 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 n
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C o s pOi t a l C
2 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 d
H
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ui s i n g a C a m b r i d g e 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 h
u
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.
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r i n a l y s e s were performed by physician i n v e s t i g a t o r s
c
i 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 methods.
a
c
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,
Informed Consent:
t
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l
Qualified candidates were presented w i t h a complete explanation
op f t h e r b a c k go 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 t
et o b e i 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 d
dures
inn 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 e
candidate understood t h e s t u d y and p e r s o n a l r i s k f a c t o r s .
Qualified candidates were asked t o r e a d and permitted t o s i g n
the c o n s e n t s t a t e m e n t .

10

Exp. 2 : S t u d y Summary ( C o n t . )
Rising S i n g l e Dose L e v e l s
Human U s e C o m m i t t e e :
T h i s f r e e s t a n d i n g c o m m i t t e e c o m p o s e d o f c o m m u n i t y members a n d
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 p m u s t
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 memb e 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 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 t t o
monitor t h e s t u d y and assure t h e s u b j e c t s ' h e a l t h and welfare
were 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 stood t h a t he 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 y
at any time.
HOUSING:
Subjects w e r e housed on 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 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 t i l i z i n g s e m i - p r i v a t e r o o m s w 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 h c 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 , games, c h a i r s , a n d desks. S u b jects, s u p e r v i s e d by t h e i n v e s t i g a t i n g team, were allowed t o
use 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 s
o 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 meals was made
a v a i l a b l e t o each o f t h e s u b j e c t s b y t h e Food S e r v i c e Department
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 a c h 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 examinations i n t h e u n i t examining room and
special t e s t s were performed i n s p e c i a l t y areas w i t h i n the
hospital.
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 h
study p e r i o d and i n c r e m e n t a l i n c r e a s e s i n doses 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 .
Clinical and laboratory evaluations:
S e r i a l comprehensive medical 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 chemical, 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 n
a l l s u b j e c t s . S p e c i a l t e s t s were performed i n s e l e c t e d groups
a t 1 0 0 0 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 1 4 0 0 mgm d o s e
detailed ophthalmologic examinations were performed before and
after dosing.
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 s y m p t o m s a n d p h y s i c a l
f 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 s
s 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 1 8 4 , 8 0 6 - H 3 P O 4 w e r e o b s e r v e d b e low t h e 1 0 0 0 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 1 0 0 0 mgm
had t r a n s i e n t s y m p t o m s 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 e
was 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 f
temporary 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 s
r 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 1 4 0 0 mgm a l l h a d s y m p t o m

11

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
patterns suggestive o f intolerance i n c l u d i n g combinations o f
lightheadedness w i t h associated 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
and 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 four hours d u r a t i o n .
Physical examinations:
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 e
s 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 g
related. T h e o t h e r s u b j e c t had a temporary decrease i n
a m p l i t u d e o f a c c o m m o d a t i o n 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 y
drug r e l a t e d .
Laboratory 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 d
to d r u g i n g e s t i o n .
Urinalyses - There were no 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 e
p 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 g
ingestion.
Electrocardiography and p h o t o t o x i c i t y t e s t i n g - No 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 were
observed. 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 s
o f t h e s t u d y.
Special t e s t s :
O r t h o s t a t i c To l e r a n c e :
Te s t s 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 1 0 0 0 mgm o f t h e d r u g . T h i s s u b j e c t
d 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 l
v 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 1 8 4 , 8 0 6 . H 3 P O 4 i n t h i s
study 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 .
Audiometry a n d Electronystagmography (ENG):
One s u b j e c t w h o i n g e s t e d 1 0 0 0 mgm o f t h e d r u g h a d a m i l d u n i lateral sensorineural hearing loss. A l l other subjects had
normal audiograms.
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 m e c h a nism 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 nystagmus p r o b a b l y r e l a t e d t o
vestibulogenic drug exposure immediately p r i o r t o s t u d y ; r e p e a t
ENG 4 w e e k s l a t e r w a s 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 t
decrease 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 l
p a t h o l o g y. E N G w a s n o r m a l w h e n 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 response 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 was
u 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 g
c 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 w a s 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 1 8 4 , 8 0 6 - H 3 P O 4
a f f e c t e d t h e v e s t i b u l a r mechanism.

12

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
Ophthalmologic e v a l u a t i o n :
Te s 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 WR
184,806.H3PO4. S u b j e c t Number 1 0 B a c o m p l a i n e d o f b l u r r e d
v 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 e
i n t h e a m p l i t u d e o f accommodation. T h i s p e r s i s t e d f o r t w o
days 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 w e e k . T h e p r e s e n c e o f
a small r e f r a c t i v e astigmatism tended t o exaggerate h i s
s y m p t o m a t o l o g y. T h e t e m p o r a r y c h a n g e i n a c c o m m o d a t i v e 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 n
o f WR 1 8 4 , 8 0 6 . H 3 P O 4 w a s 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 d
a 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 w a s m a r g i n a l a t t h e 1 0 0 0 mgm a n d d e f i n i t e a t t h e
1200 mgm d o s e l e v e l . S y m p t o m a t o l o g y w a s 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 1 4 0 0 mgm, a n d o f l e s s t h a n t w e n t y - f o u r
hours d u r a t i o n i n a l l s u b j e c t s .

13

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 - H 3 P O 4 : ( C o n t . )
Following completion o f t h e s i n g l e o r a l dose s t u d y, a
m 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 tered every e i g h t hours f o r nine doses. Symptoms o f
light-headedness and tremulousness, m i l d and temporary
o 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 mg
dose 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 f
3600 m g . T h e s t u d y w a s c o m p l e t e d O c t o b e r 1 9 7 5 . T h e
S t u d y 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 E D
9
r i c o

Tel: (202) 8 8 2
0977

EXPERIMENT NO. 2 : W R 1 8 4 , 8 0 6 . H 3 P O 4
SHORT TERM DOSAGE SAFETY AND TOLERANCE
MULTIPLE DOSE LEVELS
STUDY SUMMARY
WashingtonD
,.C
1
0
2
.

