Clinical trial NCT03261401
Conditions: Healthy
Keywords: Healthy Participants M5717 Malaria Plasmodium falciparum
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2017-09-15; Completion date: 2019-06-14
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study was to investigate the safety and tolerability of M5717 and to characterize the Pharmacokinetics (PK) /Pharmacodynamic relationship between M5717 PK and parasite clearance in healthy participants following infection with Plasmodium falciparum.

Detailed description:

Arms: arm 1: Participants received capsules containing 50 milligram (mg) of placebo matched similar to M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose. arm 2: Participants received single ascending dose (SAD) of 50 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 3: Participants received SAD of 100 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 4: Participants received SAD of 200 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 5: Participants received SAD of 400 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 6: Participants received SAD of 600 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 7: Participants received SAD of 1000 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 8: Participants in SAD received an oral dose of 1250 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 9: Participants in SAD received an oral dose of 1800 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 10: Participants in SAD received an oral dose of 2100 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 11: Participants received single oral dose of 150 mg M5717 (eight days after the administration of intravenous malaria inoculum) on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 12: Participants received single oral dose of 400 mg M5717 (eight days after the administration of intravenous malaria inoculum) on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. arm 13: Participants received single oral dose of 800 mg M5717 (eight days after the administration of intravenous malaria inoculum) on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast.
Interventions: intervention 1: M5717 intervention 2: Placebo intervention 3: M5717
Intervention descriptions: intervention 1: Participants received single ascending oral dose of M5717 after at least 8 hours of fasting together with water on Day 1, followed by a 4-hour post-dose fast intervention 2: Participants received placebo matched to M5717 intervention 3: Participants received single ascending oral dose of M5717 from Part A after at least 8 hours of fasting together with water on Day 1, followed by a 4-hour post-dose fast

Protocol documents:
Prot_000.pdf: 


