A Phase I, First-in-Human, Randomized, Double-Blind, Placebo-Controlled Trial of Single and Multiple Ascending Doses of M5717 to Assess the Safety, Tolerability and Pharmacokinetic Profile of Oral Doses, and to Assess the Antimalarial Activity of M5717 Against Plasmodium Falciparum in Healthy Male and Female Adult Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Merck KGaA, Darmstadt, Germany



M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
2/ 1 9 0
L oc al S p o ns or
Cli nic al Tri al Pr ot oc ol Versi o n
1 7
Dece m ber
2 0 1 8 
/ Versi o n 
5 . 0
i ncl u di n g 
A me n d me nt 4
Re pl aces Versi o n
1 4 J u ne 2 0 1 8 / Versi o n 4. 0 i ncl u di n g A me n d me nt 3
T his d oc u me nt is t he pr o pert y of Merc k K G a A, Dar msta dt, Ger ma n y, or o ne of its s u bsi diaries. It 
is i nte n de d f or restricte d use o nl y  an d m a y  not – i n f ull or part – be passe d o n, re pr o d uce d, 
p u blis he d or use d wit h o ut e x press per missi o n of Merc k K G a A, Dar msta dt, Ger ma n y,  or its 
s u bsi diary . C o p yri g ht © 2 0 1 8 b y M erc k KG a A, Dar msta dt, Ger ma n y, or its s u bsi diary . All ri g hts 
reser ve d.
D oc u me nt N o.
O bject N o.
P P D
P P D
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
4/ 1 9 0
5. 2. 1 0
I ncl usi o n of S pecial P o p ulati o ns ................................ ........................6 9
5. 2. 1 1
Rati o nale f or E n d p oi nts ...................................................................... 6 9
5. 3
Selecti o n of Trial P o p ulati o n ..............................................................7 0
5. 3. 1
I ncl usi o n Criteria ................................................................................ 7 0
5. 3. 2
E xcl usi o n Criteria ...............................................................................7 1
5. 4
Criteria f or I nitiati o n of Trial Treat me nt ............................................ 7 3
5. 5
Criteria f or S u bject Wit h dra wal .......................................................... 7 3
5. 5. 1
Wit h dra wal fr o m Trial Treat me nt ...................................................... 7 3
5. 5. 2
Wit h dra wal fr o m t he Trial .................................................................. 7 4
5. 5. 3
Trial St o p pi n g R ules ........................................................................... 7 5
5. 6
Pre mat ure Ter mi nati o n of t he Trial .................................................... 7 5
5. 7
Defi niti o n of E n d of Trial ................................................................... 7 6
6
I n vesti gati o nal Me dici nal Pr o d uct a n d Ot her Dr u gs Use d i n t he 
Trial ..................................................................................................... 7 6
6. 1
Descri pti o n of t he I n vesti gati o nal Me dici nal Pr o d uct ........................ 7 6
6. 2
D osa ge a n d A d mi nistrati o n................................................................ 7 6
6. 3
Assi g n me nt t o Treat me nt Gr o u ps ....................................................... 7 7
6. 4
N o ni n vesti gati o nal Me dici nal Pr o d ucts a n d Malaria I n oc ul u m t o 
be Use d ...............................................................................................7 7
6. 5
C o nc o mita nt Me dicati o ns a n d T hera pies ........................................... 7 8
6. 5. 1
Per mitte d Me dici nes ........................................................................... 7 8
6. 5. 2
Pr o hi bite d Me dici nes .......................................................................... 7 8
6. 5. 3
Ot her I nter ve nti o ns ............................................................................. 7 8
6. 5. 4
S pecial Preca uti o ns ............................................................................. 7 9
6. 5. 5
Ma na ge me nt of S pecific A d verse E ve nts or A d verse Dr u g 
Reacti o ns ............................................................................................. 7 9
6. 6
Pac ka gi n g a n d La beli n g of t he I n vesti gati o nal Me dici nal Pr o d uct 
a n d t he C halle n ge I n oc ul u m ...............................................................7 9
6. 7
Pre parati o n, Ha n dli n g, a n d St ora ge of t he I n vesti gati o nal 
Me dici nal Pr o d uct a n d t he C halle n ge I n oc ul u m
................................ 8 0
6. 8
I n vesti gati o nal Me dici nal Pr o d uct Acc o u nta bilit y ............................. 8 0
6. 9
Assess me nt of I n vesti gati o nal Me dici nal Pr o d uct C o m plia nce ......... 8 1
6. 1 0
Bli n di n g ..............................................................................................8 1
6. 1 1
E mer ge nc y  U n bli n di n g.......................................................................8 2
D oc u me nt N o.
O bject N o.
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
5/ 1 9 0
6. 1 2
Treat me nt of O ver d ose .......................................................................8 2
6. 1 3
Me dical Care of S u bjects after E n d of Trial ....................................... 8 3
7
Trial Pr oce d ures a n d Assess me nts ...................................................... 8 3
7. 1
Sc he d ule of Assess me nts .................................................................... 8 3
7. 1. 1
Scree ni n g E xa mi nati o ns ..................................................................... 8 3
7. 1. 2
Treat me nt Peri o ds ............................................................................... 8 4
7. 1. 3
A m b ula nt Visits .................................................................................. 8 4
7. 1. 4
F oll o w -u p Visits ................................................................................. 8 4
7. 1. 5
P h o ne Calls ......................................................................................... 8 4
7. 1. 6
E n d of Trial/ Earl y Ter mi nati o n Visit ................................................. 8 5
7. 2
De m o gra p hic a n d Ot her Baseli ne C haracteristics .............................. 8 5
7. 3
Efficac y  Assess me nts ......................................................................... 8 5
7. 4
Assess me nt of Safet y .......................................................................... 8 6
7. 4. 1
A d verse E ve nts ................................................................................... 8 6
7. 4. 2
Pre g na nc y  a n d I n Uter o Dr u g E x p os ure............................................. 9 1
7. 4. 3
Cli nical L a b orat or y Assess me nts ....................................................... 9 1
7. 4. 4
Vital Si g ns, P h y sical E xa mi nati o ns, a n d Ot her Assess me nts............. 9 4
7. 5
P har mac o ki netics ................................................................................ 9 7
7. 5. 1
P har mac o ki netic Sa m ples ................................................................... 9 7
7. 5. 2
P har mac o ki netic Calc ulati o ns ............................................................ 9 8
7. 6
P har mac o d y na mics ........................................................................... 1 0 0
7. 8
Ot her Assess me nts ............................................................................ 1 0 2
8
Statistics ............................................................................................ 1 0 2
8. 1
Sa m ple Size ......................................................................................1 0 2
8. 2
Ra n d o mizati o n ..................................................................................1 0 3
8. 3
E n d p oi nts .......................................................................................... 1 0 4
8. 3. 1
Pri mar y  E n d p oi nts............................................................................1 0 4
8. 3. 2
Sec o n dar y  E n d p oi nts........................................................................1 0 5
8. 4
A nal y sis Sets.....................................................................................1 0 6
8. 5
Descri pti o n of Statistical A nal y ses ...................................................1 0 6
D oc u me nt N o.
O bject N o
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
7/ 1 9 0
A p pe n di x VI :
Fitz patric k S ki n T y pe Ass ess me nt ....................................................1 2 6
A p pe n di x VII:
Pac ka ge I nserts of Pri maci n ™ a n d Ria met ® ................................... 1 2 7
A p pe n di x VIII:
Pr ot oc ol A me n d me nts a n d L ist of C ha n ges ..................................... 1 3 3
A me n d me nt 1
( 0 8 J ul y 2 0 1 7, Gl o bal)...................................................................... 1 3 4
A me n d me nt 2
( 1 3 Fe br uar y 2 0 1 8, Gl o bal) ..............................................................1 4 4
A me n d me nt 3
( 1 4 J u ne 2 0 1 8, Gl o bal) ..................................................................... 1 6 2
A me n d me nt 4
( 1 7 Dece m ber 2 0 1 8, Gl o bal) ............................................................ 1 7 7
A p pe n di x I X:
Si g nat ure Pa ges a n d Res p o nsi ble Pers o ns f or t he Trial .................... 1 8 5
Si g nat ure Pa ge – Pr ot oc ol C o -Le a d ( Me dical Res p o nsi ble) ............................................. 1 8 6
Si g nat ure Pa ge – Pr ot oc ol C o -Le a d ................................................................................. 1 8 7
Si g nat ure Pa ge – Pri nci pal I n vesti gat or ........................................................................... 1 8 8
S p o ns or Res p o nsi ble Pers o ns n ot Na me d o n t he C o ver Pa ge ......................................... 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8/ 1 9 0
T a ble of I n-Te xt T a bles
Ta ble 1 
Sc he d ule of Assess me nts: Part A ( Si n gle Asce n di n g D ose).............. 2 5
Ta ble 2
Sc he d ule of Assess me nts: Part B ( O pti o nal; M ulti ple Asce n di n g 
D ose) ................................................................................................... 2 9
Ta ble 3
Sc he d ule of Assess me nts: Part C (I n d uce d Bl o o d Sta ge Malaria 
C halle n ge M o del, Ass u mi n g Si n gle D osi n g) ..................................... 3 3
Ta ble 4
All o we d Ti me Wi n d o ws ..................................................................... 3 8
Ta ble 5
K e y  P ote ntial Ris ks............................................................................. 6 3
Ta ble 6
H u ma n E q ui vale nt D ose a n d Ma xi m u m Rec o m me n de d Starti n g 
D ose .................................................................................................... 6 6
Ta ble 7
E x pecte d Safet y Mar gi ns base d o n A U C of t he Rat ( 2 -wee k G o o d 
La b orat or y  Practice T o xic ol o g y at 1 0 0 m g/ k g) a n d C ma x of t he 
D o g ( Si n gle D ose 5 0 m g/ k g) ..............................................................6 7
Ta ble 8
Cli nical L a b orat or y E val uati o ns......................................................... 9 3
Ta ble 9
Defi niti o n of I n di vi d ual P har mac o ki netic Para meters ....................... 9 9
Ta ble 1 0
Defi niti o n of P har mac o d y na mic Para meters .................................... 1 0 1
Ta ble 1 1
M et h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps i n Part A ........ 1 0 3
Ta ble 1 2
M et h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps i n Part B ........ 1 0 4
Ta ble 1 3
Defi niti o n of Statistical A nal y sis P o p ulati o ns .................................. 1 0 6
T a ble of I n-Te xt Fi g ures
Fi g ure 1
Sc he matic Re prese ntati o n of E u kar y otic Tra nslati o n El o n gati o n 
Fact or 2............................................................................................... 4 1
Fi g ure 2
Sc he mat ic Trial Desi g n – I ndi vi d ual S u bject i n Part A ...................... 4 9
Fi g ure 3
Sc he matic Trial Desi g n C o h orts Part A ..............................................5 1
Fi g ure 4
Sc he matic Trial Desi g n - I ndi vi d ual S u bject i n Part B ....................... 5 3
Fi g ure 5
Ill ustrati o n of Relati o n bet wee n Dr u g C o nce ntrati o n, Parasite mia 
Le vels, Mi ni mal Parasitici dal C o nce ntrati o n
a n d Mi ni mal 
I n hi bit or y C o nce ntrati o n..................................................................... 5 4
Fi g ure 6
Ill ustrati o n of Ti me Sc he d ule f or C halle n ge M o del ........................... 5 6
Fi g ure 7
Sc he matic Trial Desi g n Part C ........................................................... 5 7
Fi g ure 8
Sc he matic Trial Desi g n C o h orts Part C a n d Relati o n t o Part A ......... 5 8
Fi g ure 9
Sc he matic Trial Desi g n C o h orts Part C a n d Relati o n t o Part A a n d 
Part B (if a p plica ble) ........................................................................... 5 9
D oc u me nt N o.
O bject N o.
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
9/ 1 9 0
List of A b bre vi ati o ns
A D M E
A bs or pti o n, distri b uti o n, meta b olis m a n d e xcreti o n
A E(s)
A d verse e ve nt(s)   
A E SI (s)
A d verse e ve nt (s) of s pecial i nterest
A L T
Ala ni ne a mi n otra nsferase
A S T
As partate a mi n otra nsferase
A U C
Area u n der t he bl o o d c o nce ntrati o n -ti me c ur ve
A U C 0-t
A U C fr o m ti me zer o t o t he last sa m pli n g ti me at w hic h t he c o nce ntrati o n 
is at or a b o ve L L O Q
A U C 0-t , o verall
A U C fr o m ti me zer o t o t he last sa m pli n g ti me at w hic h t he c o nce ntrati o n 
is at or a b o ve L L O Q, o ver t he e ntire m ulti ple d osi n g peri o d
A U C 0-t , o verall/ D ose
D ose -n or malize d A U C 0- t, o verall
A U C 0- ∞
A U C fr o m ti me zer o e xtra p olate d t o i nfi nit y
A U C 0- ∞, o verall
A U C fr o m ti me zer o e xtra p olate d t o i nfi nity o ver t he e ntire m ulti ple 
d osi n g peri o d
A U C 0- ∞, o verall/ D ose
D ose -n or malize d A U C 0- ∞, o verall
A U C e xtra %
T he A U C fr o m ti me tlast e xtra p olate d t o i nfi nit y gi ve n as perce nta ge of 
A U C 0- ∞
A U C 0- 2 4 h
A U C fr o m ti me zer o t o 2 4 h o urs
A U C 0- 2 4 h/ D ose
D ose -n or malize d A U C 0- 2 4 h
A U C 0- 1 4 4 h
A U C fr o m ti me zer o t o 1 4 4 h o urs
A U C 0- 1 4 4 h/ D ose
D ose -n or malize d A U C 0- 1 4 4 h
A U C 0- 1 4 4 h, o verall
A U C fr o m ti me zer o t o 1 4 4 h o urs i n Part B, i e, fr o m ti me zer o ( d osi n g 
ti me) o n Da y 1 u ntil 1 4 4 h o urs after t he Da y  1 d ose
A U C 0 - 1 4 4h, o verall/ D ose
D ose -n or malize d A U C 0- 1 4 4 h, o verall
B MI
B o d y mass i n de x
B P
Bl o o d press ure
C a v
A vera ge c o nce ntrati o n o ver t he d osi n g i nter val
CI
C o nfi de nce i nter val
C L /f
T otal b o d y  cleara nce of dr u g fr o m bl o o d f oll o wi n g oral a d mi nistrati o n
D oc u me nt N o
O bject N o.
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 2 / 1 9 0
P Ct ½
T he parasite cleara nce half -life, defi ne d as t he ti me nee de d f or 
parasite mia t o be re d uce d b y  half d uri n g t he l o g-li near p hase of parasite 
cleara nce.
Pe E F 2
Plas m o di u m e u kar y otic tra nslati o n el o n gati o n fact or 2
PI
Pri nci pal I n vesti gat or
PI C F(s)
Partici pa nt I nf or mati o n C o nse nt F or m(s)
P K
P har mac o ki netic (s)
P L D
P h os p h oli pi d osis
Q T S
Q ualitati ve T o xicit y  Scale
R acc ( A U C)
Acc u m ulati o n rati o f or A U C 0- 2 4 h, calc ulate d i n Part B as A U C 0- 2 4 h o n 
D a y 3 di vi de d b y  A U C 0 -2 4 h o n Da y 1
R acc( C ma x)
Acc u m ulati o n
rati o f or C ma x , calc ulate d i n Part B as C ma x o n D a y  3 
di vi de d b y  Cma x o n Da y 1
S A E (s)
Seri o us a d verse e ve nt (s)
S A D
Si n gle asce n di n g d ose (s)
S A P
Statistical a nal y sis pla n
S CI D
Se vere c o m bi ne d i m m u n o de ficie nt
S E
Sta n dar d err or
S M C
Safet y  M o nit ori n g C o m mittee
T E A E(s)
Treat me nt - e mer ge nt a d verse e ve nt(s)
T E M
Tra ns missi o n electr o n micr osc o p y
T H C
Tetra h y dr oca n na bi n ol
tma x
Ti me t o reac h t he ma xi m u m bl o o d c o nce ntrati o n
t> 3 n g/ m L
Ti me a b o ve or e q ual t o t he pre dicte d M 5 7 1 7 m o use MI C of 3 n g/ m L
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI
C CI
C CI
C CI
P P D

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 6 / 1 9 0
Sec o n dar y

T o c haracterize t he P K/ P D relati o ns hi p bet wee n M 5 7 1 7 
P K a n d parasite cleara nce i n 
healt h y  su bjects f oll o wi n g i nfecti o n wit h P. falci par u m bl o o d sta ge parasites d uri n g t he 
I B S M c halle n ge b y  assess me nt of t he relati o ns hi p of P K wit h t he P D para meters: parasite 
cleara nce ti me (P C T ), mi ni mal i n hi bit or y co nce ntrati o n (MI C), P Ct ½, M P C , la g ti me, a n d 
fre q ue nc y of recr u desce nce

T o c haracterize t he parasitici dal acti vit y of M 5 7 1 7 o n P. falci par u m ase x ual bl o o d sta ge 
parasites i n t he bl o o d of healt h y  s u bjects i n t he I B S M c halle n ge 

T o e val uate t he safety a n d t olera bilit y of M 5 7 1 7 i n healt h y v ol u nteers f oll o wi n g i nfecti o n 
wit h P. falci par u m bl o o d sta ge parasites d uri n g t he I B S M c halle n ge.
Met h o d ol o g y : 
P art A
Part A is a d o u ble -bli n d, ra n d o mize d, place b o -c o ntr olle d, si n gle asce n di n g d ose (S A D )
i n vesti gati o n i n c o h orts of 8 healt h y s u bjects wit h u p t o 1 1 d ose le vels. T he trial will e val uate 
t he safety, t olera bility,  an d P K pr o perties of escalati n g si n gle d oses of M 5 7 1 7 
w he n 
a d mi nistere d t o healt h y me n a n d w o me n of n o nc hil d beari n g p ote ntial u n der faste d c o n diti o ns . 
Wit hi n eac h c o h ort, s u bjects will be ra n d o ml y assi g ne d t o recei ve a si n gle d ose of M 5 7 1 7 or 
place b o i n a rati o of 6: 2, res pecti vel y. T he place b o c o ntr ol will mi ni mize bias. A 6: 2 rati o of 
M 5 7 1 7
vers us place b o is a n acce pte d sta n dar d use d i n First -i n-H u ma n ( FI H ) trials. 
A si n gle d ose of M 5 7 1 7 or matc he d place b o will be a d mi nistere d as oral ca ps ule(s) (a p pr o priate 
n u m bers of place b o, 1 0 m g , 5 0 m g, or 2 0 0 m g ca ps ules) after at least 8 h o urs of fasti n g t o get her 
wit h water o n Da y  1, f oll o we d b y a 4-h o ur p ost d ose fast. Water will be all o we d u p t o 2 h o urs 
pre d ose a n d a gai n after 2 h o urs p ost d ose. T he n u m ber a n d stre n gt h of ca ps ules t o be 
ad mi nistere d at eac h d ose will be detaile d i n t he p har mac y  ma n ual.
T he i nitial d ose i n vesti gate d was 5 0 m g . T his was l o wer t ha n t he ma xi m u m rec o m me n de d 
starti n g d ose ( M R S D) of 1 0 0 m g deri ve d fr o m t he m ost se nsiti ve n o-o bser ve d -a d verse-effe cts-
le vel (N O A E L ) wit h a safet y fact or of 1 0. T his 5 0 m g d ose was wit hi n t he ra n ge of t he i nitiall y 
pre dicte d efficaci o us d ose ra n ge, w hic h ha d bee n esti mate d t o be bet wee n 1 0 m g a n d 7 0 m g.
As t his is a FI H trial, a se nti nel d osi n g strate g y will be e m pl o ye d f or eac h d ose c o h ort i n t he 
S A D a n d m ulti ple asce n di n g d ose (M A D ) parts. U n der t he discreti o n of t he S M C, a se nti nel 
c o h ort c o nsisti n g of eit her 2 ( 1 acti ve a n d 1 place b o) or 3 ( 2 acti ve a n d 1 place b o) s u bjects will 
be d ose d first. T he I nvesti gat or will re vie w bli n de d safety data u p t o at least 3 6 h o urs after 
d osi n g fr o m t hese se nti nel s u bjects t o r ule o ut a n y i nitial, se vere ac ute reacti o ns. Pr o vi de d t he 
safety data are s u p p orti ve, t he re mai ni n g 6 ( 5 acti ve a n d 1 place b o) or 5 ( 4 acti ve a n d 1 place b o) 
s u bjects, res pecti vel y, i n t he c o h ort will be ra n d o mize d ne xt . 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 / 1 9 0
N o s u bject will be a me m ber of m ore t ha n 1 c o h ort i n a n y part of t he trial. After eac h c o h ort 
has c o m plete d 1 1 d a y s of p ost d osi n g o bser vati o n, t he Safet y M o nit ori n g C o m mittee (S M C )
will e val uate t he safety d osi n g a n d escalati o n se q ue nce a n d ma ke rec o m me n dati o ns. T he data 
o btai ne d fr o m eac h c o h ort will u n der g o a f or mal re vie w b y  the S M C t o c o nfir m t hat it is 
reas o na ble t o pr ocee d wit h t he ne xt d ose/c o h ort. A f or mal re p ort of eac h c o h ort , c o nsisti n g of 
t he data e val uate d a n d a s u m mar y of the decisi o ns ta ke n b y  the S M C , will be pr o vi de d at t he 
e n d of eac h re vie w.
A Scree ni n g peri o d will occ ur fr o m Da y  - 2 8 t o Da y  - 2. S u bjects will be a d mitte d t o t he trial
site o n D a y  -2 a n d will be resi de nt at t he trial site u n der me dical s u per visi o n u ntil disc har ge o n 
D a y  7. S u bjects will nee d t o re p ort t o t he trial site ( Da y 9 an d Da y  11), a n d will be f oll o we d 
u p b y p h o ne ( Da y  8 a n d Da y 1 0) a n d will be re q uire d t o se n d a p h ot o gra p h of t heir diar y car ds
o n t h ose da ys. O n Da y  -1, di gital 1 2- lea d electr ocar di o gra m (E C G ) rec or di n gs are i ncl u de d as 
a baseli ne f or t he i ntras u bject c o m paris o n o n matc hi n g ti me p oi nts wit h t he Da y  1 rec or di n gs
p ost d ose o ver 2 4 h o urs , c oi nci di n g wit h t he P K sa m pli n g ti me p oi nts , f or t h or o u g h assess me nt 
of Q T i nter val c orrecte d f or heart rate (Q Tc ) t o re d uce e x pecte d varia bilit y. T he di gital 1 2- lea d 
E C G base d Q Tc a nal ys is will o nl y  be perf or me d after c o m pleti o n o f t he trial b y  an e x perie nce d, 
q ualifie d, a n d certifie d car di ol o gist, pr o vi de d t he c o m p o u n d f ulfills t he e x pectati o n, a n d 
re p orte d se parately fr o m t he cli nical trial re p ort.
F oll o w -u p visits will occ ur o n D a y  13, D a y  15, Da y  17, Da y  22, a n d Da y  33, a n d a n E n d of 
Trial visit o n Da y  44 ( ± 2 da y s). I n a d diti o n, s u bjects will be re g ularly c o ntacte d (a p pr o xi matel y 
e ver y 2 t o 3 d a ys) b y  tele p h o ne d uri n g t heir a m b ulat or y peri o d. Bl o o d a n d uri ne sa m ples will 
be c ollecte d f or safet y eval uati o n ( he mat ol o g y, bi oc he mi str y, c oa g ulati o n , uri nal ys is, a n d 
a n d bl o o d sa m ples will be c ollecte d f or P K a nal ys is 
y peri o d (at ti me p oi nts i n dicate d i n t he Sc he d ule of 
Assess me nts ).
T he pla n ne d t otal d ura ti o n of t he trial f or eac h s u bject i n t he S A D p orti o n will be u p t o 
a p pr o xi matel y 12 wee ks ( u p t o 4 wee ks f or Scree ni n g, 1 da y  for d osi n g, 1- wee k resi de nc y at 
t he trial site [disc har ge o n D a y 7], a n d F oll o w -u p t hr o u g h D a y 4 4 [ ± 2 d a y s]). A n Earl y 
Ter mi nati o n visit will be c o n d ucte d f or s u bjects w h o wit h dra w, prefera bl y  perf or me d ar o u n d 
t he F oll o w- u p visit, d ue t o t he e x pecte d l o n g half-life of t he c o m p o u n d. 
P art B
T he M A D part of t he trial is o pti o nal a n d will o nl y  be c o n d ucte d if t he o bser ve d P K pr ofile 
d oes n ot all o w a d mi nisteri n g of a t olera ble si n gle d ose t hat will ac hie ve a n 8 -da y  peri o d wit h 
c o nce ntrati o ns well a b o ve t he pre dicte d mi ni mal parasitici dal c o nce ntrati o n (M P C ), ie, 
1 0 n g/ m L. T his assess me nt will be base d o n c haracteristic P K para meters, i n partic ular t he 
eli mi nati o n h alf-life, as c o m p ute d b y n o nc o m part me ntal a nal ysis, of t he P K data fr o m Part A. 
T he decisi o n will be ma de b y  the S M C f oll o wi n g c ollecti o n a n d re vie w of t he i nitial P K data 
a n d s ufficie nt safet y data fr o m t he first 2 c o h orts of Part A.
Part B is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d M A D trial a n d will e val uate t he 
safety, t olera bilit y, a n d P K of m ulti ple oral d oses ( wit hi n asce n di n g d ose c o h orts) of M 5 7 1 7 or 
place b o a d mi nistere d o ver 3 c o nsecuti ve d a y s. As f or Part A, di gital 1 2 -lea d E C G will be 
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 9 / 1 9 0
lea di n g t o recr u desce nce) will be f urt her refi ne d a n d deci de d by t he S M C. T hese d ose(s) c o ul d 
be hi g her or l o wer t ha n t he i nitiall y ad mi nistere d d ose. De pe n di n g o n t he selecte d d oses, t he 
res pecti ve n u m ber a n d stre n gt h of ca ps ules will be calc ulate d a n d a d mi nistere d as s pecifie d i n 
t he p har mac y ma n ual. 
A t hir d c o h ort will be i n vestigate d t o f urt her refi ne a n d c haracterize t he M I C de pe n di n g o n t he 
le vel of precisi o n a n d c o nfi de nce of t he o bser vati o ns i n t he first 2 c o h orts , u nless t he S M C 
deci des ot her wise. Si milar sce nari os as descri be d f or t he i nitial 2 c o h orts will be c o nsi dere d
f or t he t hir d c o h ort, wit h a n alter nati ve d osi n g ti me p oi nt if dee me d necessar y , wit h t he 
i nte nti o n t o f urt her refi ne t he m o deli n g a n d t he P hase II d ose pre dicti o ns.
A ma xi m u m of 3 c o h orts will be i n vesti gate d as a si n gle-d ose or m ulti ple -d ose e val uati o n i n 
Part C of t he trial. T he hi g hest d ose t o be i n vesti gate d i n Part C will n ot e xcee d t he hi g hest 
d ose a d mi nistere d i n Part A or Part B of t he trial. 
S u bjects will be a d mitte d t o t he trial site f or M 5 7 1 7 a d mi nistrati o n 9 da ys p ost a d mi nistrati o n 
of t he I n oc ul u m (In D 9; D a y  1). T he parasite mia of all s u bjects at I n D 9 is e x pecte d t o be 
≥5, 0 0 0 parasites/ m L . H o we ver, s u bjects ca n be a d mi nistere d M 5 7 1 7 at a n y ti me p oi nt bef ore 
or after I n D 9 at t he I n vesti gat ors discreti o n base d o n parasite mia a n d/ or cli nical s ym pt o ms.
F oll o w - u p visits will occ ur o n Da y  13, Da y  15, Da y  17, Da y  22, Da y  29, a n d Da y  33, a n d a n
E n d of Trial visit o n Da y  44 ( ± 2 d a y s). I n a d diti o n, s u bjects will be re g ularl y co ntacte d b y  
tele p h o ne dail y  while t he y are o ut patie nt s, fr o m I n oc ul u m Da y  2 t o I noc ul u m Da y  4, as well 
as o n D a y 2 3 t o D a y  25 . Safet y sa m ples will be c ollecte d f or safety e val uati o n ( he mat ol o g y, 
bi oc he mistr y , c oa g ulati o n , a n d uri nal y sis) a n d bl o o d sa m ples f or P K a n d P D a nal ysis will be 
c ollecte d t hr o u g h o ut t he resi de ntial a n d a m b ulat or y peri o d (at ti me p oi nts i n dicate d i n t he 
Sc he d ule of Assess me nts ).
T he t otal d urati o n of partici pati o n i n Part C of t he trial is a p pr o xi matel y 8 0 da y s f or eac h 
s u bject, i ncl u di n g a Scree ni n g peri o d of u p t o 2 8 da ys, 8 da ys f or t he I B S M i nc u bati o n peri o d, 
a n d 4 4 da ys of F oll o w-u p after treat me nt wit h M 5 7 1 7.
Pl a n ne d n u m ber of s u bjects: 
T ot al:  U p t o a ma xi m u m of 1 3 6 healt h y  me n a n d w o me n of n o nc hil d beari n g p ote ntial
P art A:   U p t o 8 8 s u bjects i n 1 1 c o h orts of 8 s u bjects eac h
P art B ( o pti o n al):   U p t o 2 4 s u bjects i n 3 c o h orts
P art C:   U p t o 2 4 s u bjects i n 3 c o h orts.
Pri m ar y e n d p oi nts: 
P art A

Nat ure, i nci de nce, a n d se verity of a d verse e ve nts ( A Es)/seri o us a d verse e ve nts ( S A Es), 
i ncl u di n g relati o ns hi p t o trial treat me nt, A Es/ S A Es lea di n g t o d ose m o dificati o n 
or 
disc o nti n uati o n of trial treat me nt 