INTRODUCTION:

In s i n g l e dose s t u d i e s p r e v i o u s l y reported, n o i n t o l e r a n c e
t o WR 1 8 4 , 8 0 6 . H 3 P O 4 w a s o b s e r v e d b e l o w t h e 1 0 0 0 m g d o s e
level. A t h i g h e r dose l e v e l s , lightheadedness w i t h a s s o c i ated 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 and f o c u s i n g , headache,
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 o
a 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 s
than 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 WR
cm 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 . A

t o t a l o f e i g h t study l e v e l s were used t o administer drug o r

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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 s
were 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 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 methods.
Informed Consent:
Qualified candidates were presented w i t h a complete explanat i o n o f t h e background and r a t i o n a l e f o r t h e s t u d y as w e l l
as 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 a
group 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 w a s a s certained t h a t t h e candidate understood the study and personal
r i s k f a c t o r s . Q u a l i f i e d candidates were asked t o r e a d and
permitted t o s i g n the consent statement.
Human U s e C o m m i t t e e :
T h i s f r e e s t a n d i n g c o m m i t t e e c o m p o s e d o f c o m m u n i t y members
and 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 h u m a n s u b j e c t g r o u p
must 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 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 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 t
to 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 d
welfare were g i v e n primary c o n s i d e r a t i o n . E a c h s u b j e c t
clearly understood t h a t he could terminate h i s p a r t i c i p a t i o n
in the study a t any time.
HOUSING:

Subjects were housed on t h e C l i n i c a l Research U n i t o 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 , u t i l i z i n g s e m i - p r i v a t e r o o m s
w i t h m o d e r n 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
contained 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 , games, c h a i r s a n d
desks. 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
allowed t o use t h e t e n n i s c o u r t s , swimming p o o l and 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 e
o f meals 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 e
Food S e r v i c e D e p a r t m e n t a t t h e W a 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 e
u n i t examing room and s p e c i a l t y areas 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 n u m b e r 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 d
are 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 .
Clinical and laboratory evaluations:
S e r i a l comprehensive medical 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 chemical, 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
on a l l s u b j e c t s .

16

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

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 s y m p t o m s a n d p h y s i c a l
f 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 sient diarrhea, 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 and d i s t u r b i n g dreams 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 g
drug. 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 y
f o r 3 days) complained o f vague tremulousness 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 w h e n 1 2 0 0 - 1 4 0 0 mgs o f WR
184,806.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 s
s 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 m g o f d r u g
daily experienced sleep disturbances. I n a l l subjects t h e
above 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 ated 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 .
Physical Examination:
One s u b j e c t r e c e i v i n g 3 0 0 0 m g 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 r
rash 10 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 which
was 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 l
soap 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 u p o n 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 d
contact d e r m a t i t i s b y t h e consulting dermatologist.
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 one s u b j e c t were n o t considered drug r e l a t e d .
Laboratory 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 hemat 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 amongst s u b j e c t s a d m i n i s t e r e d
drug 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 g
ingestion.
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 n
days 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 m g 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 g
drug 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 numbers
of r e d and white c e l l s i n t h e u r i n a r y sediment i n c o n t r o l and
drug 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 t
considered s t u d y r e l a t e d . N o s u b j e c t had c y l i n d r u r i a . 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
were 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 s
of t h i s s t u d y.

17

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

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 d o s e s o f WR 1 8 4 , 8 0 6 . H 3 P O 4
was 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 s
c 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 symptoms 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 s
s i n g l e dose s t u d y. Tr e m u l o u s n e s s a n d lightheadedness
occurred on t h e l a s t day o f dosing i n two s u b j e c t s r e c e i v i n g 3 6 0 0 m g 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 symptoms
and s i m i l a r i t y t o s y m p t o m s o f i n t o l e r a n c e a t 1 2 0 0 a n d 1 4 0 0
mg 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 m a y 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 s
as 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 s y m p t o m s
did n o t p e r s i s t o r increase i n s e v e r i t y w i t h continued drug
administration. N o physical o r laboratory abnormalities
were a s c r i b e d t o d r u g i n g e s t i o n .

18

4. 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 M e f l o q u i n e :
This 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 approved f o r i m p l e mentation. S c h e d u l e d t o i n i t i a t e s t u d y February 1976.
5. M e f l o q u i n e :
Safety and t o l e r a n c e s i n g l e o r a l dose repeated 7 days a f t e r
f 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 dose
l 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 t
this time would be premature.
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 m a y b e e n u m e r a t e d
as 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 C o m m i t t e e 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 U s e
Committee m e m b e r s , 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 g
studies, has performed a s i g n i f i c a n t service i n t h e areas o f
subject p r o t e c t i o n , understanding, a n d compliance. 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 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 e
and 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 R e e d
scientists increases e f f i c i e n c y and 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 l
s 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 e
study s h o u l d assure 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 c o m p o u n d b o t h b e c a u s e o f a n
acceptable t o p t o l e r a t e d dose and i n t o l e r a n c e manifested 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 s w i t h o u t a s s o c i a t e d
clinical abnoLmalities.
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 P h a s e I I c l i n i c a l t r i a l s
threatened t o o u t s t r i p needed Phase I t e s t i n g . T h i s t h r e a t
is b e i n g e l i m i n a t e d b y t h e Phase I t e s t i n g b e i n g performed
through t h i s c o n t r a c t .

19

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