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

SAP_001.pdf: 
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 Versi o n 2. 0
1/ 3 1
I nte gr ate d A n al ysis Pl a n
Cli nic al St u d y Pr ot oc ol 
I de ntific ati o n N o.
M S 2 0 1 6 1 8 - 0 0 1 3
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, 
Place 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 hy Male a n d Fe male A d ult S u bjects
St u d y P h ase
I
I n vestig ati o n al Me dici n al 
Pr o d uct(s)
M 5 7 1 7
Cli nic al St u d y 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
I nte gr ate d A n al ysis Pl a n 
A ut h or
C o or di n ati n g A ut h or
M er c k
F u n cti o n
A ut h or( s) / D at a A n al y s t( s)
I nte gr ate d A n al ysis Pl a n
D ate a n d Versi o n
1 3 Ma y 2 0 1 9 / Versi o n 2. 0
I nte gr ate d A n al ysis Pl a n 
Re vie wers
F u n cti o n
N a m e
,
,
, M er c k
, M er c k
, M er c k
 M er c k
M er c k
 M er c k
M er c k
 M er c k
 M er c k
 M er c k
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
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
P P D
P P D
P P D
C CI
C CI
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
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 Versi o n 2. 0
2/ 3 1
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - 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 Ga A, Dar msta dt, Ger ma n y or its affiliate. 
C o p yri g ht © 2 0 1 9 b y Merc k K G a A, D ar mst a dt, Ger m a n y or its aff ili ate. All ri g hts reser ve 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 Versi o n 2. 0
4/ 3 1
1
T a ble of C o nte nts
I nte grate d A nalys is Pla n ...................................................................................................... 1
Si g nat ure Pa ge
.............................................................................................................. 3
1
Ta ble of C o nte nts .................................................................................. 4
2
List of A b bre viati o ns a n d Defi niti o n of Ter ms .................................... 6
3
M o dificati o n Hist or y
.......................................................................... 1 0
4
P ur p ose of t he I nte grate d A nal y sis Pla n ............................................. 1 0
5
O bjecti ves a n d E n d p oi nts ................................................................... 1 1
6
O ver vie w of Pla n ne d A nal y ses........................................................... 1 3
6. 1
A nal y ses f or t he Safety M o nit ori n g C o m mittee Meeti n gs ................. 1 3
6. 2
Fi nal A nal ys is..................................................................................... 1 3
7
C ha n ges t o t he Pla n ne d A nal y ses i n t he Cli nical St u d y Pr ot oc ol ...... 1 3
8
Pr ot oc ol De viati o ns a n d A nal y sis Sets ............................................... 1 4
8. 1
Defi niti o n of Pr ot oc ol De viati o ns a n d A nal ys is Sets ......................... 1 4
8. 2
Defi niti o n of A nal ys is Sets a n d S u b gr o u ps........................................ 1 5
9
Ge neral S pecificati o ns f or Data A nal y ses .......................................... 1 6
1 0
St u d y  S u bjects .................................................................................... 1 7
1 0. 1
Dis p ositi o n of S u bjects a n d Disc o nti n uati o ns.................................... 1 8
1 0. 2
Pr ot oc ol De viati o ns ............................................................................ 1 8
1 0. 2. 1
I m p orta nt Pr ot oc ol De viati o ns............................................................ 1 8
1 0. 2. 2
Reas o ns Lea di n g t o t he E xcl usi o n fr o m a n A nal y sis Set ................... 1 8
1 1
De m o gra p hics a n d Ot her Baseli ne C haracteristics ............................. 1 8
1 1. 1
De m o gra p hics ..................................................................................... 1 9
1 1. 2
Me dical Hist or y .................................................................................. 1 9
1 1. 3
Ot her Baseli ne C haracteristics ............................................................ 1 9
1 2
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures ............................. 1 9
1 2. 1
Pre vi o us or C o nc o mita nt Me dicati o ns ................................................1 9
1 2. 2
Resc ue Me dicati o n ..............................................................................1 9
1 2. 3
I ntra ve n o us Malaria I n oc ul u m............................................................ 2 0
1 3
Treat me nt C o m plia nce a n d E x p os ure ................................................. 2 0
1 4
Efficac y  A nalys es ...............................................................................2 0
1 5
Safet y  A nalys es ..................................................................................2 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 Versi o n 2. 0
5/ 3 1
1 5. 1
A d verse E ve nts ...................................................................................2 0
1 5. 1. 1
All A d verse E ve nts ............................................................................. 2 0
1 5. 1. 2
A d verse E ve nts Lea di n g t o St u d y  Disc o nti n uati o n............................ 2 1
1 5. 2
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E ve nts ................................................................................... 2 1
1 5. 2. 1
Deat hs ................................................................................................. 2 1
1 5. 2. 2
Seri o us A d verse E ve nts ...................................................................... 2 1
1 5. 2. 3
Ot her Si g nifica nt A d verse E ve nt ........................................................ 2 1
1 5. 3
Cli nical L a b orat or y E val uati o n........................................................... 2 2
1 5. 4
Vital Si g ns .......................................................................................... 2 2
1 5. 5
Ot her Safet y or T olera bilit y  E val uati o ns............................................ 2 2
1 5. 5. 1
1 2-lea d Electr ocar di o gra m.................................................................. 2 2
1 6
A na l yses of Ot her E n d p oi nts ..............................................................2 3
1 6. 1
P har mac o ki netics ................................................................................ 2 3
1 6. 1. 1
Ha n dli n g of Bl o o d, Uri ne, a n d Fecal C o nce ntrati o ns ......................... 2 3
1 6. 1. 1. 1
W h ole Bl o o d....................................................................................... 2 3
1 6. 1. 1. 2
Drie d Bl o o d S p ot Assa y ..................................................................... 2 3
1 6. 1. 1. 3
Uri ne a n d Feces .................................................................................. 2 3
1 6. 1. 2
Deri vati o n of I n di vi d ual W h ole Bl o o d, Uri ne, a n d Fecal 
P har mac o ki netic Para meters ...............................................................2 3
1 6. 1. 2. 1
W h ole
Bl o o d ....................................................................................... 2 3
1 6. 1. 2. 2
Uri ne a n d Feces .................................................................................. 2 6
1 6. 1. 3
Statistical S u m mar y  a n d A nal ysis ...................................................... 2 6
1 6. 1. 4
P o p ulati o n P har mac o ki netic A nal ys is................................................ 2 8
1 6. 2
P har mac o d y na mics ( Part C) ...............................................................2 9
1 6. 2. 1
Statistical A nal y sis of P har mac o dy n a mic Para meters ........................2 9
1 6. 2. 2
Statistical S u m mar y  of P har mac o dy n a mic Meas ure me nts .................3 0
1 6. 2. 3
P K/ P D M o deli n g ................................................................................3 0
1 6. 4
Di gital Electr ocar di o gra m .................................................................. 3 0
1 7
Refer e nces ...........................................................................................3 1
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 Versi o n 2. 0
6/ 3 1
2
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms
A Da M
A nal y sis Data M o del
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 c ur ve
A U C 0- 2 4 h
A U C fr o m ti me zer o ( = d osi n g ti me) t o 2 4 h o urs p ost d ose
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 ( = d osi n g ti me) t o 1 4 4 h o urs p ost d ose
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-t
A U C fr o m ti me zer o ( = d osi n g ti me) t o t he last sa m pli n g ti me (tlast) at 
w hic h t he c o nce ntrati o n is at or a b o ve t he l o wer li mit of q ua ntificati o n
A U C 0-t/ D ose
D ose -n or malize d A U C 0-t
A U C 0- 
T he A U C fr o m ti me zer o ( d osi n g ti me) e xtra p olate d t o i nfi nit y
A U C 0- / D ose
D ose -n or malize d A U C 0- 
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- 
B MI
B o d y mass i n de x
B P
Bl o o d press ure
CI
C o nfi de nce i nter val
C L /f
A p pare nt 
t otal b o d y  cleara nce of dr u g f oll o wi n g e xtra vasc ular 
a d mi nistrati o n, ta ki n g i nt o acc o u nt t he fracti o n of d ose a bs or be d
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n
C ma x / D ose
D ose -n or malize d C ma x
C R F
Case re p ort f or m
C S R
Cli nical St u d y  Re p ort
C V %
C oefficie nt of variati o n
D B S
Drie d bl o o d s p ot
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 Versi o n 2. 0
7/ 3 1
DI P L D
Dr u g -i n d uce d p h os p h oli pi d osis
E C 5 0
Half ma xi mal effecti ve c o nce ntrati o n
E C 9 0
9 0 % of ma xi mal effecti ve c o nce ntrati o n
E C D
Earl y Cli nical De vel o p me nt
G C P
G o o d Cli nical Practice
Ge o C V %
Ge o metric c oefficie nt of variati o n
Ge o Mea n
Ge o metric mea n
I A P
I nte grate d A nalys is Pla n
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I M P
I n vesti gati o nal me dici nal pr o d uct
I V
I ntra ve n o us
z
Ter mi nal first or der (eli mi nati o n) rate c o nsta nt
L L O Q
L o wer li mit of q ua ntificati o n
L O Q
Li mit of q ua ntificati o n
M A D
M ulti ple asce n di n g d ose(s)
Ma x
Ma xi m u m
Mea n
Arit h metic mea n
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
Mi n
Mi ni m u m
M P C
Mi ni mal parasitici dal c o nce ntrati o n
m R N A
Messe n ger ri b o n ucleic aci d
N
N u m ber of n o n -missi n g o bser vati o n
N D
N o n detecta ble/ n ot detecte d 
N R
N o res ult
P C R
P ol y merase c hai n reacti o n
D oc u me nt N o
O bject N o.
C CI
C CI
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 Versi o n 2. 0
9/ 3 1
W H O D D E
T he E n ha nce d W orl d Healt h Or ga nizati o n Dr u g dicti o nar y
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 Versi o n 2. 0
1 0 /3 1
3
M o dific ati o n Hist or y
U ni q u e
I d e ntifi er f or
V er si o n
D at e of
I A P V er si o n
A ut h or
C h a n g e s fr o m t h e Pr e vi o u s V er si o n
1. 0
1 6 A U G 2 0 1 8
Ori gi n al d o c u m e nt
2 . 0
1 3 M A Y 2 0 1 9
1)
U p d at e b a s e d o n t h e l at e st Pr ot o c ol V er si o n 
5. 0 i n cl u di n g A m e n d m e nt 4
2)
Uri n e a n d f e c e s p h ar m a c o ki n et i c a n al y si s 
( S e cti o n 1 6. 1. 2. 2 ) t o b e p erf or m e d a n d 
r e p ort e d s e p ar at el y
3)
P h ar m a c o d y n a mi c p ar a m et er a n al y si s 
( S e cti o n 1 6. 2. 1 ) t o b e p erf or m e d a n d 
r e p ort e d s e p ar at el y
4
P ur p ose of t he I nte gr ate d A n al ysis Pl a n
T he p ur p ose of t his I nte grate d A nal ys is Pla n (I A P) is t o d oc u me nt tec h nical a n d detaile d 
s pecificati o ns f or t he fi nal a nal ysis of data c ollecte d f or Cli nical St u d y  Pr ot oc ol M S 2 0 1 6 1 8 - 0 0 1 3. 
Res ults of t he a nal y ses descri be d i n t his I A P will b e i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R). 
A d diti o nall y , t he pla n ne d a nal yses i de ntifie d i n t his I AP will be i ncl u de d i n re g ulat or y su b missi o ns 
or f ut ure ma n uscri pts. A n y  post -h oc, or u n pla n ne d a nal ys es perf or me d t o pr o vi de res ults f or 
i ncl usi o n i n t he C S R b ut n ot i de ntifie d i n t his pr os pecti ve I A P will be clearl y ide ntifie d i n t he C S R. 
T he I A P is base d u p o n t he Cli nical St u d y  Pr ot oc ol Versi o n 5. 0 i ncl u di n g A me n d me nt 4 a n d is 
pre pare d i n c o m plia nce wit h I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) E 9. It f oc uses o n t he 
detaile d 
descri pti o n 
of 
t he statistical 
a nal yses 
f or safety, 
p har mac o ki netics 
( P K), 
p har mac o d y n a mics ( P D), a n d ot her varia bles. Part B
of t he st u d y (m ulti ple asce n di n g d ose s
[ M A D]) is desi g nate d as o pti o nal i n t he pr ot oc ol a n d will n ot be c o n d ucte d, s o t he a nalys is is n ot 
c urre ntl y defi ne d i n t his I A P .
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
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 Versi o n 2. 0
1 1 /3 1
5
O bjecti ves a n d E n d p oi nts
T he o bjecti ves a n d e n d p oi nts bel o w pertai n t o Part A a n d Part C o nl y .
O bj e cti v e
E n d p oi nt
I A P 
S e cti o n
P A R T A
Pri m ar y
O bj e cti v e
T o i n v e sti g at e t h e s af et y a n d 
t ol er a bilit y of si n gl e a s c e n di n g or al 
d o s e s of M 5 7 1 7
Pri m ar y E n d p oi nt s

N at ur e, i n ci d e n c e, a n d s e v erit y of A E s/
S A E s, i n cl u di n g r el ati o n s hi p t o st u d y
tr e at m e nt, A E s/ S A E s l e a di n g t o d o s e 
m o difi c ati o n or di s c o nti n u ati o n of st u d y
tr e at m e nt

I n ci d e n c e of cli ni c all y si g nifi c a nt c h a n g e s 
a n d a b n or m alit i e s i n s af et y l a b or at or y 
p ar a m et er s ( h e m at ol o g y, c o a g ul ati o n, 
bi o c h e mi str y [ s p e cifi c all y A L T a n d A S T], 
a n d uri n al y si s)

I n ci d e n c e of cli ni c all y si g nifi c a nt c h a n g e s 
a n d a b n or m aliti e s i n vit al si g n s ( b o d y 
t e m p er at ur e, B P, h e art r at e, a n d 
r e s pir at or y r at e) a n d 1 2 -l e a d E C G
1 5
S e c o n d ar y  
O bj e cti v e s
T o i n v e sti g at e t h e P K of si n gl e 
a s c e n di n g or al d o s e s of M 5 7 1 7
S e c o n d ar y E n d p oi nt s