I nci de nce of cli nicall y si g nifica nt cha n ges a n d ab n or malities i n safet y la b orat or y para meters 
( he mat ol o g y, c oa g ulati o n, bi oc he mistr y [s pecificall y ala ni ne a mi n otra nsferase ( A L T) a n d 
as partate a mi n ot ra nsferase ( A S T)], a n d uri nal ys is)
D oc u me nt N o.
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
2 4 / 1 9 0
I n Part C, t he pri mar y P D vari a ble is t he P R R of ase x ual parasites base d o n q P C R a nal ysis after 
a d mi nistrati o n of M 5 7 1 7 . All P D e n d p oi nts will be descri pti vel y s u m marize d. T he n u m ber a n d 
perce nta ge of s u bjects wit h a bse nce of parasite mia ( meas ure d b y q P C R) as well as t he n u m ber 
a n d perce nta ge of s u bjects wit h recr u desce nce will be s u m marize d.
D oc u me nt N o. 0 9 0 0 ba be 8 1 1 3 de 2 b v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 1 6a 6a 6
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
2 5 / 1 9 0
T a ble 1
Sc he d ule of Assess me nts : P art A ( Si n gle Asce n di n g D ose)
A cti vit y
S cr e e ni n g
O n Tr e at m e nt Vi sit s
A m b ul at or y
Vi sit s
F oll o w -u p Vi sit s
E n d 
of 
Tri al 
Vi sit
Tri al W e e k
1
2
3 
4 
6 
7
Tri al D a y
- 2
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 3
1 5
1 7
2 2
3 3 ± 2
4 4 ± 2
H o ur aft er I M P 
a d mi ni str ati o n
Pr e
0
0. 5
1
1. 5
2
4
6
8
1 0
1 2
1 6
2 0
2 4
3 0, 3 6, 4 2
4 8
6 0
7 2
9 6
1 2 0
1 4 4
1 6 8
1 9 2
2 1 6
2 4 0
2 8 8
3 3 6
3 8 4
5 0 4
7 6 8
1 0 3 2
I nf or m e d 
C o n s e nt
X
D e m o gr a p hi c 
a n d m e di c al 
hi st or y
X
R e si d e n c y
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
a
O ut p ati e nt vi sit
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
I n cl u si o n a n d 
e x cl u si o n 
crit eri a c h e c k / 
r e c h e c k
X 
X
P h y si c al 
e x a mi n ati o n b
X
X
X
X
S er ol o g y
X
C o n c o mit a nt 
m e di c ati o n
T hr o u g h o ut t h e p eri o d
A d v er s e e v e nt s
T hr o u g h o ut t h e p eri o d
D oc u me nt N o. 
O bject N o. C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
2 6 / 1 9 0
A cti vit y
S cr e e ni n g
O n Tr e at m e nt Vi sit s
A m b ul at or y
Vi sit s
F oll o w -u p Vi sit s
E n d 
of 
Tri al 
Vi sit
Tri al W e e k
1
2
3 
4 
6 
7
Tri al D a y
- 2
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 3
1 5
1 7
2 2
3 3 ± 2
4 4 ± 2
H o ur aft er I M P 
a d mi ni str ati o n
Pr e
0
0. 5
1
1. 5
2
4
6
8
1 0
1 2
1 6
2 0
2 4
3 0, 3 6, 4 2
4 8
6 0
7 2
9 6
1 2 0
1 4 4
1 6 8
1 9 2
2 1 6
2 4 0
2 8 8
3 3 6
3 8 4
5 0 4
7 6 8
1 0 3 2
Al c o h ol br e at h 
t e st 
X 
X
Uri n e dr u g s of 
a b u s e
X 
X
F S H (f e m al e s 
o nl y)
X
R a n d o mi z ati o n
X
I M P 
a d mi ni str ati o n
X
Di ar y c ar d s c
X 
X d
X 
X d
X 
X 
X 
X 
X 
X 
X
S af et y 
l a b or at or y 
t e st se
X 
X 
X
X 
X 
X 
X f
X f
X 
X f
X 
X 
X
S af et y 
bi o c h e mi str y 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Vit al si g n s , 
r e s pir at or y 
r at eg
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X h
X h
X 
X 
X 
X
X 
X 
X 
X 
X
1 2 -l e a d E C G 
(tri pli c at e s)
X 
X i
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
2 8 / 1 9 0
f
C o a g ul ati o n n ot r e q uir e d o n D a y 7 , D a y 9 , a n d D a y 1 5.
g
O n D a y 1, a ti m e wi n d o w of 6 0 mi n ut e s i s all o w e d f or bl o o d pr e s s ur e m e a s ur e m e nt s.
h
I n c a s e t he s u bj e ct i s u n a bl e t o st a n d u p at t h e 1 6 h o ur s a n d 2 0 h o ur s p o st d o s e ti m e p oi nt s d u e t o di z zi n e s s, t h e vit al si g n s m a y b e a s s e s s e d i n t h e s u pi n e 
p o siti o n.
i
Ti m e p oi nt s o n D a y -1 will m at c h t h e ti m e p oi nt s o n D a y 1.
j
All o w e d ti m e wi n d o w s o n P K s a m pli n g ti m e s ar e d efi n e d i n  T a bl e 4.
l
Fr o m t hi s ti m e p oi nt o n uri n e o nl y.
G e n er al: At vi sit s w h er e a s s e s s m e nt ti m e p oi nt s c oi n ci d e wit h e a c h ot h er, t h e f oll o wi n g pr o c e d ur e s h o ul d b e f oll o w e d: p erf or m vit al si g n s a s s e s s m e nt s sli g htl y 
b ef or e t h e s p e cifi c ti m e p oi nt, E C G a s s e s s m e nt s o n ti m e, P K bl o o d s a m pli n g dir e ctl y f oll o wi n g E C G. U s e of a gr e e d u p o n ti m e wi n d o w s will b e all o w e d ( s p e cifi e d 
i n T a bl e 4 ).
Ti m e wi n d o w ( s e e T a bl e 4) : Sa m pl e s a n d a s s e s s m e nt s o bt ai n e d wit hi n t h e all o w e d ti m e wi n d o w fr o m d o si n g will n ot b e c a pt ur e d a s a pr ot o c ol d e vi ati o n, a s l o n g 
a s t h e e x a ct ti m e of t h e a s s e s s m e nt/ s a m pl e c oll e cti o n i s n ot e d o n t h e s o ur c e d o c u m e nt a n d d at a c oll e cti o n t o ol ( e g, e C R F).
F or t h e diff er e nt bi ol o gi c al s a m pl e s, t h e r e q uir e d t ot al a m o u nt of bl o o d, 
i s s p e cifi e d i n t h e l a b or at or y m a n u al.
D oc u me nt N o
O bject N o. 
C
C
C
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
2 9 / 1 9 0
T a ble 2
Sc he d ule of Assess me nts: P art B ( O pti o n al; M ulti ple Asce n di n g D ose)
A cti vit y
S cr e e ni n g
O n Tr e at m e nt Vi sit s
A m b ul a tor y
Vi sit s
F oll o w -u p Vi sit s
E n d 
of 
Tri al 
Vi sit
Tri al W e e k
1
2
3 
4 
6 
7
Tri al D a y
- 2
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 3
1 5
2 2
3 3 ± 2
4 4 ± 2
H o ur aft er I M P 
a d mi ni str ati o n
Pr e
0
0. 5
1. 5
2
4
6
8
1 2
1 6
2 4
4 8
4 9
5 2
5 6
6 0
6 4
7 2
9 6
1 2 0
1 4 4
1 6 8
1 9 2
2 1 4
2 4 0
2 8 8
3 3 6
5 0 4
7 6 8
1 0 3 2
I nf or m e d 
C o n s e nt
X
D e m o gr a p hi c 
a n d m e di c al 
hi st or y
X
R e si d e n c y
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
a
O ut p ati e nt vi sit
X 
X 
X 
X 
X 
X 
X 
X 
X
I n cl u si o n a n d 
e x cl u si o n 
crit eri a c h e c k / 
r e c h e c k
X 
X
P h y si c al 
e x a mi n ati o n b
X
X
X
X
S er ol o g y
X
C o n c o mit a nt 
m e di c ati o n
T hr o u g h o ut t h e p eri o d
A d v er s e e v e nt s
T hr o u g h o ut t h e p eri o d
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
3 0 / 1 9 0
A cti vit y
S cr e e ni n g
O n Tr e at m e nt Vi sit s
A m b ul a tor y
Vi sit s
F oll o w -u p Vi sit s
E n d 
of 
Tri al 
Vi sit
Tri al W e e k
1
2
3 
4 
6 
7
Tri al D a y
- 2
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 3
1 5
2 2
3 3 ± 2
4 4 ± 2
H o ur aft er I M P 
a d mi ni str ati o n
Pr e
0
0. 5
1. 5
2
4
6
8
1 2
1 6
2 4
4 8
4 9
5 2
5 6
6 0
6 4
7 2
9 6
1 2 0
1 4 4
1 6 8
1 9 2
2 1 4
2 4 0
2 8 8
3 3 6
5 0 4
7 6 8
1 0 3 2
Al c o h ol br e at h 
t e st 
X 
X
Uri n e dr u g s of 
a b u s e
X 
X
F S H (f e m al e s 
o nl y)
X
R a n d o mi z ati o n
X
I M P 
a d mi ni str ati o n
X
X 
X
Di ar y c ar d s c
X d
X 
X d
X 
X 
X 
X 
X 
X
S af et y 
l a b or at or y 
t e st se
X 
X 
X
X 
X
X 
X 
X f
X f
X 
X f
X 
X 
X
S af et y 
bi o c h e mi str y 
X 
X 
X
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Vit al si g n s , 
r e s pir at or y 
r at eg
X 
X 
X
X 
X h
X 
X 
X 
X 
X 
X
X
X 
X 
X
1 2 -l e a d E C G 
(tri pli c at e s)
X 
X i
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
3 2 / 1 9 0
i
Ti m e p oi nt s o n D a y -1 will m at c h t h e ti m e p oi nt s o n D a y 1.
j
All o w e d ti m e wi n d o w s o n P K s a m pli n g ti m e s ar e d efi n e d i n  T a bl e 4.
k 
A d diti o n al P K s a m pl e s t o b e c oll e ct e d at 3 6 h o ur s a n d 4 0 h o ur s p o st d o s e o n D a y 2.
l
P K s a m pl e s ar e t o b e c oll e ct e d pr e d o s e o n I M P a d mi ni str ati o n d a y s ( at 2 4 h o ur s o n D a y 2 a n d at 4 8 h o ur s o n D a y 3).
G e n er al: At vi sit s w h er e a s s e s s m e nt ti m e p oi nt s c oi n ci d e wit h e a c h ot h er, t h e f oll o wi n g pr o c e d ur e s h o ul d b e f oll o w e d: p erf or m vit al si g n s a s s e s s m e nt s sli g htl y 
b ef or e t h e s p e cifi c ti m e p oi nt, E C G a s s e s s m e nt s o n ti m e, P K bl o o d s a m pli n g dir e ctl y f oll o wi n g E C G. U s e of a gr e e d u p o n ti m e wi n d o w s will b e all o w e d ( s p e cifi e d 
i n T a bl e 4 ).
Ti m e wi n d o w ( s e e T a bl e 4) : Sa m pl e s a n d a s s e s s m e nt s o bt ai n e d wit hi n t h e all o w e d ti m e wi n d o w fr o m d o sin g will n ot b e c a pt ur e d a s a pr ot o c ol d e vi ati o n, a s l o n g 
a s t h e e x a ct ti m e of t h e a s s e s s m e nt/ s a m pl e c oll e cti o n i s n ot e d o n t h e s o ur c e d o c u m e nt a n d d at a c oll e cti o n t o ol ( e g, e C R F).
F or t h e diff er e nt bi ol o gi c al s a m pl e s, t h e r e q uir e d t ot al a m o u nt of bl o o d, 
i s s p e cifi e d i n t h e l a b or at or y m a n u al.
D oc u me nt N o. 
O bject N o. 
C
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
3 3 / 1 9 0
T a ble 3
Sc he d ule of Assess me nts: P art C (I n d uce d Bl o o d St a ge M al ari a C h alle n ge M o del, Ass u mi n g Si n gle D osi n g )
A cti vit y
S cr e e ni n g
I n o c ul ati o n Vi sit s
O n Tr e at m e nt Vi sit s
A m b ul a tor y Vi sit s
F oll o w -u p Vi sit s
E n d of Tri al Vi sit
Tri al W e e k
1
2 
3 
4 
5 
6 
7
Tri al D a y
I n D 1a A M
I n D 5 A M
I n D 6 A M, P M
I n D 7 A M, P M
I n D 8 A M
I n D 8 P M
1
2
3
4
5
6
7
9
1 1
1 3
1 5
1 7
2 2
2 9
3 3 ± 2
4 4 ± 2
H o ur aft er 
I M P a d mi n
Pr e
0
0. 5
1
1. 5
2
4
6
8
1 0
1 2
1 6
2 0
2 4
3 0
3 6, 4 2
4 8
5 4, 6 0, 6 6
7 2
8 4
9 6
1 2 0
1 4 4
1 9 2
2 4 0
2 8 8
3 3 6
3 8 4
5 0 4
6 7 2
7 6 8
1 0 3 2
I nf or m e d 
C o n s e nt
X
D e m o gr a p hi c 
a n d m e di c al 
hi st or y
X
R e si d e n c y
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X b
O ut p ati e nt
vi sit
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X
X c
X 
X 
X
I n cl u si o n a n d 
e x cl u si o n 
crit eri a c h e c k/ 
r e c h e c k
X 
X
X
G 6 P D st at u s/ 
t e sti n g
X
P h y si c al 
e x a mi n ati o n d
X 
X
X
X
X
X
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
3 4 / 1 9 0
A cti vit y
S cr e e ni n g
I n o c ul ati o n Vi sit s
O n Tr e at m e nt Vi sit s
A m b ul a tor y Vi sit s
F oll o w -u p Vi sit s
E n d of Tri al Vi sit
Tri al W e e k
1
2 
3 
4 
5 
6 
7
Tri al D a y
I n D 1a A M
I n D 5 A M
I n D 6 A M, P M
I n D 7 A M, P M
I n D 8 A M
I n D 8 P M
1
2
3
4
5
6
7
9
1 1
1 3
1 5
1 7
2 2
2 9
3 3 ± 2
4 4 ± 2
H o ur aft er 
I M P a d mi n
Pr e
0
0. 5
1
1. 5
2
4
6
8
1 0
1 2
1 6
2 0
2 4
3 0
3 6, 4 2
4 8
5 4, 6 0, 6 6
7 2
8 4
9 6
1 2 0
1 4 4
1 9 2
2 4 0
2 8 8
3 3 6
3 8 4
5 0 4
6 7 2
7 6 8
1 0 3 2
S er ol o g y
X
X
C o n c o mit a nt 
m e di c ati o n
T hr o u g h o ut t h e p eri o d
A d v er s e 
e v e nt s
T hr o u g h o ut t h e p eri o d
Al c o h ol 
br e at h t e st 
X 
X
X
Uri n e dr u g s of 
a b u s e
X 
X
X
F S H (f e m al e s 
o nl y)
X
I V M al ari a 
I n o c ul u m
X
I M P 
a d mi ni str ati o n
X
X e
X e
Di ar y c ar d s f
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
3 5 / 1 9 0
A cti vit y
S cr e e ni n g
I n o c ul ati o n Vi sit s
O n Tr e at m e nt Vi sit s
A m b ul a tor y Vi sit s
F oll o w -u p Vi sit s
E n d of Tri al Vi sit
Tri al W e e k
1
2 
3 
4 
5 
6 
7
Tri al D a y
I n D 1a A M
I n D 5 A M
I n D 6 A M, P M
I n D 7 A M, P M
I n D 8 A M
I n D 8 P M
1
2
3
4
5
6
7
9
1 1
1 3
1 5
1 7
2 2
2 9
3 3 ± 2
4 4 ± 2
H o ur aft er 
I M P a d mi n
Pr e
0
0. 5
1
1. 5
2
4
6
8
1 0
1 2
1 6
2 0
2 4
3 0
3 6, 4 2
4 8
5 4, 6 0, 6 6
7 2
8 4
9 6
1 2 0
1 4 4
1 9 2
2 4 0
2 8 8
3 3 6
3 8 4
5 0 4
6 7 2
7 6 8
1 0 3 2
S af et y 
l a b or at or y 
t e st sg
X 
X
X 
X
X 
X
X 
X h
X h
X 
X h
X 
X 
X 
X
S af et y 
bi o c h e mi str y
X 
X
X
X 
X 
X 
X 
X 
X 
X
X 
X 
X
R e d bl o o d 
c ell 
a nti b o di e s i
X
X
Vit al si g n s, 
r e s pir at or y 
r at ej
X
X k
X 
X
X 
X 
X 
X 
X l
X 
X 
X 
X
X 
X 
X 
X 
X
1 2 -l e a d E C G 
(tri pli c at e)
X 
X
X
X 
X 
X 
X 
X 
X 
X
X
X
X 
X 
X
P K s a m pli n g q
X r
X 
X r
X 
X r
X 
X r
X 
X r
X 
X r
X
X r,
s
X 
X r
X r
, s
X 
X r
X 
X r
X 
X r
X 
X r
X
X
r
R e s c u e 
m e di c ati o n
t
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
3 6 / 1 9 0
A cti vit y
S cr e e ni n g
I n o c ul ati o n Vi sit s
O n Tr e at m e nt Vi sit s
A m b ul a tor y Vi sit s
F oll o w -u p Vi sit s
E n d of Tri al Vi sit
Tri al W e e k
1
2 
3 
4 
5 
6 
7
Tri al D a y
I n D 1a A M
I n D 5 A M
I n D 6 A M, P M
I n D 7 A M, P M
I n D 8 A M
I n D 8 P M
1
2
3
4
5
6
7
9
1 1
1 3
1 5
1 7
2 2
2 9
3 3 ± 2
4 4 ± 2
H o ur aft er 
I M P a d mi n
Pr e
0
0. 5
1
1. 5
2
4
6
8
1 0
1 2
1 6
2 0
2 4
3 0
3 6, 4 2
4 8
5 4, 6 0, 6 6
7 2
8 4
9 6
1 2 0
1 4 4
1 9 2
2 4 0
2 8 8
3 3 6
3 8 4
5 0 4
6 7 2
7 6 8
1 0 3 2
F oll o w -u p vi a 
p h o n e c all u
X u
X u
I n o c ul u m 
s af et y 
s a m pl e v
X
X 
X
e C R F = El e ctr o ni c c a s e r e p ort f or m; E C G = el e ctr o c ar di o gr a m; F S H = f olli cl e - sti m ul ati n g h or m o n e; G 6 P D = g l u c o s e- 6-p h o s p h at e d e h y dr o g e n a s e ;
I M P = i nv e sti g ati o n al m e di ci n al pr o d u ct ; I V = i ntr a v e n o u s; I n D 1 t o I n D 9 = D a y of I n o c ul u m a d mi ni str ati o n (I n D 1) t o 9 d a y s p o st a d mi ni str ati o n of t h e I n o c ul u m (I n 
D 9) ; m R N A = m e s s e n g er ri b o n u cl ei c a ci d; 
 P K = p h ar m a c o ki n eti c ( s); Pr e = pr e d o s e; S M C = S af et y M o nit ori n g 
C o m mitt e e ; q P C R = q u a ntit ati v e p ol y m er a s e c h ai n r e a cti o n.
a
T h e s c h e d ul e a s s u m e d tr e at m e nt o n I n D 9 = T ri al D a y 1.
b
Di s c h ar g e of s u bj e ct s c a n o c c ur b et w e e n D a y 4 t o D a y 7 at t h e di s cr eti o n of t h e I n v e sti g at or o n a d vi c e of t h e S M C ( b a s e d o n e x p eri e n c e wit h P art A).
c
I n P art C, a n a m b ul a nt vi sit will b e p erf or m e d o n D a y 2 2 f or s u bj e ct s wit h br e a kt hr o u g h i nf e cti o n s f or t h e a d mi ni str ati o n of r e s c u e m e di c ati o n.
d 
A st a n d ar d f ull p h y si c al e x a mi n ati o n, i n cl u di n g e x a mi n ati o n of all b o d y s y st e m s, will b e p erf or m e d at S cr e e ni n g a n d t h e E n d of Tri al vi sit ( D a y 4 4 ± 2 d a y s) , 
i n cl u di n g g e n er al a p p e ar a n c e, s ki n, h e a d, n e c k (i n cl u di n g t h yr oi d), e y e s, e ar s, n o s e, t hr o at, c ar di o v a s c ul ar a n d p ul m o n ar y s yst e m, a b d o m e n, n e ur ol o gi c al, 
p eri p h er al v a s c ul ar, a n d m u s c ul o s k el et al s y st e m. At ot h er ti m e
p oi nt s a n a b br e vi at e d p h y si c al e x a mi n ati o n m u st
b e p erf or m e d. A d diti o n al p h y si c al 
e x a mi n ati o n s m a y b e p erf or m e d a s d e e m e d n e c e s s ar y, p er t h e I n v e sti g at or’ s di s cr eti o n.
e
I M P a d mi ni str ati o n o n D a y 2 a n d D a y 3 i n c a s e P art C will b e e v al u at e d wit h m ulti ple d o s e s b a s e d o n P K d at a fr o m P art A a n d B .
f  
Di ar y c ar d s will b e pr o vi d e d t o s u bj e ct s f or c oll e cti o n of d at a r el ati n g t o t h eir d ail y p h y si c al a cti vit y, d ail y u s e of s u n s cr e e n/ ot h er m et h o d s of s u n pr ot e cti o n, 
d ail y al c o h ol c o n s u m pti o n, a n d if a p pli c a bl e, t h eir or al ( s u bli n g u al) t e m p er at ur e. S u bj e ct s will bri n g t h eir c o m pl et e d di ar y c ar d s wit h t h e m t o t h e tri al sit e f or 
all a m b ul a nt, F oll o w -u p, a n d E n d of Tri al vi sit s.
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
3 7 / 1 9 0
g
O nl y h e m at ol o g y, c o a g ul ati o n , a n d uri n al y si s ( di p sti c k).
h
C o a g ul ati o n n ot r e q uir e d o n D a y 7 , D a y 9 , a n d D a y 1 5.
i
S a m pl e s will b e c oll e ct e d a n d a n al y z e d f or t h e d et e cti o n of s er o c o n v er si o n a g ai n st s o m e r ar e bl o o d st a g e p at h o g e n s or r e d bl o o d c ell a nti b o di e s.
j
O n D a y 1, a ti m e wi n d o w of 6 0 mi n ut e s i s all o w e d f or bl o o d pr e s s ur e m e a s ur e m e nt s.
k 
V it al si g n s a s s e s s m e nt s pri or t o a d mi ni str ati o n of m al ari a i n o c ul u m (I n D 1) a s w ell a s 1 h o ur p o st i n o c ul ati o n (I n D 1) .
l 
I n c a s e t h e s u bj e ct i s u n a bl e t o st a n d u p at t h e 1 6 h o ur s p o st d o s e ti m e p oi nt d u e t o di z zi n e s s, t h e vit al si g n s m a y b e a s s e s se d i n t h e s u pi n e p o siti o n.
q
At vi sit s w h er e a s s e s s m e nt ti m e p oi nt s c oi n ci d e wit h e a c h ot h er, t h e f oll o wi n g pr o c e d ur e s h o ul d b e f oll o w e d: p erf or m vit al si g n s a s s e s s m e nt s sli g htl y b ef or e 
t h e s p e cifi c ti m e p oi nt, E C G a s s e s s m e nt s o n ti m e, P K bl o o d s a m pli n g dir e ctl y f oll o wi n g E C G. U s e of a gr e e d u p o n ti m e wi n d o w s will b e all o w e d ( s p e cifi e d i n 
T a bl e 4 ).
r
I n cl u di n g dri e d bl o o d s p ot a s s e s s m e nt s at alt er n at e s a m pl e s ( pr e d o s e, 1, 2, 6 , 1 0, 1 6, 2 4 , 3 6, 4 8 , 9 6 , 1 4 4 , 2 4 0 , 5 0 4, a n d 1 0 3 2 h o ur s) .
s 
I n c a s e P art C will b e e v al u at e d wit h m ulti pl e d o s e s b a s e d o n P K d at a fr o m P art A a n d B , P K s a m pl e s ar e t o b e c oll e ct e d pr e d o s e o n I M P a d mi ni str ati o n 
d a y s ( at 2 4 h o ur s o n D a y 2 a n d at 4 8 h o ur s o n D a y 3).
t
Ri a m et a n d Pri m a ci n . If r e s c u e m e di c ati o n s ar e r e quir e d pri or t o D a y 2 2, s af et y a s s e s s m e nt s m u st
b e p erf or m e d pr e a d mi ni str ati o n of Ri a m et. T hi s 
a s s e s s m e nt will i n cl u d e h e m at ol o g y, bi o c h e mi str y, E C G, vit al si g n s, p h y si c al e x a mi n ati o n, c o a g ul ati o n pr ofil e, a n d uri n al y si s. H o w e v er, r e d bl o o d c ell 
a ut o -a nti b o di e s , a n d s er u m st or a g e c oll e cti o n will still b e c oll e ct e d at D a y 2 2 r e g ar dl e s s of t h e tri al d a y t h at r e s c u e m e di c ati o n s ar e a d mi ni st er e d. 
A d mi ni str ati o n of r e s c u e m e di c ati o n s pri or t o D a y 2 2 will b e d et er mi n e d at t h e I n v e sti g at or s di s cr eti o n u si n g t h e f o ll o wi n g crit eri a:

F ail ur e of cl e ar a n c e: d efi n e d a s f ail ur e t o cl e ar p ar a sit e mi a b y at l e a st 1 0 -f ol d at 7 2 h o ur s p o st I M P a d mi ni str ati o n

R e cr u d e s c e n c e: d efi n e d a s ≥5 0 0 0 bl o o d st a g e p ar a sit e s/ m L a n d a 2 -f ol d p ar a sit e mi a i n cr e a s e wit hi n 4 8 h o ur s, or r e-o c c ur r e n c e of m al ari a s y m pt o m s 
wit h a m al ari a cli ni c al s c or e > 6.
u 
S u bj e ct will b e c o nt a ct e d d ail y vi a p h o n e c all s w hil e o ut p ati e nt, fr o m I n o c ul u m D a y 2 t o I n o c ul u m D a y 4, a s w ell a s o n D a y 2 3 t o D a y 2 5, f or a s af et y c h e c k 
a n d c o m pli a n c e of r e s c u e m e di c ati o n u s e. 
v
S er u m s a m pl e s will b e c oll e ct e d at I n o c ul u m D a y 1 ( pr e i n o c ul ati o n), D a y 2 2 ( pr e Ri a m et tr e at m e nt) a n d t h e E n d of Tri al vi sit ( D a y 4 4 [ ± 2 d a y s]). T h e s e 
s a m pl e s will b e st or e d a n d will b e u s e d o nl y i n c a s e a n y s af et y c o n c er n s ari s e a n d a d diti o n al s af et y p ar a m et er t e sti n g i s r e q uir e d.
Ti m e wi n d o w: S a m pl e s a n d a s s e s s m e nt s o bt ai n e d wit hi n t h e all o w e d ti m e wi n d o w fr o m d o si n g will n ot b e c a pt ur e d a s a pr ot o c ol d e vi ati o n, a s l o n g a s t h e e x a ct 
ti m e of t h e a s s e s s m e nt/ s a m pl e c oll e cti o n i s n ot e d o n t h e s o ur c e d o c u m e nt a n d d at a c oll e cti o n t o ol ( e g, e C R F).
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
3 8 / 1 9 0
T a ble 4
All o we d Ti me Wi n d o ws
Ti m e P oi nt
T ol er a n c e Wi n d o w
P h ar m a c o ki n eti c/
( bl o o d s a m pl e s)
Pr e d o s e
- 6 0 mi n t o 0 h
0. 5 h t o 1. 5 h p o st
± 3 mi n
2 h p o st
± 3 mi n
4 h t o 2 0 h p o st
± 5 mi n
2 4 h t o 7 2 h p o st
± 1 0 mi n
8 4 h t o 1 4 4 h p o st
± 2 h
1 9 2 h t o 3 8 4 h p o st
± 6 h
5 0 4 h p o st
± 2 4 h
7 6 8 h p o st
± 4 8 h
1 0 3 2 h p o st
± 4 8 h
1 2 -L e a d El e ctr o c ar di o gr a m/ Vit al Si g n s/ R e s pir at or y  R at e/ T e m p er at ur e/ S af et y L a b or at or y  S a m pl e s
Pr e d o s e
- 9 0 mi n t o 0 h
0. 5 h t o 1 . 5 h p o st
± 1 0 mi n
2 h p o st
± 1 0 mi n
4 h t o 2 0 h p o st
± 1 0 mi n
2 4 h t o 7 2 h p o st
± 2 0 mi n
8 4 h t o 1 4 4 h p o st
± 2 h
1 9 2 h t o 3 8 4 h p o st
± 6 h
5 0 4 h p o st
± 2 4 h
7 6 8 h p o st
± 4 8 h
1 0 3 2 h p o st
± 4 8 h
Bl o o d Pr e s s ur e M e a s ur e m e nt s
D a y 1
± 6 0 mi n
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
4 0 / 1 9 0
La b orat or y  sa m ple pr ocessi n g, ha n dli n g, a n d st ora ge i nstr ucti o ns, as well as d ose pre parati o n a n d 
dis pe nsi n g details, will be prese nte d i n se parate ma n uals t hat will be pre pare d b y  t he C R O a n d/ or 
t he testi n g la b orat ories i n c o or di nati o n wit h t he S p o ns or.
Si g nat ure pa ges f or t he Pr ot oc ol C o -Lea d s a n d t he PI , as well as a list of S p o ns or res p o nsi ble 
pers o ns , are i n A p pe n di x I X.
T he trial will a p pear i n t he f oll o wi n g cli nical trial re gistries: Cli nical Trials. g o v.
Details of str uct ures a n d ass ociate d pr oce d ures will be defi ne d i n a se parate Ma n ual of O perati o ns , 
w hic h will be pre pare d u n der t he s u per visi o n of t he Cli nical Trial Lea der.
3
B ac k gr o u n d I nf or m ati o n
3. 1
M al ari a
Acc or di n g t o t he latest esti mates, release d i n Dece m ber 2 0 1 6 b y W orl d Healt h Or ga nizati o n, 
w orl d wi de t here were a b o ut 2 1 2 milli o n cases of malaria i n 2 0 1 5 ( wit h a n u ncertai nt y  ra n ge of 
1 4 8 milli o n t o 3 0 4 milli o n) a n d a n esti mate d 4 2 9, 0 0 0 deat hs ( wit h a n u ncertai nt y  ra n ge of 2 3 5, 0 0 0 
t o 6 3 9, 0 0 0) ( 1). M ost deat hs ( 7 0 %) occ ur a m o n g c hil dre n bel o w t he a ge of 5 ye ars, mai nl y  in 
Africa. H u ma n mala ria is ca use d b y  4 Plas m o di u m parasite s pecies (P. falci par u m, P. vi va x , 
P. malariae
a n d P. o vale), tra ns mitte d t o h u ma ns b y  A n o p heles
m os q uit oes, calle d “ malaria 
vect ors” . P. falci par u m a n d P. vi va x are t he m ost c o m m o n. P. falci par u m is t he dea dliest w hereas
P. vi va x tri g gers a rec urre nt f or m of malaria t hat, if left u ntreate d, m a y  lea d t o se vere ill ness.
Malaria is a n ac ute fe brile ill ness. I n a no n i m m u ne i n di vi d ual, s ym pt o ms a p pear fr o m 7 d a y s u p 
t o 1 5 da y s after t he i nfecti ve m os q uit o bite. T he first s ym pt o ms – fe ver, hea dac he, c hills a n d 
v o miti n g – m a y  be mil d a n d diffic ult t o rec o g nize as malaria. If n ot treate d wit hi n 2 4 h o urs, 
P. falci par u m malaria ca n pr o gress fr o m ac ute cli nical disease t o se vere ill ness ofte n lea di n g t o 
deat h. C hil dre n wit h severe malaria fre q ue ntly de vel o p o ne or m ore of t he f oll o wi n g s ym pt o ms: 
se vere a ne mia, res pirat or y distress i n relati o n t o meta b olic aci d osis, or cere bral malaria. Als o i n 
a d ults, m ulti ple or ga ns are us uall y i n v ol ve d. I n malaria-e n de mic areas, pers o ns ma y  de vel o p 
partial i m m u nit y, res ulti n g i n > 8 0 % of i nfecti o ns bei n g as y m pt o matic i n regi o ns of hi g h 
tra ns missi o n. N o n se vere malaria of all 4 Plas m o di u m parasite s pecies ca n be c ure d wit h pr o per 
treat me nt. 
T he g oal of dr u g c o m bi nati o n t hera py f or parasitic di seases s uc h as malaria is t o pre ve nt t he 
e mer ge nce of resista nce, w hile pr o vi di n g a d diti o nal be nefit f or t he treat me nt b y  pr o vi di n g a hi g her 
c ure rate. T he rati o nale be hi n d t he de vel o p me nt of arte misi ni n-base d c o m bi nati o n t hera pies was 
t o c o m bi ne a ver y fast-acti n g c o m p o u n d (a n arte misi ni n deri vati ve) t hat will destr o y > 8 0 % of t he 
parasites wit hi n t he first 2 4 h o urs (re d uci n g s ym pt o ms ra pi dl y) wit h a l o n g-acti n g c o m p o u n d, s uc h 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
4 1 / 1 9 0
as a 4 -a mi n o q ui n oli ne, t hat will pr o vi de s o me pr otecti o n a gai nst rei nfecti o n ( p ost-treat me nt 
pr o p h y la xis). Arte misi ni n deri vati ves ha ve a ver y ra pi d m o de of acti o n a n d kill hi g h n u m bers of 
parasites, destr o yi n g > 8 0 % of t he parasite bi o mass a n d as s uc h re d uce t he pr o ba bilit y  to select 
resista nce a gai nst t he l o n g-acti n g part ner c o m p o u n d. Treat me nt wit h a n arte misi ni n deri vati ve 
al o ne (s uc h as artes u nate) re q uires 7- d a y d osi n g d ue t o its s h ort h alf-life of a b o ut 1 h o ur a n d ofte n 
res ults i n i nc o m plete disa p peara nce of t he parasites, w hic h ma y  res ult i n resista nce. T he 
c o m bi nati o n wit h a l o n g -acti n g part ner s y n er gizes t he i nitial parasite killi n g rate, w hile pr o vi di n g 
pr ol o n ge d a nti parasitic pr otecti o n a n d all o wi n g re d ucti o n i n t he treat me nt c o urse t o 3 d a y s. 
3. 2
M 5 7 1 7, 
a Pl as m o di u m
E u k ar y oti c Tr a nsl ati o n El o n g ati o n 
F act or 2 I n hi bit or
T he e xter nal Tra nslati o nal I n n o vati o n Platf or m Malaria I n n o vati o n Cl uster has i n -lice nse d a dr u g 
ca n di date fr o m t he Me dici nes f or Malaria Ve nt u re at t he precli nical sta ge. T he m olec ule, na me d 
D D D 1 0 7 4 9 8, M 5 7 1 7 (t his is t he na me t hat will be use d t hr o u g h o ut t his d oc u me nt), or Plas m o di u m 
e u kar yotic tra nslati o n el o n gati o n fact or 2 ( Pe EF 2) i n hi bit or, is a 
 