P K p ar a m et er s f or M 5 7 1 7: C m a x , tm a x, λ z, 
t½ , A U C ( A U C0- ∞, A U C0-t , a n d A U C0- 1 4 4 h ), 
A U C e xtr a % , C L/f, Vz/f, a n d d o s e-n or m ali z e d 
A U C 0- ∞, A U C 0- 1 4 4 h , A U C 0-t , a n d C m a x , a s 
w ell a s t> 1 0 n g/ m L a n d t > 3 n g/ m L
1 6. 1. 2
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 Versi o n 2. 0
1 2 /3 1
O bj e cti v e
E n d p oi nt
I A P 
S e cti o n
P A R T C
Pri m ar y
O bj e cti v e
T o c h ar a ct eri z e t h e P K/ P D r el ati o n s hi p 
b et w e e n M 5 7 1 7 P K a n d p ar a sit e 
cl e ar a n c e i n h e alt h y s u bj e ct s f oll o wi n g 
i nf e cti o n wit h P. f al ci p ar u m bl o o d 
st a g e p ar a sit e s d uri n g t h e I B S M 
c h all e n g e b y a s s e s s m e nt of t h e P K -t o-
P R R r el ati o n s hi p
Pri m ar y E n d p oi nt s

P R R a s o b s er v e d t hr o u g h q P C R a n al y si s

All M 5 7 1 7 P K p ar a m et er s a s d efi n e d i n 
P art A or P art B ( d e p e n di n g o n d o si n g 
r e gi m e n i n P art C)
1 6. 2 , 
1 6. 1. 2
S e c o n d ar y  
O bj e cti v e s
T o c h ar a ct eri z e t h e P K/ P D r el ati o n s hi p 
b et w e e n M 5 7 1 7 P K a n d p ar a sit e 
cl e ar a n c e i n h e alt h y s u bj e ct s f oll o wi n g 
i nf e cti o n wit h P. f al ci p ar u m bl o o d 
st a g e p ar a sit e s d uri n g t h e I B S M 
c h all e n g e b y a s s e s s m e nt of t h e 
r el ati o n s hi p of P K wit h t h e P D 
p ar a m et er s: P C T, M I C, P Ct 1/ 2 , M P C, 
l a g ti m e, a n d fr e q u e n c y of 
r e cr u d e s c e n c e
S e c o n d ar y E n d p oi nt s

P C T, MI C, P Ct 1/ 2 , M P C, l a g p h a s e

N u m b er a n d p er c e nt a g e of s u bj e ct s wit h 
r e cr u d e s c e n c e
1 6. 2
T o c h ar a ct eri z e t h e p ar a siti ci d al 
a cti vit y of M 5 7 1 7 o n P. f al ci p ar u m 
a s e x u al bl o o d st a g e p ar a sit e s i n t h e 
bl o o d of h e alt h y s u bj e ct s i n t h e I B S M 
c h all e n g e
T o e v al u at e t h e s af et y a n d t ol er a bilit y 
of M 5 7 1 7 i n h e alt h y v ol u nt e er s 
f oll o wi n g i nf e cti o n wit h P. f al ci p ar u m 
bl o o d st a g e p ar a sit e s d uri n g t h e I B S M 
c h all e n g e

M al ari a Cli ni c al S c or e

N at ur e, i n ci d e n c e, a n d s e v erit y of 
A E s/ S A E s, i n cl u di n g r el ati o n s hi p t o st u d y
tr e at m e nt, A E s/ S A E s l e a di n g t o d o s e 
m o difi c ati o n or di s c o nti n u ati o n o f st u d y
tr e at m e nt

I n ci d e n c e of cli ni c all y si g nifi c a nt c h a n g e s 
a n d a b n or m aliti e s i n s af et y l a b or at or y 
p ar a m et er s ( h e m at ol o g y, c o a g ul ati o n, 
bi o c h e mi str y [ s p e cifi c all y A L T a n d A S T], 
a n d uri n al y si s)

I n ci d e n c e of cli ni c all y si g nifi c a nt c h a n g e s 
a n d a b n or m aliti e s i n vit al si g n s ( b o d y 
t e m p er at ur e, B P, h e art r at e, a n d 
r e s pir at or y r at e) a n d 1 2 -l e a d E C G
1 5
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 Versi o n 2. 0
1 4 /3 1
c o m bi ni n g/c o m pari n g P K e x p os ures bet wee n si n gle d oses a n d m ulti ple d oses (ie, Part B). Si nce 
Part B is n ot bei n g c o n d ucte d, t hese para meters are n ot bei n g calc ulate d f or Parts A a n d C.
A c orrelati o n a nal ys is of M 5 7 1 7 c o nce ntrati o ns fr o m drie d bl o o d s p ot ( D B S) assa y an d w h ole 
bl o o d will be perf or me d as descri be d i n Secti o n  1 6. 1. 3.
8
Pr ot oc ol De vi ati o ns a n d A n al ysis Sets
8. 1
Defi niti o n of Pr ot oc ol De vi ati o ns a n d A n al ysis Sets
I m p orta nt pr ot oc ol de viati o ns or e ve nts are pr ot oc ol de viati o ns a n d e ve nts t hat mi g ht si g nifica ntl y 
affect t he c o m plete ness, acc urac y, a n d/ or relia bilit y of t he st u d y data or t hat mi g ht si g nifica ntl y 
affect a s u bject's ri g hts, safety, or well -bei n g. 
A s u bset of t hese i m p orta nt pr ot oc ol de viati o ns or e ve nts t hat lea d t o t he e xcl usi o n of a s u bject 
fr o m a n a nal ysis set (see Secti o n 8. 2 ) are c o nsi dere d cli nicall y i m p orta nt.
T he f oll o wi n g i m p orta nt de viati o ns or e ve nts will be i de ntifie d a n d c o nfir me d pri or t o or at t he 
Data Re vie w Meeti n g:

S u bjects w h o are d ose d o n t he st u d y des pite n ot satisf yi n g t he i ncl usi o n criteria

S u bjects w h o de vel o p wit h dra wal cri teria w hilst o n t he st u d y b ut are n ot wit h dra w n

S u bjects w h o recei ve t he wr o n g treat me nt or a n i nc orrect d ose

S u bjects w h o recei ve a n e xcl u de d c o nc o mita nt me dicati o n

De viati o n fr o m G o o d Cli nical Practice ( G C P)

Ot her e ve nts/fact ors relate d t o P K a n d/ or P D, w hic h i ncl u de, b ut ma y  n ot be li mite d t o, e ve nts 
t hat c o ul d affect P K a n d/ or P D, will be e val uate d o n a case-b y -case basis:
o
V o miti n g f oll o wi n g oral d osi n g (t hese i nsta nces will be disc usse d o n a case -b y  case basis)
o
Sa m ple pr ocessi n g err ors t hat ma y  lea d t o i nacc urate bi oa nalyt ical or P D res ults
o
I nc o m plete data ( d ue t o l ost sa m ples, i ns ufficie nt sa m ple v ol u mes f or assa y, etc.) 
o
I nacc urate d osi n g or d osi n g err ors
o
I na de q uate fasti n g pri or t o a n d f oll o wi n g d osi n g
o
C o nc o mita nt me dicati o n vi olati o ns (refer t o Secti o n 6. 5. 2 of Cli nical St u d y P r ot oc ol), t hat 
c o ul d affect P K or P D .
I n case of a de viati o n or e ve nt t hat ma y  affect P K a n d/ or P D data , c ollecte d P K a n d/ or P D data 
w hic h is li kel y to be affecte d m a y  be e xcl u de d fr o m t he st u d y res ults after c o ns ultati o n a n d 
a gree me nt wit h S p o ns or or s p o ns or re prese ntati ve. T hese de viati o ns or e ve nts c o ul d be classifie d 
as cli nicall y i m p orta nt a n d c o nfir me d pri or t o or at t he Data Re vie w Meeti n g bef ore data base l oc k 
a n d u n bli n di n g of P art A. Ot her c ha n ges t o t he pr oce d ures or e ve nts w hic h d o n ot si g nifica ntl y 
i m pact t he q ualit y  of t he P K a n d/ or P D data will n ot lea d t o e x cl usi o n fr o m t he P K a n d/ or P D 
A nal y sis Sets. A c o m m o n e xa m ple of a n e ve nt w hic h us uall y d oes n ot lea d t o e xcl usi o n fr o m t he 
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 Versi o n 2. 0
1 6 /3 1
9
Ge ner al S pecific ati o ns f or D at a A n al yse s
Data will ge nerall y be prese nte d se paratel y f or eac h part ( Part A or Part C) of t he st u d y , alt h o u g h 
s o me c o m bi nati o n of data acr oss parts ma y be d o ne, w here a p pr o priate (see Secti o n 1 6. 1. 3) .
D etails o n P K a n d P D data prese ntati o n ca n be f o u n d i n Secti o n 1 6.
Listi n gs
All listi n gs will be s orte d b y  treat me nt/d ose, s u bject, a n d/ or n o mi nal ti me p oi nt, as a p pr o priate. 
Data w hic h are o nl y meas ure d bef ore a d mi nistrati o n of t he i n vesti gati o nal me dici nal pr o d uct 
(I M P) will be s orte d b y s u bject a n d n o mi nal ti me p oi nt (if a p pr o priate).
Safet y  data will be re p orte d a n d a nal yz e d wit h t he sa me precisi o n as t he s o urce data pr o vi de d ,
re gar dless of h o w ma ny s i g nifica nt fi g ures or deci mal places t he data carr y.
T a bles a n d Descri pti ve St atistics
All data will be s u m marize d b y  st u d y part, d ose gr o u p , d a y , a n d/ or n o mi nal ti me p oi nt, as 
a p pr o priate. Data f or s u bjects w h o recei ve d place b o will be p o ole d acr oss d osi n g c o h orts 
bel o n gi n g t o t he sa me trial part. Re peate d a n d u nsc he d ule d meas ure me nts i ncl u de d i n t he listi n gs 
will n ot be use d f or statistical a nal yses or s u m maries, u nless t he re peate d meas ure me nt was 
perf or me d d ue t o u nrelia ble val ues/tec h nical reas o ns, e g, cl otte d sa m ples. 
Prese nt ati o n of C o nti n u o us a n d Q u alit ati ve V ari a bles f or De m o gr a p hics, Ot her B aseli ne 
C h ar acteristics, a n d S afet y 
C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics, ie: 

n u m ber of s u bjects, n u m ber of s u bjects wit h n o n -missi n g val ues

mea n, sta n dar d de viati o n (S D )

me dia n, 2 5t h Perce ntile - 7 5t h Perce ntile ( Q 1 -Q 3)

mi ni m u m ( Mi n) a n d ma xi m u m ( Ma x).
Q ualitati ve varia bles will be s u m marize d b y  c o u nts a n d perce nta ges.
U nless ot her wise state d, t he calc ulati o n of pr o p orti o ns will be base d o n t he n u m ber of s u bjects i n 
t he a nal ysis set of i nterest. T heref ore , c o u nts of missi n g o bser vati o ns will be i ncl u de d i n t he 
de n o mi nat or a n d prese nte d as a se parate cate g or y .
W he n t he a nal ys is refers o nl y  to certai n visits, perce nta ges will be base d o n t he n u m ber of s u bjects 
still prese nt i n t he st u d y at t hat visit, u nless ot her wise s pecifie d.
Mea n, Me dia n, Q 1, Q 3, Mi n, a n d Ma x will ha ve t he sa me precisi o n as c ollecte d f or S D T M datasets 
f or n o n- deri ve d data. Sta n dar d de viati o n will be prese nte d wit h o ne di git m ore t ha n t he mea n. 
Statistics o n deri ve d data will be r o u n de d t o reas o na ble di gits w hereas ma xi mal di gits s h o ul d b e 
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 Versi o n 2. 0
1 7 /3 1
a vaila ble i n A nal ys is Data M o del ( A Da M) datasets. Perce nta ge a n d perce nt c ha n ge fr o m baseli ne 
will be re p orte d usi n g 1 deci mal di git, if n ot ot her wise s pecifie d.  
Defi niti o n of B aseli ne
If n ot ot her wise s pecifie d, “ Baseli ne” refers t o t he last sc he d ule d meas ure me nt bef ore t he I M P 
a d mi nistrati o n, as a p pr o priate. H o we ver, if a s u bject is missi n g t he baseli ne c ollecti o n, t he 
pre vi o us n o n- missi n g e val uati o n (as a p plica ble) will bec o me t he baseli ne val ue. Baseli ne of 
la b orat or y para meters will c orres p o n d t o D a y  1 pre d ose f or Part A, a n d Da y  - 1 f or Part C. Baseli ne 
will c orres p o n d t o Da y  1 pre d ose f or all parts of t he st u d y f or vital si g ns a n d safet y EC Gs . Baseli ne 
of bi o mar kers will c orres p o n d t o Da y  -1 f or Part A,
C o m m o n C alc ul ati o ns 
F or q ua ntitati ve meas ure me nts:
C ha n ge fr o m b aseli ne will be calc ulate d as: Test Val ue at Visit X – Baseli ne Val ue
A ge [ years] : ([ date of i nf or me d c o nse nt - date of birt h] + 1)/ 3 6 5. 2 5 
Defi niti o n of D ur ati o n
D urati o n i n d a y s will be calc ulate d b y  the differe nce of start a n d st o p date + 1 if n ot ot her wise 
s pecifie d.
H a n dli n g of Missi n g D at a
U nless ot her wise s pecifie d, missi n g data will n ot be re place d. 
Ha n dli n g of missi n g data f or P K para meter calc ulati o ns are disc usse d u n der Secti o n 1 6. 1.
S oft w are
P har mac o ki netic p ara meters will be deri ve d usi n g t he vali date d c o m p uter pr o gra m P h oe ni x ®
Wi n N o nli n
® 6. 4 or hi g her , a n d/ or S A S ® ( Statistical A nal y sis S y ste m, S A S -I nstit ute, Car y , N ort h 
Car oli na, U S A) Wi n d o ws Versi o n 9. 4 or hi g her. P har mac o d y na mic para meters (e xcl u di n g t h ose 
calc ulate d b y P K/ P D m o deli n g; see Secti o n  1 6. 2. 3 ) will be deri ve d usi n g S A S ® . P har mac o ki netic 
a n d P D ta bles, fi g ures, a n d listi n gs f or t he fi nal a nal ysis will be de vel o pe d usi n g S A S ® . All ot her 
statistical a nal yses will be perf or me d usi n g S A S ® .
1 0
St u d y S u bjects
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or re p orti n g s u bject dis p ositi o n a n d 
treat me nt/st u d y disc o nti n uati o ns. A d diti o nall y , pr oce d ures f or re p orti n g pr ot oc ol de viati o ns are 
pr o vi de 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 Versi o n 2. 0
1 9 /3 1
1 1. 1
De m o gr a p hics
Descri pti ve statistics will be prese nte d f or a ge, hei g ht, wei g ht, a n d b o d y  mass i n de x (B MI ). 
Fre q ue nc y  co u nts a n d perce nta ges will be prese nte d f or se x, race, et h nicit y, a n d s ki n t ype. T he 
s u m mar y will be perf or me d b y d ose a n d o verall.
1 1. 2
Me dic al Hist or y
Me di cal hist or y will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A), V ersi o n 2 0. 1, a n d liste d.
1 1. 3
Ot her B aseli ne C h ar acteristics
Ot her baseli ne meas ure me nts, s uc h as vir us scree n, alc o h ol a n d dr u gs of a b use scree n, pre g na nc y  
test a n d f ollicle-sti m ulati n g h or m o ne assess me nt i n w o me n, nic oti ne a n d alc o h ol c o ns u m pti o n, 
will be liste d.
I n ad diti o n, g l uc ose- 6-p h os p hate de h y dr o ge nase stat us will be liste d f or Part C.
1 2
P re vi o us or C o nc o mit a nt Me dic ati o ns/ Pr oce d ures
1 2. 1
Pre vi o us or C o nc o mit a nt Me dic ati o ns
Me dicati o ns will be prese nte d f or t he Safet y A nal ysis Set.
Pre vi o us me dicati o ns are defi ne d as a n y me dicati o n disc o nti n ue d pri or t o t he I M P a d mi nistrati o n. 
C o nc o mita nt me dicati o ns are defi ne d as a n y m e dicati o n ta ke n d uri n g t he c o urse of t he st ud y , wit h 
a starti n g date greater t ha n or e q ual t o t he I M P a d mi nistrati o n, or wit h a starti n g date pri or t o t he 
I M P a d mi nistrati o n a n d o n g oi n g at t he ti me of t he I M P a d mi nistrati o n.
T he E n ha nce d W orl d Healt h Or ga nizati o n Dr u g dicti o nar y  (W H O D D E), V ersi o n S E P 2 0 1 7 , will 
be use d f or c o di n g of pri or a n d c o nc o mita nt me dicati o ns a n d t he y will be descri be d usi n g Preferre d 
Ter m ( P T) as a p plica ble.
Pre vi o us a n d c o nc o mita nt me dicati o ns will be liste d. C o nc o mita nt pr oce d ures, if a n y, will als o be 
liste d.
1 2. 2
Resc ue Me dic ati o n
S u bjects i n Part C will be prescri be d a n a p pr o ve d re gi me n f or c urati ve t hera py f or malaria, t o 
ass ure fi nal parasite cleara nce, at recr u desce nce or at t he e n d of t he st u d y.
Resc ue me dicati o n data will be liste d b y  s u bject, i ncl u di n g da y after i noc ul u m a d mi ni strati o 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 Versi o n 2. 0
2 0 /3 1
1 2. 3
I ntr a ve n o us M al ari a I n oc ul u m
I ntra ve n o us (IV) i n oc ul u m will be a d mi nistere d at Da y  - 8 i n Part C. Data will be pr o vi de d i n a 
listi n g.
1 3
Tre at me nt C o m pli a nce a n d E x p os ure
T he I M P will be a d mi nistere d at t he st u d y site u n der s u per visi o n. T he a d mi nistrati o n of I M P will 
be liste d. 
1 4
Effic ac y A n al yses
T here are n o efficac y  e n d p oi nts defi ne d f or Part A .
F or Part C, parasitical effect of M 5 7 1 7 wi ll be a nal yze d as s pecifie d i n S ecti o n 1 6. 2 . T he malaria 
cli nical sc ore will be a nal yze d as descri be d i n Secti o n  1 5. 2. 3.  
1 5
S afe t y A n al yses
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or s u m marizi n g safet y en d p oi nts t hat are 
c o m m o n acr oss cli nical st u dies s uc h as A Es , la b orat or y tests a n d vital si g ns.
All safety a nal ys es will be perf or me d f or t he Safet y  Anal ys is Set a n d will be prese nte d b y  part a n d 
d ose. A n a d diti o nal c ol u m n f or all acti ve d oses of M 5 7 1 7 ma y be prese nte d w he n s pecifie d .
1 5. 1
A d verse E ve nts
All A Es rec or de d d uri n g t he c o urse of t he st u d y will be c o de d wit h t he Me d D R A,
V ersi o n 2 0. 1 , 
a n d assi g ne d t o a S ys te m Or ga n C lass ( S O C) a n d a P T. 
Treat me nt -e mer ge nt A Es ( T E A Es) are t h ose e ve nts wit h o nset dates o n or after t he first I MP 
a d mi nistrati o n. A n y  AE occ urri n g bef ore t he I MP a d mi nistrati o n o n Da y 1 a n d res ol ve d bef ore 
I M P a d mi nistrati o n or n ot w orse ni n g after I M P a d mi nistrati o n will be i ncl u de d i n t he A E listi n gs, 
b ut will n ot be i ncl u de d i n t he s u m mar y ta bles ( u nless ot her wise state d). T hese will be referre d t o 
as “ pre -treat me nt” A Es.
I n case A E -relate d dates are partial, t he a vaila ble i nf or mati o n will be use d i n a c o nser vati ve 
a p pr oac h t o deter mi ne w het her t he A E is treat me nt- e mer ge nt.
All a nal y ses descri be d i n t his secti o n will be base d o n T EA Es if n ot ot her wise s pecifie d.
1 5. 1. 1
All A d verse E ve nts
Treat me nt -e mer ge nt A Es will be s u m marize d b y d ose a n d o verall i n ta bles wit h:

T he n u m ber a n d perce nta ge of s u bjects wit h a n y T E A E, a n y I M P-relate d T E A E, a n y seri o us 
T E A E, a n y I M P-relate d seri o us T E A E, a n y Gra de ≥3 T E A E, a n y I M P-relate d Gra de ≥3 T E A E, 
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 Versi o n 2. 0
2 1 /3 1
a n y A Es of s pecial i nterest ( A E SI), a ny T E A E lea di n g t o deat h, a n y I M P -relate d T E A E lea di n g 
t o deat h, a ny T E A E lea di n g t o st u d y disc o nti n uati o n

T he n u m ber a n d perce nta ge of s u bjects wit h at least o ne T E A E b y S O C a n d P T

T he n u m ber a n d perce nta ge of s u bjects wit h at least o ne T E A E b y w orst gra de, S O C , a n d P T 

T he n u m ber a n d perce nta ge of s u bjects wit h at least o ne I MP -relate d T E A E b y  S O C a n d P T

T he n u m ber a n d perce nta ge of s u bjects wit h at least o ne T E A E b y  PT o nl y , s orte d i n decreasi n g 
i nci de nce o verall

T he n u m ber a n d perce nta ge of s u bjects wit h n o n -seri o us T E A Es b y  S O C a n d P T

T he n u m ber a n d perce nta ge of s u bjects wit h at least o ne A E SI  rec or de d b y S O C a n d P T .
U nless ot her wise state d, A Es will be dis pla y e d wit h S O C ter ms a n d P Ts wit hi n eac h S O C ter m 
s orte d al p ha beticall y. 
F or deter mi ni n g i nci de nce c o u nts, wit hi n eac h le vel of T E A E t er m, if a s u bject e x perie nces m ore 
t ha n o ne occ urre nce, t he s u bject will o nl y be c o u nte d o nce f or t hat T E A E. 
If a n A E is re p orte d f or a gi ve n s u bject m ore t ha n o nce d uri n g treat me nt, t he w orst se verit y an d 
t he w orst relati o ns hi p t o st u d y treat me nt will be ta b ulate d.
A d verse e ve nts relate d t o I M P are t h ose e ve nts wit h relati o ns hi p missi n g, u n k n o w n or y es.
I n case a s u bject ha d e ve nts wit h missi n g a n d n o n -missi n g se verity, t he ma xi m u m
n o n- missi n g  
se verity will be dis pla ye d.
1 5. 1. 2
A d verse E ve nts Le a di n g t o St u d y Di sc o nti n u ati o n
A listi n g of T E A Es lea di n g t o st u d y disc o nti n uati o n, if a n y , will be pr o vi de d.
1 5. 2
De at hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts
1 5. 2. 1
De at hs
A listi n g of deat hs, if a n y, will be pr o vi de d. 
1 5. 2. 2
Seri o us A d verse E ve nts
A listi n g of seri o us A Es (S A Es ), if a n y, will be pr o vi de d.
1 5. 2. 3
Ot her Si g nific a nt A d verse E ve nt
T he f oll o wi n g will be c o nsi dere d as A E SIs i n t his st u d y :