tar geti n g Pe E F 2, w hic h is a critical e nz yme i n v ol ve d i n pr otei n s ynt hesis. T his e E F 2 is o ne of 
se veral esse ntial el o n gati o n fact ors re q uire d i n e u kar yotic pr otei n s ynt hesis, b y  me diati n g 
g ua n osi ne tri p h os p hate -de pe n de nt tra nsl ocati o n of t he ri b os o me al o n g messe n ger R N A ( m R N A), 
as s h o w n i n Fi g ure 1.
Fi g ure 1
Sc he m atic 
Re prese nt ati o n 
of 
E u k ar y otic 
Tr a nsl ati o n 
El o n g ati o n 
F act or 2
e E F 2 = E u k ar y oti c tr a n sl ati o n el o n g ati o n f a ct or 2 ; G D P = g u a n o si n e di p h o s p h at e ; G T P = g u a n o si n e trip h o s p h at e ; 
m R N A = m e s s e n g er ri b o n u cl ei c a ci d.
M 5 7 1 7 is a hi g hl y p ote nt a n d selecti ve c o m p o u n d t hat acts o n t he ase x ual i ntraer y t hr oc ytic f or ms 
of t he h u ma n malaria parasites P. falci par u m a n d P. vi va x as well as o n li ver a n d ga met oc y te f or ms 
of t he parasites. It is orall y bi oa vaila ble , a n d dis pla y s P K a n d P D pr o perties c o m pati ble wit h a l o n g 
d urati o n of acti o n f or t he treat me nt of ac ute, u nc o m plicate d malaria i nfecti o ns d ue to P. falci par u m 
a n d P. vi va x. M 5 7 1 7 has t he p ote ntial t o be de vel o pe d as a si n gle-d ose c ure a n d t o bec o me t he 
m ost efficaci o us a nti malarial c o m p o u n d a n d he nce t he treat me nt of c h oice ( best i n class) f or 
u nc o m plicate d malaria i n c o m bi nati o n t hera p y. I n a d di ti o n, M 5 7 1 7 is a n o vel a ge nt (first i n class) 
wit h a mec ha nis m of acti o n differe nt fr o m all ot her a nti malarial dr u gs , wit h acti vit y agai nst 
parasites t hat ha ve s h o w n resista nce t o cli nicall y  use d c o m p o u n ds. 
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
4 2 / 1 9 0
D ue t o its i n hi bit or y effects o n ga met oc y te f or mati o n, it als o has t he p ote ntial t o act as a 
tra ns missi o n bl oc ker. Fi nall y , d ue t o its pre dicte d l o n g h alf-life a n d its acti vit y agai nst 
pre -er yt hr oc ytic sta ges, M 5 7 1 7 has t he p ote ntial t o be de vel o pe d i n t he c he m o pr otecti o n i n dicati o n 
t o pr otect a gai nst d e vel o p me nt of malaria i n e n de mic c o u ntries (c he m o pre ve nti o n) a n d f or 
tra velers (c he m o pr o p hyl a xis).
3. 3
Tri al R ati o n ale
T his is a First -i n-H u ma n ( FI H) trial wit h M 5 7 1 7 a n d c o nsists of 3 parts. 
I n Part A, t he trial will first e val uate t he safet y, t olera bilit y , a n d P K pr o perties of si n gle asce n di n g 
d oses ( S A D) of M 5 7 1 7 
w he n a d mi nistere d t o healt h y  me n a n d w o me n of n o n c hil d beari n g 
p ote ntial ( W N C B P) u n der faste d c o n diti o ns. Si nce e m br yo- fetal t o xicit y trials ha ve n ot yet bee n 
perf or me d, t he trial is restricte d t o W N C B P. 
I n Part B, m ulti ple asce n di n g d oses ( M A D) of M 5 7 1 7 will be a d mi nistere d as 3 c o nsec uti ve dail y 
d oses u n der t he sa me c o n diti o ns a n d i n t he sa me p o p ulati o n. Part B will o nl y  b e c o n d ucte d if t he 
o bser ve d h alf-life i n Part A is m uc h s h orter ( by > 5 0 %) t ha n t he 2 5 7 h o urs c urre ntl y pre dicte d 
fr o m precli nical data a n d d oes n ot all o w f or a d mi nisteri n g a t olera ble si n gle d ose t hat c o vers a n 
8- d a y  peri o d wit h c o nce ntrati o ns a b o ve t he mi ni mal parasitici dal c o nce ntrati o n ( M P C; defi ne d i n 
Ta ble 1 0) of 1 0 n g/ m L . T he c haracteristic P K para meters, i n partic ular t he eli mi nati o n h alf-life, as 
c o m p ute d b y  no n c o m part me ntal a nal ysis will i nf or m t his decisi o n. T hree da y s is t he ma xi m u m 
n u m ber of dail y d oses i n t his t hera pe utic i n dicati o n , relate d t o a n e x pecte d decrease i n c o m plia nce 
i n t he case of a l o n ger d urati o n of daily d osi n g (2) . 
Part C
will i n vesti gate t he effects of si n gle or m ulti ple d oses (i n case t he cli nical re gi men 
necessitates m ulti ple d osi n g base d o n Part A) of M 5 7 1 7 o n P. falci par u m cleara nce ki netics i n 
healt h y  s u bjects usi n g t he In d uce d Bl o o d Sta ge Malaria (I B S M) c halle n ge m o del as d escri be d b y 
Mc Cart h y et al ( 3).
Part A c o m me nced wit h a starti n g d ose of 5 0 m g. T his 5 0 m g d ose was wit hi n t he ra n ge of t he 
i nitiall y pre d icte d efficaci o us d ose ( E D) w hic h ha d bee n esti mate d t o be bet wee n 1 0 m g  a n d
7 0 m g. ( See Secti o n 5. 2. 9 f or a disc ussi o n o n t he j ustificati o n f or d ose.) T he dail y  dose i n Part B
will n ot be hi g her t ha n d oses alrea dy i n vesti gate d i n Part A. F or t he I B S M c halle n ge m o del 
( Part C), a ma xi m u m of 3 c o h orts are i ncl u de d, t o assess t he parasitici dal acti vit y of M 5 7 1 7
f oll o we d by a n e val uati o n of t he P K/ P D relati o ns hi p.
A d diti o nal i nf or mati o n is i ncl u de d i n t he scie ntific rati o nale of t he trial desi g n ( Secti o n  5. 2. 1 ) a n d 
j ustificati o n f or t he d ose ( Secti o n 5. 2. 9).
Refer t o t he I n vesti gat or’s Br oc h ure (I B) f or f urt her i nf ormati o n a b o ut t he n o ncli nical pr o gra ms 
a n d G ui da nce f or t he I n vesti gat or.
T he S p o ns or will i m me diatel y notif y  the PI if a n y ad diti o nal safet y or t o xic ol o g y inf or mati o n 
bec o mes a vaila ble d uri n g t he trial.
D oc u me nt N o
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
4 3 / 1 9 0
T his cli nical trial will be c o n d ucte d i n c o m plia nce wit h t he cli nical trial pr ot oc ol, I nter nati o nal 
C o u ncil f or Har m o nizati o n (I CH) G o o d Cli nical Practice (G C P ), a n d a n y a d diti o nal a p plica ble 
re g ulat or y re q uire me nts.
Base d o n t he a vaila ble n o ncli nical data t o date, t he c o n d u ct of t he trial s pecifie d i n t his pr ot oc ol is 
c o nsi dere d j ustifia ble. 
3. 3. 1
O ver all Ris k  Assess me nt
I n li ne wit h t he c urre nt g ui deli ne ( C o m mittee f or Me dici n al Pr o d ucts f or H u ma n Use G ui deli ne 
o n Strate gies t o Ide ntif y  an d Miti gate Ris ks f or Cli nical Trials wit h I MP, E M E A/ C o m mittee f or 
Me dici nal Pr o d ucts f or H u ma n Use / S W P/ 2 8 3 6 7/ 0 7) a ris k assess me nt was perf or me d f or t he 
M 5 7 1 7 m olec ule re gar di n g its m o de of acti o n, nat ure of t he tar get, a n d rele va nce of a ni mal s pecies 
a n d m o dels.
T he m o de of acti o n is ne w f or a molec ule effecti ve i n malaria, ie, i n hi biti o n of Pe E F 2, w hic h is 
i n v ol ve d i n pr otei n s ynt hesis a n d t heref ore n o cli nical/t hera pe utic e x perie nce fr o m ot her e xisti n g 
m olec ules ca n be gai ne d. H o we ver , t he c o m p o u n d is hi g hl y  selecti ve f or t he Plas m o di u m
el o n gati o n fact or a n d d oes n ot cr oss-react wit h 
h u ma n el o n gati o n fact ors at rele va nt 
c o nce ntrati o ns. T he 
m ost 
rele va nt a ni mal m o dels 
f or malaria 
are se vere c o m bi ne d 
i m m u n o deficie nt ( S CI D) mice i njecte d wit h i nfecte d h u ma n er yt hr oc y tes a n d t hese m o dels were 
use d t o gi ve a n esti mati o n of t he mi ni mal i n hi bit or y c o nce ntrati o n ( MI C) a n d M P C nee de d t o be 
effecti ve a gai nst t he parasite. I n a d diti o n, i n stan dar d rat a n d d o g re peat-d ose 2- wee k t o xicit y trials,
little t o xicit y of t he c o m p o u n d was i de ntifie d a n d li ver, l ym p hatics , a n d e pit helia of t he 
gastr oi ntesti nal tract were i de ntifie d as t he tar get or ga ns (f or details please refer t o t he I B). O ne 
maj or o bser vati o n i n t he rat was a d verse li ver i nj ury d ue t o p h os p h oli pi d osis ( P L D) s ym pt o ms at 
a d ose a b o ve t he n o -o bser ve d - a d verse-effect s-le vel ( N O A E L). A n ot her 
o bser vati o n was 
a bs or pti o n of ultra vi olet (U V ) li g ht at 2 9 0 n m a n d 3 3 6 n m as well as a p ositi ve i n vitr o 
p h ot ot o xicit y  ( 3 T 3) assa y.
I n s u m mar y, i n refere nce t o t he m o de of acti o n, t he nat ure of t he tar get wit h hi g h specificit y  for 
Pe E F 2 , a n d t he a vaila bilit y of t o xicit y data fr o m 2 rele va nt a ni mal s pecies, M 5 7 1 7 was n ot 
classifie d as a hi g h -ris k m olec ule a n d t he N O A E L a p pr oac h was a p plie d t o s u p p ort t he starti ng 
d ose. T he pre dicte d l o n g h alf-life of t he c o m p o u n d d oes i nfl ue nce t he desi g n of t he FI H trial, 
warra nti n g a lo n ger d urati o n of o bser vati o n t ha n is t ypical i n a P hase I trial . 
3. 3. 2
Be nef it a n d R is k (S i n gle A sce n di n g D ose / Multi ple A sce n di n g 
D ose P art)
T he be nefit -ris k relati o ns hi p has bee n carefull y  co nsi dere d i n t he pla n ni n g of t he trial. Base d o n 
t he n o ncli nical safet y pr ofile a n d t he e x pecte d hi g h efficac y a gai nst Plas m o di u m , it is a ntici pate d 
t hat M 5 7 1 7 will ha ve a p ositi ve be nefit -ris k pr ofile t o warra nt trials i n healt h y  vol u nteers if 
c o n d ucte d u n der well -c o ntr olle d c o n diti o ns, i ncl u di n g i n-h o use c o nfi ne me nt peri o ds, e xte nsi ve 
m o nit ori n g , a n d pr otecti ve meas ures f or c o ntrace pti o n a n d p h ot ot o xicit y . T his i nitial trial i n 
healt h y  v ol u nteers will be f oll o we d b y  su bse q ue nt pr o of - of-c o nce pt trials i n malaria -i nfecte d 
patie nts, w here M 5 7 1 7 will be teste d as a m o n ot hera p y or i n c o m bi nati o n wit h a part ner m olec ule . 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
4 5 / 1 9 0
4. 2
Sec o n d ar y O bjecti ves
P art A

T o i n vesti gate t he P K of si n gle asce n di n g oral d oses of M 5 7 1 7.
P art B ( o pti o n al)

T o i n vesti gate t he P K of m ulti ple ( 3 -da y ) asce n di n g oral d oses of M 5 7 1 7.
P art C

T o c haracterize t he P K/ P D relati o ns hi p bet wee n M 5 7 1 7 P K a n d parasite cleara nce i n healt h y 
s u bjects f oll o wi n g i nfecti o n wit h P. falci par u m bl o o d sta ge parasites d uri n g t he I B S M c halle n ge
b y  assess me nt of t he relati o ns hi p of P K wit h t he P D para meters: P C T, MI C, P Ct ½, M P C , la g 
ti me, a n d fre q ue nc y of recr u desce nce.

T o c haracterize t he parasitici dal acti vit y of M 5 7 1 7 
o n P. falci par u m ase x ual bl o o d sta ge 
parasites i n t he bl o o d of healt h y  s u bjects i n t he I B S M c halle n ge 

T o e val uate t he safet y a n d t olera bilit y  of M5 7 1 7 i n healt h y v ol u nteers f oll o wi n g i nfecti o n wit h 
P. falci par u m bl o o d sta ge parasites d uri n g t he I B S M c halle n ge.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
4 6 / 1 9 0
5
I n vesti g ati o n al Pl a n
5. 1
O ver all Tri al Desi g n a n d Pl a n
T his is a P hase I, FI H, 3- part trial i n healt h y s u bjects at a si n gle trial site. T he trial is e x pecte d t o 
start (first s u bject’s first visit) i n A u g ust 2 0 1 7. T he last s u bject’s last visit date will de pe n d o n t he 
n u m ber of c o h orts e nr olle d as deter mi ne d b y t he S M C (latest J ul y  2 0 1 9).
T he trial c o nsists of t he f oll o wi n g parts: S A D ( Part A), M A D
(Part B) a n d t he I B S M c halle n ge 
m o del ( Part C). 
U p t o a ma xi m u m of 8 8 healt h y  me n a n d w o me n
of n o nc hil d beari n g p ote ntial ( W N C B P)
(c o nsi deri n g u p t o 1 1 c o h orts of 8 s u bjects eac h) i n Part A, u p t o 2 4 s u bjects i n 3 c o h orts i n Part B, 
a n d u p t o 2 4 s u bjects i n Part C), 1 8 t o 5 5 ye ars of a ge (i ncl usi ve) will partici pate i n t his trial. N o 
s u bject will be a me m ber of m ore t ha n 1 c o h ort i n a n y part of t he trial.
A detaile d sc he d ule of trial pr oce d ures/assess me nts is pr o vi de d i n t he Sc he d ule of Assess me nts 
(see Ta ble 1 t o Ta ble 3 ).
5. 2
Disc ussi o n of Tri al Desi g n
5. 2. 1
Scie ntific R ati o n ale f or Tri al Desi g n
M 5 7 1 7 is a ne w c he mical e ntit y wit h hi g h p ote nc y  agai nst m ulti -sta ge f or ms of P. falci par u m, 
i n hi biti n g a ne w tar get, Pe E F 2. T his tar get is i n v ol ve d i n t he g ua n osi ne tri p h os p hate- de pe n de nt 
tra nsl ocati o n of t he ri b os o me a n d is esse ntial f or pr otei n sy nt hesis. H u ma n , C yn o m ol g us m o n ke y , 
rat, a n d m o use e E F 2 are hi g hly c o nser ve d a n d o nl y differ b y less t ha n 1 % fr o m eac h ot her, w hilst 
P. falci par u m se q ue nce is o nl y  63. 7 % i de ntical t o t he ma m malia n se q ue nces. Fr o m t he data 
ge nerate d t h us far, M 5 7 1 7 see ms t o be hi g hl y sele cti ve f or t he Plas m o di u m s pecies a n d as s uc h n o 
effects o n pr otei n s ynt hesis i n h u ma ns are t o be e x pecte d. T he a vaila ble data fr o m t he pi v otal G o o d 
La b orat or y  Practice ( G L P) t o xic ol o g y trials i n t he rat a n d d o g di d n ot s u g gest ot her wise. 
I n c o ntrast t o man y  c urre nt FI H trials, n o 
 f o o d-effect trial is i ncl u de d i n t his pr ot oc ol, 
si nce t he c o m p o u n d is pre dicte d t o be a Bi o p har mace ut ics Classificati o n S y ste m Class I/III 
c o m p o u n d, wit h a pre dicte d hi g h oral bi oa vaila bilit y  (ar o u n d 9 0 %). Base d o n literat ure pertai ni n g 
t o Class I/III c o m p o u n ds, t he hi g h pre dicte d bi oa vaila bilit y  an d a de dicate d Gastr o Pl us 
si m ulati o n ™ ( Si m ulati o ns Pl us, I nc., La ncaster, Calif or nia, U S ) ( w hic h all o ws t he si m ulati o n of 
t he a bs or pti o n of a c o m p o u n d i n faste d a n d fe d c o n diti o ns, base d o n t he p h y sical a n d c he mical 
pr o perties of t he m olec ule), a p ositi ve f o o d effect is dee me d u nli kel y  (4, 5 ). T he ris k f or patie nts 
D oc u me nt N o
O bject N o
C CI
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
4 7 / 1 9 0
i n P hase II t o s h o w i ncrease d e x p os ure a n d e ns ui n g safet y iss ues i n case t he me dicati o n is 
acci de ntall y ta ke n wit h f o o d is t h us mi ni mal. In case M 5 7 1 7
pr o ves t o be a Class III c o m p o u n d, a 
ne gati ve f o o d effect ca n n ot be e xcl u de d. A de dicate d, f ully p o were d f o o d-effect trial will be 
c o n d ucte d later i n de vel o p me n t wit h t he fi nal f or m ulati o n a n d w he n m ore i nf or mati o n o n t he E D
a n d h u ma n varia bilit y is a vaila ble. 
T he i nte n de d patie nt p o p ulati o n f or M 5 7 1 7 is pe o ple i nfecte d wit h P. falci par u m , b ut t he FI H trial
is perf or me d i n healt h y v ol u nteers t o c haracterize t he safety, t olera bilit y  a n d P K of t he c o m p o u n d 
i n h u ma ns i n t he a bse nce of a n y disease -relate d a n d p ote ntiall y  co nf o u n di n g fact ors. T he safety,  
t olera bilit y, P K a n d 
 data fr o m Part C will su p p ort decisi o n -ma ki n g o n w het her, 
a n d wit h w hic h d ose, t o f urt her i n vesti gate M 5 7 1 7
i n a P hase II/pr o of -of -c o nce pt patie nt trial
w here t he dr u g ca n di date ma y
be e val uate d as m o n ot hera p y or i n c o m bi nati o n wit h a part ner 
m olec ule .
T he trial will be c o n d ucte d i n healt h y  male a n d fe male s u bjects ( W N C B P) w h o are free fr o m a ny 
u n derl y i n g c o n diti o ns w hic h c o ul d affect i nter pretati o n of t he safet y res ults. T he i ncl usi o n criteria 
were c h ose n t o hel p e ns ure t he i ncl usi o n of o nl y healt h y s u bjects. A dditi o nal criteria are i n place 
t o e ns ure t he safety a n d well bei n g of s u bjects. 
Part A a n d Part B of t he trial will be place b o -c o ntr olle d, t o facilitate i de ntificati o n of effects relate d 
t o a d mi nistrati o n of M 5 7 1 7 . Part C will be o pe n-la bel a n d o nly treat s u bjects wit h M 5 7 1 7 . 
5. 2. 2
P art A
Part A is a d o u ble -bli n d, ra n d o mize d, place b o -c o ntr olle d, S A D i n vesti gati o n i n c o h orts of 
8 healt h y  s u bjects wit h u p t o 1 1 d ose le vels. T he trial will e val uate t he safet y, t olera bilit y, a n d P K 
pr o perties of escalati n g si n gle d oses of M 5 7 1 7 w he n a d mi nistere d t o healt h y  me n a nd W N C B P 
u n der faste d c o n diti o ns . 
Wit hi n eac h c o h ort, s u bjects will be ra n d o mly assi g ne d t o recei ve a si n gle d ose of M 5 7 1 7 or 
place b o i n a rati o of 6: 2, res pecti vely. T he place b o c o ntr ol will facilitate i de ntificati o n of effects 
relate d t o a d mi nistrati o n of M 5 7 1 7 rat her t ha n t he trial pr oc e d ures or sit uati o n, ie, t o mi ni mize 
bias. A 6: 2 rati o of M 5 7 1 7 vers us place b o is a n acce pte d sta n dar d use d i n FI H trials. 
A si n gle d ose of M 5 7 1 7 or matc he d place b o will be a d mi nistere d as oral ca ps ule(s) (a p pr o priate 
n u m bers of place b o, 1 0 m g , 5 0 m g , or 2 0 0 m g  ca ps ules) after at least 8 h o urs of fasti n g t o get her 
wit h water o n D a y  1, f oll o we d b y  a 4-h o ur p ost d ose fast. Water will be all o we d u p t o 2 h o urs 
pre d ose a n d a gai n after 2 h o urs p ost d ose. T he n u m ber a n d stre n gt h of ca ps ules t o be a d mi nistere d 
at each d ose le vel will be detaile d i n t he p har mac y ma n ual.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
4 8 / 1 9 0
T he i nitial d ose i n vesti gate d was 5 0 m g. T his was l o wer t ha n t he M R S D
of 1 0 0 m g deri ve d fr o m 
t he m ost se nsiti ve N O A E L wit h a safety fact or of 1 0. F urt her details o n t he calc ulati o n of t he 
M R S D a n d starti n g d ose are gi ve n i n Secti o n 5. 2. 9 . T his 5 0 m g d ose was
wit hi n t he i nitiall y 
pre dicte d E D ra n ge, w hic h ha d bee n esti mate d t o be bet wee n 1 0 m g a n d 7 0 m g.
As t his is a FI H trial, a se nti nel d osi n g strate g y will be e m pl o ye d f or eac h d ose c o h ort i n Part A 
a n d Part B, e xce pt i n case s u bjects are a d mi nistere d a si milar or l o wer d ose t ha n a n alrea d y 
a d mi nistere d d ose. U n der t he discreti o n of t he S M C, a senti nel c o h ort c o nsisti n g of eit her 
2 ( 1 acti ve a n d 1 place b o) or 3 s u bjects ( 2 acti ve a n d 1 place b o) will be d ose d first. T he I n vesti gat or 
will re vie w bli n de d safet y data u p t o at least 3 6 h o urs after d osi n g (tma x is e x pecte d t o be ar o u n d 
1 6 h o urs) fr o m t hese se nti nel s u bjects t o r ule o ut a n y  initial, se vere ac ute reacti o ns. Pr o vi d e d t he 
safety data are s u p p orti ve, t he re mai ni n g 6 ( 5 acti ve a n d 1 place b o) or 5 ( 4 acti ve a n d 1 place b o) 
s u bjects, res pecti vely, i n t he c o h ort will be ra n d o mize d t he f oll o wi n g da y or later, or di vi de d o ver 
se veral c o nsec uti ve da ys, de pe n di n g o n l o gistic feasi bilit y. 
After eac h c o h ort has c o m plete d 1 1 d a y s of p ost d osi n g o bser vati o n, t he S M C will e val uate t he 
safety d osi n g a n d escalati o n se q ue nce a n d ma ke rec o m me n dati o ns o n a n o n g o i n g basis. T he data
o btai ne d fr o m eac h c o h ort will be q ualit y -c hec ke d bef ore bei n g pr o vi de d bli n de d t o t he S M C. T he 
data o btai ne d fr o m eac h c o h ort will u n der g o a f or mal re vie w b y  the S M C t o c o nfir m t hat it is 
reas o na ble t o pr ocee d wit h t he ne xt d ose/c o h ort. A f or mal re p ort of eac h c o h ort, c o nsisti n g of t he 
data e val uate d a n d a s u m mar y of t he decisi o ns ta ke n b y  the S M C , will be pr o vi de d at t he e n d of 
eac h re vie w. 
A S cree ni n g peri o d will occ ur fr o m D a y  -2 8 t o Da y  - 2. S u bjects will be a d mitte d t o t he trial site 
o n D a y  -2 a n d will be resi de nt at t he trial site u n der me dical s u per visi o n u ntil disc har ge o n Da y 7 . 
O n D a y  - 1, di gital 1 2- lea d E C G rec or di n gs are i ncl u de d as a baseli ne f or t he i ntras u bject 
c o m paris o n of matc hi n g ti me p oi nts wit h t he Da y  1 rec or di n gs p ost d ose o ver 2 4 h o urs , c oi nci di n g 
wit h t he P K sa m pli n g ti me p oi nts , f or t h or o u g h Q Tc assess me nt t o re d uce e x pecte d varia bilit y .
T he di gital 1 2- lea d E C G base d Q Tc a nal ys is will o nl y  be perf or me d after c o m pleti o n of t he trial
b y  an e x perie nce d, q ualifie d, a n d certifie d car di ol o gist, pr o vi de d t he c o m p o u n d f ulfills t he 
e x pectati o n, a n d re p orte d se paratel y  fr o m t he cli nical trial re p ort.
A sc he matic prese ntati o n of t he Part A trial desi g n f or eac h s u bject is prese nte d i n  Fi g ure 2.   
D oc u me nt N o
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8 -0 0 1 3
5 1 /1 9 0
Fi g ure 3 
Sc he m atic Tri al Desi g n C o h orts P art A
S A D = Si n gl e a s c e n di n g d o s e ( s); S M C A 1 t o A 5 = S af et y M o nit ori n g C o m mitt e e P art A C o h ort 1 t o C o h ort 5 .
T h e S M C m a y d e ci d e, o n t h e b a si s of s u p p orti v e s af et y a n d P K d at a, t o i n cr e a s e t h e d o s e i n C o h ort 4 ( S A D 4) t o 
4 0 0 m g (i n st e a d of 3 0 0 m g), a n d i n C o h ort 5 ( S A D 5) t o 6 0 0 m g ( s e e al s o S e cti o n  5. 2. 9 ). D uri n g t h e c o n d u ct of t h e 
tri al, t h e S M C r e c o m m e n d e d t o a d d 2 a d diti o n al S A D c o h ort s of 1 ,0 0 0 m g a n d 1 ,5 0 0 m g t o P art A. A c c or di n gl y, S M C 
r e vi e w m e eti n g s will b e al s o p erf or m e d aft er e a c h c o h ort ( S A D 6, a n d S A D 7).
F oll o w i n g c o m pleti o n of t he first 2 c o h ort s ( 5 0 m g a n d 1 0 0 m g ), t he S M C will re vie w all safet y 
data u p t o at least Da y  1 1 ( A Es, safet y la b orat or y res ults, a n d vital si g ns) a n d a n y ot her a vaila ble 
data (i ncl u di n g P K data u p t o at least 1 4 4 h o urs p ost d ose) i n a d o u ble -bli n d fas hi o n, t o deter mi ne 
w het her t he pre dicte d P K a n d t he o bser ve d P K are i n li ne wit h si m ulati o ns a n d w het her escalati o n 
t o t he ne xt d ose le vel is a p pr o priate. As t he P K is pre dicte d t o be d ose -li near a n d si nce t he 
c o m p o u n d is e x pecte d t o be B C S C lass 1/ 3 wit h hi g h bi oa vaila bilit y , n o f urt her o n li ne P K data 
will be e val uate d f or S M C decisi o ns, u nless P K o bser vati o ns warra nt t his .
If t he P K para meters of t he first 2 c o h orts are i n li ne wit h t he pre dicti o n, f urt her se q ue ntial d osi n g 
of e g, 2 0 0 m g , 3 0 0 m g , a n d 4 0 0 m g ( or 2 0 0 m g , 4 0 0 m g, a n d 6 0 0 m g) ca n be i nitiate d, wit h a n 
S M C re vie w of safet y  data c o veri n g at least 1 1 d a y s after eac h d osi n g c o h ort, wit h a d diti o nal P K 
data of t he prece di n g c o h ort(s), as a p plica ble. If P K para meters are hi g her or l o wer t ha n pre dicte d, 
t he d ose escalati o n sc he me ca n be a dj uste d b y  the S M C base d o n o n g oi n g safety fi n di n gs. Trial
st o p pi n g r ules are defi ne d i n Secti o n 5. 5. 3 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
5 3 / 1 9 0
T hree M A D c o h orts of 8 s u bjects eac h are pla n ne d i n Part B. I n eac h d ose c o h ort, se nti nel d osi n g 
as d o ne i n part A will be i ncl u de d ( 2 s u bjects d ose d o n D a y  1, t he re mai ni n g 6 s u bjects d ose d at 
least 2 4 t o 4 8 h o urs later). T he S M C will deci de o n t he d osi n g a n d escalati o n se q ue nce.
A Scree ni n g peri o d will occ ur fr o m D a y  -2 8 t o Da y  - 1. S u bjects will be a d mitte d t o t he trial site 
o n Da y  -2 a n d will be resi de nt i n t he trial site u n der me dical s u per visi o n u ntil disc har ge, w hic h is 
pla n ne d after c o m pleti o n of all trial-relate d assess me nts o n Da y  7 at t he discreti o n of t he 
I n vesti gat or. S u bjects will nee d t o re p ort t o t he trial site ( Da y 9 a n d Da y 1 1), a n d will be f oll o we d 
u p b y  p h o ne ( Da y 8 a n d Da y 1 0) a n d will be re q uire d t o se n d a p h ot o gra p h of t heir diar y car ds o n 
t h ose da ys. 
F oll o w -u p visits will occ ur o n Da y  1 3, D a y 1 5, D a y 2 2, a n d D a y  3 3, a n d a n E n d of Trial visit o n
D a y  44 ( ± 2 d a y s) (Fi g ure 4 ). I n ad diti o n, s u bjects will be re g ularly c o ntacte d (a p pr o xi matel y ever y 
2 t o 3 d a y s) b y  tele p h o ne d uri n g t heir a m b ulat or y peri o d. Bl o o d a n d uri ne sa m ples will be c ollecte d 
f or safety e val uat i o n ( he mat ol o g y, bi oc he mistr y , c oa g ulati o n , uri nal ys is, a n d
) as will bl o o d 
sa m ples f or P K a nal ys is t hr o u g h o ut t he resi de ntial a n d a m b ulat or y peri o d (at ti me p oi nts i n dicate d 
i n Ta ble 2 ).
Fi g ure 4
Sc he m atic Tri al Desi g n - I n di vi d u al S u bject i n P art B
E C G = el e ctr o c ar di o gr a m; I M P = i n v e sti g ati o n al m e di ci n al pr o d u ct.
5. 2. 4
P art C
T he o bjecti ve of t his trial part is t o e val uate t he P K/ P D relati o ns hi p bet wee n M 5 7 1 7 P K a n d 
parasite cleara nce. T he e v ol uti o n of t he parasite mia will be f oll o we d a n d meas ure d b y  qua ntitati ve 
p ol y merase c hai n reacti o n ( q P C R) o ver ti me, f oll o wi n g t he i n oc ulati o n a n d t he treat me nt wit h
M 5 7 1 7 . T his all o ws a calc ulati o n or m o de li n g of t he parasite re d ucti o n rati o (P R R ), para site 
cleara nce h alf-life, MI C , a n d M P C of M 5 7 1 7 f or P. falci par u m i n t he h u ma n malaria c halle n ge 
m o del a n d will be use d t o i nf or m o n t he d ose ra n ge i n patie nt p o p ulati o n s. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
5 4 / 1 9 0
T he pri mar y o bjecti ve varia ble is P R R of ase x ual parasites base d o n q P C R after a d mi nistrati o n of 
M 5 7 1 7. T he P R R f or ase x ual parasites will be esti mate d usi n g t he sl o pe of t he o pti mal fit of t he 
l o g-li near relati o ns hi p of t he parasite mia deca y. 
T he M I C is defi ne d as t he dr u g c o nce ntrati o n at w hic h t he relati ve rate of c ha n ge i n parasite mia is 
e q ual t o zer o (see Fi g ure 5 ); t he M P C re prese nts t he l owest dr u g c o nce ntrati o n a b o ve w hic h 
parasites decli ne at a ma xi mal rate. I n ot her w or ds, t he MI C is t he dr u g c o nce ntrati o n at w hic h t he 
rate of parasite killi n g is e q ual t o t he rate of parasite re pr o d ucti o n a n d re prese nts a “stea d y state”. 
I m plicit i n t his defi niti o n is t he ass u m pti o n t hat t he M P C a n d MI C val ues are i n varia nt of t he d ose 
a d mi nistere d. A n a p pr o xi mati o n of t he M P C
a n d MI C val ues i n healt h y s u bjects i nfecte d wit h l o w 
n u m bers of parasites will hel p i n i de ntif yi n g t he o pti mal d ose of M 5 7 1 7 f or su bse q ue nt P hase II 
trials i n patie nts a n d will re d uce t he n u m ber of patie nts i n t he P hase II trials b y  re d uci n g t he n u m ber 
of d oses t hat will nee d t o be i n vest i gate d. T he M P C a n d MI C val ues will be t he maj or para meters 
t o c o nsi der i n pla n ni n g f or a f ut ure c o m bi nati o n a nti malarial re gi me n.
Fi g ure 5
Ill ustr ati o n of Rel ati o n 
bet wee n Dr u g 
C o nce ntr ati o n, 
P ar asite mi a 
Le vels, Mi ni m al 
P ar asitici d al C o nce ntr ati o n a n d Mi ni m al 
I n hi bit or y 
C o nce ntr ati o n
MI C = M i ni m al i n hi bit or y c o n c e ntr ati o n; M P C = mi ni m al p ar a sit a ci d al c o n c e ntr ati o n; P C R = p ol y m er a s e c h ai n 
r e a cti o n.
Part C ma y be i nitiate d o nce t he safet y a n d P K data of at least t he first 2 c o h orts of Part A, ie, t he 
5 0 m g a n d 1 0 0 m g d ose gr o u ps , or t he tar gete d t hera pe utic e x p os ure ra n ge ha ve bee n assesse d. I n 
case m ulti ple d osi n g ( Part B) is dee me d necessar y base d o n t he res ults of Part A, m ulti ple d osi n g 
i n Part C m ulti ple d osi n g ma y be i nitiate d after a nal ysis of 1 or 2 c o h orts i n Part B (safety d ata a n d 
P K), wit h t he decisi o n t o be ma de b y t he S M C. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
5 6 / 1 9 0
Fi g ure 6
Ill ustr ati o n of Ti me Sc he d ule f or C h alle n ge M o del
I n D 1 t o I n D 9 = D a y of I n o c ul u m a d mi ni str ati o n (I n D 1) t o 9 d a y s p o st a d mi ni str ati o n of t h e I n o c ul u m (I n D 9); 
I M P = i n v e sti g ati o n al m e di ci n al pr o d u ct; I V = i ntr a v e n o u s.
T hi s e x a m pl e a s s u m e s t h at t h e I M P i s a d mi ni st er e d o n In o c ul u m D a y 9 .
I n or der t o be a ble t o o bser ve t he MI C a n d m o del
t he M P C, o ne nee ds t o assess t he dr u g 
c o nce ntrati o n at t he ti me t hat parasite c o u nt is at its l o west le vel. T his i m plies t hat t he l o west 
parasite c o u nt m ust be o bser ve d. Pr o vi de d t hat a hi g h e n o u g h d ose is a d mi nistere d, t he MI C s h o ul d 
be reac he d after t he s u bject has rec o vere d fr o m a n y cli nical s ym pt o ms of malaria, a n d w he n 
parasite de nsities ha ve falle n bel o w t he le vel of micr osc o pic detecti o n, as t he se nsiti vit y of 
micr osc o p y i s o nl y  5 0/ μ L (a p pr o xi matel y 1 08 parasites t otal). Se nsiti ve q P C R met h o ds n o w all o w 
ti mel y (assa y ti me a p pr o xi matel y 4 ho urs) detecti o n of ver y  lo w parasitic de nsities ( bel o w 
1 0 0 parasites/ m L , w hic h re prese nts se nsiti vit y up t o 1, 0 0 0 ti mes greater t ha n t hic k bl o o d s mears 
b y  micr osc o p y ), s o it is p ossi ble t o f oll o w t he s u b-late nt parasite mia le vels as t he y decli ne a n d 
t he n rise a gai n. O nce t here is clear e vi de nce b y  real-ti me q P C R t hat parasite mia is risi n g 
( parasite mia of ≥5, 0 0 0 ase x ual bl o o d sta ge parasites a n d i ncreasi n g 2-f ol d wit hi n 4 8 h o urs), 
resc ue me dicati o n will b e a d mi nistere d at t he decisi o n/ discreti o n of t he I nvesti gat or. T he s u bject 
will t h us be c ure d of t heir i nfecti o n bef ore or at e mer ge nce of a d va nce d cli nical s ym pt o ms
of 
malaria i nfecti o n .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
5 7 / 1 9 0
All s u bjects i n a gi ve n c o h ort will be i n oc ulate d wit hi n a peri o d of 6 0 mi n utes. 
A ma xi m u m of 3 c o h orts will be i n vesti gate d as a si n gle-d ose or m ulti ple -d ose e val uati o n i n Part C 
of t he trial. T he hi g hest d ose t o be i n vesti gate d i n Part C will n ot e xcee d t he hi g hest d ose 
a d mi nistere d i n Part A or Part B of t he trial. 
S u bjects will be a d mitte d t o t he trial site f or M 5 7 1 7 a d mi nistrati o n 9 da y s p ost a d mi nistrati o n of 
t he I noc ul u m (I n D 9; D a y  1). T he parasite mia of all s u bjects at I n D9 is e x pecte d t o be 
≥5, 0 0 0 parasites/ m L . H o we ver, s u bjects ca n be a d mi nistere d M 5 7 1 7 at a n y ti me p oi nt bef ore or 
after I n D 9 at t he I n vesti gat ors discreti o n base d o n parasite mia a n d/ or cli nical s y m pt o ms.
T he t otal d urati o n of partici pati o n i n Part C of t he trial is a p pr o xi matel y  8 0 da ys f or eac h s u bject, 
i ncl u di n g a Scree ni n g peri o d of u p t o 2 8 da ys, 8 da ys f or t he I B S M i nc u bati o n peri o d, a n d 4 4 da ys 
of F oll o w -u p after treat me nt wit h M 5 7 1 7.
A sc he matic prese ntati o n of t he Part C trial desi g n is prese nte d i n  Fi g ure 7.
Fi g ure 7
Sc he m atic Tri al Desi g n P art C
I M P = I n v e sti g ati o n al m e di ci n al pr o d u ct; I V = i ntr a v e n o u s; P C R = p ol y m er a s e c h ai n r e a cti o n.
Fi g ure 8 dis pla y s t he p ossi ble relati o ns hi ps bet wee n Part A a n d Part C of t he trial, i n case P K, 
safety, a n d t olera bilit y data fr o m t he first 2 c o h orts s u p p ort a d mi nisteri n g a t olera ble si n gle d ose 
t hat c o vers a n 8-d a y  peri o d wit h c o nce ntrati o ns well a b o ve t he M P C, ie, 1 0 n g/ m L. T he S M C will 
assess o n t he basis of acc u m ulate d e x p os ure a n d safety data, if Part C ca n be i nitiate d after t he 
sec o n d c o h ort i n Part A (S A D 2: 1 0 0 m g), or if f urt her si n gle d ose(s) i n Part A nee d t o be 
i n vesti gate d bef ore i nitiati o n of Part C at t he a p pr o priate, t o be deter mi ne d, pre dicte d E D .
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
6 0 / 1 9 0
res p o nsi ble f or mai ntai ni n g a n acc urate i n ve nt or y a n d acc o u nta bilit y rec or d of dr u g s u p plies f or 
t his trial.