V o miti n g or diarr hea
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 Versi o n 2. 0
2 3 /3 1
1 6
A n al yses of Ot her E n d p oi nts
1 6. 1
P h ar m ac o k i netics
1 6. 1. 1
H a n dli n g of Bl o o d , Uri ne , a n d Fec al C o nce ntr ati o n s
1 6. 1. 1. 1
W h ole Bl o o d
C o nce ntrati o ns of M 5 7 1 7 i n w h ole bl o o d will be meas ure d i n all c o h orts i n Parts A a n d C. 
A d diti o nall y , c o nce ntrati o ns of M 5 7 1 7 meta b olites m a y be meas ure d i n w h ole bl o o d fr o m male 
s u bjects recei vi n g M 5 7 1 7 treat me nt i n Part A (all c o h orts).
Pre d ose sa m ples t hat occ ur bef ore dr u g a d mi nistrati o n will be assi g ne d a ti me of 0 h o urs, as if t he 
sa m ple ha d bee n ta ke n si m ulta ne o usl y wit h the st u d y  dr u g a d mi nistrati o n. 
C o nce ntrati o n v al ues bel o w t he l o wer li mit of q ua ntificati o n of t he assa y ( L L O Q) will be ta ke n as 
zer o f or s u m mar y statistics of P K c o nce ntrati o n data. 
I n case of c o nce ntrati o ns a b o ve t he u p per li mit of q ua ntificati o n ( U LO Q) , t he c o nce ntrati o n will 
be set t o missi n g .
Missi n g c o nce ntrati o ns ( e g, n o sa m ple, i ns ufficie nt sa m ple v ol u me f or a nal ysis, n o res ult or res ult 
n ot vali d) will be re p ort e d a n d use d ge nerall y as n o res ult ( “ N R” ). 
1 6. 1. 1. 2
Drie d Bl o o d S p ot Ass a y 
C o nce ntrati o ns of M 5 7 1 7 i n D B S sa m ples will be meas ure d at selecte d ti me p oi nts i n Part C
c o h orts .
C o nce ntrati o n val ues bel o w t he L L O Q of t he assa y will be ta ke n as zer o f or s u m mar y statistics of 
D B S P K c o nce ntrati o n data.
1 6. 1. 1. 3
Uri ne a n d Feces
Dail y  24- h o ur uri ne a n d feces m a y  be c ollecte d i n male s u bjects o nl y  in o ne of t he c o h orts i n Part A 
d uri n g t he resi de ntial peri o d ( u p t o Da y  7), a n d uri ne ma y  be c ollecte d d uri n g t he a m b ula nt peri o ds 
( 2 4-h o ur c ollecti o ns ar o u n d Da y 1 5, Da y  2 2, Day 3 3, a n d Da y 4 4 ). Uri ne a n d fecal c o nce ntrati o ns 
f or M 5 7 1 7 a n d/ or meta b olites, if a vaila ble, will be re p orte d i n a se parate re p ort.
1 6. 1. 2
Deri v ati o n of I n di vi d u al W h ole B l o o d, Uri ne, a n d Fec al 
P h ar m ac o k i netic P ar a meters
1 6. 1. 2. 1
W h ole Bl o o d
P har mac o ki netic para meters will be calc ulate d b
usi n g sta n dar d n o n- c o m part me ntal 
met h o ds a n d t he act ual a d mi nistere d d ose. P K para meters will be calc ulate d usi n g t he act ual 
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 Versi o n 2. 0
2 4 /3 1
ela pse d ti me si nce d osi n g, gi ve n wit h a precisi o n of 1 4 si g nifica nt di gits.  I n cases w here t he act ual 
sa m pli n g ti me is missi n g, calc ulati o ns will be perf or me d usi n g t he n o mi nal ti me. Ot her wise, t here 
will be n o f urt her i m p utati o n of missi n g data.
T he f oll o wi n g para meters will be calc ulate d fr o m M 5 7 1 7 w h ole bl o o d c o nce ntrati o ns i n Part A 
a n d Part C. If M 5 7 1 7 w h ole bl o o d meta b olite c once ntrati o ns are a vaila ble i n Part A, para meters 
ma y  als o be calc ulate d f or t hese meta b olites (if a p plica ble, a n d if s ufficie nt data are a vaila ble).
S y m b ol
Defi niti o n
A U C 0-t
T he A U C fr o m ti me zer o ( = d osi n g ti me) t o t he last sa m pli n g ti me (tlast) at 
w hic h t he c o nce ntrati o n is at or a b o ve t he l o wer li mit of q ua ntificati o n. 
Calc ulate d usi n g t he mi xe d l o g li near tra pez o i dal r ule (li near u p, l o g d o w n).
A U C 0- t / D ose
T he d ose -n or malize d A U C 0-t. N or malize d usi n g t he act ual d ose, usi n g t he 
f or m ula A U C 0- t / Do se.
A U C 0- 1 4 4 h
T he A U C fr o m ti me zer o ( = d osi n g ti me) t o 1 4 4 h o urs p ost d ose. Calc ulate d 
usi n g t he mi xe d l o g li near tra pez oi dal r ule (li near u p, l o g d o w n).
A U C 0- 1 4 4 h
/ D ose
T he d ose -n or malize d A U C 0- 1 4 4 h. N or malize d usi n g t he act ual d ose, usi n g t he 
f or m ula A U C 0- 1 4 4 h / D ose. 
A U C 0- 
T he A U C fr o m ti me zer o ( d osi n g ti me) e xtra p olate d t o i nfi nit y, base d o n t he 
pre dicte d val ue f or t he c o nce ntrati o n at tlast, a n d esti mate d usi n g t he li near 
re gressi o n fr o m t he deter mi nati o n of t he ter mi nal first or der (eli mi nati o n) rate 
c o nsta nt (λ z). A U C 0 -= A U C 0-t+ C last pre d/ λz.
A U C 0- ∞ / D ose
T he d ose -n or malize d
A U C 0- . N or mali ze d usi n g act ual d ose, usi n g t he 
f or m ula A U C 0- ∞ / D ose. 
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 e xtra % = (e xtra p olate d area/ A U C 0- ∞) * 1 0 0. 
C L /f
T he 
a p pare nt t otal b o d y  cleara nce of dr u g f oll o wi n g e xtra vasc ular 
a d mi nistrati o n, ta ki n g i nt o acc o u nt t he fracti o n of 
d ose 
a bs or be d. 
C L /f = D ose / A U C0- ∞. Calc ulate d f or M 5 7 1 7 o nl y.
C ma x
Ma xi m u m o bser ve d c o n ce ntrati o 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 Versi o n 2. 0
2 5 /3 1
S y m b ol
Defi niti o n
C ma x
/ D ose
T he d ose -n or malize d C ma x . N or malize d usi n g t he act ual d ose, a n d t he f or m ula 
C ma x / D ose. 
z
Ter mi nal first or der (eli mi nati o n) rate c o nsta nt. Deter mi ne d fr o m t he ter mi nal 
sl o pe of t he l o g-tra nsf or me d c o nce ntrati o n c ur ve usi n g li near re gressi o n o n 
ter mi nal data p oi nts of t he c ur ve. 
t1/ 2
A p pare nt ter mi nal half -life. t1/ 2  = l n ( 2)/ λ z. 
tma x
T he ti me t o reac h t he ma xi m u m o bser ve d c o nce ntrati o n collecte d d uri n g a 
d osi n g i nter val (i n case of m ulti ple/i de ntical C ma x val ues , t he first occ urre nce 
will be use d ). 
V Z/f
T he a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase f oll o wi n g 
e xtra vasc ular a d mi nistrati o n, base d o n t he fracti o n of d ose a bs or be d. V z/f = 
D ose/( A U C 0- ∞* λ z) f oll o wi n g si n gle d ose. Calc ulate d f or M 5 7 1 7 o nl y.
t> 3 n g/ m L
Ti me a b o ve or e q ual t o t he pr e dicte d M 5 7 1 7 
m o use mi ni m u m i n hi bit or y 
c o nce ntrati o n (MI C) of 3 n g/ m L. 
t> 1 0 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 ni mal parasitici dal 
c o nce ntrati o n (M P C ) of 1 0 n g/ m L. 
F or C L /f a n d V Z/f a n d all d ose -n or malize d para meters, t he act ual M 5 7 1 7 d ose after a dj ust me nt f or 
m olec ular wei g ht differe nces bet wee n salt a n d free base f or m will be use d f or calc ulati o n of t hese 
para meters (i e, A dj uste d d os e = D ose * 4 6 2. 5 6/ 5 8 0. 6 5), w here 4 6 2. 5 6 a n d 5 8 0. 6 5 are t he 
m olec ular wei g hts of t he M 5 7 1 7 free ba se a n d s ucci nate salt, res pecti vely.
T he f oll o wi n g P K para meters will be calc ulate d f or dia g n ostic p ur p oses a n d liste d f or Part A a n d 
Part C , b ut will n ot be s u m marize d:

T he ti me i nter val ( h) of t he l o g -li near re gressi o n ( λz l o w, λz u p p) t o deter mi ne λz. 