Ria met ( 2 0 m g  arte met her a n d 1 2 0 m g l u mefa ntri ne) oral ta blets. A c o urse of treat me nt 
c o m prises 6 d oses of 4 ta blets eac h (t otal c o urse of 2 4 ta blets) gi ve n over a peri o d of 6 0 h o urs. 
F o ur oral ta blets are a d mi nistere d as a si n gle-d ose, a d mi nist ere d t wice dail y  at 1 2 h o ur i nter vals, 
ie, ti me 0, 1 2 h o urs, 2 4 h o urs, 3 6 h o urs, 4 8 h o urs, a n d 6 0 h o urs. Eac h d ose of ta blets 
a d mi nistere d orall y s h o ul d be c o ns u me d wit h f o o d 

Pri maci n ( 7. 5 m g pri ma q ui ne p h os p hate) oral ta blets: T o clear ga met oc y tes of P. falci par u m, 
s u bjects will recei ve 4 5 m g as a si n gle d ose wit h f o o d at t he e n d of t heir Ria met treat me nt if 
ga met oc y tes are i de ntifie d b y ga met oc yte-s pecific P C R.
C o m p uls or y  co m me nce me nt of cleara nce me dicati o n will occ ur n o later t ha n 2 1 d a y s after t he last 
d ose of M 5 7 1 7 . A d mi nistrati o n of resc ue me dicati o ns pri or t o Da y  22 will be deter mi ne d at t he 
I n vesti gat or’s discreti o n usi n g t he f oll o wi n g criteria:

Fail ure of cleara nce: defi ne d as fail ure t o clear parasite mia b y  at least 1 0-f ol d at 7 2 h o urs p ost 
I M P a d mi nistrati o n

Recr u desce nce: defi ne d as ≥ 5 0 0 0 bl o o d sta ge parasites/ m L  an d a 2- f ol d parasite mia i ncrease 
wit hi n 4 8 h o urs, or re -occ urre nce of malaria s y m pt o ms wit h a ma laria cli nical sc ore > 6.
Earl y i nter ve nti o n ca n occ ur if eit her p o or res p o nses or fast res p o nses are see n f oll o wi n g M 5 7 1 7
treat me nt. T his fle xi bilit y is desi g ne d t o e ns ure s u bject safety a n d t o a v oi d s u bject i nc o n ve nie nce 
if usef ul data ca n n ot be o btai ne d . H o we ver, pre -e m pti ve resc ue treat me nt ca n c o m me nce w he ne ver 
dee me d necessar y  b y t he I n vesti gat or.
S u bjects will be m o nit ore d, eit her i n t he trial site, or b y tele p h o ne f or 3 d a y s t o e ns ure a d here nce 
t o t he resc ue me dicati o n t hera py. I n a n y case, safet y assess me nts s h o ul d be perf or me d pri or t o 
a d mi nistrati o n of t he resc ue me dicati o n a n d rec or de d i n t he e C R F.
Bl o o d a n d uri ne sa m ples will be c ollecte d f or safety e val uati o n ( he mat ol o g y, bi oc he mistr y , 
c oa g ulati o n , uri nal ys is, a n d 
) as will bl o o d sa m ples f or P K t hr o u g h o ut t he resi de ntial a n d 
a m b ula nt peri o d (at ti me p oi nts i n dicate d i n Ta ble 3 ). T his will i ncl u de he mat ol o g y , bi oc he mistr y ,
E C G, vital si g ns, p h y sical e xa mi nati o n, c oa g ulati o n pr ofile a n d uri nal y sis. H o we ver, ser ol o g y, re d 
bl o o d cell a ut o-a nti b o dies , a n d ser u m st ora ge c ollecti o n will still be c ollecte d at D a y  22 re gar dless 
of t he st u d y  d a y t hat resc ue me dicati o ns are a d mi nistere d.
D oc u me nt N o
O bject N o
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
6 1 / 1 9 0
5. 2. 8
S afet y M o nit ori n g C o m mittee a n d Decisi o n Criteri a
T he S M C will be set u p as descri be d i n t he S M C c harter. 
T he S M C will dete r mi ne:

D ose escalati o n / de-escalati o n

T er mi nati o n of f urt her d ose escalati o n i n Part A if it is e x pecte d t hat f urt her escalati o n will n ot 
be t olerate d or if it is deter mi ne d t hat a ma xi m u m e x p os ure ma y  be reac he d ( Secti o n 5. 5. 3)

T he nee d t o start a m ul ti ple d osi n g re gi me n i n Part B

T he ti mi n g t o start Part C

T he res pecti ve d ose(s) a n d d ose escalati o ns t o be e val uate d i n Part B a n d Part C

Re q uest u n bli n di n g of data, if dee me d necessar y

S us pe nsi o n of e nr oll me nt, trial m o dificati o n, or trial ter mi nati o n.
P art A a n d P art B
T he S M C will re g ularly meet at a p pr o xi matel y Da y 25 afte r all s u bjects i n a gi ve n S A D/ M A D 
c o h ort ha ve recei ve d a d mi nistrati o n of M 5 7 1 7 or matc hi n g place b o. A me dical m o nit ori n g re p ort 
s u m marizi n g all safet y an d t olera bilit y data ( A Es, safety la b orat or y data, E C G , a n d vital si g ns) 
c ollecte d fr o m mi ni mall y  6 su bj ects u p t o a n d i ncl u di n g D a y  1 1 (ar o u n d 1 me dia n h alf -life) f or 
S A D c o h orts will be pr o vi de d t o t he S M C f or re vie w. T he me dical m o nit ori n g re p ort ma y  als o 
i ncl u de a s u m mar y of t he safety data f or all pre vi o us d ose c o h orts, w he n a p pr o priate. T he first 
2 S M C meeti n gs i n t he S A D part ( Part A) will als o c o ntai n P K data fr o m 6 s u bjects u p t o 1 4 4 h o urs
p ost d ose . F or later S M C meeti n gs, P K data of t he prece di n g c o h ort (s) will be re vie we d as 
a p plica ble t o s u p p ort t he safety a n d t olera bility assess m e nt, as dee me d necessar y  by t he S M C . 
Safet y  la b orat or y an d P K data i ncl u de d i n t he m o nit ori n g re p ort t o be pr o vi de d t o t he S M C will 
u n der g o q ualit y  c o ntr ol b y t he res pecti ve la b orat or y(ies) res p o nsi ble f or t his data. 
I n a d diti o n, t he S M C ca n m o dif y  PK sa m pli n g ti mes a nd/ or E C G rec or di n g ti mes base d o n ne w 
i nf or mati o n recei ve d (eg, t o better ali g n wit h ti mi n g of tma x ) b ut is n ot all o we d t o i ncrease t he 
n u m ber of P K sa m pli n g p oi nts u nless b y  a me n di n g t he cli nical trial pr ot oc ol. 
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
6 2 / 1 9 0
I n case of a safet y c o n cer n, t he S M C me m bers are all o we d t o re q uest i m me diate u n bli n di n g of t he 
data. I n t he pi v otal t o xic ol o g y st u dies, v o miti n g a n d diarr hea were i de ntifie d as d ose -li miti n g 
e ve nts, s o t hese e ve nts will be caref ull y mo nit ore d. T he S M C m a y  als o re q uest access t o u n bli n de d 
P K data i n case t he nee d arises , t o e val uate t he c orrelati o n bet wee n e x p os ure a n d safety data 
re vie we d by t he S M C.
O nce t he S M C has defi ne d a d ose, base d o n safet y data, t hat d oes n ot all o w f urt her escalati o n of 
t he d ose, t he S M C ma y  rec o m me n d testi n g l o wer d oses acc or di n g t o t he sa me Sc he d ule of 
Assess me nts as f or t he ot her c o h orts, if t his is dee me d necessar y  to bet ter c haracterize t he safety 
a n d/or P K pr ofile of M 5 7 1 7 pri or t o ter mi nati o n of Part A.
P art C
T he S M C will re vie w all a vaila ble safety ( u p t o at least Da y  11) a n d P K/ P D data ( u p t o at least 
D a y  9) after s u bjects of eac h c o h ort ha ve bee n treate d a n d will deci de w het her a n a d diti o nal c o h ort 
nee ds t o be i ncl u de d, as well as t he d ose t o be i n vesti gate d i n t hat c o h ort. I n pri nci ple, a ma xi m u m 
of 3 d oses are f oresee n t o acc uratel y descri be t he P K/ P D c orrelati o n . I n a d diti o n, t he S M C ma y 
m o dif y  PC R sa m pli n g ti mes a n d t he n u m ber of sa m ples base d o n ne w i nf or mati o n recei ve d (e g, t o 
better ali g n wit h ti mi n g of t he P R R).
5. 2. 9
J ustific ati o n f or D ose
I n refere nce t o its m o de of acti o n, t he selecti vit y of t he e E F2 tar get f or Plas m o di u m a n d t he 
a vaila bilit y of data fr o m a rele va nt a ni mal s pecies m o del f or pre dicti n g h u ma n res p o nses, M 5 7 1 7 
was n ot classifie d as a hi g h -ris k m olec ule a n d t he N O A E L a p pr oac h was a p plie d t o s u p p ort t he 
starti n g d ose. 
T he starti n g d ose f or t he first h u ma n use of M 5 7 1 7 was deter mi ne d base d o n t he f oll o wi n g fact ors 
w hic h are detaile d i n t he f oll o wi n g secti o ns:

I de ntificati o n of a M R S D, usi n g t he N O A E L i de ntifie d i n pi v otal G L P t o xic ol o g y st u dies i n 
t he m ost se nsiti ve s pecies, as rec o m me n de d b y  the F D A G ui da nce Esti mati n g t he Ma xi m u m 
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
6 3 / 1 9 0
Safe Starti n g D ose i n I nitial Cli nical Trials f or T hera pe utics i n A d ult Healt h y V ol u nteers 2 0 0 5
( 7)

C o nsi derati o n of N O A E L e x p os ures reac he d i n a ni mal t o xicit y  st u dies

P K/ P D m o deli n g of pre cli nical data f or t he p ur p ose of pre dic ti n g t he E D ra n ge i n h u ma ns.
I n t he 1 4- d a y  to xic ol o g y trial i n d o gs, M 5 7 1 7 was a d mi nistere d orall y  2 ti mes f or a peri o d of 
3 da y s wit h 2 d a y s i n bet wee n, f oll o we d b y  4 da ys of treat me nt. I n t he 1 4- da y  to xic ol o g y  trial i n 
rats, M 5 7 1 7 was a d mi nistere d orall y  2 ti mes f or a peri o d of 3 d a y s, wit h 6 d a y s i n bet wee n. A n 
e xte nsi ve s u m mar y of all t o xic ol o g y fi n di n gs is gi ve n i n t he I B. T he mai n o bser vati o ns are 
s u m marize d i n Ta ble 5 al o n g wit h t he pla n h o w t o a de q uatel y m o nit or t hese p ote ntial fi n di n gs. 
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
6 4 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
6 5 / 1 9 0
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
6 6/ 1 9 0
a n d gl o mer ular p o d oc y tes occ urs fre q ue ntly, wit h t he de vel o p me nt of t he re nal t o xicities of 
a mi n o gl yc osi des a n d c hl or o q ui ne, res pecti vel y. 
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
6 7 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
6 8 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
6 9 / 1 9 0
5. 2. 1 0
I ncl usi o n of S peci al P o p ul ati o ns
N ot a p plica ble .
5. 2. 1 1
R ati o n ale f or E n d p oi nts
Sta n dar d safet y, t olera bilit y a n d P K of M 5 7 1 7 will be deter mi ne d usi n g t he f oll o wi n g para meters: 

N at ure, i nci de nce, a n d se verity of A Es /S A Es , i ncl u di n g relati o ns hi p t o trial treat me nt, 
A Es/ S A Es lea di n g t o d ose m o dificati o n or disc o nti n uati o n of trial treat me nt

Safet y  la b orat or y para meters ( he mat ol o g y, c oa g ulati o n, bi oc he mistr y [s pecifically A L T a n d 
A S T], uri nal y sis, a n d 
)
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
7 0 / 1 9 0

Vital si g ns ( b o d y te m perat ure, B P , heart rate), res pirat or y rate, a n d 1 2- lea d E C G. T he di g ital 
1 2- lea d E C G will be use d f or c o nc e ntrati o n Q Tc a nal ys is

Bl o o d c o nce ntrati o ns of M 5 7 1 7 will be use d t o deter mi ne t he sta n dar d PK para meters i n eac h 
trial part

P R R , P C T , a n d MIC are vali date d e n d p oi nts f or P K/ P D a nal ysis of malaria c o m p o u n ds
5. 3
Selecti o n of Tri al P o p ul ati o n
O nl y pers o ns meeti n g all i ncl usi o n criteria a n d n o ne of t he e xcl usi o n cr iteria ma y be e nr olle d i nt o 
t he trial as s u bjects. Pri or t o perf or mi n g a n y trial assess me nts n ot part of t he s u bject’s r o uti ne 
me dical care, t he I n vesti gat or will e ns ure t hat t he s u bject has pr o vi de d writte n i nf or me d c o nse nt 
f oll o wi n g t he pr oce d ure descri be d i n Secti o n 9. 2.
I ncl usi o n a n d e xcl usi o n criteria are t o be c hec ke d at Scree ni n g a n d Da y -1/ Da y  -2 of Part A a n d 
Part B u nless ot her wise state d. 
F or Part C t he criteria ha ve t o be c hec ke d at Scree ni n g, pri or t o i n oc ulati o n a n d a gai n pri or t o I M P 
a d mi nistrati o n.
5. 3. 1
I ncl usi o n Criteri a
1.
A d ult me n a n d W N C B P,
1 8 t o 5 5 ye ars of a ge (i ncl usi ve), wit h t otal b o d y wei g ht ≥ 5 0. 0 k g 
a n d b o d y mass i n de x ( BMI ) bet wee n 1 9. 0 k g/ m2 a n d 2 9. 9 k g/ m 2 (i ncl usi ve). 
2.
A fe male s u bject is eli gi ble t o partici pate if s he is n ot breastfee di n g a n d n ot a w o ma n of 
c hil d beari n g p ote ntial ( W O C B P as defi ne d i n A p pe n di x I) c o nfir me d at S cree ni n g b y  fulfilli n g 
o ne of t he f oll o wi n g criteria:
a.
P ost me n o pa usal defi ne d as ha vi n g a me n orr hea f or ≥ 1 2 c o nsec uti ve m o nt hs f oll o wi n g 
cessati o n of all e x o ge n o us h or m o nal treat me nts , a n d i ncrease d f ollicle-sti m ulati n g 
h or m o ne ( F S H) > 4 0 mI U/ m L.
b.
D oc u me ntati o n of irre versi ble s ur gical sterilizati o n b y h ysterect o m y, bilateral 
o o p h orect o m y , or bilateral sal pi n gect o m y. Tu bal li gati o n al o ne is n ot s ufficie nt .
3.
A male par tici pa nt m ust a gree t o use a c o n d o m wit h or wit h o ut s per mici de d uri n g se x ual 
acti vit y wit h a fe male pa rt ner of c hil d beari n g p ote ntial a n d t o ha ve t heir fe male part ner use a 
hi g hl y effecti ve c o ntrace pti o n (ie, met h o ds wit h a fail ure rate of less t ha n 1 % pe r ye ar) as 
detaile d i n A p pe n di x I of t his pr ot oc ol, d uri n g t he treatme nt peri o d a n d f or at least 2 0 wee ks 
after t he last d ose of I M P a d mi nistrati o n a n d t o refrai n fr o m d o nati n g s per m d uri n g t his peri o d.
4.
Healt h y as assesse d b y t he I n vesti gat or wit h n o cli nicall y si g nifica nt a b n or malit y  ide ntifie d o n 
p h y sical e xa mi nati o n or la b orat or y eval uati o n a n d n o acti ve cli nicall y si g nifica nt dis or der, 
c o n diti o n, i nfecti o n or disease t hat wo ul d p ose a ris k t o s u bject safet y or i nterfere wit h t he trial
e val uati o n, pr oce d ures, or c o m pleti o n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
7 1 / 1 9 0
5.
Sta ble n o n s m o kers f or at least 6 m o nt hs prece di n g Scree ni n g.
6.
A ble a n d willi n g t o c o m pl y wit h restricti o ns o n e x p os ure t o s u nli g ht a n d t o gi ve writte n 
i nf or me d c o nse nt. 
7.
Part C a d diti o nal: D o n ot li ve al o ne (fr o m start of malaria i n oc ulati o n u ntil at least t he e n d of 
t he a nti malarial dr u g treat me nt), willi n g t o pr o vi de c o ntact details of a pers o n li vi n g wit h t he m,
a n d be c o ntacta ble a n d a vaila ble f or t he d ur ati o n of t he trial; n o hist or y  of p ossi ble malaria 
e x p os ure. 
5. 3. 2
E xcl usi o n Criteri a
5. 3. 2. 1
P art A, P art B, a n d P art C
1.
Hist or y  or prese nce of cli nicall y rele va nt res pirat or y, gastr oi ntesti nal, re nal, he patic, 
he mat ol o gical, 
l ym p hatic, 
ne ur ol o gical, 
car di o vasc ular, 
ps yc hiatric, 
m usc ul os keletal, 
ge nit o uri nar y , i m m u n ol o gical, der mat ol o gical, c o n necti ve tiss ue diseases or dis or ders.
2.
Hist or y  of a n y mali g na nc y e xce pt s ur gicall y c ure d s ki n ca ncers.
3.
Hist or y  of rele va nt dr u g h y perse nsiti vit y , ascertai ne d or pres u m pti ve aller g y/ h yperse nsiti vit y  
t o t he acti ve dr u g s u bsta nce a n d/ or f or m ulati o n i n gre die nts; hist or y  of seri o us aller gic reacti o ns 
lea di n g t o h os pitalizati o n or a n y ot her aller gic reacti o n i n g e neral, w hic h t he I n vesti gat or 
c o nsi ders ma y affect t he safety of t he s u bject a n d/ or o utc o me of t he trial. 
4.
Hist or y  of alc o h olis m or dr u g a b use. 
5.
Li ver f u ncti o ns tests :
a.
a b o ve t he la b orat or y refere nce ra n ge t he da y bef ore I M P a d mi nistrati o n (Da y  - 1) f or 
Par t A a n d Part B 
b.
≥ 3 × U L N f or I n oc ul u m Da y 8 i n Part C . 
6.
Creati ni ne cleara nce < 9 0 m L / mi n as esti mate d usi n g t he C oc kcr oft a n d Ga ult e q uati o n at 
Scree ni n g. 
7.
Se mi -s u pi ne B P > 1 4 0/ 9 0 m m H g at Da y -1 (t his ma y  be re peate d o nce). 
8.
Electr ocar di o gra m s h o ws a Q T inter val c orrecte d f or heart rate acc or di n g t o Fri dericia’s 
f or m ula (Q Tc F ) > 4 5 0 ms, P R > 2 1 0 ms, Q R S D > 1 2 0 ms at Scree ni n g a n d pre d ose. 
9.
C o ns u m pti o n of a n a vera ge wee kl y i nta ke of > 1 4 dri n ks/ wee k f or me n or > 7 dri n ks/ wee k f or 
w o me n. O ne dri n k is e q ui vale nt t o 1 2 g alc o h ol = 5 o u nces ( 1 5 0 m L ) of wi ne or 1 2 o u nces 
( 3 6 0 m L) of beer or 1. 5 o u nces ( 4 5 m L ) or 8 0-pr o of distille d s pirits.
1 0. P ositi ve f or he patitis B s urface a nti ge n, he patitis B c ore a nti b o d y, he patitis C a nti b o d y or 
h u ma n i m m u n o deficie nc y vir us ( HI V) I a n d II tests at Scree ni n g.
1 1. P ositi ve f or dr u gs of a b use, n ic oti ne/c oti ni ne or alc o h ol o n Scree ni n g or (eac h) a d missi o n .
1 2. Use of a n y i n vesti gati o nal dr u g i n a n y c li nical trial wit hi n 9 0 d a y s fr o m t he last a d mi nistrati o n, 
or o n e xte n de d f oll o w-u p i n a clinical trial, e ve n if t he last a d mi nistrati o n of a n I M P was 
> 9 0 d a y s a g o.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
7 2 / 1 9 0
1 3. D o nati o n or l oss of m ore t ha n 4 5 0 m L  of bl o o d i n t he 9 0 da y s pri or t o Scree ni n g.
1 4. E xcessi ve c o ns u m pti o n of xa nt hi ne -c o ntai ni n g f o o d or be vera ges ( > 5 c u ps of c offee per d a y  
or e q ui vale nt) or i na bilit y to st o p c o ns u mi n g caffei ne, fr o m 4 8 h o urs
pri or t o I MP
a d mi nistrati o n u ntil 4 8 h o ur s after I M P a d mi nistrati o n.
1 5. I nta ke of gra pefr uit, Se ville ora n ge s, cra n berries , star fr uit or juices of t hese fr uits, as well as 
q ui ni ne -c o ntai ni n g f o o d/ be vera ges (e g, t o nic water, bitter le m o n), wit hi n 1 4 da y s pri or t o I MP
a d mi nistrati o n u ntil t he e n d of t he resi de ntial peri o d .
1 6. I ngesti o n of a n y p o p p y s ee ds wit hi n 2 4 h o urs pri or t o eac h Dr u g A b use Scree ni n g.
1 7. Use of a n y prescri be d me dici ne or o ver -t he-c o u nter dr u g ( ot her t ha n occasi o nal i b u pr ofe n 
[ < 1 g] or paraceta m ol [ < 1 g], or vita mi ns a n d mi nerals) wit hi n 2 wee ks/ 5 ti mes t he h alf-life
of t he res pecti ve dr u g, w hic he ver is t he l o n ger, pri or t o t he first a d mi nistrati o n of I M P. See 
Secti o n 6. 5 f or details re gar di n g per mitte d/ pr o hi bite d me dicati o ns t hr o u g h o ut t he d urati o n of 
t he trial.
1 8. Use of dr u gs a n d her bal re me dies wit h e nz yme i n d uci n g pr o perties s uc h as St. J o h n’s W ort, 
wit hi n 4 wee ks bef ore t he first a d mi nistrati o n of I MP u ntil t he E n d of Trial visit . See 
Secti o n 6. 5 f or details re gar di n g per mitte d/ pr o hi bite d me dicati o ns t hr o u g h o ut t he d urati o n of 
t he trial.
1 9. I na bilit y to refrai n fr o m ta ki n g u p a n y ne w u nacc ust o me d e xercise fr o m Scree ni n g u ntil t he 
E n d of Trial visit . 
2 0. I na bilit y t o c o m m u nicate relia bl y wit h trial site pers o n nel or c o nsi dere d b y t he I n vesti gat or t o
be u na ble t o or u nli kel y t o c o o perate wit h t he re q uire me nts of t he trial.
2 1. Ha vi n g s ki n T y pe I, ie, al wa ys b ur ns, ne ver ta ns ( pale peac h c o m ple xi o n; bl o n d or re d hair; 
b l ue e yes; frec kles; acc or di n g t o t he Fitz patric k scale i n A p pe n di x V I).
5. 3. 2. 2
A d diti o n al f or P art C
2 2. A n y  hist or y of malaria.
2 3. Partici pati o n i n a pre vi o us malaria vacci ne trial.
2 4. Partici pati o n i n a pre vi o us h u ma n malaria c halle n ge trial.
2 5. Has tra velle d t o or li ve d (> 2 wee ks) i n a malaria -e n de mic area/re gi o n d uri n g t he past 
1 2 m o nt hs.
Malaria -e n de micit y 
will 
be 
assesse d 
b y  
co ns ulti n g 
htt ps:// ma p. o x.ac. u k/c o u ntr y -pr ofiles/ #!/ .
2 6. Pla n t o tra vel t o a malaria -e n de mic area/re gi o n d uri n g t he c o urse of t he trial.
2 7. Has e vi de nce of i ncrease d car di o vasc ular disease ris k ( defi ne d as 5 -ye ar ris k > 1 0 %, f or t h ose 
> 3 5 ye ars of a ge, as deter mi ne d b y  the A ustralia n A bs ol ute Car di o vasc ular Disease Ris k
Calc ulat or. Ris k fact ors i ncl u de se x, a ge, s yst olic B P
( m m/ H g), s m o ki n g stat us, t otal 
c h olester ol a n d hi g h -de nsit y  li p o pr otei n ( H D L) c h olester ol ( m m ol/ L), a n d re p orte d dia betes 
stat us.
2 8. Fre q ue nt hea dac hes a n d/ or mi grai ne, rec urre nt na usea, a n d/ or v o miti n g (> 2 ti mes per m o nt h).
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
7 3 / 1 9 0
2 9. Prese nce of ac ute i nfecti o us disease or fe ver (ie, s u bli n g ual te m perat ure ≥ 3 8. 0° C) wit hi n t he 
5 da y s pri or t o i n oc ulati o n wit h malaria parasites.
3 0. Hist or y  of s ple nect o my.
3 1. Partici pa nt u n willi n g t o defer bl o o d d o nati o ns f or 6 m o nt hs.
3 2. P artici pa nt w h o has pre vi o usl y  recei ve d a bl o o d tra nsf usi o n a n d/ or tests p ositi ve f or re d bl o o d 
cell a nti b o dies.
3 3. A n y  cortic oster oi ds, a nti-i nfla m mat or y dr u gs, i m m u n o m o d ulat ors or a ntic oa g ula nts i n t he past 
3 
m o nt hs. 
A n y  
partici pa nt 
c urre ntl y 
recei vi n g 
or 
ha vi n g 
pre vi o usl y  
recei ve d 
i m m u n os u p pressi ve 
t hera py, 
i ncl u di n g 
s yste mic 
c ortic oster oi ds 
i ncl u di n g 
a dre n oc ortic otr o p hic h or m o ne or i n hale d ster oi ds i n d osa ges w hic h are ass ociate d wit h 
h y p ot hala mic -pit uitar y -a dre nal a xis s u p pressi o n or c hr o nic use of i n hale d hi g h -p ote nc y 
c ortic oster oi ds.
3 4. A n y  rece nt (wit hi n 6 wee ks fr o m Scree ni n g) or c urre nt sys te mic t hera p y wit h dr u gs k n o w n t o 
ha ve 
p ote ntial 
a nti malarial acti vit y eg,
tri met h o pri m/s ulfa met h o xaz ole, tetrac ycli ne, 
d o x y c ycli ne, er yt hr o myci n, clarit hr o m yci n, azit hr o m yci n, cli n da m yci n, rifa m pici n, ne wer 
q ui n ol o nes, 
be nz o diaze pi nes, 
fl u narizi ne, 
fl u o xeti ne, 
met h otre xate, 
c hl or o q ui ne, 
h y dr o x yc hl or o q ui ne.
3 5. K n o w n aller g y or a d versit y to o ne of t he resc ue me dicati o n pr o p ose d f or t he c halle n ge trial
i ncl u di n g k n o w n or c o nfir me d deficie nc y  f or gl uc ose-6- p h os p hate de h y dr o ge nase ( G 6 P D).
5. 4
Criteri a f or I niti ati o n of Tri al Tre at me nt
S u bjects w h o f ulfill t he eli gi bilit y criteria will be e nr olle d i nt o t he trial. Ra n d o mizati o n pr oce d ures 
f or Part A a n d Part B are descri be d i n Secti o n 8. 2.
5. 5
Criteri a f or S u bject Wit h dr a w al
5. 5. 1
Wit h dr a w al fr o m Tri al Tre at me nt
As o nl y  a si n gle d ose will be gi ve n i n Part A, s u bjects ca n n ot be wit h dra w n fr o m treat me nt b ut 
ca n be wit h dra w n fr o m t he trial (see Secti o n  5. 5. 2 ). I n ad diti o n t o t he r ules f or wit h dra wal fr o m 
t he trial, s u bjects i n Part B m ust be wit h dra w n fr o m f urt her treat me nt wit h t he I MP if a n y of t he 
f oll o wi n g occ urs: 

Meets a n e xcl usi o n criteri o n as liste d i n Secti o n  5. 3. 2

Use of a n o n per mitte d c o nc o mita nt me dicati o n. H o we ver, a n y  me dicati o ns t hat are c o nsi dere d 
necessar y  f or t he s u bject’s well bei n g ma y be gi ve n at t he discreti o n of t he I n vesti gat or

A Es, if disc o nti n uati o n of I M P is desire d or c o nsi dere d necessar y  by t he I n vesti gat or a n d/ or t he 
s u bject

Pr ot oc ol n o nc o m plia nce j u d ge d as si g nifica nt b y t he I nvesti gat or a n d/ or t he S p o ns or i ncl u di n g 
n o nc o m plia nce t o t he re q uire d trial c o nsi derati o ns (e g, caffei ne i nta ke/f o o d/ diet re q uire me nts)

A n y  e ve nts t hat u nacce pta bl y e n da n ger t he safety of t he s u bject
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
7 4 / 1 9 0

A L T or A S T > 5 x U L N

A L T or A S T > 3 x U L N a n d t otal bilir u bi n > 2 x U L N or I nter nati o nal N or malize d Rati o [IN R] 
> 1. 5

A L T o r A S T > 3 x U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt 
pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %).
M 5 7 1 7 a d mi nistrati o n will be s us pe n de d a n d a s u bject will be wit h dra w n fr o m t he I M P f or a n y o f 
t he a b o ve e ve nts a n d a p pr o priate me dical care will be pr o vi de d. S u bjects wit h dra w n fr o m t he I M P 
m ust c o m plete t he E n d of Trial visit as descri be d i n t he Sc he d ule of Assess me nts (Ta ble 1 t o 
Ta ble 3) . I n a n y case, t he a p pr o priate electr o nic case re p ort f or m (e C R F) secti o n m ust be 
c o m plete d.
5. 5. 2
Wit h dr a w al fr o m t he Tri al
S u bjects ma y wit h dra w fr o m t he trial at a n y ti me wit h o ut gi vi n g a reas o n. Wit h dra wal of c o nse nt 
will be c o nsi dere d wit h dra wal fr o m t he trial. W here ver p ossi ble, s u bjects will be f oll o we d u p u ntil 
4 4 da y s f oll o wi n g a d mi nistrati o n of M 5 7 1 7 a n d t he y will be as ke d t o c o m plete t he E n d of Trial 
visit.
A s u bject m ust be wit h dra w n i f a n y of t he f oll o wi n g occ ur d uri n g t he trial:

Use of a n o n per mitte d c o n c o mita nt me dicati o n. H o we ver, a n y me dicati o ns t hat are c o nsi dere d 
necessar y  f or t he s u bject’s well bei n g ma y be gi ve n at t he discreti o n of t he In vesti gat or

Pr ot oc ol n o nc o m plia nce j u d ge d as si g nifica nt b y  t he I n vesti gat or, i ncl u di n g n o nc o m plia nce t o 
t he re q uire d trial c o nsi derati o ns (e g, caffei ne i nta ke/ f o o d/ diet re q uire me nts)

S u bject l ost t o f oll o w - u p

Partici pati o n i n a n ot her cli nical trial d uri n g t he d urati o n of t his trial

A n y  e ve nts t hat u nacce pta bl y e n da n ger t he safet y of t he s u bject (e g, occ urre nce of a n S A E)

A L T or A S T > 5 x U L N. ( Part A a n d Part B; Part C bef ore I M P a d mi nistrati o n )

A L T or A S T > 3 x U L N, a n d t otal bilir u bi n > 2 x  UL N or I N R > 1. 5 ( Part A a n d Part B; Part C 
bef ore I M P a d mi nistrati o n )

A L T o r A S T > 3 x U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt 
pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %). ( Part A a n d Part B; Part C bef ore 
I M P a d mi nistrati o n ).
I n case li ver f u ncti o n test dera n ge me nts are o bser ve d, t he S M C w o ul d nee d t o re vie w t he data; t he 
s u bjects w h o ha ve bee n treate d wit h M 5 7 1 7 will be f oll o we d u p a n d
mi g ht re mai n o n trial, rat her 
t ha n bei n g wit h dra w n, u nless a decisi o n is ma de ot her wise b y t he I n vesti gat or a n d/ or t he S M C.
If a s u bject has faile d t o atte n d sc he d ule d trial assess me nts, t he I n vesti gat or m ust deter mi ne t he 
reas o ns a n d t he circ u msta nces as c o m pletel y a n d acc uratel y as p ossi ble. If t here is a me dical reas o n 
f or t he wit h dra wal, t he s u bject will re mai n u n der t he s u per visi o n of t he I nvesti gat or u ntil 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
7 5 / 1 9 0
satisfact or y healt h has ret ur ne d or care has bee n tra nsferre d t o t he s u bject’s ge neral practiti o ner or 
t o a h os pital c o ns ulta nt. I n case a s u bject has t o be wit h dra w n fr o m t he trial, t he Trial M o nit or a n d  
Cli nical Trial L ea der at t he L o cal a n d F u n di n g S p o ns or s will be i nf or me d i m me diatel y. T he nee d 
f or re place me nt of s u bjects will be disc usse d wit h t he S p o ns or o n a case-b y -case deter mi nati o n. 
F urt her details o n s u bject re place me nt are pr o vi de d i n Secti o n  8. 2.
5. 5. 3
Tri al St o p pi n g R ules
Al o n g wit h t he P K e val uati o ns d uri n g d ose -escalati o n i n Part A a n d Part B, st o p pi n g r ules will be 
use d t o deter mi ne w het her f urt her d ose escalati o n s h o ul d be st o p pe d. D ose escalati o n ma y  b e 
st o p pe d if it is deter mi ne d t hat t he li mits of safet y a n d/ or t olera bilit y ha ve bee n reac he d or w he n 
a n e x p os ure a b o ve t he N O A E L is f oresee n/reac he d. T his decisi o n will be ma de after re vie w of t he 
acc u m ulati n g data b y  the S M C. T he S M C ma y  not o verr ule t he I n vesti gat ors’ decisi o n t o st o p d ose 
escalati o n. If d ose escalati o n is st o p pe d d ue t o a n y of t hese fi n di n gs, a d diti o nal c o h orts m a y  recei ve 
i nter me diate d oses of M 5 7 1 7 pr o vi de d t hese d oses are c o nsi dere d b y  the S M C as li kel y to be 
t olerate d a n d t o pr o vi d e a d diti o nal scie ntific val ue.
D ose escalati o n i n Part A a n d Part B will be s us pe n de d a n d f urt her re vie w c o n d ucte d b y t he S M C, 
if a n y of t he f oll o wi n g c o n diti o ns are met wit hi n a gi ve n c o h ort:

A n S A E occ urs i n 1 or m ore dr u g -treate d s u bjects a n d is s h o w n to be relate d t o I M P

T w o ( 2) or m ore dr u g -treate d s u bjects ha vi n g Q ualitati ve T o xicit y  Scale ( Q T S) Gra de 3 ( or 
hi g her) e ve nts i n t he sa me or ga n or b o d y s ys te m

Fift y  (5 0) perce nt or m ore of dr u g -treate d s u bjects ha vi n g a Q T S Gra de 2 ( or hi g her) e ve nt i n 
t he sa me or ga n or b o dy s ys te m

A n y  ot her e ve nt i n dr u g-treate d s u bjects occ urs a n d is dee me d t o p ose a n u nacce pta ble ris k t o 
s u bjects. 