N u m ber of data p oi nts ( N λ) i ncl u de d i n t he l o g-li near re gressi o n a nalys is t o deter mi ne λz.

G o o d ness of fit statistic ( Rs q) f or calc ulati o n of λ z.  
T he re gressi o n a nal ys is f or λ z s h o ul d c o ntai n data fr o m at least 3 differe nt ti me p oi nts i n t he 
ter mi nal p ha se c o nsiste nt wit h t he assess me nt of a strai g ht li ne o n t he l o g-tra nsf or me d scale. 
P h oe ni x Wi n N o nli n best fit met h o d ol o g y  will be use d as sta n dar d. H o we ver, i n s o me cases, f urt her 
a dj ust me nt ma y  be ma de
b y  the p har mac o ki neticist, if warra nte d,
after a gree m e nt fr o m t he 
S p o ns or. T he last q ua ntifia ble c o nce ntrati o n s h o ul d al wa ys be i ncl u de d i n t he re gressi o n a nal ysis, 
w hile t he c o nce ntrati o n at t ma x a n d a n y c o nce ntrati o ns bel o w t he L L O Q w hic h occ ur after t he last 
q ua ntifia ble data p oi nt s h o ul d n ot be use 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 Versi o n 2. 0
2 6 /3 1
T h e R s q s h o ul d be ≥0. 8 0 0 a n d t he o bser vati o n peri o d o ver w hic h t he re gressi o n li ne is esti mate d 
s h o ul d be at least t w o-f ol d t he res ulti n g t1/ 2 itself. If t hese criteria are n ot met, t he n t he rate 
c o nsta nts a n d all deri ve d para meters will be i ncl u de d i n t he p ara meter o ut p uts a n d descri pti ve 
statistics b ut will be fla g ge d a n d disc usse d a p pr o priatel y. T he A U C e xtra % s h o ul d be less t ha n 2 0. 0 %. 
If t his criteri o n is n ot met, A U C 0 -a n d all deri ve d para meters will be i ncl u de d i n t he para meter 
o ut p uts a n d descri pti ve statistics b ut will be fla g ge d a n d disc usse d a p pr o priatel y. A n y f la gs s h o ul d 
be i ncl u de d i n t he st u d y  s pecific S D T M. 
Partial areas s h o ul d be calc ulate d usi n g t he n o mi nal d osi n g i nter val, as defi ne d i n t he cli nical trial 
pr ot oc ol . T he act ual d osi n g i nter val calc ulate d fr o m case re p ort f or m (C R F ) ti me data s h o ul d n ot 
be use d. 
C o nce ntrati o ns bel o w t he L L O Q at a n y p oi nt i n t he pr ofile will be ta ke n as zer o f or calc ulati n g t he 
A U C. P red ose sa m ples t hat occ ur bef ore t he first dr u g a d mi nistratio n will be assi g ne d a ti me of 
0 h o urs, as if t he sa m ple ha d bee n ta ke n si m ulta ne o usl y  wit h t he st u d y dr u g a d mi nistrati o n. 
T he P h oe ni x Wi n N o nli n N C A C ore O ut p ut will be pr o vi de d i n a se parate listi n g.
1 6. 1. 2. 2
Uri ne a n d Feces
Uri ne a n d fecal para meters f or M 5 7 1 7 a n d/ or meta b olites, if calc ulate d, will be re p orte d i n a 
se parate re p ort.
1 6. 1. 3 
St atistic al S u m m ar y a n d A n al ys is
F or Parts A a n d C, w h ole bl o o d P K para meters (as descri be d i n Secti o n 1 6. 1. 2. 1) will be 
calc ulate d, if esti ma ble, usi n g act ual ela pse d ti mes a n d n o nc o m part me ntal met h o ds,
All statistical a nal yses a n d descri pti ve s u m maries of P K c o nce ntrati o ns a n d P K para meters will be 
perf or me d o n t he P K A nal y sis Set. A n y P K c o nce ntrati o ns or P K para meters e xcl u de d fr o m t he 
P K A nal y sis Set will be liste d a n d fla g ge d.
D oc u me nt N o.
O bject N o.
C CI
C CI
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 Versi o n 2. 0
2 7 /3 1
P har mac o ki netic c o nce ntrati o ns will be re p orte d a n d a nal yze d wit h t he sa me preci si o n as t he 
s o urce data pr o vi de d b y t he bi oa nalyt ical la b orat or y or cli nical la b orat or y. Act ual ela pse d sa m ple 
c ollecti o n ti mes will be a nal yze d u nr o u n de d ( ma xi m u m of 1 4 si g nifica nt di gits) , b ut will be 
r o u n de d t o t w o deci mal places wit h u nits of h o urs f or re p orti n g p ur p oses i n b y-s u bject listi n gs. 
P har mac o ki netic para meters will be a nal yze d u nr o u n de d, b ut will be r o u n de d t o 3 si g nifica nt di gits 
f or re p orti n g, e xce pt f or para meters directl y  obtai ne d fr o m t he s o urce data (s uc h as C ma x ) w hic h 
will be re p orted wit h t he sa me precisi o n as t he s o urce data , a n d tma x w hic h will be re p orte d t o 2 
deci mal places . I n e x p ort datasets, as well as i n t he S D T M P P/ X D d o mai n, P K/ P D para meters will 
be pr o vi de d wit h f ull precisi o n, a n d will n ot be r o u n de d.
Prese nt ati o n of P K B l o o d C o nce ntr ati o ns
M 5 7 1 7 P K w h ole bl o o d c o nce ntrati o n data i ncl u di n g drie d bl o o d s p ot assa y c o nce ntrati o ns will 
be descri pti vel y  su m marize d usi n g: n u m ber of n o n -missi n g o bser vati o ns ( N), arit h metic mea n 
( Mea n), S D, c oefficie nt of variati o n ( C V %), Mi n, Me dia n, a n d Ma x. 
Descri pti ve statistics of w h ole bl o o d c o nce ntrati o n data i ncl u di n g drie d bl o o d s p ot assa y 
c o nce ntrati o ns will be calc ulate d usi n g val ues wit h t he sa me precisi o n as t he s o urce data, a n d 
r o u n de d f or re p orti n g p ur p oses o nl y . T he f oll o wi n g P K c on ve nti o ns will be a p plie d w he n re p orti n g 
descri pti ve statistics: 
Mea n, Mi n, Me dia n, Ma x: 
3 si g nifica nt di gits
S D:
4 si g nifica nt di gits
C V %:
1 deci mal place 
Prese nt ati o n of P K P ar a meters
Calc ulate d P K para meters will be descri pti vel y  s u m marize d usi n g: N, Mea n, S D, C V %, Mi n, 
Me dia n, Ma x, ge o metric mea n ( Ge o Mea n), t he ge o metric c oefficie nt of variati o n ( Ge o C V %) a n d 
t he l o wer a n d u p per b o u n ds of t he 9 5 % c o nfi de nce i nter val ( CI) f or t he Ge o Mea n ( LCI  9 5 % G M, 
U CI  95 % G M). Ge o Mea n, Ge o C V, L C I 9 5 % G M, a n d U CI  95 % G M will n ot be prese nte d f or 
tma x .
Descri pti ve statistics of P K para meter data will be calc ulate d usi n g f ull precisi o n val ues, a n d 
r o u n de d f or re p orti n g p ur p oses o nl y. 
T he f oll o wi n g c o n ve nti o ns will be a p plie d w he n re p orti n g descri pti ve statistics of P K para meter 
data , e xce pt f or tma x w hic h will use t he sa me le vel of deci mal precisi o n (i nstea d of si g nifica nt 
di gits) as s pecifie d bel o w :
Mea ns, Mi n, Me dia n, Ma x, Ge o Mea n, 9 5 % CI : 
3 si g nifica nt di gits
S D:
4 si g nifica nt di gits
C V %, Ge o C V %:
1 deci mal place 
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 Versi o n 2. 0
2 8 /3 1
St atistic al A n al ys is
All P K w h ole bl o o d c o nce ntrati o ns i ncl u di n g drie d bl o o d s p ot assa y co nce ntrati o ns , a n d w h ole 
bl o o d P K para meters will be descri pti vel y  su m marize d b y  trial part , a nal yte, a n d d ose gr o u p as 
descri be d a b o ve. A listi n g of P K bl o o d sa m ple c ollecti o n ti mes as well as deri ve d sa m pli n g ti me 
de viati o ns will als o be pr o vi de d. 
P K uri ne a n d fecal sa m ple c ollecti o n start a n d st o p ti mes, a n d uri ne v ol u mes a n d fecal wei g hts 
will be liste d.
I n di vi d ual w h ole bl o o d c o nce ntrati o n-ti me pr ofiles b y  trial part , a nal yt e, a n d d ose gr o u p will be 
create d usi n g t he act ual ti me p oi nts a n d t he n u meric c o nce ntrati o n data. T hese fi g ures will i ncl u de 
pl ots of all s u bjects i n t he sa me d ose gr o u p o n t he sa me pl ot (s pa g hetti pl ots), as well a s se parate 
pl ots f or i n di vi d ual s u bjects ( by- s u bject pl ots). Arit h metic mea n w h ole bl o o d co nce ntrati o n -ti me 
pr ofiles b y  trial part , a nal yte, a n d d ose gr o u p will be pr o vi de d usi n g n o mi nal ti me p oi nts a n d t he 
n u meric c o nce ntrati o n data. All c o nce ntrati o n-ti me pl ots f or P K data will be prese nte d b ot h o n a 
li near a n d o n a se mi-l o garit h mic scale. Mea n pl ots will i ncl u de S D err or bars w he n pl otte d o n a 
li near scale.
Li near scatter pl ots of i n divi d ual a n d ge o metric mea n val ues of n o n- n or malize d a n d d ose -
n or malize d para meters [ A U C0- ∞, A U C 0-t, A U C 0- 1 4 4 h, a n d C ma x ] vers us M 5 7 1 7 d ose ( o n c o nti n u o us 
scale) will be pre pare d, as a p pr o priate. B o x pl ots of t he d ose -n or malize d para meters vers us M 5 7 1 7 
d ose ( o n c o nti n u o us scale) will be pre pare d. W he n a p plica ble , para meters fr o m Part A a n d Part C 
will be c o m bi ne d o n t he sa me pl ot (f or scatter pl ots, differe nt s y m b ols will be use d f or data fr o m 
t he differe nt st u d y parts). Ot her wise, pl ots will be pre pare d se parately b y trial part, as a p plica ble. 
T he a nal ysis of d ose pr o p orti o nalit y of si n gle-d ose P K para meters of M 5 7 1 7 will be q ua ntifie d as 
part of a n e x pl orat or y anal ys is usi n g t he p o wer m o del o n t he ori gi nal para meters (l n[ P K 
para meter] = α + β x l n[ d ose]).  This a nal ys is will be base d o n A U C 0- ∞, A U C 0-t, A U C 0- 1 4 4 h, a n d 
C ma x i n Part A a n d Part C . T he i nterce pt α a n d t he sl o pe β t o get her wit h 9 0 % CIs will be esti mate d 
a n d prese nte d. A p- val ue testi n g w het her β = 1 will als o be prese nte d. F or a gi ve n para meter, a
mi ni m u m of 3 val ues m ust be a vaila ble f or a d ose le vel, f or t hat d ose le vel t o be i ncl u de d i n t he 
d ose pr o p orti o nalit y  a nal ysis.
A listi n g of t he P K bl o o d sa m ple c ollecti o n ti mes f or t he D B S assa y (f or sa m ples c ollecte d fr o m 
s u bjects i n C o h orts 1 a n d 2 of Part C) as well as deri ve d sa m pli n g ti me de viati o ns will be pr o vi de d.
A c orrelati o n a nal ys is of D B S c o nce ntrati o ns vers us c orres p o n di n g w h ole bl o o d c o nce ntrati o ns 
meas ure d at t he sa me n o mi nal ti me will be perf or me d. T he c o nce ntrati o n data will be l o g-
tra nsf or me d f or t he a nal ysis. T he esti mate f or c orrelati o n c oefficie nt (r) a n d p- val ue testi n g 
w het her r = 0 will be prese nte d.
1 6. 1. 4
P o p ul ati o n P h ar m ac o ki netic A n al ysis
T he P K a n d c o variate data fr o m t his st u d y will be a n al yze d j ointl y wit h d ata fr o m ot her st u dies by
n o n li near m i xe d effect a p p r oach i n or d er t o describ e t h e P K c o nce nt rati o n tim e pr ofile, t o i de ntify
c o variates e x plai ni n g ( part of ) t he bet wee n s u bject P K varia bil it y, a n d t o estim ate t he resi d ual P K
varia bil it y.
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 Versi o n 2. 0
3 0 /3 1
1 6. 2. 2
St atistic al S u m m ar y of P h ar m ac o d y n a mic Me as ure me nt s
T he parasite mia data will be descri pti vel y s u m marize d b y  d ose gr o u p a n d meas ure me nt ti me . 
I n di vi d ual parasite mia -ti me pr ofiles b y  dose gr o u p will be create d usi n g t he act ual meas ure me nt 
ti me p oi nts a n d t he n u meric parasite mia data (ie, ge o metric mea n of t he s u bject’s re plicates, at 
eac h ti me p oi nt) . Arit h metic mea n paras ite mia-ti me pr ofiles b y  dose gr o u p will als o be pr o vi de d 
usi n g n o mi nal ti me p oi nts. All parasite mia -ti me pl ots will be prese nte d o n a se mi-l o garit h mic 
scale. 
O verla y  pl ots of i n di vi d ual parasite mia-ti me pr ofiles ( o n se mi-l o garit h mic scale) a n d w h ole bl o o d
c o nce ntrati o n -ti me pr ofiles ( o n li near scale) will be pr o vi de d. O verla y  pl ots of arit h metic mea n 
parasite mia -ti me pr ofiles ( o n se mi-l o garit h mic scale) a n d arit h metic mea n 
w h ole 
bl o o d 
c o nce ntrati o n -ti me pr ofiles ( o n li near scale) will als o be pr o vi de d by d ose gr o u p .
A n y  parasite mia data e xcl u de d fr o m t he P D A nal y sis Set will be liste d a n d fla g ge d. A d diti o nal 
statistical s u m maries a n d prese ntati o ns of t he P D c o nce ntrati o n data w o ul d
be descri be d a n d 
re p orte d se parately.
1 6. 2. 3
P K/ P D M o deli n g
T he met h o d ol o g y  for P K/ P D m o deli n g will be defi ne d i n a se parate a nal ysis pla n a n d will be 
re p orte d i n a P K/ P D m o deli n g re p ort se parated fr o m t he C S R.
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 Versi o n 2. 0
3 1 /3 1
1 7
R efere nces
T here are n o refere nces.
D oc u me nt N o.
O bject N o.
C CI
C CI


E L E C T R O NI C SI G N A T U R E S
D oc u me nt: ct p- ms 2 0 1 6 1 8- 0 0 1 3-i a p- v 2- 0
Si g ne d B y
E ve nt N a me
Me a ni n g of Si g n at ure
Ser ver D ate
( d d- M M M- y y y y
H H: m m ‘ G M T’ Z)
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val
1 4- Ma y- 2 0 1 9 0 7: 4 6
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
Tec h nical A p pr o val
1 4- Ma y- 2 0 1 9 0 8: 2 3
D oc u me nt N o.
O bject N o
P P D
P P D
C CI
C CI