If, base d o n t he o bser ve d P K data, t he gr o u p mea n A U C0-t ( base d o n t otal bl o o d c o nce ntrati o n) 
of t he ne xt pla n ne d d ose is pr o jecte d t o e xcee d t he e x p os u re at t he N O A E L 
( 3 2 0, 0 0 0 n g × h/ m L) t hat d ose mi g ht n ot be e x pl ore d. M o difie d d oses ma y  be e x pl ore d if t he y 
are n ot e x pecte d t o e xcee d t he P K st o p pi n g criteria.

O nce it is c o nfir me d b y  the S M C, after re vie w of t he data, t hat o ne of t hese criteria has bee n 
met a n d dr u g -relate d ness has bee n esta blis he d, d ose-escalati o n will be st o p pe d.
I n case of a n S A E, d osi n g will cease if t he S A E is deter mi ne d t o be eit her dr u g -relate d or u n k n o w n. 
Eac h S A E will be f oll o we d u ntil res ol uti o n or d ur i n g 5 half-li ves of M 5 7 1 7.
If t he trial is ter mi nate d, s u bjects w h o ha ve recei ve d M 5 7 1 7 
will be f oll o we d f or safety 
assess me nts as descri be d i n t he E n d of Trial visit.
5. 6
Pre m at ure Ter mi n ati o n of t he Tri al
T he cli nical trial m a y  be ter mi nate d pre mat urel y or sus pe n de d at t he re q uest of t he S p o ns or, t he 
PI , t he et hics c o m mittee, or t he S M C i n case n e w safet y or efficac y i nf or mati o n lea ds t o a n 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
7 6 / 1 9 0
u nfa v ora ble ris k-be nefit j u d g me nt f or t he I M P. A d diti o nall y , t he S p o ns or ma y  disc o nti n ue t he trial
if it bec o mes u nj usti fia ble f or me dical or et hical reas o ns, f or p o or e nr oll me nt, or beca use of
disc o nti n uati o n of cli nical de vel o p me nt of t he I MP or f or safet y reas o ns.
L ocal Healt h A ut h orities ( T hera pe utic G o o ds A d mi nistrati o n) a n d t he I n de pe n de nt Et hics 
C o m mittee (IE C ) (
- H R E C) will be i nf or me d a b o ut t he disc o nti n uati o n of t he trial i n 
acc or da nce wit h a p plica ble re g ulati o ns.
5. 7
Defi niti o n of E n d of Tri al
F or a d mi nistrati ve a n d safet y  re p orti n g p ur p oses, t he e n d of trial will be defi ne d as t he d a y  of t he 
last s u bject’s last visit.
6
I n vesti g ati o n al Me dici n al Pr o d uct a n d Ot her Dr u gs Use d i n 
t he Tri al
T he ter m “ I M P” refers t o a p har mace utical f or m of a n acti ve s u bsta nce or a place b o bei n g teste d 
or use d as a refere nce treat me nt or t hera py i n a cli nical trial, i ncl u di n g pr o d uc ts t hat ha ve a 
mar keti n g a ut h orizati o n b ut are f or m ulate d, pac ka ge d , or a d mi nistere d differe ntl y  fr o m t he 
a ut h orize d f or m, use d f or a n u na ut h orize d i n dicati o n, or use d t o gai n f urt her i nf or mati o n a b o ut t he 
a ut h orize d f or m .
6. 1
Descri pti o n of t he I n vesti g ati o n al Me dici n al Pr o d uct
M 5 7 1 7: Ca ps ules c o ntai ni n g 1 0 m g, 5 0 m g, or 2 0 0 m g of M 5 7 1 7 
. De pe n di n g o n t he d ose 
t o be a d mi nistere d, t he e xact n u m ber a n d stre n gt h of ca ps ules will be calc ulate d as detaile d i n t he 
p har mac y  ma n ual. 
Place b o: Ca ps u les c o ntai ni n g 5 0 m g  of place b o matc he d t o a si milar n u m ber of ca ps ules wit h 
M 5 7 1 7.
M 5 7 1 7 a n d matc hi n g place b o ha ve t he 
.
6. 2
D os a ge a n d A d mi nistr ati o n
M 5 7 1 7 will be a d mi nistere d i n eac h trial part, as i n dicate d bel o w. I n eac h trial part, su bjects will 
fast fr o m 8 h o urs pri or u ntil 4 h o urs after eac h d ose. Water will be all o we d u p t o 2 h o urs pre d ose 
a n d a gai n after 2 h o urs p ost d ose. T he date a n d ti me of eac h d ose a d mi nistrati o n will be rec or de d 
i n t he e C R F. T he ma xi m u m d ose le vel w h ic h ma y be a d mi nistere d i n t his trial was i nitiall y set at 
6 0 0 m g dail y a n d re-e val uate d t o 1, 5 0 0 m g dail y b y  t he S M C.
Part A: O ne si n gle oral d ose of M 5 7 1 7 or place b o after a n 8- h o ur fasti n g peri o d, ta ke n t o get her 
wit h 2 5 0 m L  of water , f oll o we d b y  a 4- h o ur p ost d ose fast. Water will be all o we d u p t o 2 h o urs 
pre d ose a n d a gai n after 2 h o urs p ost d ose.
Part B: O ne si n gle oral d ose of M 5 7 1 7 or place b o after a n 8 -h o ur pre d ose fasti n g peri o d, ta ke n 
t o get her wit h 2 5 0 m L  of water , f oll o we d b y  a 4-h o ur p ost d ose fast, o n 3 c o nsec uti ve d a y s ( o nce 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
7 8 / 1 9 0
u ntil re q uire d. T he c o nte nts of t he la bel f or dr u g t o be a d mi nistere d t o t he partici pa nts will be i n 
acc or da nce wit h all a p plica ble re g ulat or y  re q uire me nts. T he i n oc ul u m str ai n (P. falci par u m 3 D 7) 
use d i n t he c halle n ge m o del has bee n pr o ve n t o be se nsiti ve t o t he resc ue me dicati o n s.
T he resc ue dr u gs, ie, Ria met, Pri maci n, Malar o ne a n d i ntra ve n o us artes u nate will be i n ve nt orie d 
pri or t o t he be gi n ni n g of trial e nr oll me nt o n trial acc o u nta bilit y l o gs i n re gar ds t o c o n diti o n u p o n 
recei pt, i ncl u di n g l ot n u m bers. T he I n vesti gat or or q ualifie d desi g nee will e ns ure t hat t he recei ve d 
dr u gs are t he s pecifie d f or m ulati o n. T he site p har macist or q ualifie d desi g nee is res p o nsi ble f or 
mai ntai ni n g a n acc urate i n ve nt or y  a n d acc o u nta bilit y rec or d of dr u g s u p plies f or t his trial. 
6. 5
C o nc o mit a nt Me dic ati o ns a n d T her a pies
T he I n vesti gat or will rec or d all c o nc o mita nt me dicati o ns ta ke n b y  the s u bject d uri n g t he trial, fr o m 
t he date of si g nat ure of i nf or me d c o nse nt, i n t he a p pr o priate secti o n of t he e C R F, n oti n g t he na me, 
d ose, d urati o n a n d i n dicati o n of eac h dr u g. C o nc o mita nt
pr oce d ures a n d a n y c ha n ges t o a 
c o nc o mita nt me dicati o n or ot her i nter ve nti o n s h o ul d als o be rec or de d i n t he e C R F.
Me dicati o n hist or y  (3 m o nt hs pri or t o Scree ni n g) m ust be rec or de d, n oti n g t he ge neric na me, 
gale nic f or m, a n d d ose, r o ute of a d mi nistrati o n, d urati o n a n d i n dicati o n of eac h dr u g.
6. 5. 1
Per mitte d Me dici nes
I b u pr ofe n is t he preferre d s y m pt o matic treat me nt f or malaria sy m pt o ms occ urri n g d uri n g t he trial. 
Paraceta m ol , w hic h ma y facilitate li ver e nzy m e ele vati o ns i n t he c o nte x t of malaria i n oc ulati o n i n 
n o n i m m u ne s u bjects, s h o ul d be a v oi de d. D oses of paraceta m ol u p t o 1 g per da y, at t he discreti o n 
of t he I n vesti gat or, ma y  be all o we d b ut o nl y if i b u pr ofe n is c o ntrai n dicate d or c o nsi dere d 
i ns ufficie nt t o treat t he s y m pt o ms. N o ot her c o nc o mita nt me dicati o n or o ver -t he-c o u nter pr o d ucts 
s h o ul d be a d mi nistere d u nless dee me d necessar y b y  the I n vesti gat or. A n y  me dicati o ns t hat are 
c o nsi dere d necessar y  t o pr otect s u bject welfare a n d will n ot i nterfere wit h t he I M P m a y  b e gi ve n 
at t he I n vesti gat or’s discreti o n. Res c ue me dicati o ns ma y  be a d mi nistere d t o a d dress a d verse 
reacti o ns or a ntici pate d e mer ge nc y sit uati o ns.
6. 5. 2
Pr o hi bite d Me dici nes
T he s u bjects are pr o hi bite d fr o m usi n g prescri pti o n me dicati o ns wit hi n 2 wee ks or 5 half -li ves, 
w hic he ver is l o n ger, pri or t o t he first I MP a d mi nistrati o n, d uri n g t he trial, a n d u ntil after t he 
F oll o w -u p visit (t his i ncl u des vita mi ns, a n d mi nerals). S u bjects are als o pr o hi bite d fr o m usi n g 
dr u gs/ her bal me dicati o ns, i ncl u di n g o ver -t he-c o u nter a nd nat ural pr o d ucts, wit h e nz y me -i n d uci n g 
pr o perties, s uc h as St. J o h n’s W ort, wit hi n 4 wee ks pri or t o t he first I M P a d mi nistrati o n
u ntil e n d 
of trial a n d e nz yme i n hi bit ors d uri n g t he trial. Use of a n y i n vesti gati o nal a ge nt is n ot per mitte d 
wit hi n 8 wee ks bef ore d osi n g.
6. 5. 3
Ot her I nter ve nti o ns
N ot a p plic a ble.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8 0 / 1 9 0
T he c halle n ge i n oc ul u m s yri n ges will be la bele d i n acc or da nce wit h t he G M P re q uire me nts.
6. 7
Pre p ar ati o n, H a n dli n g , a n d St or a ge of t he I n vesti g ati o n al 
Me d ici n al Pr o d uct a n d t he C h alle n ge I n oc ul u m
All P arts
T he p har mac y  or desi g nee will recei ve t he I M P a n d t he c halle n ge i n oc ul u m la bele d a n d pac ka ge d 
acc or di n g t o t he l ocal re g ulat or y re q uire me nts a n d t he st ora ge re q uire me nts. M 5 7 1 7
will be 
s hi p pe d i n rea dy t o use ca ps ule f or m ulati o n. T he res p o nsi ble P har macist will dis pe nse t he 
necessar y  am o u nt of t he I M P. Detaile d g ui da nce will be pr o vi de d i n t he p har mac y ma n ual. T he 
I M P s u p plies will be rec or de d i n a n I M P i n ve nt or y.
M 5 7 1 7
m ust be caref ull y st ore d at t he trial site i n a cl ose d r o o m or ca bi net wit h restricte d access, 
safely a n d se parately fr o m ot her dr u gs a n d pr otecte d fr o m e n vir o n me ntal e xtre mes u ntil use d i n 
t he trial. M 5 7 1 7
a n d place b o s h o ul d o nl y be tra ns p orte d a n d st ore d i n t he ori gi nal pac ka ge . 
 
A n y de viati o ns fr o m t he 
rec o m me n de d tra ns p ort a n d st ora ge c o n diti o ns s h o ul d be i m me diatel y re p orte d t o t he S p o ns or, 
a n d t he I M P s h o ul d n ot be use d u ntil a ut h orizati o n has bee n recei ve d fr o m t he S p o ns or. T he 
pre parati o n, ha n dli n g a n d st ora ge of t he I M P will be d oc u me nte d i n t he p har mac y ma n ual.
P art C o nl y
O n I n D1, t he fr oze n bl o o d ali q u ots will be t ha we d a n d use d t o pre pare t he s yri n ges c o ntai ni n g t he 
c halle n ge i n oc ula at 
 O ne vial c o ntai ni n g t he P. falci par u m 3 D 7 c halle n ge 
i n oc ul u m is s ufficie nt t o pre pare t he malaria c halle n ge d ose f or all s u bjects per c o h ort. T he ti me 
bet wee n pre parati o n of t he fi nal i n oc ul u m a n d i n oc ulati o n will be a ma xi m u m of 2 h o u rs, d uri n g 
w hic h ti me all pre pare d i n oc ula will be st ore d at t he re q uire d te m perat ure. 
T he I M P m ust n ot be use d f or a n y p ur p ose ot her t ha n t he trial i n q uesti o n.
It m ust be e ns ure d at t he trial site t hat t he I MP a n d t he c halle n ge i n oc ul u m is n ot use d after t he 
use -b y  date. T his is t o be cl osel y m o nit ore d by t he res p o nsi ble M o nit or.
F urt her details ma y  be pr o vi de d i n t he p har mac y ma n ual.
6. 8
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y
T he I n vesti gat or or s uita bl y qualifie d desi g nee is res p o nsi ble f or e ns uri n g I M P, i n oc ul u m, a n d
resc ue me dicati o ns acc o u nta bilit y, i ncl u di n g rec o nciliati o n of dr u gs a n d mai nte na nce of rec or ds.

U p o n recei pt of t he I M P/i n oc ul u m/resc ue me dicati o ns , t he res p o nsi ble pers o n will c hec k f or 
acc urate deli ver y  an d ac k n o wle d ge recei pt b y  si g ni n g or i nitiali n g a n d dati n g t he a p pr o priate
d oc u me ntati o n a n d ret ur ni n g it t o t he l ocati o n s pecifie d. A c o p y will be arc hi ve d f or t he 
I n vesti gat or Site File
D oc u me nt N o. 
O bject N o. 
C CI
C CI
P P D
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8 1 / 1 9 0

I M P/i n oc ul u m/resc ue 
me dicati o ns dis pe nsi n g will be rec or de d o n t he a p pr o priate dr u g 
acc o u nta bilit y for ms s o t hat acc urate rec or ds will be a vaila ble f or verifi cati o n at eac h 
m o nit ori n g visit

Trial site I MP/i n oc ul u m/resc ue me dicati o ns acc o u nta bilit y rec or ds will i ncl u de t he f oll o wi n g

C o nfir mati o n of I M P/i n oc ul u m/resc ue me dicat i o ns recei pt, i n g o o d c o n diti o n a n d i n t he 
defi ne d te m perat ure ra n ge

T he i n ve nt or y of I M P/i n oc ul u m/resc ue me dicati o ns
pr o vi de d f or t he cli nical trial a n d 
pre pare d at t he site

T he u se of eac h d ose by eac h s u bject

T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y u n use d I M P/i n oc ul u m/resc ue 
me dicati o ns

Dates, 
q ua ntities, 
batc h 
n u m bers, 
vial 
n u m bers, 
e x pir y 
dates, f or m ulati o n (f or 
I M P/i n oc ul u m/resc ue me dicati o ns
pre pare d at t he site), a n d t he i n di vi d ual s u bject trial
n u m bers.
T he I n vesti gat or site s h o ul d mai ntai n rec or ds, w hic h
a de q uatel y d oc u me nt t hat s u bjects were 
pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d all I MP/i n oc ul u m/resc ue me dicati o ns pr o vi de d 
were f ull y  rec o ncile d.
U n use d I M P/i n oc ul u m/resc ue me dicati o ns
m ust n ot be discar de d a n d/ or use d f or a n y p ur p ose 
ot her t ha n t he prese nt trial. N o I MP/i n oc ul u m/resc ue me dicati o ns
t hat is dis pe nse d t o a s u bject 
ma y be re dis pe nse d t o a differe nt s u bject.
A Trial M o nit or will peri o dicall y  collect t he I MP/i n oc ul u m/resc ue me dica ti o ns acc o u nta bilit y 
f or ms.
6. 9
Assess me nt of I n vesti g ati o n al Me dici n al Pr o d uct C o m pli a nce
T he I MP will be a d mi nistere d b y  the trial site pers o n nel wit hi n t he c o nfi nes of t he trial site. A 
m o ut h a n d ha n d c hec k will be perf or me d after eac h d ose a d mi nistrati o n t o e ns ure t hat all d oses 
ha ve bee n s wall o we d.
6. 1 0
Bli n di n g
T he trial will be d o u ble -bli n d i n Part A a n d Part B. Part C will be o pe n -la bel. Bli n di n g will be 
mai ntai ne d t hr o u g h o ut t he d urati o n of t he rele va nt trial part, ie, u ntil t he data base loc k of Part A
a n d u ntil t he data base l oc k of Part B. T he ra n d o mizati o n list is t o be ke pt strictl y co nfi de ntial, 
accessi ble o nl y  to a ut h orize d pers o ns (e g, ra n d o mizati o n statisticia n, p har macists, a n d t he 
bi oa nal y tical la b orat ories t hat pre pare a n d a nalyz e rele va nt sa m ples), u ntil t he ti me of u n bli n di n g. 
I nteri m P K a nal ys es will be perf or me d bli n de d (ie, utilizi n g d u m m y  su bject n u m bers w hic h ca n n ot 
be li n ke d t o t he s u bject i de ntifiers use d i n t he trial site). I n ad diti o n, data listi n gs (ie, utilizi n g 
d u m m y  su bject n u m be rs differe nt fr o m t h ose use d f or t he P K a nal ys is) will be pr o vi de d i n a 
bli n de d ma n ner t o s u p p ort d ose escalati o n or d ose m o dificati o n decisi o ns b y t he S M C. After eac h 
c o h ort i n Part A a n d Part B, t he S M C will re vie w data o n safet y a n d t olera bilit y. T heir e ns ui n g
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8 2 / 1 9 0
decisi o n will ge nerall y  be ma de wit h o ut brea ki n g t he ra n d o mizati o n c o de. If j u d ge d necessar y b y 
t he S M C, a n i n di vi d ual s u bject or t he c o m plete c o h ort ma y be u n bli n de d d uri n g e val uati o n of t he 
trial data. Bef ore u n bli n di n g, t he S M C s h o ul d d oc u me nt t he decisi o n t o u n bli n d a n d a n y pla n ne d 
acti o n t o be ta ke n base d o n t he re veale d treat me nt all ocati o n. 
O nl y  w he n t he trial (all 3 parts) is c o m plete d, data base l oc ke d, t he data file verifie d, a n d pr ot oc ol 
de viati o ns deter mi ne d, will t he dr u g c o des be br o ke n a n d ma de a vaila ble f or data a nal ys is. 
H o we ver, if t he S p o ns or deci des t o l oc k t he data base c orres p o n di n g t o a trial part (ie, Part A, or 
Part B, or Part C) f or t he p ur p ose of a fi nal a nal ysis of t hat trial part, t he n t hat trial part m a y  be 
u n bli n de d afte r t he data file is verifie d a n d pr ot oc ol de viati o ns deter mi ne d. F urt her m ore, if t he 
S p o ns or c o nsi ders it necessar y  for ti mel y decisi o n-ma ki n g, a trial-i n de pe n de nt statisticia n/ mo deler 
ma y  b e directe d t o recei ve t he ra n d o mizati o n c o de f or a trial part after t he trial is c o m plete d, b ut 
pri or t o data base l oc k, f or t hat trial part. All brea ks of t he trial bli n d m ust be a de q uatel y 
d oc u me nte d.
6. 1 1
E mer ge nc y U n bli n di n g
P art A a n d P art B o nl y
T he trial bli n d ma y  be br o ke n f or a n i n di vi d ual s u bject o nl y  if k n o wle d ge of t he I M P is esse ntial 
f or cli nical ma na ge me nt of t he s u bject. T he I n vesti gat or or desi g nee will u n bli n d t he s u bject usi n g 
t he i n di vi d ual c o de-brea k e n vel o pe pr o vi de d b y  the ra n d o mizati o n statisticia n. T he I n vesti gat or 
m ust pr o m ptl y  ex plai n t he reas o n f or a n y u n bli n di n g of a n I M P t o t he S p o ns or wit h o ut re veali n g 
t he res ult t o a n y Sp o ns or e m pl o yee e xce pt t he desi g nate d Dr u g Safet y re prese ntati ve ( usi n g t he 
E mer ge nc y  U n bli n di n g N otificati o n F or m).
T he I n vesti gat or m ust rec or d t he date of u n bli n di n g a n d t he reaso n i n t he e C R F. C o ntact 
i nf or mati o n f or brea ki n g t he bli n d i n a n e mer ge nc y is gi ve n o n t he s u bject e mer ge nc y car d 
pr o vi de d t o eac h s u bject. U n der certai n circ u msta nces, Dr u g Safet y m a y  be re q uire d t o u n bli n d 
t he treat me nt assi g n me nt f or a n i n di vi d ual s u bject f oll o wi n g a n S A E or ot her seri o us e ve nt; f or 
e xa m ple, if a n e x pe dite d re g ulat or y  re p ort is re q uire d. 
O nce t he treat me nt c o de has bee n br o ke n f or a s u bject, a d mi nistrati o n of I M Ps will be st o p pe d a n d 
t he s u bject will be wit h dra w n fr o m t he trial. T he s u bject will atte n d t he Earl y Ter mi nati o n visit.
6. 1 2
Tre at me nt of O ver d ose
A n o ver d ose is defi ne d as a n y dose greater t ha n t he hi g hest dail y d ose i ncl u de d i n a cli nical trial
pr ot oc ol or pla n ne d f or a n i n di vi d ual s u bject e nr olle d i n t he trial. E ve n if it d oes n ot meet ot her 
criteria f or a n S A E, an y  over d ose m ust be rec or de d i n t he trial me dicati o n secti o n of t he eC R F a n d
re p orte d t o Dr u g Safet y i n a n e x pe dite d ma n ner usi n g t he S A E Re p ort F or m , a n d f oll o wi n g t he 
pr oce d ure i n Secti o n  7. 4.
T he effects of a n M 5 7 1 7 o ver d ose are u n k n o w n, a n d t heref ore n o sta n dar d treat me nt is c urre ntl y 
esta blis he d. I n t he e ve nt of a n o ver d ose, t he In vesti gat or or treati n g p h y sicia n s h o ul d use 
a p pr o priate cli nical j u d g me nt f or t he e val uati o n a n d ma na ge me nt of a n y cl i nical si g ns, s y m pt o ms, 
a n d la b orat or y res ults.
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8 3 / 1 9 0
Refer t o t he pac ka ge i nsert s of t he resc ue me dicati o n i n A p pe n di x VI I f or details re gar di n g t he 
effects a n d ma na ge me nt of a n o ver d ose .
6. 1 3
Me dic al C are of S u bjects after E n d of Tri al
I n t his trial i n healt h y  su bjects, n o f urt her treat me nt or me dical care is pla n ne d or re q uire d after 
t he e n d of t he trial.
7
Tri al Pr oce d ures a n d Assess me nts
Pri or t o perf or mi n g a n y trial assess me nts, t he I n vesti gat or will e ns ure t hat t he s u bject has pr o vi de d 
writte n i nf or me d c o nse nt acc or di n g t o t he pr oce d ure descri be d i n Secti o n  9. 2 .
A s u bject i de ntifier (see Secti o n  6. 3 ) will be assi g ne d f or eac h s u bject f or w h o m writte n i nf or me d 
c o nse nt has bee n o btai ne d. 
All eff orts s h o ul d be ma de t o perf or m assess me nts as cl ose as p ossi ble t o t he sc he d ule d ti me p oi nts. 
C o m plia nce t o pr ot oc ol s pecific re q uire me nts will be c hec ke d at eac h visit a n d s u bject s are gi ve n 
re mi n ders eac h ti me t he y lea ve t he trial site.
At visits w here assess me nt ti me p oi nts c oi nci de wit h eac h ot her, t he f oll o wi n g pr oce d ure s h o ul d 
be f oll o we d: perf or m vital si g ns assess me nts sli g htl y bef ore t he s pecific ti me p oi nt, E C G 
assess me nts o n ti me, P K bl o o d sa m pli n g directl y f oll o wi n g E C G. 
Sa m ples a n d assess me nts o btai ne d wit hi n t he defi ne d wi n d o w (see Ta ble 4) fr o m d osi n g will n ot 
be ca pt ure d as a pr ot oc ol de viati o n, as l o n g as t he e xact ti me of t he assess me nt/sa m ple c ollecti o n 
is n ote d o n t he s o urce d oc u me nt a n d data c ollecti o n t o ol (e g, e C R F). 
7. 1
Sc he d ule of Assess me nts
T he Sc he d ule of Assess me nts f or Part A, Part B, a n d Part C i s pr o vi de d i n Ta ble 1 t o Ta ble 3.
7. 1. 1
Scree ni n g E x a mi n ati o n s
All s u bjects will u n der g o a n e ntr y exa mi nati o n t o e val uate t heir healt h stat us. T his e x a mi nati o n 
will be c o n d ucte d n ot m ore t ha n 2 8 d a y s pri or t o t he pla n ne d first I M P or i n oc ul u m a d mi nistrati o n. 
O nl y  su bjects w h o meet t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria will be e nr olle d i n
t he trial.
Pri or t o a n y  Scree ni n g e xa mi nati o ns t he s u bjects ha ve t o si g n t he Partici pa nt I nf or mati o n C o nse nt 
F or m ( PI CF) . T he assess me nts t o be perf or me d at Scree ni n g are i n dicate d i n t he Sc he d ule of 
As sess me nts (Ta ble 1 t o Ta ble 3 ). Safet y l a b orat or y assess me nts wit h res ults o utsi de of t he n or mal 
la b orat or y ra n ge ma y be re peate d o nce.
S u bjects w h o fail t o meet t he pr ot oc ol s pecifie d i ncl usi o n - or e xcl usi o n criteria, or w h o wit h dra w 
t heir c o nse nt i n t he Scree ni n g peri o d are c o nsi dere d scree ni n g fail ures. T he f oll o wi n g data, as a 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8 4 / 1 9 0
mi ni m u m, s h o ul d be rec or de d f or t hese s u bjects: date of i nf or me d c o nse nt, i ncl usi o n/e xcl usi o n 
criteria, de m o gra p hics (i ncl u di n g a ge, se x ( ge n der), wei g ht, a n d hei g ht), A Es (if a n y) fr o m t he 
date of i nf or me d c o nse nt u ntil t he s u bject is c o nsi dere d a scree n fail ure b y t he I n vesti gat or, reas o n 
f or scree ni n g fail ure, a n d t he In vesti gat or’s si g nat ure.
7. 1. 2
Tre at me nt Peri o ds
A re vie w a n d u p date of t he s u bject’s i ncl usi o n/e xcl usi o n criteria t o e ns ure t he s u bject re mai ns 
eli gi ble f or partici pati o n i n t he trial s h o ul d be perf or me d pri or t o a d missi on t o t he trial site. Eli gi ble 
s u bjects will be ra n d o mize d t o acti ve treat me nt or place b o i n Part A a n d Part B, or e nr olle d t o t he 
c halle n ge a n d acti ve treat me nt i n Part C. S u bjects will be a d mitte d t o t he trial site o n Da y - 2 f or 
Part A a n d Part B, a n d D a y 1 f or Part C. S u bjects will be disc har ge d after c o m pleti o n of t he 
re q uire d assess me nts o n D a y  7 for Part A a n d Part B, a n d bet wee n D a y  4 to Da y  7, at t he discreti o n 
of t he I n vesti gat or o n a d vice of t he S M C . 
T he assess me nts t o be perf or me d at s pecific ti me p oi nts are i n dicate d i n t he Sc he d ule of 
Assess me nts (Ta ble 1 t o Ta ble 3) .
7. 1. 3
A m b ul a nt Visits
A m b ula nt visits will be perf or me d at re g ular i nter vals fr o m Da y  8 o n war ds f or Part A a n d Part B. 
I n Part C, a m b ula nt visits will be perf or me d o n I n oc ul u m Da ys pri or t o IM P a d mi nistrati o n a n d at 
re g ular i nter vals fr o m D a y 4 o n war ds . I n Part C, a n a m b ula nt visit will be perf or me d o n Da y 2 2
f or s u bjects wit h brea kthr o u g h i nfecti o ns f or t he a d mi nistrati o n of resc ue me dicati o n.
I n a d diti o n, s u bjects will be re g ularly c o ntacte d (a p pr o xi matel y ev er y  2 to 3 da y s) b y  tele p h o ne 
d uri n g t heir a m b ula nt peri o d.
T he assess me nts t o be perf or me d at s pecific ti me p oi nts are i n dicate d i n t he Sc he d ule of 
Assess me nts (Ta ble 1 t o Ta ble 3 ).
7. 1. 4
F oll o w -u p Visit s
S u bjects will be as ke d t o ret ur n t o t he trial site f or F oll o w - u p visit s o n Da y  13, Da y  15, Da y  17
( Part A a n d Part C) , D a y  2 2, D a y  29 ( Part C o nl y),  Day 3 3, a n d D a y  44 f or Part A, Part B , a n d Part 
C. T he assess me nts t o be perf or me d at t hese ti me p oi nts are i n dicate d i n t he Sc he d ule of 
Assess me nts (Ta ble 1 t o Ta ble 3 ).
7. 1. 5
P h o ne C alls
O n Da y  8 a n d Da y 1 0 of Part A a n d Part B, s u bjects ma y be c o ntacte d b y  t he trial site via a p h o ne 
call or s u bjects ma y  te xt a p h ot o of t heir c o m plete d diar y  car d i nstea d of visiti n g t he trial site. I n 
Part C, t he s u bject will be c o ntacte d dail y via p h o ne calls w hil e o ut patie nt, fr o m I n oc ul u m Da y 2
t o I noc ul u m Da y  4, as well as o n D a y  2 3 t o D a y 25, f or a safety c hec k a n d c o m plia nce of resc ue 
me dicati o n use.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8 5 / 1 9 0
7. 1. 6
E n d of Tri al / E arl y Ter mi n ati o n Visit
T he E n d of Trial e xa mi nati o n has t o verif y  that all val ues teste d i n t he Scree ni n g ha ve re mai ne d 
wit hi n a cli nicall y  acce pta ble ra n ge. T he rele va nt tests will be perf or me d o n Da y 4 4 ( ± 2 da y s) f or 
Part A, Part B, a n d Part C. T he assess me nts t o be perf or me d at t hese ti me p oi nts are i n dicate d i n 
t he Sc he d ule of Assess me nts (Ta ble 1 t o Ta ble 3 ).
U nacce pta ble val ues a n d A Es will be f oll o we d u p u ntil t he y ret ur n t o baseli ne /res ol ve d or t here is 
a n a de q uate e x pla nati o n w hic h is n ot relate d t o t he trial.
7. 2
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics
At S creeni n g, t he f oll o wi n g de m o gra p hic data will be c ollecte d: d ate of birt h , se x ( ge n der), race, 
a n d et h nicit y.
F urt her m ore , t he f oll o wi n g will be d oc u me nte d:

H ei g ht, wei g ht, a n d B M I

S ki n t y p e acc or di n g t o t he Fitz patric k scale (A p pe n di x V I)

Cli nicall y  rele va nt fi n di n gs i n t he me dical hist or y are rec or de d

Pri or me dicati o n s wit hi n 4 wee ks (a n y me dicati o n wit h e nz yme i n d uci n g or i n hi biti n g 
pr o perties) or 2 wee ks (a n y prescri be d me dic i ne or o ver -t he-c o u nter dr u g [ ot her t ha n occasi o nal 
i b u pr ofe n < 1 g or paraceta m ol < 1 g ] or dietar y  su p ple me nt i ncl u di n g her bal re me dies, 
vita mi ns, a n d mi nerals

S m o ki n g stat us, alc o h ol i nta ke

Fe male stat us ( W N C B P, p ost me n o pa usal, sterilizati o n).
7. 3
Effic ac y Assess me nts
Cli nic al e n d p oi nts: Part A a n d B; n ot a p plica ble. 
Cli nic al e n d p oi nts: Part C; Parasitical effect of M 5 7 1 7, defi ne d as t he re d ucti o n a n d/ or cleara nce
of parasite mia b y q P C R u p t o Da y 8, (see Secti o n  5. 2. 4 ). 
T he malaria cli nical sc ore is defi ne d i n A p pe n di x IV
a n d nee ds t o be assesse d i n case a n y 
malaria -relate d s ym pt o ms are see n.
S urr o g ate e n d p oi nts : N ot a p plica ble.
F oll o w -u p: N ot a p plica ble. 
Efficac y  exa mi nati o ns will be sc he d ule d acc or di n g t o t he a p plica ble Sc he d ule of Assess me nts 
(Ta ble 3) .
D oc u me nt N o
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8 6 / 1 9 0
7. 4
Assess me nt of S afet y
T he safety pr ofile of t he I MP will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d a nal y sis of 
baseli ne me dical c o n diti o ns, A Es , p h y sical e xa mi nati o n fi n di n gs i ncl u di n g vital si g ns, 1 2-lea d
E C G s, a n d safety la b orat or y tests.
C o m pre he nsi ve assess me nt of a n y ap pare nt t o xicit y ex perie nce d b y  eac h s u bject will be perf or me d 
fr o m t he ti me of gi vi n g i nf or me d c o nse nt a n d t hr o u g h o ut t he trial. T he I n vesti gat or will re p ort a n y 
A Es , w het her o bser ve d b y  the I n vesti gat or or re p orte d b y  the s u bject (see Secti o n 7. 4. 1. 2) . T he 
re p orti n g peri o d f or A E s is descri be d i n Secti o n 7. 4. 1. 3. T he e x pecte d si g ns a n d s ym pt o ms of 
malaria after a d mi nistrati o n of t he i n oc ul u m i n Part C is detaile d i n  A p pe n di x V .
7. 4. 1
A d verse E ve nts
7. 4. 1. 1
A d verse E ve nt Defi niti o ns
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct, re gar dless of ca usal relati o ns hi p wit h t his treat me nt. A n 
A E ca n t heref ore be a n y unfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y 
fi n di n g), sy m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her 
or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct. 
F or s ur gical or dia g n ostic pr oce d ures, t he c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ure is 
c o nsi dere d as t he A E rat her t ha n t he pr oce d ure itself.
T he I n vesti gat or m ust assess t he se verity of A E s acc or di n g t o t he Q T S as descri b e d i n t he “ T o xicit y 
Gra di n g Scale f or Healt h y  Ad ult a n d A d olesce nt V ol u nteers E nr olle d i n Pre ve nti ve Vacci ne 
Cli nical Trials” , as f oll o ws:
Mil d
( Gr a de 1):
T he s u bject is a ware of t he e ve nt or s y m pt o m, b ut t he e ve nt or s ym pt o m is 
easil y t olerate d.
M o der ate
( Gr a de 2): T he s u bject e x perie nces s ufficie nt disc o mf ort t o i nterfere wit h or re d uce 
his or her us ual le vel of acti vit y .
Se vere ( Gr a de 3):
Si g nifica nt i m pair me nt of f u ncti o ni n g: t he s u bject is u na ble t o carr y o ut his 
or her us ual acti vities.
P ote nti all y L ife-T hre ate ni n g ( Gr a de 4):
E xtre me li mitati o n t o dail y  acti vit y. Si g nifica nt 
assista nce 
re q uire d. 
Si g nifica nt 
me dical 
i nter ve nti o n, h os pital or h os pice care ver y li kel y.
I n vesti gat ors m ust als o s yste maticall y assess t he ca usal relati o ns hi p of A Es t o t he I MP or i n oc ul u m 
usi n g t he f oll o wi n g defi niti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E 
t o t he IM P
i ncl u de, b ut ma y n ot be li mite d t o, te m p oral relatio ns hi p bet wee n t he A E a n d t he I M P, 
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8 7 / 1 9 0
k n o w n (fr o m a ni mal st u dies) si de effects of t he I M P, k n o w n si de effects of t he i n oc ul u m, me dical 
hist or y , c o nc o mita nt me dicati o n, c o urse of t he u n derl yi n g disease, trial pr oce d ures.
U nrel ate d:
N ot reas o na bl y relate d t o t he I M P or i n oc ul u m or resc ue me dicati o n . A E c o ul d n ot 
me dicall y  ( p har mac ol o gicall y/cli nicall y) be attri b ute d t o t he I MP/ i n oc ul u m/resc ue 
me dicati o n u n der i n vesti gati o n i n t his cli nical trial pr ot oc ol. A reas o na ble alter nati ve 
e x pla nati o n m ust be a vaila ble.
Rel ate d:
S us pecte d t o be reas o na bl y relate d t o t he I M P or i n oc ulu m or resc ue me dicati o n . A E 
c o ul d 
me dicall y 
( p har mac ol o gicall y/cli nicall y) 
be 
attrib ute d 
t o 
t he 
I M P/i n oc ul u m/resc ue me dicati o n u n der i n vesti gati o n i n t his cli nical trial pr ot oc ol. 
T he o utc o me s h o ul d be e ntere d wit h ter ms descri be d bel o w:

Rec o vere d wit h o ut se q uelae 

Rec o vere d wit h se q uelae

O n g oi n g

Fatal 

U n k n o w n.
I n case of a fatalit y, t he ca use of deat h is c o nsi dere d as t he S A E, a n d t he deat h is c o nsi dere d as its 
O U T C O M E.
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n or m al I n vesti g ati o n al Fi n di n gs
A b n or mal la b orat or y  fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs s h o ul d n ot be re p orte d 
as A Es u nless t h e y are ass ociate d wit h cli nical si g ns a n d s ym pt o ms, 
lea d t o treat me nt 
disc o nti n uati o n or are c o nsi dere d ot her wise me dicall y  im p orta nt b y  the I n vesti gat or. If a la b orat or y
a b n or malit y fulfills t hese criteria, t he i de ntifie d me dical c o n diti o n m ust be re p orte d as t he A E 
rat her t ha n t he a b n or mal val ue itself.
Seri o us A d verse E ve nt s
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

Is life-t hreate ni n g. (N ote: T he ter m “life -t hreate ni n g” refers t o a n e ve nt i n w hic h t he s u bject is 
at ris k of deat h at t he ti me of t he e ve nt, n ot a n e ve nt t hat h y p ot heticall y  mi g ht ha ve ca used deat h 
if it was m ore se vere )

Re q uires i n patie nt h os pitalizati o n or pr ol o n g s a n e xisti n g h os pitalizati o n

Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacity

Is a c o n ge nital a n o maly or birt h defect
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8 8 / 1 9 0

Is ot her wise c o nsi dere d t o be me dicall y  im p orta nt. ( N ote: I mp orta nt me dical e ve nts t hat ma y 
n ot res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y  be c o nsi dere d as S A Es 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he s u bject or ma y 
re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. E xa m ples 
of s uc h e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y 
r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, 
or t he de vel o p me nt o f dr u g de pe n de nc y or dr u g a b use).
F or t he p ur p oses of re p orti n g, a n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a n 
I M P/i n oc ul u m is als o c o nsi dere d a n S A E a n d s h o ul d be re p orte d i n a n e x pe dite d ma n ner , as 
descri be d i n Secti o n  7. 4. 1. 4.
E ve nts t h at D o N ot Meet t he Defi niti o n of a n S A E
Electi ve h os pitalizati o ns t o si m plif y  trial treat me nt or trial pr oce d ures (f or e xa m ple, a n o ver ni g ht 
sta y to m o nit or i nitiati o n of treat me nt wit h t he I M P is n ot c o nsi dere d a n S A E . H o we ver, all e ve nts 
lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d pr ol o n gati o n of a n electi ve h os pitalizati o n (f or 
e xa m ple, u n desira ble effects of a n y ad mi nistere d treat me nt) m ust be d oc u me nte d a n d re p orte d as 
S A Es.
E ve nts N ot t o Be C o nsi dere d as A Es/ S A Es
Me dical c o n diti o ns prese nt at t he i nitial trial visit t hat d o n ot w orse n i n se verit y or fre q ue nc y duri n g 
t he trial are defi ne d as Baseli ne Me dical C o n diti o ns, a n d are n ot t o be c o nsi dere d A Es.
A d verse E ve nts of S peci al I nterest 
T he assess me nts t o be perf or me d f or assess me nt of A E SI s is detaile d i n Secti o n 7. 4. 4. 7.
T he f oll o wi n g are i de ntifie d as A E SIs i n t his trial:

V o miti n g or diarr hea

Li ver e nz y me ele vati o ns ( A L T/ A S T/ Bilir u bi n)

C uta ne o us reacti o ns (l ocal t olera bilit y CR F f or se verity of re d ness, s welli n g, i n d urati o n, 
br uisi n g, a n d itc hi n g)

P h ot ose nsiti vit y /li g ht se nsiti vit y 

Pre g na nc y  i n a fe male part ner of a male s u bject. 
A E SI s f or m o nit ori n g s h o ul d be re p orte d f oll o wi n g t he pr oce d ure f or a n S A E descri be d i n
S ecti o n 7. 4. 1. 4.
7. 4. 1. 2
Met h o ds of Rec or di n g a n d Assessi n g A d verse E ve nts
At eac h trial visit, t he s u bject will be q uerie d o n c ha n ges i n his or her c o n diti o n. D uri n g t he 
re p orti n g peri o d , a n y u nfa v ora ble c ha n ges i n t he s u bject’s c o n diti o n will be rec or de d as A Es, 
w het her re p orte d b y t he s u bject or o bser ve d b y t he In vesti gat or. 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
8 9 / 1 9 0
C o m plete, acc urate, a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d ( defi ne d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he eC R F. 
A m o n g t hese A Es, all S A Es a n d all n o nseri o us A E SI s m ust be a d diti o nall y doc u me nte d a n d 
re p orte d usi n g a Seri o us A d verse E ve nt Re p ort F or m as descri be d i n Secti o n  7. 4. 1. 4.
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates [a n d ti mes, w he n it is i m p orta nt t o assess t he ti me of A E o nset relati ve t o t he 
rec or de d treat me nt a d mi nistrati o n ti me]), its se verit y (acc or di n g t o t he Q T S as descri be d i n t he 
“ T o xicit y Gra di n g Scale f or Healt h y  Ad ult a n d A d olesce nt V ol u nteers E nr olle d i n Pre ve nti ve 
Vacci ne Cli nical Trials ”), its ca usal relati o ns hi p wit h t he I MP or resc ue me dicati o n , a n y ot her 
p ote ntial ca usal fact ors, a n y  treat me nt gi ve n or ot her acti o n ta ke n (i ncl u di n g d ose m o dificati o n or 
disc o nti n uati o n of t he I M P), a n d its o utc o me. I n ad diti o n, seri o us cases s h o ul d be i de ntifie d a n d 
t he a p pr o priate seri o us ness criteria d oc u me nte d. 
S pecific g ui da nce ca n be f o u n d i n t he e C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns pr o vi de d 
b y  t he C R O i n c o or di nati o n wit h of t he S p o ns or .
7. 4. 1. 3
Defi niti o n of t he A d verse E ve nt Re p orti n g Peri o d
T he A E re p orti n g peri o d f or safety s ur veilla nce be gi ns w he n t he s u bject is i nitiall y i ncl u de d i n a n y 
part ( Part A, B, or C) of t he trial ( date of first si g nat ure of i nf or me d c o nse nt/ date of first si g nat ure
of first i nf or me d c o nse nt) a n d c o nti n ues u ntil t he E n d of Trial v isit ( Da y 4 4 ± 2 d a y s) f or t he 
s u bject. 
7. 4. 1. 4
Pr oce d ure f or Re p orti n g Seri o us A d verse E ve nts, A d verse 
E ve nts of S peci al I nterest a n d D ose Li miti n g T o xicities
Seri o us A d verse E ve nts
I n t he e ve nt o f a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I n vesti gat or m ust 
i m me diatel y (wit hi n a ma xi m u m of 2 4 H O U R S after bec o mi n g a ware of t he e ve nt) i nf or m t he 
S p o ns or s, b ot h F u n di n g a n d t he L ocal S p o ns or, or t heir desi g nee b y  fa x or b y e-mail . All writ te n 
re p orts s h o ul d be tra ns mitte d usi n g t he S A E Re p ort F or m, w hic h m ust be c o m plete d b y  th e 
I n vesti gat or f oll o wi n g s pecific c o m pleti o n i nstr ucti o ns.
W he n a n S A E ( or f oll o w- u p i nf or mati o n) is re p orte d b y  tele p h o ne, a writte n re p ort m ust be se nt 
i m me diatel y t hereafter b y fa x or e-mail. Re p orti n g pr oce d ures a n d ti meli nes are t he sa me f or a n y 
ne w f oll o w - u p i nf or mati o n o n a pre vi o usly re p orte d S A E.
Na mes, a d dresses, tele p h o ne-, a n d fa x n u m bers f or S A E re p orti n g will be i ncl u de d i n t he 
trial-s pecific S A E Re p ort F or m.
All writte n re p orts s h o ul d be tra ns mitte d wit h t he S A E Re p ort F or m, w hic h m ust be c o m plete d b y 
t he In vesti gat or f oll o wi n g s pecific c o m pleti o n i nstr ucti o ns.
Rele va nt pa ges fr o m t he e C R F m a y  be pr o vi de d i n parallel (f or e xa m ple, me dical hist or y , 
c o nc o mita nt dr u gs). A d diti o nal d oc u me nts ma y  be pr o vi de d b y  the I n vesti gat or, if a vaila ble (f or 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
9 0 / 1 9 0
e xa m ple, la b orat or y res ults, h os pital re p ort, a ut o ps y re p ort). I n all cases, t he i nf or mati o n pr o vi de d 
o n t he S A E Re p ort F or m m ust be c o nsiste nt wit h t he data o n t he e ve nt t hat are rec or de d i n t he 
c orres p o n di n g secti o n of t he e C R F.
T he I n vesti gat or m ust res p o n d t o a n y re q uest f or f oll o w- u p i nf or mati o n (f or e xa m ple, a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y questi o n t he 
S p o ns or s/ desi g nees m a y  ha ve o n t he A E wit hi n t he sa me ti meli nes as t h ose n ote d a b o ve f or i nitial 
re p orts. T his is necessar y  to e ns ure pr o m pt assess me nt of t he e ve nt b y  the S p o ns or or desi g nee a n d 
(as a p plica ble) t o all o w t he S p o ns ors t o meet strict re g ulat or y  ti meli nes ass ociate d wit h e x pe dite d 
safety re p orti n g o bli gati o ns.
Re q uests f or f oll o w -u p will us uall y  be ma de via t he res p o nsi ble M o nit or, alt h o u g h i n e xce pti o nal 
circ u msta nces t he Gl o bal Patie nt Safet y  de part me nt ma y  co ntact t he I nvesti gat or directl y t o o btai n 
f urt her i nf or mati o n or t o disc uss t he e ve nt.
A d verse E ve nts of S peci al I nterest
I n t he e ve nt of a n o nseri o us A E SI , t he In vesti gat or will c o m plete t he A E SI Re p ort F or m a n d se n d 
it t o t he S p o ns ors/desi g nee s wit hi n a ma xi m u m of 2 4 H O U R S after bec o mi n g a ware of t he e ve nt .
Na mes, a d dresses, tele p h o ne -, a n d fa x n u m bers f or A E SI re p orti n g will be i ncl u de d on t he Re p ort 
F or m. Seri o us A E SIs ha ve t o be re p orte d i n a n e x pe dite d ma n ner as S A Es as o utli ne d a b o ve. 
7. 4. 1. 5
S afet y Re p orti n g t o He alt h
A ut h orities, I n de pe n de nt Et hics 
C o m mittees/ I nstit uti o n al Re vie w B o ar ds a n d I n vesti g at ors
T he L o cal S p o ns or will se n d a p pr o priate safety n otificati o ns t o t he L o cal Healt h A ut h orities 
( T hera pe utic G o o ds A d mi nistrati o n) i n acc or da nce wit h a p plica ble la ws a nd re g ulati o ns.
T he I n vesti gat or m ust c o m pl y wit h a n y a p plica ble site-s pecific re q uire me nts relate d t o t he 
re p orti n g of S A Es ( partic ularl y deat hs) i n v ol vi n g trial s u bjects t o t he H R E C t hat a p pr o ve d t he trial.
I n acc or da nce wit h I CH G C P, t he S p o ns or s/ desi g nees will i nf or m t he I n vesti gat or of “fi n di n gs 
t hat c o ul d a d versel y affect t he safety of s u bjects, i m pact t he c o n d uct of t he trial or alter t he H R E C ’s
a p pr o val/fa v ora ble o pi ni o n t o c o nti n ue t he trial.” I n partic ular a n d i n li ne wit h res pecti ve 
re g ulati o ns, t he S p o ns or s/ desi g nees will i nf or m t he I n vesti gat or of A Es t hat are b ot h seri o us a n d 
u ne x pecte d a n d are c o nsi dere d t o be relate d t o t he a d mi nistere d pr o d uct (“s us pecte d u ne x pecte d 
seri o us a d verse reacti o ns”). T he I n vesti gat or s h o ul d place c o pies of Safet y Re p orts i n t he 
I n vesti gat or Site File. Nati o nal re g ulati o ns wit h re gar d t o Safet y Re p ort n otificati o ns t o 
I n vesti gat ors will be ta ke n i nt o acc o u nt.
W he n s pecificall y re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or s/ desi g nees will pr o vi de 
a p pr o priate Safet y R e p orts direct l y to t he c o ncer ne d lea d H R E C a n d will mai ntai n rec or ds of t hese 
n otificati o ns. W he n direct re p orti n g is n ot clearl y  defi ne d b y  nati o nal or site-s pecific re g ulati o ns, 
t he I nvesti gat or will be res p o nsi ble f or pr o m ptl y n otif y i n g t he c o ncerne d H R E C of a n y Safet y 
Re p orts pr o vi de d b y  the S p o ns or s/ desi g nees a n d of fili n g c o pies of all relate d c orres p o n de nce i n 
t he In vesti gat or Site File.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
9 1 / 1 9 0
7. 4. 1. 6
M o nit ori n g of S u bjects wit h A d verse E ve nts
A d verse e ve nts are rec or de d a n d assesse d c o nti n u o usl y thr o u g h o ut t he trial (see Secti o n 7. 4. 1. 3 ) 
a n d are assesse d f or fi nal o utc o me at t he E n d of Trial v isit). All S A Es/ A E SIs o n g oi n g at t he E n d 
of Trial vi sit m ust be m o nit ore d a n d f oll o we d u p b y t he I n vesti gat or u ntil sta bilizati o n or u ntil t he 
o utc o me is k n o w n, u nless t he s u bject is d oc u me nte d as “l ost t o f oll o w-u p”. Reas o na ble atte m pts 
t o o btai n t his i nf or mati o n m ust be ma de a n d d oc u me nte d. It is als o t he res p o nsi bilit y of t he 
I n vesti gat or t o e ns ure t hat a n y necessar y ad diti o nal t hera pe utic meas ures a n d f oll o w-u p pr oce d ures 
are perf or me d. 
7. 4. 2
Pre g n a nc y a n d I n Uter o Dr u g E x p os ure 
P re g na ncies i n fe male part ners of male s u bjects are c o nsi dere d t o be A E s. All pre g na ncies wit h a n 
esti mate d c o nce pti o n date d uri n g t he peri o d defi ne d i n Secti o n 7. 4. 1. 3 m ust be rec or de d b y  
c o n ve nti o n i n t he A E 
pa ge/secti o n o f t he eC R F. 
T he 
I n vesti gat or m ust 
n otif y  th e 
S p o ns or s/ desi g nees i n a n e x pe dite d ma n ner of a n y pre g na nc y usi n g t he Pre g na nc y  Re p ort F or m, 
w hic h m ust be tra ns mitte d acc or di n g t o t he sa me pr ocess as descri be d f or S A E re p orti n g i n Secti o n 
7. 4. 1. 4.  
I n vesti gat ors m ust 
acti vel y foll o w u p, d oc u me nt a n d re p ort o n t he o utc o me of all t hese 
pre g na ncies, e ve n if t he s u bjects are wit h dra w n fr o m t he trial.
T he I n vesti gat or m ust n otif y  the S p o ns or s/ desi g nees of t hese o utc o mes usi n g t he Pre g na nc y 
Re p ort F or m . If a n a b n or mal o utc o me occ urs , t he S eri o us A d verse E ve nt Re p ort F or m will be use d 
if t he s u bject s ustai ns a n e ve nt a n d t he Pare nt -C hil d/ Fet us A d verse E ve nt Re p or t F or m if t he 
c hil d/fet us s ustai ns a n e ve nt.
A n y  ab n or mal o utc o me m ust be re p orte d i n a n e x pe dite d ma n ner as descri be d i n Secti o n  7. 4. 1. 4,  
w hile n o r mal o utc o mes m ust be re p orte d wit hi n 4 5 da ys after deli ver y.
7. 4. 3
Cli nic al L a b or at or y Assess me nts
A list of la b orat or y refere nce ra n ges will be pr o vi de d t o t he S p o ns or s/ desi g nees bef ore s hi p me nt 
of t he I M P. A n y c ha n ge i n la b orat or y refere nce ra n ges d uri n g t he trial will a d diti o nall y be 
f or war de d t o t he S p o ns ors/ desi g nees.
All r o uti ne la b orat or y anal y ses will be d o ne at a la b orat or y facilit y local t o t he trial site, a n d 
rele va nt res ults s h o ul d be a vaila ble bef ore a d mi nistrati o n of t he I M P. T he re p ort of t he res ults m ust 
be retai ne d as a part of t he s u bject’s me dical rec or d or s o urce d oc u me nts. Bl o o d a n d uri ne sa m ples 
will be c ollecte d f or t he la b orat or y tests s pecifie d i n Ta ble 8,  f oll o wi n g t he ti mi n g n ote d i n t he 
Sc he d ule of Assess me nts (Ta ble 1 t o Ta ble 3 ). All sa m ples s h o ul d be clearl y i de ntifie d.  
F or t hat p ur p ose of safety l a b orat or y bl o o d sa m ple c ollecti o n a n d P K/ P D sa m ple c ollecti o n d uri n g 
t he resi de nc y peri o ds, eac h s u bject will u n der g o ca n n ulati o n wit h a n a p pr opriate ga u ge ca n n ula. 
T he ca n n ula will be fl us he d wit h 5 m L  of 0. 9 % s o di u m c hl ori de bef ore sa m ple c ollecti o n. T he 
ca n n ula will t he n be re m o ve d, a n d he m ostasis e ns ure d b y  t he use of a n a p pr o priate dressi n g.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
9 2 / 1 9 0
T he act ual date a n d ti me of t he bl o o d sa m ple c ollecti o n will be rec or de d i n t he s u bject’s e C R F. 
T he details of sa m ple c ollecti o n, sa m ple t u be la belli n g, sa m ple pre parati o n a n d pr ocessi n g, 
st ora ge, a n d s hi p pi n g pr oce d ures will be descri be d i n a se parate la b orat or y ma n ual or ma n ual of 
o perati o ns.
T he total bl o o d v ol u me t o be dra w n fr o m eac h s u bject f or pla n ne d assess me nts d uri n g t he trial will 
n ot e xcee d a sta n dar d u nit of bl o o d (a p pr o xi matel y  4 5 0 m L ).
7. 4. 3. 1
S afet y L a b or at or y Assess me nts
All la b orat or y exa mi nati o ns will be carrie d o ut u n der fasti n g c o n diti o ns of at least 8 h o urs f or 
Scree ni n g a n d s u bse q ue nt bi oc he mistr y  assess me nts. T he list of safet y la b orat or y e xa mi nati o ns is 
dis pla y e d i n Ta ble 8.
S o me ad diti o nal para meters mi g ht be r o uti nel y anal y ze d b y  the la b orat or y after a b n or mal fi n di n gs, 
s uc h as ma n ual 
differe ntial bl o o d c o u nt, dire ct/i n direct bilir u bi n, creati ne p h os p h o ki nase 
m y ocar dial/ brai n t ype fracti o n, ha pt o gl o bi n, he m ol y sis i n de x, or mi R 2 2 i n Part C. A d diti o nal 
la b orat or y safety e xa mi nati o ns d uri n g t he c o urse of t he trial are at t he discreti o n of t he I n vesti gat or.
D oc u me nt N o
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
9 3 / 1 9 0
T a ble 8
Cli nic al L a b or at or y E v al u ati o ns
Bi o c h e mi str y
A s p art at e a mi n otr a n sf er a s e
Al a ni n e a mi n otr a n sf er a s e
Al k ali n e p h o s p h at a s e
G a m m a - gl ut a m yl-tr a n sf er a s e
L a ct at e d e h y dr o g e n a s e
Cr e ati n e p h o s p h o ki n a s e a
Bilir u bi n (t ot al)
a
C h ol e st er ol b
Tri gl y c eri d e s b
H D L c h ol e st er ol b
A m yl a s e
Li p a s e
Uri c a ci d
S o di u m
P ot a s si u m
C hl ori d e
C al ci u m
M a g n e si u m
b
Bi c ar b o n at e
P h o s p h at e
Cr e ati ni n e
Ur e a
Gl u c o s e (f a sti n g)
H e m at ol o g y  
H e m at o crit
H e m o gl o bi n
R e d bl o o d c ell c o u nt
M e a n c or p u s c ul ar v ol u m e
M e a n c or p u s c ul ar h e m o gl o bi n
M e a n c or p u s c ul ar h e m o gl o bi n 
c o n c e ntr ati o n
Pl at el et c o u nt 
W h it e bl o o d c ell c o u nt
R eti c ul o c yt e c o u nt 
W h it e bl o o d c ell diff er e nti al s a n d 
a b s ol ut e c o u nt s a :
B a s o p hil s
E o si n o p hil s
L y m p h o c yt e s
M o n o c yt e s
N e utr o p hil s 
Uri n al y si s 
p H
Nitrit e
Pr ot ei n 
Gl u c o s e
K et o n e b o di e s
Ur o bili n o g e n 
Bilir u bi n
W h it e bl o o d c ell c o u nt
M i cr o s c o pi c e x a mi n ati o nc
Uri n e dr u g 
s cr e e n
C o c ai n e
A m p h et a mi n e s
M et h a m p h et a mi n e s
O pi at e s
B ar bit ur at e s
M D M A ( e c st a s y )
B e n z o di a z e pi n e
M et h a d o n e
T H C ( c a n n a bi n oi d s )
P h e n c y cli di n e
Tri c y cli c a nti d e pr e s s a nt s
P ar a c et a m ol
S er ol o g y
H e p atiti s B s urf a c e a nti g e n 
H e p atiti s B c or e a nti b o d y
H e p atiti s C a nti b o d y
H u m a n i m m u n o d efi ci e n c y vir u s ( HI V) I a n d II a nti b o di e s
R e d bl o o d c ell a nti b o di e s ( P art C o nl y)
C o a g ul ati o n
Pr ot hr o m bi n ti m e (I N R), 
A cti v at e d p arti al t hr o m b o pl a sti n ti m e 
Ot h er t e st s
Uri n e c oti ni n e
Al c o h ol br e at h al y z er
F olli cl e -sti m ul ati n g h or m o n e (f or p o st m e n o p a u s al w o m e n)
Gl u c o s e - 6-p h o s p h at e d e h y dr o g e n a s e s t at u s/t e sti n g ( P art C o nl y)
H D L = Hi g h -d e n sit y li p o pr ot ei n ; I N R = I nt er n ati o n al N or m ali z e d R ati o: 
M D M A
= 3, 4 -m et h yl e n e di o x y m et h a m p h et a mi n e ; T H C = t etr a h y dr o c a n n a bi n ol.
a 
I n c a s e of a b n or m al fi n di n g s m a n u al diff er e nti al bl o o d c o u nt, dir e ct/i n dir e ct bilir u bi n a n d cr e ati n e 
p h o s p h o ki n a s e m y o c ar di al/ br ai n t y p e fr a cti o n or ot h er a s s e s s m e nt s c a n b e r e q u e st e d b y t h e I n v e sti g at or.
b
S cr e e ni n g o nl y.
c
O nl y if bl o o d, pr ot ei n, nitrit e, or w hit e bl o o d c ell c o u n t ar e p o siti v e o n t h e di p sti c k.
7. 4. 3. 2
Se mi -Q u a ntit ati ve Uri n al ysis
T he list of se mi -q ua ntitati ve uri nal y sis e xa mi nati o ns is dis pla ye d i n Ta ble 8.
O n p ositi ve fi n di n gs or o n de ma n d of t he I n vesti gat or, a s u bsi diar y micr osc o pic e xa mi nati o n of 
t he se di me nt will be perf or me d. A d diti o nal la b orat or y exa mi nati o ns d uri n g t he c o urse of t he trial
are at t he discreti o n of t he I n vesti gat or .
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
9 4 / 1 9 0
7. 4. 3. 3
F ollicle - Sti m ul ati n g H or m o ne
F S H will be i n vesti gate d at Scree ni n g t o c o nfir m p ost me n o pa usal stat us (fe males o nl y ).
7. 4. 3. 4
Ser ol o g y
Ser ol o g y  for he patitis a n d HI V, i ncl u di n g HI V a nti b o dies, H Bs -A g a n d a nti b o dies a gai nst he patitis 
C vir us will be i n vesti gate d at Scree ni n g. I n Part C, sa m ples will be c ollecte d a n d a nalyz e d f or t he 
detecti o n of ser oc o n versi o n a gai nst s o me rare bl o o d sta ge pat h o ge ns or re d bl o o d cell a nti b o dies 
at ti me p oi nts i n dicate d i n  Ta ble 3.
7. 4. 3. 5
Gl uc ose - 6-P h os p h ate De h y dr o ge n ase St at us
I n Part C, s u bjects’ G 6 P D stat us will be deter mi ne d at Scree ni n g t o e xcl u de s u bjects wit h k n o w n 
or meas ure d G 6 P D deficie nc y .
7. 4. 3. 6
I n oc ul u m S afet y S a m ple
I n Part C, ser u m sa m ples will be c ollecte d fr o m eac h s u bject at I n oc ul u m Da y  1 ( pre i n oc ulati o n), 
D a y  2 2 ( pre Ria met treat me nt) a n d t he E n d of Trial visit (Da y 4 4 [ ± 2 da y s]). T hese sa m ples will 
be st ore d a n d will be use d o nl y  i n case a n y safet y c o ncer ns arise a n d a d diti o nal safety para meter 
testi n g is re q uire d.
7. 4. 4
Vit al Si g ns, P h ysic al E x a mi n ati o ns, a n d Ot her Assess me nts
7. 4. 4. 1
Vit al Si g ns
Vital si g ns i ncl u de b o d y te m perat ure, B P , a n d heart rate.
Bl o o d press ure will be meas ure d acc or di n g t o t he Ri va/ R occi met h o d usi n g a n a ut o mate d de vice, 
w hi c h als o i n dicates t he c orres p o n di n g heart rate i n beats per mi n ute. Bl o o d press ure a n d heart 
rate will be meas ure d after at least 5 mi n utes i n a rec u m be nt p ositi o n, e xce pt at pre d ose, 8 h o urs, 
1 6 h o urs, a n d 2 4 h o urs after d osi n g, w he n i n a d diti o n als o ort h ostatic meas ure me nts will be 
c o n d ucte d. O n D a y  1, a ti me wi n d o w of 6 0 mi n utes is all o we d f or bl o o d press ure meas ure me nts.
I n case t he s u bject is u na ble t o sta n d u p at t he 1 6 h o urs (a n d/ or 2 0 h o urs f or Part A) p ost d ose ti me 
p oi nt d ue t o dizzi ness, t he vital si g ns m a y  be assesse d i n t he s u pi ne p ositi o n. B o d y te m perat ure 
will be meas ure d orall y (s u bli n g ual) . Vital si g ns will be meas ure d at sc he d ule d visits acc or di n g t o 
t he a p plica ble Sc he d ule of Assess me nts (Ta ble 1 t o Ta ble 3 ). F urt her vital si g n meas ure me nts 
d uri n g t he c o urse of t he trial are at t he discreti o n of t he I n vesti gat or.
7. 4. 4. 2
P h ysic al E x a mi n ati o n
A sta n dar d f ull p h y sical e xa mi nati o n, i ncl u di n g e xa mi nati o n of all b o d y  sys te ms, will be 
perf or me d at Scree ni n g a n d t he E n d of Trial visit ( Da y 44 ± 2 d a y s), i ncl u di n g ge neral a p peara nce, 
s kin, hea d, nec k (i ncl u di n g t h yr oi d), e yes, ears, n ose, t hr oat, car di o vasc ular a n d p ul m o nar y  sys te m, 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
9 5 / 1 9 0
a b d o me n, ne ur ol o gical, peri p heral vasc ular, a n d m usc ul os keletal s yste m. At ot her ti me p oi nts a n 
a b bre viate d p h ys ical e xa mi nati o n m ust be perf or me d.
Res pirat o r y rate will be assesse d at ti me p oi nts i n dicate d i n t he Sc he d ule of Assess me nts (Ta ble 1
t o Ta ble 3) .
P h y sical e xa mi nati o ns will be sc he d ule d acc or di n g t o t he a p plica ble Sc he d ule of Assess me nts 
(Ta ble 1 t o Ta ble 3 ). F urt her me dical e xa mi nati o ns d uri n g t he c o urse of t he trial are at t he 
discreti o n of t he I n vesti gat or. 
7. 4. 4. 3
Alc o h ol Bre at h Test
A c o m merciall y a vaila ble breat halyz er test will be use d t o deter mi ne t he c o nce ntrati o n of alc o h ol 
i n s u bject’s breat h acc or di n g t o t he Sc he d ule of Assess me nts (Ta ble 1 t o Ta ble 3 ). 
A d diti o nal alc o h ol breat h tests d uri n g t he c o urse of t he trial are at t he discreti o n of t he I n vesti gat or.
7. 4. 4. 4
Uri ne Dr u g Scree n
S p ot uri ne will be assesse d f or recreati o nal dr u gs acc or di n g t o t he Sc he d ule of Assess me nts 
(Ta ble 1 t o Ta ble 3 ). T he list of uri ne dr u g scree n e xa mi nati o ns is dis pla ye d i n Ta ble 8.
A d diti o nal uri ne dr u g sc ree ns d uri n g t he c o urse of t he trial are at t he discreti o n of t he I n vesti gat or.
7. 4. 4. 5
1 2 -Le a d Electr oc ar di o gr a m
T he 1 2- Lea d E C G rec or ds will be use d f or o n- ti me car diac safety m o nit ori n g. Bef ore ta ki n g t he 
E C G t he s u bject has t o re mai n i n a rec u m be nt p ositi o n f or at least 5 mi n utes . A f ull sta n dar d 
1 2- lea d E C G (I, II, III, a V R, a V L, a V F, V 1-V 6) f or a b o ut 5 sec o n ds (3 a djace nt beats, cali brati o n: 
5 0
m m/sec 1 0 m m/ m V) a n d a r hyt h m rec or di n g fr o m lea d II f or 6 0 seco n ds ( Cali brati o n: 
1 0 m m/sec 1 2, 5 m m/ m V) is rec or de d acc or di n g t o t he Sc he d ule of Assess me nts (Ta ble 1 t o 
Ta ble 3 ).
Safet y  12 -lea d E C Gs will be rea d l ocall y an d m o nit ore d i n real ti me. E C G pri nt o uts s h o ul d be 
si g ne d a n d date d by t he pers o n perf or mi n g t he E C G. T he 1 2-lea d E C G will be a nal yze d, assesse d 
f or pla usi bilit y a n d cli nical rele va nce, a n d si g ne d b y t he I n vesti gat or. T he cli nical rele va nce of the 
E C G will be assesse d b y  the In vesti gat or, b ut a n y val ues o utsi de t he “ Refere nce Ra n ges f or A E 
Re p orti n g” will be assesse d as cli nicall y rele va nt.
A d diti o nal E C Gs d uri n g t he c o urse of t h e trial are at t he discreti o n of t he In vesti gat or. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
9 6 / 1 9 0
7. 4. 4. 7
S pecific Pl a n ne d Assess me nts or A d verse E ve nts of S peci al 
I nterest

V o miti n g, diarr hea. I n case of v o miti n g s u bjects s h o ul d n ot be re-d ose d a n d t he y sh o ul d be ke pt 
i n t he trial, h o we ver t he I n vesti gat or ca n deci de w het her t o sc he d ule t he fi nal F oll o w - u p visit 
earlier

Li ver e nz y mes ( A L T/ A S T/ Bilir u bi n)

C uta ne o us reacti o ns (l ocal t olera bilit y CR F f or se verity of re d ness, s welli n g, i n d urati o n, 
br uisi n g, a n d itc hi n g)

P h ot ose nsiti vit y/li g ht se nsiti vit y  

Pre g na nc y  in a fe male part ner of a m ale s u bject. A n y  su bject’s fe male part ner w h o bec o mes 
pre g na nt d uri n g t he trial or i n t he f oll o wi n g 2 0 wee ks after t he last d osi n g s h o ul d be f oll o we d 
t hr o u g h deli ver y  or ter mi nati o n of t he pre g na nc y. Pre g na nc y  is re p orte d t o t he S p o ns or b y  
c o m pleti o n of t h e pre g na nc y f or m.
7. 4. 4. 8
Di ar y C ar ds
Diar y  car ds will be pr o vi de d t o s u bjects w he n lea vi n g c o nfi ne me nt f or c ollecti o n of data relati n g 
t o t heir dail y  ph y sical acti vit y, dail y use of s u nscree n/ ot her met h o ds of s u n pr otecti o n, dail y 
alc o h ol c o ns u m pti o n, a n d if a p plica ble t heir oral (s u bli n g ual) te m perat ure. S u bjects will bri n g t heir 
c o m plete d diar y  car ds wit h t he m t o t he trial site f or all a m b ula nt, F oll o w - u p, a n d E n d of Trial 
visits (Ta ble 1, Ta ble 2 , a n d Ta ble 3 ).
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
9 8 / 1 9 0
Details o n sa m ple c ollecti o n, pre parati o n f or pr ocessi n g, s hi p me nt, a n d a nal y sis will be s pecifie d 
i n a se parate la b orat or y ma n ual.
7. 5. 2
P h ar m ac o k i netic C alc ul ati o ns
I n di vi d ual w h ole bl o o d P K para meters will be calc ulate d usi n g act ual sa m pli n g ti mes, w here 
a vaila ble. I n cases w here t he act ual sa m pli n g ti me is missi n g (e g, I nter me diar y SM C re p orts) 
calc ulati o ns wil l be perf or me d usi n g t he sc he d ule d ti me. T he pre d ose sa m ples will be c o nsi dere d 
as if t he y ha d bee n ta ke n si m ulta ne o usl y wit h t he a d mi nistrati o n.
7. 5. 2. 1
W h ole Bl o o d
F or eac h s u bject wit h e val ua ble w h ole bl o o d P K data, t he f oll o wi n g P K para meters will be 
calc ulated fr o m M 5 7 1 7
w h ole bl o o d c o nce ntrati o ns ge nerate d fr o m t he vali date d bi oa nal yt ical 
assa ys:
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
9 9 / 1 9 0
P art A a n d P art B
T a ble 9
Defi niti o n of In di vi d u al P h ar m ac o ki netic P ar a meters
P ar a m et er
D efi niti o n
A U C 0-t
Ar e a u n d er t h e bl o o d c o n c e ntr ati o n -ti m e c ur v e ( A U C) fr o m ti m e z er o t o t h e l a st s a m pli n g 
ti m e at w hi c h t h e c o n c e ntr ati o n i s at or a b o v e L L O Q, c al c ul at e d a c c or di n g t o t h e mi x e d l o g 
li n e ar tr a p e z oi d al r ul e (i e, li n e ar u p/l o g d o w n). T hi s will b e c al c ul at e d f or P art A , a n d f or 
D a y 1 a n d D a y 3 of P art B.
A U C 0-t , o v er all
T h e A U C 0-t o v er t h e e ntir e d o si n g ti m e p eri o d i n P art B, i e , fr o m ti m e z er o ( d o si n g ti m e) o n 
D a y 1 t o t h e l a st s a m pli n g ti m e at w hi c h t h e c o n c e ntr ati o n i s at or a b o v e L L O Q o n D a y 3, 
c al c ul at e d a c c or di n g t o t h e mi x e d lo g li n e ar tr a p e z oi d al r ul e (i e , li n e ar u p/l o g d o w n).
A U C 0- ∞
T h e A U C fr o m ti m e z er o ( d o si n g ti m e) e xtr a p ol at e d t o i nfi nit y, b a s e d o n t h e pr e di ct e d v al u e 
f or t h e c o n c e ntr ati o n at tl a st, a s e sti m at e d u si n g t h e li n e ar r e gr e s si o n fr o m λ z d et er mi n ati o n. 
A U C 0- ∞= A U C 0-t + C l a st pr e d/ λ z. T hi s will b e c al c ul at e d f or P art A. 
A U C 0- ∞, o v er all
T h e A U C 0- ∞o v er t h e e ntir e d o si n g ti m e p eri o d i n P art B, i e , fr o m ti m e z er o ( d o si n g ti m e) o n 
D a y 1, e xtr a p ol at e d t o i nfi nit y f oll o wi n g t h e d o s e o n D a y 3, b a s e d o n t h e pr e di ct e d v al u e f or 
t h e c o n c e ntr ati o n at tl a st, o n D a y 3, a s e sti m at e d u si n g t h e li n e ar r e gr e s si o n fr o m λ z
d et er mi n ati o n.
A U C 0- 2 4 h
A U C fr o m ti m e z er o t o 2 4 h o ur s . T hi s will b e c al c ul at e d f or P art A, a n d f or D a y 1 a n d D a y 3 
of P art B.
A U C 0- 1 4 4 h
A U C fr o m ti m e z er o t o 1 4 4 h o ur s. T hi s will b e c al c ul at e d f or P art A, a n d f or D a y 3 of 
P art B.
A U C 0- 1 4 4 h. o v er all
A U C fr o m ti m e z er o t o 1 4 4 h o ur s i n P art B, i e, fr o m ti m e z er o ( d o si n g ti m e) o n D a y 1 u ntil 
1 4 4 h o ur s aft er t h e D a y 1 d o s e.
C m a x
M a xi m u m bl o o d c o n c e ntr ati o n o b s er v e d . T hi s will b e c al c ul at e d f or P art A, a n d f or D a y 1 
a n d D a y 3 of P art B.
tm a x
Ti m e t o r e a c h t h e m a xi m u m bl o o d c o n c e ntr ati o n . T hi s will b e c al c ul at e d f or P art A, a n d f or 
D a y 1 a n d D a y 3 of P art B.
t½
A p p ar e nt t er mi n al h alf -lif e, c al c ul at e d a s l n 2/ λ z. T his will b e c al c ul at e d f or P art A a n d D a y 3 
of P art B . 
λ z 
T er mi n al fir st or d er ( eli mi n ati o n) r at e c o n st a nt. T hi s will b e c al c ul at e d f or P art A a n d D a y 3 
of P art B .
C L/f 
T ot al b o d y cl e ar a n c e of dr u g fr o m bl o o d f oll o wi n g or al a d mi ni str ati o n. T hi s will b e 
c al c ul at e d f or P art A. 
C L/f , o v er all
T ot al b o d y cl e ar a n c e of dr u g fr o m bl o o d f oll o wi n g or al a d mi ni str ati o n. T hi s will b e 
c al c ul at e d o v er t h e e ntir e d o si n g a n d P K s a m pli n g p eri o d i n P art B . 
V z/f 
A p p ar e nt v ol u m e of di stri b uti o n d uri n g t h e t er mi n al p h a s e f oll o wi n g e xtr a v a s c ul ar 
a d mi ni str ati o n. T hi s will b e c al c ul at e d f or P art A.
V z/f,o v er all 
A p p ar e nt v ol u m e of di stri b uti o n d uri n g t h e t er mi n al p h a s e f oll o wi n g e xtr a v a s c ul a r 
a d mi ni str ati o n. T hi s will b e c al c ul at e d o v er t h e e ntir e d o si n g a n d P K s a m pli n g p eri o d i n 
P art B .
A U C e xtr a %
T h e A U C fr o m ti m e t l a st e xtr a p ol at e d t o i nfi nit y gi v e n a s p er c e nt a g e of A U C 0- ∞. T hi s will b e 
c al c ul at e d f or P art A. F or P art B, t hi s will b e c al c ul at e d f or A U C 0- ∞, o v er all, a n d f or A U C 0- ∞o n 
D a y 1 if A U C 0- ∞if a c c ur at el y e sti m a bl e.
A U C 0-t / D o s e 
D o s e -n or m ali z e d A U C 0-t . T hi s will b e c al c ul at e d f or P art A , a n d o n D a y 1 a n d D a y 3 of 
P art B. 
A U C 0-t , o v er all/ D o s e 
D o s e -n or m ali z e d A U C 0-t , o v er all. T hi s will b e c al c ul at e d f or P art B.
A U C 0- ∞/ D o s e
D o s e -n or m ali z e d A U C 0- ∞. T hi s will b e c al c ul at e d f or P art A. 
A U C 0- ∞, o v er all/ D o s e
D o s e -n or m ali z e d A U C 0- ∞, o v er all. T hi s will b e c al c ul at e d f or P art B.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 0 0 / 1 9 0
P ar a m et er
D efi niti o n
C m a x/ D o s e
D o s e -n or m ali z e d C m a x . T hi s will b e c al c ul at e d f or P art A, a n d f or D a y 1 a n d D a y 3 of 
P art B.
A U C 0- 2 4 h / D o s e
D o s e -n or m ali z e d A U C 0- 2 4 h . T hi s will b e c al c ul at e d f or P art A, a n d f or D a y 1 a n d D a y 3 of 
P art B.
A U C 0- 1 4 4 h / D o s e
D o s e -n or m ali z e d A U C 0- 1 4 4 h . T hi s will b e c al c ul at e d f or P art A, a n d f or D a y 3 of P art B.
A U C 0- 1 4 4 h, o v er all / D o s e
D o s e -n or m ali z e d A U C 0- 1 4 4 h, o v er all . T hi s will b e c al c ul at e d f or P art B.
R a c c ( A U C)
A c c u m ul ati o n r ati o f or A U C 0- 2 4 h , c al c ul at e d i n P art B a s A U C 0- 2 4 h o n D a y 3 di vi d e d b y 
A U C 0- 2 4 h o n D a y 1
R a c c( C m a x)
A c c u m ul ati o n r ati o f or C m a x, c al c ul at e d i n P art B a s C m a x o n D a y 3 di vi d e d b y C m a x o n D a y 1
t> 1 0 n g/ m L
Ti m e a b o v e or e q u al t o t h e pr e di ct e d M 5 7 1 7 m o u s e M P C o f 1 0 n g/ m L. C al c ul at e d f or 
P art A, a n d f or P art B o v er t h e e ntir e d o si n g ti m e p eri o d.
t> 3 n g/ m L
Ti m e a b o v e or e q u al t o t h e pr e di ct e d M 5 7 1 7 m o u s e MI C of 3 n g/ m L. C al c ul at e d f or P art A, 
a n d f or P art B o v er t h e e ntir e d o si n g ti m e p eri o d.
L L O Q = L o w er li mit of q u a ntifi c ati o n ; MI C = mi ni m al i n hi bit or y c o n c e ntr ati o n; M P C = mi ni mal p ar a siti ci d al 
c o n c e ntr ati o n.
A d diti o nal P K para meters ma y  be calc ulate d.
P art C
If t he trial desi g n of Part C is si n gle d ose, w h ole bl o o d P K para meters as descri be d f or Part A 
(Ta ble 9 ) will be calc ulate d. Alter nati vel y, if t he trial desi g n of Part C is m ulti ple d ose, w h ole 
bl o o d P K para meters as descri be d f or Part B (Ta ble 9 ) will be calc ulate d.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 0 2 / 1 9 0
8
St atistics
8. 1
S a m ple Size
Gi ve n t he e x pl orat or y nat ure of t his trial, t he sa m ple size i n Part A a n d Part B is n ot base d o n 
f or mal statistical calc ulati o ns. T he sa m ple size is base d o n e x perie nce fr o m pre vi o us si milar 
P hase I trials w hic h will pr o vi de s ufficie nt safety a n d t olera bilit y data f or M 5 7 1 7 t o ac hie ve t he 
o bjecti ves fr o m Part A a n d Part B of t he trial w hile e x p osi n g as fe w s u bjects as p ossi ble t o t he 
I M P a n d pr oce d ures. 
F or Part C, t he o bjecti ve is t o defi ne t he P K/ P D relati o ns hi p of M 5 7 1 7. Hist oricall y , 8 partici pa nts 
i n a d ose c o h ort ha ve pr o ve n s ufficie nt t o c haracterize t he effects of a dr u g o n malaria parasite 
ki netics f oll o wi n g i n d ucti o n i n healt h y  vol u nteers usi n g i n oc ulati o n wit h 
bl o o d sta ge 
P. falci par u m. T heref ore, t he sa m ple size of t he c urre nt trial f or P. falci par u m i nfecti o n ( n = 8 per 
c o h ort) is c o m para ble wit h pre vi o us trials, a n d base d o n pre vi o usl y p u blis he d e x perie nce ( 3, 1 0). 
T w o or 3 c o h orts s h o ul d be s ufficie nt t o ac hie ve t he o bjecti ve i n Part C, w hic h is t o defi ne t he 
P R R, t he maj or P D para meter, a n d t o deri ve t h e MIC a n d M P C of t he c o m p o u n d.
As t he e xact n u m ber of s u bjects s h o wi n g recr u desce nce is u n k n o w n, 3 c o h orts are pla n ne d t o b e 
a ble t o e val uate a hi g her or l o wer d ose of I M P t o c ollect s ufficie nt data o n s u bjects s h o wi n g c ure 
as well as recr u desce nce. 
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 0 3 / 1 9 0
I n Part C, su bjects w h o are wit h dra w n fr o m t he trial b y  t h e In vesti gat or d ue t o A Es after t he start 
of t he i n oc ul u m will ge nerall y n ot be re place d. T he fi nal decisi o n will be ta ke n after disc ussi o n 
wit h t he S p o ns or.
8. 2
R a n d o miz ati o n
P art A
D ose c o h orts i ncl u di n g 8 s u bjects eac h are pla n ne d i n P art A. D ose a d mi nistrati o n f or eac h d ose 
c o h ort will pr ocee d wit h 2 s u bjects i n a se nti nel c o h ort. I n eac h d ose c o h ort, 8 s u bjects will be 
ra n d o mize d i n a d o u ble -bli n d fas hi o n t o M 5 7 1 7 or place b o i n a rati o of 6: 2, res pecti vely, s uc h t hat 
f or t he first 2 s u bjects i n t he se nti nel c o h ort, 1 s u bject will recei ve M 5 7 1 7 a n d 1 s u bject will recei ve 
place b o.
De pe n di n g o n a vaila ble safet y d ata t he S M C ca n deci de t o start t he c o h ort wit h 3 se nti nel s u bjects 
( 2 M 5 7 1 7 : 1 place b o).
T he ra n d o mizati o n will be ge nerate d f or eac h c o h ort usi n g c o nsec uti ve ra n d o mizati o n c o des a n d 
s u bjects will be all ocate d t o M 5 7 1 7 or place b o i n a rati o as prese nte d i n Ta ble 1 1.
T a ble 1 1
M et h o d of Assi g ni n g S u bjects t o Tre at me nt Gr o u ps i n P art A
C o h ort
S u bj e ct 
N u m b er
( S cr e e ni n g 
N u m b er)
R a n d o mi z ati o n 
N u m b er
R e pl a c e m e nt 
R a n d o mi z ati o n 
N u m b er
R ati o of S u bj e ct 
A s si g n m e nt 
( A cti v e: Pl a c e b o)
C o h ort 1 Si n gl e A s c e n di n g D o s e 
1 1 x x
R A 1 1 0 1 -1 1 0 8
R A 1 1 5 1 -1 1 5 8
6: 2 ( S e nti n el 1: 1; 
R e m ai n d er 5: 1)
C o h ort 2 Si n gl e A s c e n di n g D o s e 
1 2 x x
R A 1 2 0 1 -1 2 0 8
R A 1 2 5 1 -1 2 5 8
6: 2 ( S e nti n el 1: 1; 
R e m ai n d er 5: 1)
C o h ort 3 Si n gl e A s c e n di n g D o s e 
1 3 x x
R A 1 3 0 1 -1 3 0 8
R A 1 3 5 1 -1 3 5 8
6: 2 ( S e nti n el 1: 1; 
R e m ai n d er 5: 1)
C o h ort 4 Si n gl e A s c e n di n g D o s e 
1 4 x x
R A 1 4 0 1 -1 4 0 8
R A 1 4 5 1 -1 4 5 8
6: 2 ( S e nti n el 1: 1; 
R e m ai n d er 5: 1)
C o h ort 5 Si n gl e A s c e n di n g D o s e 
1 5 x x
R A 1 5 0 1 -1 5 0 8
R A 1 5 5 1 -1 5 5 8
6: 2 ( S e nti n el 1: 1; 
R e m ai n d er 5: 1)
C o h ort 6 Si n gl e A s c e n di n g D o s e
1 6 x x
R A 1 6 0 1 -1 6 0 8
R A 1 6 5 1 -1 6 5 8
6: 2 ( S e nti n el 1: 1; 
R e m ai n d er 5: 1)
C o h ort 7 Si n gl e A s c e n di n g D o s e
1 7 x x
R A 1 7 2 1 -1 7 2 8
R A 1 7 7 1 -1 7 7 8
6: 2 ( S e nti n el 2 : 1; 
R e m ai n d er 4 : 1)
F or t he a d diti o nal S A D c o h orts, t he ra n d o mizati o n will be ge nerate d base d o n t he S M C decisi o n 
o n t he n u m ber of s u bjects i n t he se n ti nel gr o u p ( 2 or 3 se nti nel s u bjects).
P art B
T hree asce n di n g d ose c o h orts of 8 s u bjects eac h are pla n ne d i n Part B , s h o ul d t hat part of t he trial 
be c o n d ucte d . Wit hi n eac h d ose c o h ort, 8 s u bjects will be ra n d o mize d i n a d o u ble -bli n d fas hi o n t o 
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 0 4 / 1 9 0
M 5 7 1 7 or p lace b o i n a rati o of 6: 2, res pecti vel y suc h t hat f or t he first 2 s u bjects i n t he se nti nel 
c o h ort, 1 s u bject will recei ve M 5 7 1 7 a n d 1 s u bject will recei ve place b o. T he ra n d o mizati o n will 
be ge nerate d f or eac h c o h ort usi n g c o nsec uti ve ra n d o mizati o n c o des as prese nte d i n  Ta ble 1 2.
T a ble 1 2
M et h o d of Assi g ni n g S u bjects t o Tre at me nt Gr o u ps i n P art B
C o h ort
S u bj e ct 
N u m b er
( S cr e e ni n g 
N u m b er)
R a n d o mi z ati o n 
N u m b er
R e pl a c e m e nt 
S u bj e ct N u m b er
R ati o of S u bj e ct 
A s si g n m e nt 
( A cti v e: Pl a c e b o)
C o h ort 1 M ulti pl e A s c e n di n g 
D o s e
2 1 x x
R A 2 1 0 1 -2 1 0 8
R A 2 1 5 1 -2 1 5 8
6: 2 ( S e nti n el 1: 1; 
R e m ai n d er 5: 1)
C o h ort 2 M ulti pl e A s c e n di n g 
D o s e
2 2 x x
R A 2 2 0 1 -2 2 0 8
R A 2 2 5 1 -2 2 5 8
6: 2 ( S e nti n el 1: 1; 
R e m ai n d er 5: 1)
C o h ort 3 M ulti pl e A s c e n di n g 
D o s e
2 3 x x
R A 2 3 0 1 -2 3 0 8
R A 2 3 5 1 -2 3 5 8
6: 2 ( S e nti n el 1: 1; 
R e m ai n d er 5: 1)
S u bject Re pl ace me nt f or P art A a n d P art B
S u bjects w h o are wit h dra w n fr o m t he trial b y  the I n vesti gat or d ue t o A Es after t he start of 
a d mi nistrati o n of t he I MP will n ot be re pla ce d. S u bjects w h o wit h dra w f or a n y ot her reas o n ma y 
be re place d after disc ussi o n wit h t he S p o ns or. I n Part A a n d Part B, re place me nt s u bjects, if 
utilize d, will recei ve t he sa me treat me nt as t he s u bject t he y are re placi n g, usi n g a ra n d o mizati o n 
n u m ber i ncr e me nte d b y 5 0 as s h o w n a b o ve.
8. 3
E n d p oi nts
8. 3. 1
Pri m ar y E n d p oi nts
P art A

Nat ure, i nci de nce, a n d se verity of A Es /S A Es , i ncl u di n g relati o ns hi p t o trial treat me nt, 
A Es/ S A Es lea di n g t o d ose m o dificati o n or disc o nti n uati o n of trial treat me nt 

I nci de nce of cli nically si g nifica nt c ha n ges a n d a b n or malities i n safet y la b orat or y para meters 
( he mat ol o g y, c oa g ulati o n, bioc he mistr y  [s pecificall y A L T a n d A S T], a n d uri nal ysis)

I nci de nce of cli nicall y si gnifica nt c ha n ges a n d a b n or malities i n v ital si g ns ( b o d y te m perat ure, 
B P, a n d heart rate ), res pirat or y rate, a n d 1 2- lea d E C G.
P art B ( o pti o n al)

Nat ure, i nci de nce, a n d se verity of A Es /S A Es , i ncl u di n g relati o ns hi p t o trial treat me nt, 
A Es/ S A Es lea di n g t o d ose m o dificati o n or disc o nti n uati o n of trial treat me nt 

I nci de nce a n d cli nically si g nifica nt c ha n ges a n d a b n or malities i n safet y la b orat or y para meters 
( he mat ol o g y, c oa g ulati o n, bi oc he mistr y [s pecificall y A L T a n d A S T] a n d uri nal ysis)

I nci de nce a n d cli nicall y si g nifica nt c ha n ges a n d a b n or malities i n vital si g ns ( b o d y te m perat ure, 
B P, a nd heart rate), res pirat or y rate, a n d 1 2 -lea d E C G.
P art C
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 0 5 / 1 9 0

P R R as o bser ve d t hr o u g h q ua ntitati ve p ol y merase c hai n reacti o n ( q P C R) a nal ysis

All M 5 7 1 7 P K para meters as defi ne d i n Part A or Part B ( de pe n di n g o n d osi n g re gi me n i n 
Part C) .
8. 3. 2
Sec o n d ar y E n d p oi nts
P art A

P K para meters f or M 5 7 1 7.
P art B ( o pti o n al)

P K para meters f or M 5 7 1 7.
P art C

P C T , MIC, P Ct ½, M P C, la g p hase, n u m ber of s u bjects wit h recr u desce nce

Malaria Cli nical Sc ore

Nat ure, i nci de nce, a n d se verity of A Es/ S A Es, i ncl u di n g relati o ns hi p t o trial treat me nt, 
A Es/ S A Es lea di n g t o d ose m o dificati o n or disc o nti n uati o n of trial treat me nt 

I nci de nce of cli nically si g nifica nt c ha n ges a n d a b n or malities i n safet y la b orat or y para meters 
( he mat ol o g y, c oa g ulati o n, bi oc he mistr y [s pecificall y A L T a n d A S T], a n d uri nal ysis)

I nci de nce of cli nicall y si gnifica nt c ha n ges a n d a b n or malities i n v ital si g ns ( b o d y t em perat ure, 
B P, a n d heart rate ), res pirat or y rate, a n d 1 2 -lea d E C G.
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 0 6 / 1 9 0
8. 4
A n al ysis Sets
F or p ur p oses of a nal y sis, t he f oll o wi n g p o p ulati o ns are defi ne d:
T a ble 1 3
Defi niti o n of St atistic al A n al ysis P o p ul ati o ns
P o p ul ati o n
D e s cri pti o n
E nr oll e d 
T h e E nr oll e d A n al y si s S et will i n cl u d e all s u bj e ct s w h o pr o vi d e d si g n e d i nf or m e d 
c o n s e nt, r e g ar dl e s s of tr e at m e nt st at u s i n t h e tri al. T hi s s et will b e u s e d f or s u bj e ct
di s p o siti o n.
S af et y
T h e S af et y A n al y si s S et will i n cl u d e all s u bj e ct s w h o r e c ei v e at l e a st o n e d o s e of 
i n v e sti g ati o n al m e di ci n al pr o d u ct ( M 5 7 1 7 or pl a c e b o f or P art A a n d P art B; M 5 7 1 7 f or 
P art C). S u bj e ct s will b e a n al y z e d a c c or di n g t o t h e a ct u al tr e at m e nt t h e y r e c ei v e.
P h ar m a c o ki n eti c 
T h e P h ar m a c o ki n eti c A n al y si s S et will c o n si st of all s u bj e ct s w h o r e c ei v e at l e a st o n e 
d o s e of M 5 7 1 7, h a v e n o cli ni c all y i m p ort a nt pr ot o c ol d e vi ati o n s or i m p ort a nt e v e nt s 
aff e cti n g p h ar m a c o ki n eti c s, a n d pr o vi d e at l e a st o n e ( m e a s ur a bl e) p o st d o s e 
c o n c e ntr ati o n. S u bj e ct s will b e a n al y z e d a c c or di n g t o t h e a ct u al tr e at m e nt t h e y r e c ei v e. 
All p h ar m a c o ki n eti c a n al y s e s will b e b a s e d o n t hi s a n al y si s s et. 
S u bj e ct s w h o r e c ei v e pl a c e b o will n ot b e p art of t h e P h ar m a c o ki n eti c A n al y si s S et.
P h ar m a c o d y n a mi c 
T h e P h ar m a c o d y n a mi c A n al y si s S et will b e d efi n e d f or t h e P art C o nl y. T h e 
P h ar m a c o d y n a mi c A n al y si s S et will i n cl u d e all s u bj e ct s w h o r e c ei v e at l e a st o n e d o s e 
of M 5 7 1 7 i n P art C wit h o ut cli ni c all y i m p ort a nt pr ot o c ol d e vi ati o n s or i m p ort a nt e v e nt s 
aff e cti n g p h ar m a c o d y n a mi c s . S u bj e ct s i n t h e P h ar m a c o d y n a mi c A n al y si s S et m u st 
h a v e e v al u a bl e p h ar m a c o d y n a mi c d at a. All p h ar m a c o d y n a mi c a n al y s e s will b e b a s e d 
o n t hi s a n al y si s s et.
8. 5
Descri pti o n of St atistic al A n al yses
8. 5. 1
Ge ner al C o nsi der ati o ns
T he res ults of t his trial will be re p orte d usi n g s u m mar y ta bles, fig ures, a n d data listi n gs, as 
a p pr o priate. All data will be s u m marize d b y  trial part, d ose le vel a n d/ or sc he d ule d ti me p oi nt, as 
a p pr o priate a n d ot her wise s pecifie d.
F or de m o gra p hic, baseli ne a n d safet y assess me nts, c o nti n u o us meas ure me nts will be s u m marize d 
b y  means of descri pti ve statistics (ie, n u m ber a n d perce nta ge of o bser vati o ns, n u m ber a n d 
perce nta ge of missi n g o bser vati o ns, mea n, sta n dar d de viati o n, me dia n, 2 5 t h a n d 7 5 t h perce ntiles, 
mi ni m u m, a n d ma xi m u m) a n d cate g orical data will be s u m marize d b y  m ea ns of fre q ue nc y ta bles 
(ie, c o u nt a n d perce nta ges), if n ot state d ot her wise.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 0 7 / 1 9 0
Gi ve n its e x pl orat or y nat ure, n o f or mal statistical h y p ot hesis testi n g will be perf or me d i n t his trial. 
Data will be prese nte d b y  act ual d ose or treat me nt, a n d s u bjects recei vi n g place b o will be p o ole d 
acr oss d osi n g c o h orts f or t he p ur p oses of s u m marizi n g t he safety res ults ( Part A a n d Part B). 
Missi n g data will res ult i n a re d uce d sa m ple size f or t hat para meter. Si nce t he statistical a nal y ses 
will be pre d o mi na ntl y  descri pti ve pre se ntati o ns i n ta bles a n d i n di vi d ual data listi n gs, n o acti o n 
will be ta ke n t o ha n dle missi n g data. A s u bject w h o wit h dra ws pri or t o t he last pla n ne d o bser vati o n 
i n a trial peri o d will be i ncl u de d i n t he a nal ys es u p t o t he ti me of disc o nti n uati o n.
P K
c o nce ntrati o ns i n bl o o d, a n d P K a n d P D para meters will be prese nte d i n ta bles a n d 
descri pti vel y s u m marize d b y  trial part, d ose le vel, trial da y , a n d/ or n o mi nal ti me p oi nt, as 
a p pr o priate, usi n g n, arit h metic mea n, sta n dar d de viati o n, me dia n, mi ni m u m, ma xi m u m, a n d 
C V %. Val ues bel o w t he L L O Q will be ta ke n as zer o f or descri pti ve statistics of P K c o nce ntrati o ns. 
Descri pti ve statistics of P K a n d P D para meters will a d diti onall y  sh o w t he Ge o Mea n, t he ge o metric 
C V % , a n d t he 9 5 % CI f or t he Ge o Mea n.
Gra p hical dis pla y s will be gi ve n, w here a p pr o priate. Details of t he statistical a nal ys is will be 
descri be d i n t he statistical a nal y sis pla n ( S A P). 
8. 5. 2
A n al ysis of Pri m ar y E n d p oi nts
8. 5. 2. 1
S af et y
P art A a n d P art B
Safet y  data a nal ysis will be c o n d ucte d o n t he Safet y A nal ysis Set. T he n u m ber a n d perce nta ge of 
s u bjects e x perie nci n g o ne or m ore A Es will be s u m marize d b y  dose le vel gr o u p, relati o ns hi p t o 
I M P, a n d se verity. A Es will be c o de d usi n g M e dical Dicti o nar y  for Re g ulat or y  Acti vities 
ter mi n ol o g y. La b orat or y  para meters will be s u m marize d usi n g descri pti ve statistics, b y  post d ose 
s hifts relati ve t o baseli ne, a n d data listi n gs of a b n or mal res ults as a p pr o priate. Vital si g ns a n d E C G 
data will be s u m marize d f or o bser ve d a n d c ha n ges -fr o m-baseli ne val ues b y  dose le vel usi n g 
descri pti ve statistics. Cli nicall y  note w ort h y  EC G fi n di n gs f or i n di vi d ual s u bjects will be liste d a n d 
s u m marize d as a p pr o priate. 
8. 5. 2. 2 
P h ar m ac o k i netics
P art C
All P K bl o o d c o nce ntrati o ns a n d P K para meters will be descri pti vel y  su m marize d b y  trial part, 
d ose le vel, trial d a y , a n d/ or n o mi nal ti me p oi nt , as descri be d i n Secti o n 8. 5. 1.  F or calc ulati on of 
descri pti ve statistics of bl o o d c o nce ntrati o ns, v al ues bel o w t he L L O Q will be set t o zer o.
T he statistical a nal ysis of d ose pr o p orti o nalit y  (a n d t he statistical a nal ysis of li nearit y an d 
acc u m ulati o n, if a p plica ble, de pe n di n g o n t he trial desi g n of Part C) t hat is descri be d i n 
Secti o n 8. 5. 3. 1,  will be re peate d after i ncl u di n g a p plica ble P K para meters fr o m Part C.
D oc u me nt N o
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 0 8 / 1 9 0
8. 5. 2. 3
P h ar m ac o d y n a mics
P art C
T he pri mar y P D varia ble is t he P R R of ase x ual parasites base d o n q P C R after a d mi nistrati o n of 
M 5 7 1 7. Sec o n dar y  PD varia bles are P C T, MI C, P Ct ½, a n d M P C (calc ulati o n t o be descri be d i n 
t he S A P), cli nical sc ore, a n d t he n u m ber a n d perce nta ge of s u bjects wit h recr u descence. 
Statisticall y , recr u desce nce is defi ne d as a n i ncrease i n parasite mia > 1 l o g, o ver 2 or m ore 
c o nsec uti ve q P C R res ults. T o be c o nsi dere d recr u desce nce t his i ncrease m ust occ ur after t he i nitial 
decrease i n parasite mia p ost -I MP a d mi nistrati o n.
T he P R R f or ase x ual parasites will be esti mate d usi n g t he sl o pe of t he o pti mal fit of t he l o g-li near 
relati o ns hi p of t he parasite mia deca y base d o n t he P D A nal ysis Set. T he o pti mal fit ca n be deri ve d 
usi n g s u m marize d re plicate parasite mia data, w hic h ha ve bee n clea ne d b y  deali n g wit h p ote ntial 
o utliers, val ues bel o w t he li mit of detecti o n a n d n o ndetecta ble val ues ( N D). T he o pti mal fit of t he 
l o g-li near parasite mia -b y -ti me relati o ns hi p is deter mi ne d b y  usi n g left a n d ri g ht ce ns ori n g t o 
s yste maticall y re m o ve t he p ote ntial la g p hase a n d tail p hase of t he parasite mia deca y . T he deca y 
rate, esti mate d by t he sl o pe c oefficie nt fr o m t he l o g -li near deca y re gressi o n of q P C R data, will be 
calc ulate d f or eac h s u bject. T he o verall c o h ort-d ose s pecific P R R will be esti mate d wit h its 9 5 % 
CI  by c alc ulati n g t he wei g hte d a vera ge sl o pe esti mate a n d c orres p o n di n g sta ndar d err or (S E ) usi n g 
a n i n verse-varia nce met h o d. O nl y  s u bjects w h o ha ve o pti mal re gressi o n m o dels wit h a p pr o priate 
fit c o ntri b ute t o war d t he d ose-s pecific P R R. 
F or a n y re plicate parasit e mia val ues bel o w L L O Q, t he val ue is s u bstit ute d wit h L O Q/ 2. T he L O Q 
is ass u me d t o be 6 4 parasites/ m L of bl o o d, base d o n p u blis he d data ( 9). F or a n y val ues t hat were 
n ot detecte d ( N D) t he val ue is set t o 1, s uc h t hat w he n t he data is l o g 1 0 tra nsf or me d t he N D = l o g 1 0 
( 1) = 0. If all re plicates f or a s u bject wit hi n a ti me p oi nt are N D, t he first ti me p oi nt wit h all N D is 
i ncl u de d i n m o del fitti n g, a n d all s u bse q ue nt ti me p oi nts are set t o ‘ missi n g’, re gar dless of w het he r 
parasit e mia val ues i ncrease d after war ds d ue t o p ote ntial recr u desce nce of malaria i nfecti o n. T he 
data use d f or all s u bse q ue nt m o del selecti o n a n d fitti n g calc ulati o ns is c o m prise d of arit h metic 
mea n of t he re plicate l o g1 0 parasite mia val ue per ti me p oi nt per s u bject u p t o t he first ti me all 
re plicates are N D. 
T he al g orit h m t o o btai n t he l o g -li near deca y for eac h s u bject is base d o n t he l o g -li near re gressi o n 
detaile d i n E q uati o n ( 1), w here Ti me is t he n u m ber of h o urs si nce a d mi nistrati o n of a nti malarial 
treat me nt (   = 1, …, ) , a n d   a n d   are t he i nterce pt a n d sl o pe esti mates, res pecti vel y.  
l o g          =   +         ( 1)
Base d o n t he clea ne d a n d pr ocesse d parasit e mia data f or eac h s u bject, t he iterati ve al g orit h m t o 
deter mi ne t he o pti mal l o g-li near deca y  for eac h s u bject is s u m marize d bel o w. T he iterati ve 
al g orit h m is c o nti n ue d u ntil a mi ni m u m of 4 o bser vati o ns are a vaila ble. 
T he o pti mal l o g-li near re gressi o n m o del f or a s u bject is dee me d a n a p pr o priate fit if t he o verall 
m o del p- val ue < 0. 0 0 1. 
D oc u me nt N o
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 1 0 / 1 9 0
8. 5. 3. 2
Ot her Sec o n d ar y E n d p oi nts
P art C
All s ec o n dar y P D varia bles, i ncl u di n g P C T, MI C, P Ct ½, M P C, la g p hase , a n d cli nical sc ore, will 
be descri pti vel y s u m marize d. F urt her details will be pr o vi de d i n t he S A P as well as f or t he n u m ber 
a n d perce nta ge of s u bjects wit h recr u desce nce. P C T a n d MIC are defi ne d i n Ta ble 1 0.  T he MI C is 
t he dr u g c o nce ntrati o n at w hic h t he relati ve rate of c ha n ge i n parasite mia is e q ual t o zer o (see 
Fi g ure 5 ). I n ot her w or ds, t he MIC is t he dr u g c o nce ntrati o n at w hic h t he rate of parasite killi n g is 
e q ual t o t he rate of parasite re pr o d ucti o n a n d re prese nts a “stea d y s tate”. I m plicit i n t his defi niti o n 
is t he ass u m pti o n t hat t he MIC val ue is i n varia nt of t he d ose a d mi nistere d.
Safet y  data will be si milarl y anal y ze d as descri be d f or t he safet y anal ys is i n Part A a n d Part B i n 
Secti o n 8. 5. 2 .
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 1 1 / 1 9 0
8. 6
I nteri m a n d A d diti o n al Pl a n ne d A n al yses
N o f or mal i nteri m statistical a nal ys is is pla n ne d. H o we ver, t o s u p p ort ti mel y decisi o n - ma ki n g, t he 
S p o ns or ma y  deci de t o perf or m a fi nal a nal ys is of a trial part after t he c o m pleti o n of a trial part. 
T he data f o r t hat trial part will be l oc ke d a n d u n bli n de d as descri be d i n Secti o n  6. 1 0.
A n S M C will be esta blis he d acc or di n g t o t he S M C c harter. Me m bers hi p, m a n date, a n d pr ocesses 
of t he S M C will be detaile d i n t he S M C C harter. I nf or mati o n re gar di n g t he S M C decisi o n criteria 
are pr o vi de d i n Secti o n  5. 2. 8.
9
Et hic al a n d Re g ul at or y As pects
9. 1
Res p o nsi bilities of t he I n vesti g at or
T he I nvesti gat or is res p o nsi ble f or t he c o n d uct of t he trial at t he site a n d will e ns ure t hat t he trial
is perf or me d i n acc or da nce wit h t his pr ot oc ol, t he et hical pri nci ples o utli ne d i n t he Declarati o n of 
Helsi n ki, t he N otes f or G ui da nce o n G C P
( C P M P/I CH / 1 3 5/ 9 5), as a d o pte d b y  the A ustralia n 
T hera pe ut ic G o o ds A d mi nistrati o n ( 2 0 0 0) (N H M R C Nati o nal State me nt o n Et hical C o n d uct i n 
H u ma n Researc h ), a n d a n y ot her a p plica ble re g ulati o ns. T he I nvesti gat or m ust e ns ure t hat o nl y  
s u bjects w h o ha ve gi ve n i nf or me d c o nse nt are i ncl u de d i n t he trial.
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 1 2 / 1 9 0
9. 2
S u bject I nf or m ati o n a n d I nf or me d C o nse nt
A n u nc o n diti o nal prere q uisite f or eac h s u bject pri or t o partici pati o n i n t he trial is writte n i nf or me d 
c o nse nt , w h ic h m ust be gi ve n bef ore a n y trial-relate d acti vities are carrie d o ut. A de q uate 
i nf or mati o n m ust t heref ore be gi ve n t o t he s u bject b y  the I n vesti gat or or a n a p pr o priate desi g nee 
(if l ocal re g ulati o ns per mit) bef ore i nf or me d c o nse nt is o btai ne d. 
A s u bject i nf or mati o n s heet m ust be pre pare d i n t he l ocal la n g ua ge i n acc or da nce wit h I CH G C P
a n d pr o vi de d t o t he s u bject f or t he p ur p ose of o btai ni n g i nf or me d c o nse nt. I n a d diti o n t o pr o vi di n g  
t his writte n i nf or mati o n t o a p ote ntial s u bject, t he I n vesti gat or or a desi g nate will i nf or m t he s u bject 
ver ball y of all perti ne nt as pects of t he trial, usi n g la n g ua ge c h ose n s o t hat t he i nf or mati o n ca n be 
f ull y an d rea dily u n derst o o d b y  la ypers o ns. T he s u bject will be gi ve n s ufficie nt ti me t o rea d t he 
i nf or mati o n a n d t he o p p ort u nit y  to as k q uesti o ns a n d t o re q uest a d diti o nal i nf or mati o n a n d 
clarificati o n.
If per mitte d b y nati o nal re g ulati o ns, a pers o n ot her t ha n t he I n vesti gat or ma y  inf or m t he s u bject 
a b o ut t he trial a n d si g n t he P I CF, as a b o ve.
After t he i nf or mati o n is pr o v i de d b y  the I n vesti gat or, t he P I CF m ust be si g ne d a n d pers o nall y 
date d b y t he s u bject a n d t he I n vesti gat or .
T he si g ne d a n d date d declarati o n of i nf or me d c o nse nt will re mai n at t he I n vesti gat or’s site, a n d 
m ust be safel y arc hi ve d b y  t he I n vesti gat or/ desi g nee s o t hat t he f or ms ca n be retrie ve d at a ny t i me 
f or m o nit ori n g, a u diti n g a n d i ns pecti o n p ur p oses. A c o p y of t he si g ne d a n d date d P I CF s h o ul d be 
pr o vi de d t o t he s u bject pri or t o partici pati o n.
W he ne ver i m p orta nt ne w i nf or mati o n bec o mes a vaila ble t hat m a y  be rele va nt t o t he s u bject’s 
c o nse nt, t he writte n s u bject i nf or mati o n s heet a n d a n y ot her writte n i nf or mati o n t o be pr o vi de d t o 
t he s u bjects will be re vise d b y  the S p o ns or s/ desi g nees a n d be s u b mitte d a gai n t o t he 
 
H R E C f or re vie w a n d fa v ora ble o pi ni o n. T he I n vesti gat or / desi g nee will e x plai n t he c ha n ges t o t he 
pre vi o us versi o n t o eac h trial s u bject t he a gree d, re vise d i nf or mati o n will be pr o vi de d t o eac h 
s u bject i n t he trial f or si g ni n g a n d dati n g.
9. 3
S u bject I de ntific ati o n a n d Pri v ac y
A u ni q ue s u bject n u m ber will be assi g ne d t o eac h s u bject at i ncl usi o n , i m me diatel y after i nf or me d 
c o nse nt has bee n o btai ne d. T his n u m ber will ser ve as t he s u bject’s i de ntifier i n t he trial as well as 
i n t he cli nical trial data base. All s u bject data c ollecte d i n t he trial w ill be st ore d u n der t his n u m ber. 
O nl y  the I n vesti gat or will be a ble t o li n k t he s u bject’s trial data t o a n i n di vi d ual s u bject via a n 
i de ntificati o n list ke pt at t he site. F or eac h s u bject, ori gi nal me dical data will be accessi ble f or t he 
p ur p oses of s o urce data verificati o n b y  the M o nit or, a u dits a n d Healt h A ut h orit y i ns pecti o ns, b ut 
patie nt c o nfi de ntialit y will be strictl y mai ntai ne d.
Data pr otecti o n a n d pri vac y  re g ulati o ns will be o bser ve d i n ca pt uri n g, f or war di n g, pr ocessi n g, a n d 
st ori n g s u bject data. S u bjects will be i nf or me d acc or di n gl y, a n d will be re q ueste d t o gi ve t heir 
c o nse nt o n data ha n dli n g pr oce d ures i n acc or da nce wit h nati o nal re g ulati o ns.
D oc u me nt N o. 
O bject N o
C CI
C CI
P P D

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 1 3 / 1 9 0
9. 4
E mer ge nc y Me dic al S u p p ort a n d S u bject C ar d
S u bjects will be pr o vi de d wit h E mer ge nc y Me dical S u p p ort car ds s u p plie d b y t he trial site f or use
d uri n g trial partici pati o n i n or der t o pr o vi de cli nical trial s u bjects wit h a wa y  of i de ntif yi n g 
t he msel ves as partici pati n g i n a cli nical trial a n d t o gi ve healt h care pr o vi d ers access t o a n y
i nf or mati o n a b o ut t his partici pati o n t hat ma y  be nee de d t o deter mi ne t he c o urse of me dical 
treat me nt f or t he s u bject. T he i nf or mati o n pr o vi de d o n t he E mer ge nc y  Me dical S u p p ort car d m a y  
i ncl u de t he pr ocess f or e mer ge nc y u n bli n di n g (if a p plica ble).
T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical trial I n vesti gat or cari n g f or t he 
affecte d s u bject. T he I n vesti gat or a grees t o pr o vi de his or her e mer ge nc y co ntact i nf or mati o n o n 
t he car d f or t his p ur p ose. If t he I n vesti gat or is a vaila ble w he n a n e ve nt occ urs, t he y will a ns wer 
a n y questi o ns. A n y  su bse q ue nt acti o n (f or e xa m ple, u n bli n di n g) will f oll o w t he sta n dar d pr ocess 
esta blis he d f or I n vesti gat ors.
I n cases w here t he I n vesti gat or is n ot a vaila ble, t he P hase I facility will pr o vi de t he a p pr o priate 
mea ns t o c o ntact a p h y sicia n. T his i ncl u des t he pr o visi o n of a 2 4- h o ur c o ntact n u m ber at t he 
facilit y, w here b y t he healt h care pr o vi ders will be gi ve n access t o a n a p pr o priate p h y sicia n t o assist 
wit h t he me dical e mer ge nc y an d t o pr o v i de s u p p ort f or t he p ote ntial u n bli n di n g of t he s u bject 
c o ncer ne d.
9. 5
Cli nic al Tri al I ns ur a nce a n d C o m pe ns ati o n t o S u bjects
I ns ura nce c o vera ge wi ll be pr o vi de d f or eac h c o u ntr y partici pati n g t o t he trial. I ns ura nce c o n diti o ns 
s hall meet g o o d l ocal sta n dar ds, as a p plica ble.
9. 6
I n de pe n de nt Et hics C o m mittee
( H u m a n Rese arc h 
Et hics 
C o m mittee)
Pri or t o c o m me nce me nt of t he trial at a gi ve n site, t his cli nical trial pr ot oc ol will be s u b mitte d 
t o get her wit h its ass ociate d d oc u me nts (e g, t he PI C F) t o t he res p o nsi ble H R E C f or its fa v ora ble 
o pi ni o n or a p pr o val , w hic h will be file d i n t he I nvesti gat or Site File . A c o p y will be file d i n t he
S p o ns or Trial Master File at t he C R O .
T he H R E C will pr o vi de a n a p pr o val letter t hat will clearl y i de ntif y t he trial n u m ber a n d list all 
d o c u me nts a nt t heir versi o n n u m bers t hat were re vie we d a n d a p pr o ve d b y  the c o m mittee (e g, t he 
cli nical trial pr ot oc ol a n d P I CF). 
A me n d me nts t o t his cli nical trial pr ot oc ol will als o be s u b mitte d t o t he c o ncer ne d H R E C, bef ore 
i m ple me ntati o n of s u bsta ntial c ha n ges (see Secti o n 1 0. 5 ). Rele va nt safet y inf or mati o n will be 
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 1 4 / 19 0
s u b mitte d t o t he H R E C d uri n g t he c o urse of t he trial i n acc or da nce wit h nati o nal re g ulati o ns a n d 
re q uire me nts.
9. 7
He alt h A ut h orities
T he cli nical trial pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n (f or e xa m ple, I M P D ossier a n d P I CF ) 
will be s u b mitte d or n otifie d t o t he Healt h A ut h orities i n acc or da nce wit h all l ocal a n d nati o nal 
re g ulati o ns f or t he trial site.
F or A ustralia: t he I B, P I C F, cli nical trial pr ot oc ol, a n d E x pert t o xic ol o g y re p ort will be s u b mitte d
t o H R E C f or a p pr o val a n d after a p pr o val, n otifie d t o t he Healt h A ut h orities , usi n g t he C T N 
sc he me, i n acc or da nce wit h all l ocal a n d nati o nal re g ulati o ns f or t he trial site.
1 0
Tri al M a n a ge me nt
1 0. 1
C ase Re p ort F or m H a n dli n g
Refer t o t he Ma n ual of O perati o ns
f or e C R F C o m pleti o n Gui deli nes.  
T he mai n p ur p ose of t he e C R F is t o o btai n data re q uire d b y  the cli nical trial pr ot oc ol i n a c o m plete, 
acc urate, le gi ble a n d ti mel y. T he data i n t he e C R F s h o ul d be c o nsiste nt wit h t he rele va nt s o urce 
d oc u me nts.
T he I n vesti gat or or desi g nee is res p o nsi ble f or e ns uri n g t hat t he data c ollecte d i n t he c o urse of t his 
trial is acc urate a n d d oc u me nte d a p pr o priatel y o n all a p plica ble f or ms. T he y  will t he n be 
pr ocesse d, e val uate d, a n d st ore d i n a n o n ym o us f or m i n acc or da nce wit h a p plica ble data pr otecti o n 
re g ulati o ns. T he I n vesti gat or m ust e ns ure t hat t he e C R Fs a n d a n y ot her ass ociate d d oc u me nts 
f or war de d t o S p o ns or or its desi g nate d or ga nizati o n c o ntai n n o me nti o n of a n y s u bject na mes.
T he data will be e ntere d i nt o a vali date d data base. T he S p o ns or or its desi g nee will be res p o nsi ble 
f or data pr ocessi n g, i n acc or da nce wit h t he S p o ns or’s data ma na ge me nt pr oce d ures. Data base l oc k 
will occ ur o nce q ualit y  c o ntr ol a n d q ualit y ass ura nce pr oce d ures ha ve bee n c o m plete d. P D F files 
of t he e C R Fs will be pr o vi de d t o t he I n vesti gat ors at t he c o m pleti o n of t he trial.
1 0. 2
S o urce D at a a n d S u bject Files
T he I n vesti gat or m ust kee p a file ( me dical file, ori gi nal me dical rec or ds) o n pa per or electr o nicall y 
f or e ver y s u bject i n t he trial. It m ust be p ossi ble t o i de ntif y eac h s u bject b y usi n g t his s u bject file. 
T his file will c o ntai n t he de m o gra p hic a n d me dica l i nf or mati o n f or t he s u bject liste d bel o w a n d 
s h o ul d be as c o m plete as p ossi ble. 

S u bject’s f ull na me, d ate of birt h, se x, h ei g ht, wei g ht, a n d s ki n ty pe

Me dical hist or y  a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita nt t hera pies (i ncl u di n g c ha n ges d uri n g t he trial)

Trial i de ntificati o n, t hat is, t he S p o ns or trial n u m ber f or t his cli nical trial, a n d s u bject n u m ber
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 1 5 / 1 9 0

Date s f or e ntr y i nt o t he trial (i nf or me d c o nse nt) a n d visits t o t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t his cli nical trial pr ot oc ol

All A E s o bser ve d i n t he s u bject, i ncl u di n g se verit y , relati o ns hi p a n d o utc o me of A Es

Date t hat t he s u bject left t he trial i ncl u di n g a n y reas o n f or earl y wit h dra wal fr o m t he trial or 
I M P (if a p plica ble).
A ll d oc u me nts c o ntai ni n g s o urce data m ust be file d, i nclu di n g , b ut n ot li mite d t o t he ori gi nal 
pri nt o uts of t he data rec or de d or ge nerate d b y  aut o mate d i nstr u me nts, p h ot o gra p hic ne gati ves, 
E C G rec or di n gs, a n d la b orat or y res ults. S uc h d oc u me nts m ust bear t he su bject n u m ber a n d t he 
date of t he pr oce d ure. If p ossi ble, t his inf or mati o n s h o ul d be pri nte d b y  the i nstr u me nt use d t o 
perf or m t he assess me nt or meas ure me nt. I nf or mati o n t hat ca n n ot be pri nte d b y  an a ut o mate d 
i nstr u me nt will be e ntere d ma n uall y. As necessa r y, medical e val uati o n of s uc h rec or ds s h o ul d be 
perf or me d; all e val uati o ns s h o ul d be d oc u me nte d , si g ne d, a n d date d b y t he I n vesti gat or.
Electr o nic s u bject files will be pri nte d w he ne ver t he M o nit or perf or ms s o urce data verificati o n. 
Pri nt o uts m ust be si g n e d a n d date d b y  t he I n vesti gat or, c o u ntersi g ne d b y  t he M o nit or a n d ke pt i n 
a safe place at t he site.
1 0. 3
I n vesti g at or Site File a n d Arc hi vi n g
U p o n i nitiati o n of t he trial, the I n vesti gat or will be pr o vi de d wit h a n I n vesti gat or Site File 
c o ntai ni n g all necessar y  trial d oc u me nts , w hic h will be c o m plete d t hr o u g h o ut t he trial a n d u p date d 
as necessar y. T he file m ust be a vaila ble f or re vie w b y  t he M o nit or, d uri n g S p o ns or a u dit s a n d f or 
i ns pecti o n b y Healt h A ut h orities d uri n g a n d after t he trial, a n d m ust be safel y arc hi ve d f or at least 
1 5 ye ars ( or l o n ger, per l ocal re q uire me nts or as ot her wise n otifie d b y  the S p o ns or) after t he e n d 
of t he trial. T he d oc u me nts t o be arc hi ve d i ncl u de t he S u bject I de ntificati o n Li st a n d t he si g ne d 
s u bject P I CF s. If arc hi vi n g of t he I n vesti gat or Site File is n o l o n ger p ossi ble at t he site, t he 
I n vesti gat or m ust n otif y t he S p o ns ors/ desi g nees.
All ori gi nal s u bject files ( me dical rec or ds) m ust be st ore d at t he site ( h os pital, researc h i nstit ute, 
or practice) f or t he l o n gest p ossi ble ti me per mitte d b y  the a p plica ble re g ulati o ns, a n d/ or as per I CH 
G C P g ui deli nes, w hic he ver is l o n ger. I n a n y case, t he I n vesti gat or s h o ul d e ns ure t hat n o 
destr ucti o n of me dical rec or ds is perf or me d wit h o ut t he writte n a p pr o val of t he S p o ns or.
1 0. 4
M o nit ori n g, 
Q u alit y Ass ur a nce 
a n d I ns pecti o n b y He alt h 
A ut h orities
T his trial will be m o nit ore d i n acc or da nce wit h t he I C H G C P a n d a n y o t her a p plica ble re g ulati o ns. 
T he site M o nit or will perf or m visits t o t he trial site at re g ular i nter vals.
T he cli nical trial pr ot oc ol , eac h ste p of t he data ca pt ure pr oce d ure, a n d t he ha n dli n g of t he data, 
i ncl u di n g t he fi nal cli nical trial re p ort, will be s u bject t o i n de pe n de nt Q ualit y Ass ura nce acti vities. 
A u dits ma y  be c o n d ucte d at a n y t i me d uri n g or after t he trial t o e ns ure t he val i dit y a n d i nte grit y of 
t he trial data. Re prese ntati ves of t he Q ualit y  Ass ura nce u nit fr o m t he S p o ns or or a desi g nate d 
or ga nizati o n, as well as Healt h A ut h orities, m ust be per mitte d t o access all trial d oc u me nts a n d 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 1 7 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 1 8 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 1 9 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 2 0 / 1 9 0
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 2 1 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 2 2 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 2 3 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 2 4 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 2 5 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 2 6 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8 -0 0 1 3
1 2 7 /1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8 -0 0 1 3
1 2 8 /1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8 -0 0 1 3
1 2 9 /1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8 -0 0 1 3
1 3 0 /1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8 -0 0 1 3
1 3 1 /1 9 0
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 3 3 / 1 9 0
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 3 4 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 3 5 / 1 9 0
M aj or Scie ntific C h a n ges
C o m p aris o n wit h Cli nic al Tri al Pr ot oc ol Versi o n 1. 0, 1 4 J u ne 2 0 1 7
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 3 6 / 1 9 0
D oc u me nt N o
O bject N o. 
6
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 3 7 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 3 8 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 3 9 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 4 0 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 4 1 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 4 2 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 4 3 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 4 4 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 4 5 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 4 6 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 4 7 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 4 8 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 4 9 / 1 9 0
C h a n g e
S e cti o n
Pr e vi o u s W or di n g a
N e w  W or di n gb
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 5 0 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 5 1 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 5 2 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 5 3 / 1 9 0
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 5 4 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 5 5 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 5 6 / 1 9 0
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 5 7 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 5 8 / 1 9 0
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 5 9 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 6 1 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 6 2 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 6 3 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 6 4 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 6 5 / 1 9 0
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 6 6 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 6 7 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 6 8 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 6 9 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 0 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 1 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 2 / 1 9 0
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 3 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 4 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 5 / 1 9 0
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 6 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 7 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 8 / 19 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 7 9 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 8 1 / 1 9 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 8 2 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 8 3 / 1 9 0
D oc u me nt N o
O bject N o
C CI
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 8 6 / 1 9 0
Si g n at ure P a ge – Pr ot oc ol C o -Le a d ( Me dic al Res p o nsi ble)
Tri al Title:
A 
P hase 
I, 
First -i n-H u ma n, 
Ra n d o mize d, 
D o u ble- Bli n d, Plac e b o - C o ntr olle d Trial of Si n gle a n d 
M ulti ple Asce n di n g D oses of M 5 7 1 7 t o Assess t he 
Safet y , T olera bilit y a n d P har mac o ki netic Pr ofile of 
Oral D oses, a n d t o Assess t he A nti malarial Acti vit y  of 
M 5 7 1 7 A gai nst Plas m o di u m falci par u m i n Healt h y  
Male a n d Fe male A d ult S u bjects
Cli nic al Tri al Pr ot oc ol N u m ber :
M S 2 0 1 6 1 8 - 0 0 1 3
I N D N u m ber:
N ot A p plica ble
E u dr a C T N u m ber:
N ot A p plica ble
Cli nic al 
Tri al 
Pr ot oc ol 
D ate 
/ 
Versi o n:
1 7
Dece m ber
2 0 1 8 
/ Versi o n 
5 . 0 i ncl u di n g 
A me n d me nt 4
Pr ot oc ol C o -Le a d ( Me dic al Res p o nsi ble):
I a p pr o ve t he desi g n of t he cli nical trial:
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
Na me, aca de mic de gree:
F u ncti o n / Title:
Me dical Res p o nsi ble/ Se ni or Me dical Lea d
I nstit uti o n:
Merc k K Ga A
A d dress:
Fra n kf urter Strasse 2 5 0, P ostc o de: F 1 3 0/ 0 0 5, 6 4 2 9 3 Dar m sta dt, 
Ger ma n y
Tele p h o ne n u m ber:
Fa x n u m ber:
E- mail a d dress:
D oc u me nt N o. 
O bject N o. 
P PI
P PI
P PI
P P D
P P D
P P D
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 8 7 / 1 9 0
Si g n at ure P a ge – Pr ot oc ol C o -Le a d
Tri al Title:
A 
P hase 
I, 
First -i n-H u ma n, 
Ra n d o mize d, 
D o u ble- Bli n d, Plac e b o -C o ntr olle d Trial of Si n gle a n d 
M ulti ple Asce n di n g D oses of M 5 7 1 7 t o Assess t he 
Safet y , T olera bilit y a n d P har mac o ki netic Pr ofile of 
Oral D oses, a n d t o Assess t he A nti malarial Acti vit y  of 
M 5 7 1 7 A gai nst Plas m o di u m falci par u m i n Healt h y  
Male a n d Fe male A d ult S u bjects
Cli nic al Tri al Pr ot oc ol N u m ber :
M S 2 0 1 6 1 8 - 0 0 1 3 
I N D N u m ber:
N ot A p plica ble
E u dr a C T N u m ber:
N ot A p plica ble
Cli nic al 
Tri al
Pr ot oc ol 
D ate 
/ 
Versi o n:
1 7
Dece m ber
2 0 1 8 
/ Versi o n 
5 . 0 i ncl u di n g 
A me n d me nt 4
Pr ot oc ol C o -Le a d:
I a p pr o ve t he desi g n of t he cli nical trial:
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
Fa x n u m ber:
-
E- mail a d dress:
D oc u me nt N o
O bject N o
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 8 8 / 1 9 0
Si g n at ure P a ge – Pri nci p al I n vesti g at or
Tri al Title
A 
P hase 
I, 
First-i n-H u ma n, 
Ra n d o mize d, 
D o u ble- Bli n d, Plac e b o-C o ntr olle d Trial of Si n gle a n d 
M ulti ple Asce n di n g D oses of M 5 7 1 7 t o Assess t he 
Safet y , T olera bilit y  an d P har mac o ki netic Pr ofile of 
Oral D oses, a n d t o Assess t he A nti malarial Acti vit y  of 
M 5 7 1 7 A gai nst Plas m o di u m falci par u m i n Healt h y 
Male a n d Fe male A d ult S u bjects
Cli nic al Tri al Pr ot oc ol N u m ber :
M S 2 0 1 6 1 8 - 0 0 1 3
I N D N u m ber:
N ot A p plica ble
E u dr a C T N u m ber :
N ot A p plica ble
Cli nic al Tri al Pr ot oc ol D ate / 
Versi o n :
1 7
Dece m ber
2 0 1 8 
/ Versi o n 
5 . 0 i ncl u di n g 
A me n d me nt 4
Ce nter N u m ber :
0 1
Pri nci p al I n vesti g at or :
I, t he u n dersi g ne d, a m res p o nsi ble f or t he c o n d uct of t he trial at t his site a n d affir m t hat I 
u n dersta n d a n d will c o n d uct t he trial acc or di n g t o t he cli nical trial pr ot oc ol, a n y a p pr o ve d pr ot oc ol 
a me n d me nts, I nter nati o nal C o u ncil f or Har m o niz ati o n G o o d Cli nical Practice ( T o pic E 6) , T he 
Nati o nal State me nt , a n d all a p p lica ble Healt h A ut h orit y re q uire me nts a n d nati o nal la ws.
I a gree t o i nf or m all partici pa nts t hat t he trial dr u g is bei n g use d f or i n vesti gati o nal p ur p oses a n d I 
will e ns ure t hat t he re q uire me nts relate d t o o btai ni n g i nf or me d c o nse nt are i n acc or da nce wit h I C H 
G ui deli nes f or G C P S ecti o n 4. 8 a n d l ocal re q uire me nts.
I a gree t o re p ort a d verse e ve nts t hat occ ur i n t he c o urse of t he trial t o t he S p o ns or i n acc or da nce 
wit h I C H G ui deli nes f or G C P Se cti o n 4. 1 1 a n d l ocal re q uire me nts.
I ha ve rea d a n d u n dersta n d t he i nf or mati o n i n t he I n vesti gat or’s Br oc h ure, i ncl u di n g t he p ote ntial 
ris ks a n d si de effects of t he trial dr u g.
I a gree t o pr o m ptl y  re p ort t o t he H R E C all c ha n ges i n t he researc h acti vit y an d all u na ntici pa te d 
pr o ble ms i n v ol vi n g ris k t o p artici pa nts. I will n ot ma ke a n y c ha n ges t o t he c o n d uct of t he trial
wit h o ut H R E C a n d S p o ns or a p pr o val, e xce pt w he n necessar y  to eli mi nate a p pare n t i m me diate 
har m t o p artici pa nts.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 7 1 7
FI H Tri al of S A D, M A D a n d M al ari a C h alle n ge M o del i n He alt h y S u bjects
M S 2 0 1 6 1 8- 0 0 1 3
1 9 0 / 1 9 0
S p o ns or Res p o nsi ble Pers o ns n ot N a me d o n t he C o ver P a ge
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
E M D Ser o n o, I nc.
A d dress:
4 5 A Mi d dlese x T ur n pi ke - C 1 0 5 G, Billerica, Massac h usetts, U nite d 
States of A merica
Tele p h o ne n u m ber:
Fa x n u m ber:
-
E- mail a d dress:
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
Fa x n u m ber:
E- mail a d dress:
D oc u me nt N o. 
O bject N o
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI
C CI